(Am Medicine - Com) 82734JJ

ACCP Pulmonary
Medicine
Board Review:
26th Edition
The American Board of Internal Medicine (ABIM) is not affiliated with, nor does it endorse,
preparatory examination review programs or other continuing medical education. The
content of the ACCP Pulmonary Medicine Board Review: 26th Edition is developed
independently by the American College of Chest Physicians (ACCP), which has no
knowledge of or access to ABIM examination material.
The views expressed herein are those of the authors and do not necessarily reflect the
views of the ACCP. Use of trade names or names of commercial sources is for information
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Copyright Ó 2012 by the AMERICAN COLLEGE OF CHEST PHYSICIANS.
Copyright not claimed on material authored by the US Government. All rights reserved.
No part of this book may be reproduced in any manner without permission of the publisher.
Published by the
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Contents
Chapter 1. Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
COL Lisa K. Moores, MC, USA, FCCP
Chapter 2. Pulmonary Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Chapter 3. Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Sidney S. Braman, MD, FCCP
Chapter 4. Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Chapter 5. Cardiopulmonary Exercise Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Darcy D. Marciniuk, MD, FCCP
Chapter 6. Pulmonary Function Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Chapter 7. Ethics in Pulmonary and Critical Care Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Mark J. Rosen, MD, FCCP
Chapter 8. Other Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Chapter 9. Thoracic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Rakesh D. Shah, MD, FCCP
Chapter 10. Bronchoscopy and Interventional Pulmonology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

David Feller-Kopman, MD, FCCP
Chapter 11. Pulmonary Complications of Cardiothoracic Surgery and Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Bruce P. Krieger, MD, FCCP
Chapter 12. Sleep Science and Polysomnography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Teofilo Lee-Chiong Jr., MD, FCCP
Chapter 13. Sleep-Related Breathing Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Chapter 14. Other Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Chapter 15. Epidemiology and Statistics for the Boards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Andrew F. Shorr, MD, MPH, FCCP
Chapter 16. Fungal Infections in Pulmonary Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Chapter 17. Drug-Induced Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

David W. Kamp, MD, FCCP
Chapter 18. Pneumoconiosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Chapter 19. Acid-Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Janice L. Zimmerman, MD, FCCP
ACCP Pulmonary Medicine Board Review: 26th Edition iii

Chapter 20. Hemodynamic Monitoring and Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Chapter 21. Community-Acquired Pneumonia: Advances in Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

Ronald F. Grossman, MD, FCCP
Chapter 22. Hospital-Acquired and Ventilator-Associated Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

Chapter 23. Hypoxemic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Curtis N. Sessler, MD, FCCP
Chapter 24. Mechanical Ventilatory Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Chapter 25. Hypercapnic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Chapter 26. Respiratory Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

John D. Buckley, MD, MPH, FCCP
Chapter 27. Unusual and Uncommon Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Jay H. Ryu, MD, FCCP
Chapter 28. Mediastinal and Other Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Chapter 29. Lung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

Stephanie M. Levine, MD, FCCP
Chapter 30. Women’s Issues in Pulmonary Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

Chapter 31. Eosinophilic Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Chapter 32. Tuberculosis and Other Mycobacterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

David Ashkin, MD
Chapter 33. Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia/Fibrosis, and Sarcoidosis . . 499
Joseph P. Lynch III, MD, FCCP
Chapter 34. Rare Interstitial Lung Diseases: Pulmonary Langerhans Cell Histiocytosis,
Lymphangioleiomyomatosis, and Cryptogenic Organizing Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Chapter 35. Pulmonary Vasculitis and Alveolar Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595

Ulrich Specks, MD
Chapter 36. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Gerard A. Silvestri, MD, MS, FCCP
Chapter 37. Pathology of Lung Cancer, COPD, and Diseases of the Airways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Andrew Churg, MD
Chapter 38. Pathology of Diffuse Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Andrew Churg, MD
Chapter 39. Pleural Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641

Michael H. Baumann, MD, MS, FCCP
iv Contents
Chapter 40. Occupational and Environmental Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Clayton T. Cowl, MD, MS, FCCP
Chapter 41. Altitude Physiology and Illness, Diving Medicine, and Hyperbaric Oxygen Therapy . . . . . . . . . . . 681
Chapter 42. Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689

ACCP Pulmonary Medicine Board Review: 26th Edition v

Authors
David Ashkin, MD David W. Kamp, MD, FCCP Mark J. Rosen, MD, FCCP
Medical Executive Director, A. G. Holley Professor of Medicine Division of Pulmonary, Critical Care, and
State TB Hospital Associate Chief, Division of Pulmonary and Sleep Medicine
Florida State TB Health Officer, Florida Critical Care Medicine North Shore University Hospital and LIJ
Department of Health Northwestern University Feinberg School of Medical Center
Adjunct Assistant Professor, Division of Medicine Professor of Medicine, Hofstra University
Pulmonary and Critical Care Medicine Chicago, IL North Shore
University of Florida College of Medicine LIJ School of Medicine
Gainesville, FL Bruce P. Krieger, MD, FCCP New Hyde Park, NY
Visiting Associate Professor, Division of Professor of Medicine
Pulmonary and Critical Care Medicine Miller School of Medicine Jay H. Ryu, MD, FCCP
University of Miami School of Medicine University of Miami Professor of Medicine
Miami, FL Associate Medical Director Mayo Clinic College of Medicine
Consultant, Division of Pulmonary and
Critical Care Center
Michael H. Baumann, MD, MS, FCCP Memorial Hospital Critical Care Medicine
Chief Quality Officer Jacksonville, FL Director, Interstitial Lung Disease Clinic
Medical Director, Quality and Clinical Sys- Mayo Clinic
tems Improvement Rochester, MN
Professor of Medicine Teofilo L. Lee-Chiong Jr., MD, FCCP
Professor of Medicine Curtis N. Sessler, MD, FCCP
Division of Pulmonary and Critical Care
Medicine Chief, Division of Sleep Medicine Orhan Muren Professor of Medicine
University of Mississippi Medical Center Department of Medicine Division of Pulmonary and Critical Care
Jackson, MS National Jewish Health Medicine
Associate Professor of Medicine Director, Center for Adult Critical Care
Sidney S. Braman, MD, FCCP University of Colorado Denver School of Virginia Commonwealth University Health
Professor of Medicine Medicine System
Director, Pulmonary Disease Management Denver, CO Richmond, VA
Catherine and Henry Gaisman Division of
Pulmonary, Critical Care Medicine and Stephanie M. Levine, MD, FCCP Rakesh D. Shah, MD, FCCP
Sleep Medicine Professor of Medicine Chief of Thoracic Radiology
Mount Sinai School of Medicine Division of Pulmonary Diseases and Critical Department of Radiology
New York, NY Care Medicine North Shore University Hospital
Pulmonary and Critical Care Fellowship Manhasset, NY
Jack D. Buckley, MD, MPH, FCCP
Vice Chair of Quality Program Director
Indiana University School of Medicine University of Texas Health Science Center
San Antonio, TX Associate Chief of Pulmonary and Critical
Indianapolis, IN Care
Associate Professor of Medicine
Andrew M. Churg, MD Joseph P. Lynch III, MD, FCCP
Professor of Pathology Washington Hospital Center
Professor of Clinical Medicine Washington, DC
University of British Columbia Associate Chief, Pulmonary and Critical
Vancouver, BC, Canada Care Medicine and Hospitalists Gerard A. Silvestri, MD, MS, FCCP
Clayton T. Cowl, MD, MS, FCCP David Geffen School of Medicine Professor of Medicine
Associate Professor of Medicine University of California, Los Angeles Division of Pulmonary and Critical Care
Los Angeles, CA Medicine
Mayo Clinic College of Medicine
Division of Pulmonary and Critical Care Medical University of South Carolina
Medicine Darcy D. Marciniuk, MD, FCCP Charleston, SC
Division of Preventive, Occupational, and Professor and Vice-Chair, Department of
Aerospace Medicine Medicine Ulrich Specks, MD
Mayo Clinic University of Saskatchewan Professor of Medicine
Rochester, MN Royal University Hospital Division of Pulmonary and Critical Care
Saskatoon, SK, Canada Medicine
David Feller-Kopman, MD, FCCP Mayo Clinic
Director, Bronchoscopy and Interventional COL Lisa K. Moores, MC, USA, FCCP Rochester, MN
Pulmonology Assistant Dean for Clinical Sciences
Associate Professor of Medicine Janice L. Zimmerman, MD, FCCP
Professor of Medicine Professor of Clinical Medicine
Johns Hopkins Hospital The Uniformed Services University of the
Baltimore, MD Weill Cornell Medical College
Health Sciences Division Head, Critical Care
Ronald F. Grossman, MD, FCCP Bethesda, MD Department of Medicine
Professor of Medicine Director, Medical ICU
University of Toronto The Methodist Hospital
Staff Respirologist Houston, TX
Credit Valley Hospital
Mississauga, ON, Canada
vi Chapter 20. Hemodynamic Monitoring and Shock (Zimmerman)

DISCLOSURE OF AUTHORS’ CONFLICTS OF INTEREST
The American College of Chest Physicians (ACCP) remains strongly committed to providing the best available evidence-based clinical
information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our
committee members. It is not the intent of the ACCP to eliminate all situations of potential conflict of interest, but rather to enable those
who are working with the ACCP to recognize situations that may be subject to question by others. All disclosed conflicts of interest are
reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to
ensure that such situations are properly evaluated and, if necessary, resolved. The ACCP educational standards pertaining to conflict of
interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of
science. Through our review process, all ACCP CME activities are ensured of independent, objective, scientifically balanced information.
Disclosure of any or no relationships is made available for all educational activities.
The following authors of the ACCP Pulmonary Medicine Board Review: 26th Edition have disclosed to the ACCP that a relationship does exist
with the respective company/organization as it relates to their presentation of material and should be communicated to the participants of
this educational activity:
Authors Relationship
Sidney S. Braman, Consultant fee, speakers bureau, advisory committee, etc: GlaxoSmithKline,
MD, FCCP Novartis, Sunovion, Genentech
Jack D. Buckley, Fiduciary Position (of any other organization, association, society, etc, other than
MD, MPH, FCCP ACCP): Association of Pulmonary and Critical Care Program Directors
David Feller-Kopman, Consultant fee, speakers bureau, advisory committee, etc: Olympus, Inc., CareFusion
MD, FCCP Inc., Boston Scientific
Product/procedure/technique that is considered research and is NOT yet approved
for any purpose: Bronchus technologies: Virtual bronchoscopic navigation system
Ronald F. Grossman, Consultant fee, speakers bureau, advisory committee, etc: Advisory Boards for
MD, FCCP GlaxoSmithKline, Bayer, Novartis, Nycomed, Abbott Labs
Other/Research contracts: GlaxoSmithKline, Novartis
David Kamp, MD, FCCP Grant monies (from sources other than industry): VA Merit Review
Fiduciary Position (of any other organization, association, society, etc, other than
ACCP): Associate Editor - Translational Research
Consultant fee, speaker bureau, advisory committee, etc: GlaxoSmithKline, Pfizer
Bruce P. Krieger, Speakers bureau: Pfizer. Advisory committee: Boerhinger-Ingelheim, Schering-
MD, FCCP Plough
Teofilo L. Lee-Chiong Jr., Grant Monies (from sources other than industry): NIH
MD, FCCP
Grant Monies (from industry-related sources): Embla, Respironics
Employee: Philips Respironics (Medical Liaison Officer)
Consultant fee, speaker bureau, advisory committee, etc: Consultant for Sleep
Medicine Clinics (Elsevier), Consultant for CareCore National
Darcy D. Marciniuk, University Grant Monies: Dalhousie University, McGill University
MD, FCCP
Grant Monies (from sources other than industry): Canadian Agency for Drugs and
Technologies in Health, Canadian Institutes of Health Research, Lung Association of
Saskatchewan, Public Health Agency of Canada, Royal University Hospital
Foundation, Saskatoon Health Region, Saskatchewan Ministry of Health
Grant Monies (from industry-related sources): AstraZeneca, Boehringer-Ingelheim,
GlaxoSmithKline, Forest Research, Novartis, Nycomed, Pfizer, Shering-Plough
Employee: University of Saskatchewan
Fiduciary Position (of any other organization, association, society, etc, other than
ACCP): Lung Association of Saskatchewan
Consultant fee, speakers bureau, advisory committee, etc: Canadian Lung
Association, Health Canada, Health Quality Council (Saskatchewan), Public Health
Agency of Canada, Saskatchewan Medical Association, Saskatoon Health Region
Mark J. Rosen, MD, FCCP Product/procedure/technique that is considered research and is NOT yet approved
for any purpose: B glucan in PCP
Andrew F. Shorr, Consultant fee, speakers bureau, advisory committee, etc: Relevant to stats – None;
MD, MPH, FCCP relevant to fungus – speaker and consultant for Pfizer and Astellas
ACCP Pulmonary Medicine Board Review: 26th Edition vii

Gerard A. Silvestri, Grant Monies (from sources other than industry): Duke Endowment; virtual tumor
MD, MS, FCCP board NCI – K24 DOD computer aided cancer detection
Grant Monies (from industry related sources): Allegro diagnostics Olympus America
Boston Scientific Corporation
Consultant fee, speakers bureau, advisory committee, etc: Olympus America
Speaker Bureau: Olympus America diagnostics
Ulrich Specks, MD Grant Monies (from sources other than industry): NIAID, NIAMS
Consultant fee, speakers bureau, advisory committee, etc: Consulting fees from
Genentech Inc.
Product/procedure/technique that is considered research and is NOT yet approved
for any purpose: All medications/interventions used for the treatment of ANCA-
associated vasculitis except the use of glucocorticoids and rituximab represent off-
label use for this indication.
The following authors of the ACCP Pulmonary Medicine Board Review: 26th Edition have indicated to the ACCP that no potential conflict
of interest exists with any respective company/organization, and this should be communicated to the participants of this educational
activity:
David Ashkin, MD Stephanie M. Levine, MD, FCCP Curtis N. Sessler, MD, FCCP
Michael H. Baumann, MD, MS, FCCP Joseph P. Lynch III, MD, FCCP Rakesh D. Shah, MD, FCCP
Andrew M. Churg, MD COL Lisa K. Moores, MC, USA, FCCP Janice L. Zimmerman, MD, FCCP
Clayton T. Cowl, MD, MS, FCCP Jay H. Ryu, MD, FCCP
viii
Needs Assessment
Rely on the ACCP Pulmonary Medicine Board Review 2012: 26th Edition to review the type of information you should know for the
Pulmonary Disease Subspecialty Board Examination of the American Board of Internal Medicine (ABIM). Designed as the best preparation
for anyone taking the exam, this comprehensive, exam-focused review will cover current pulmonary literature and management strategies
for patients with pulmonary disease.
The ABIM Pulmonary Disease Subspecialty Board Examination tests knowledge and clinical judgment in crucial areas of pulmonary
medicine. This premier course will review the information you should know for the exam. Course content mirrors the content of the exam,
as outlined by the ABIM, and includes the following topics:
Asthma 7%
Cell/Molecular biology 3.5%
Congenital/Neuromuscular/Skeletal 2%
COPD 7%
Critical care, non-lung 4%
Critical care, lung 9%
Epidemiology, ethics, and statistics 4%
ILD-related disorders 6%
Infections 3%
Neoplasms 9%
Obstructive airways disease, other 2%
Occupational and environmental disease 5%
Physiology and metabolism 4%
Pleural disease 5%
Quality, safety and complications 5%
Sleep, nonrespiratory 2%
Sleep, Respiratory 8%
Transplantation 2%
Vascular diseases 2.5%
Total 100%
Target Audience
Physicians in critical care and pulmonary medicine
Fellows in critical care and pulmonary medicine
Advanced critical care nurse practitioners
Advanced respiratory therapy practitioners
Physician assistants
General Publications Disclaimer

The American College of Chest Physicians (‘‘ACCP’’) and its officers, regents, executive committee members, related entities, employees,
representatives and other agents (collectively, ‘‘ACCP Parties’’) are not responsible in any capacity for, do not warrant and expressly
disclaim all liability for, any content whatsoever in any ACCP publication or other product (in any medium) and the use or reliance on any
such content, all such responsibility being solely that of the authors or the advertisers, as the case may be. By way of example, without
limiting the foregoing, this disclaimer of liability applies to the accuracy, completeness, effectiveness, quality, appearance, ideas, or
products, as the case may be, of or resulting from any statements, references, articles, positions, claimed diagnosis, claimed possible
treatments, services, or advertising, express or implied, contained in any ACCP publication or other product. Furthermore, the content
should not be considered medical advice and is not intended to replace consultation with a qualified medical professional. Under no
circumstances, including negligence, shall any of the ACCP Parties be liable for any DIRECT, INDIRECT, INCIDENTAL, SPECIAL or
CONSEQUENTIAL DAMAGES, or LOST PROFITS that result from any of the foregoing, regardless of legal theory and whether or not
claimant was advised of the possibility of such damages.
ACCP Pulmonary Medicine Board Review: 26th Edition ix

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by helping people make the most of each breath.
Chapter 1. Unusual Lung Infection, Bronchiectasis, and
Cystic Fibrosis
Objectives: suppressed patients, particularly those with

Review the presentation, diagnosis, and treatment of defects in cellular immunity. Other presentations
actinomycosis and nocardiosis infection in the lung. include cellulitis, the lymphocutaneous syn-
List the causes of bronchiectasis.

drome, actinomycetoma, and keratitis. Nocardia
Review the therapeutic options for the treatment of
bronchiectasis. spp are aerobic, nonmobile, and non-spore-
Review the genetic disorders that lead to cystic fibrosis forming organisms that live as soil saprophytes.
(CF). In tissue specimens, the organisms reveal deli-
Introduce the newer therapeutic approaches in the
treatment of pulmonary disease in patients with CF. cate branching filamentous forms that are gram-
positive and usually acid fast if weak decoloriz-
ing agents are used for the stains.1 Seven species
Key words: actinomycosis; bronchiectasis; cystic fibrosis;
nocardiosis have been associated with human disease.
Nocardia asteroides is the most common species
Synopsis: associated with invasive disease. Nocardia farcin-
Pulmonary nocardiosis and actinomycosis are rare but often ica is less common and is associated with
severe infections that occur in immunocompromised (the dissemination. Other species known to cause
former) and immunocompetent hosts. They are often not human infection are Nocardia pseudobrasiliensis
suspected initially and can present with extensive local or
disseminated disease. They share many common clinical and Nocardia brasiliensis.2
and radiographic features and can be difficult to delineate Epidemiology/Pathogenesis: Nocardia spp are
from one another. It is important to do so, however, as the common natural inhabitants of the soil through-
antimicrobials of choice and duration of therapy differ. The
out the world. The aerosol route is the main
epidemiology, clinical presentation, imaging, diagnosis, and
treatment of both are reviewed. Bronchiectasis is a syn- portal of entry, although ingestion of contami-
drome, with many underlying etiologies and associations, nated food or direct inoculation of the organism
that has been defined as an irreversible dilation and due to trauma can also lead to infection.1,2
destruction of one or more bronchi, and inadequate
clearance and pooling of mucus in the airways. Cystic
Epidemics within the hospital environment are
fibrosis (CF) is a common genetic disorder that accounts for rare, and person-to-person transmission has only
many cases of bronchiectasis. Treatment of CF involves rarely been suggested. The disease has been
chest physiotherapy, mucolytic agents, antibiotics, and
reported worldwide and is more common in men
antiinflammatory agents. Gene therapy is a promising
approach still being investigated. Treatment of non-CF than women (approximately 3:1, respectively).3
bronchiectasis has been less well studied, and many of the Although Nocardia can occur as a primary
recommendations are extrapolated from studies of patients pulmonary pathogen in patients with no under-
with CF.
lying disease, it is frequently recognized as an
opportunistic disease, especially among patients
with cell-mediated immune deficiencies, includ-
Unusual Lung Infections ing transplantation (highest frequency in those
who have undergone lung transplantation),
Nocardiosis lymphoma, and AIDS. Therapy with corticoste-
roids is the most important risk factor.3 High-
Nocardiosis refers to invasive disease caused dose corticosteroids, cytomegalovirus infection
by members of the genus Nocardia. Respiratory in the past 6 months, and high calcineurin
tract disease and extrapulmonary dissemination inhibitor levels (cyclosporine or tacrolimus) are
are the most common manifestations. Pulmonary independent risk factors for Nocardia infection in
infection is increasingly being seen in immuno- organ transplant recipients. In HIV-positive
ACCP Pulmonary Medicine Board Review: 26th Edition 1

persons, nocardiosis most often presents with a disseminated disease, the initial respiratory tract
CD4þ lymphocyte concentration of ,100 cells/ involvement does not elicit symptoms. As noted
lL, but can occur in patients with counts ,250 above, nocardiosis has the propensity for dis-
cells/lL. Nocardiosis has also been reported to semination to the brain, but other extrapulmo-
be associated with pulmonary alveolar proteino- nary sites include the skin, bone, and muscle. In
sis, mycobacterial diseases, and chronic granulo- the CNS, Nocardia brain abscesses may be single
matous disease. Finally, nocardiosis is not or multiple. Nocardia is not usually recovered
uncommon in COPD patients receiving chronic from the cerebrospinal fluid.
corticosteroid treatment, but it is also increasing- Radiographic Manifestations: The chest radio-
ly being seen in patients with COPD who have graphic patterns are variable. The most frequent
received a recent short course of corticosteroids manifestation is an airspace consolidation, usu-
for an exacerbation. Case series over time reveal ally homogeneous, but occasionally patchy. Bi-
an increasing percentage of patients with COPD lateral involvement is common.3 Nodules, either
as the underlying risk. When COPD is the main single or multiple, maybe confused with meta-
underlying infection, the disease is almost static carcinoma.1 The most common radiograph-
always isolated to the lungs.3 Impairment of ic manifestation is cavitation, which is found in
local lung defenses plays a role.4 Lesions are both consolidations and nodules. Pleural in-
characterized by necrotizing abscesses that are volvement with an empyema is present in
not well encapsulated and spread easily. Granu- approximately one-third of cases.2
loma formation and fibrosis are infrequent.1 Diagnosis: In most cases of pneumonia,
Because of its propensity for hematogenous sputum smear findings are negative. Bronchos-
dissemination, Nocardia is often associated with copy may be necessary to obtain an adequate
metastatic spread, especially to the brain (in up specimen for the characteristic gram-positive
to one-third of cases). Dissemination is more filaments that may be acid fast and often take
common in patients with underlying HIV and in up silver stains.1 Cultures for Nocardia require
patients with alcoholism.2,4 Chest wall invasion special handling because colonies may not
may occur but is uncommon.1 appear for 2 to 4 weeks. Blood cultures require
Clinical Manifestations: Important features of incubation aerobically for up to 4 weeks. Ad-
Nocardia infection include diverse clinical and vances in DNA extraction and real-time PCR
radiographic presentations, the ability to dissem- assays may allow for identification of most
inate to any organ system in the body, and the Nocardia spp within hours.3 The isolation of
tendency to relapse or remain unresponsive to Nocardia from the sputum in a nonimmunosup-
therapy. The nonspecific features make diagnosis pressed patient without radiographic abnormal-
challenging, and the disease is often not suspect- ities may represent colonization. However, a
ed early on in the patient’s course of symptoms. sputum culture that is positive for Nocardia in
The median time to diagnosis ranges from 40 to an immunosuppressed patient more often indi-
55 days in reported series.2 Nocardial pneumonia cates disease.4 A number of serologic tests have
is the most common respiratory tract presenta- been evaluated, but the diversity of species
tion.3 Although the clinical course may be acute known to cause disease and the potential lack
in immunosuppressed patients, typically, the of sensitivity for detecting an antibody response
patients have a subacute presentation consisting in immunocompromised patients have limited
of several weeks of symptoms. Cough, purulent their practical use.3
sputum, occasional hemoptysis, night sweats, Treatment: Sulfonamide agents remain the
and pleuritic pain are common symptoms.3 drugs of choice for nocardiosis (sulfadiazine or
Superior vena cava syndrome, mediastinitis, sulfisoxazole, 6 to 8 g/d, then decreasing to 4 g/d
and pericarditis have been reported from direct as the disease is controlled). The combination of
spread from the lungs. Nocardia rarely involves trimethoprim and sulfamethoxazole (TMP-SMX)
the chest wall. In approximately 50% of pulmo- is thought to be an equally effective alternate
nary cases, extrapulmonary dissemination oc- choice.2 Unfortunately, disease does occasionally
curs. In a significant number of cases of occur in patients receiving TMP-SMX prophylaxis,
2 Chapter 1. Unusual Lung Infection, Bronchiectasis, and Cystic Fibrosis (Moores)

particularly in patients with malignancy or HIV Epidemiology/Pathogenesis: The organisms are
infection.3 Minocycline is an alternative choice for a normal inhabitant of the human oropharynx,
an oral medication in those patients who have and are frequently found in dental caries and at
sulfa allergies. IV regimens include amikacin, the gingival margins of persons with poor oral
ceftriaxone, cefotaxime, ceftizoxime, and imipen- hygiene. Actinomycosis is most commonly
em. Linezolid has now been shown in vitro to be caused by Actinomyces israelii. Actinomycotic
highly effective against most strains of Nocardia. infections in the lung are, however, usually
However, the high cost and serious potential polymicrobial. In tissue, actinomycotic infection
toxicities currently relegate this agent to refractory grows in microcolonies or granules. Because
cases. Because of the risk of relapse, patients who these granules are yellow, they are often called
have intact host defenses are generally treated for 6 sulfur granules, although they contain minimal
to 12 months, whereas deficient hosts and those amounts of sulfa. Actinomycosis of the respira-
with CNS involvement are treated for 12 months. If tory tract is acquired most commonly by aspira-
ongoing steroid or cytotoxic therapy is required, tion, but direct extension of the disease from the
prolonged maintenance therapy may be needed.3 head and neck or abdominal cavity can occur.
When the CNS is involved, treatment with The peak incidence is reported in the fourth and
cefotaxime or ceftriaxone in addition to the TMP- fifth decades of life; nearly all series have
SMX is recommended.4 Surgical drainage should reported a male predominance (3:1, respectively).
The pulmonary form typically constitutes only
be considered for patients with brain abscesses,
15% of reported cases, but has been as high as
empyema, and subcutaneous abscesses.1 Mortality
50% in some series. Most infections occur in
due to pulmonary nocardiosis is high (15%–40%),
individuals who are immunocompetent. Howev-
and increases significantly with CNS involvement.
er, some cases have been reported in patients
Delay in diagnosis and treatment affects progno-
with impaired host defenses. Patients with
sis. It is therefore imperative that practitioners
alcoholism and poor dental hygiene are at
have a high index of suspicion in evaluating
increased risk. The pulmonary form has also
patients who are immunosuppressed or have
been reported in patients with chronic lung
significant chronic lung disease.
disease, including COPD and bronchiectasis.1
The presentation of pulmonary actinomycosis
Actinomycosis
has changed in recent years to a less aggressive
infection, which is likely related to improved oral
Actinomycosis is a slowly progressive infec-
hygiene and increased use of penicillin, even
tious disease that is caused by anaerobic, gram- when the specific diagnosis is not suspected.
positive, non-spore-forming bacteria. They were Clinical Manifestations: Actinomycosis most
originally misclassified as fungi.5 The word commonly presents as a disease of the cervico-
actinomycosis is derived from the Greek terms facial region following dental extraction, with
aktino (the radiating appearance of the sulfur osteomyelitis of the mandible or a soft tissue
granule) and mykos (mycotic disease). The abscess that drains through the skin. Pulmonary
classic clinical picture is a cervicofacial disease actinomycosis usually presents with an indolent
in which the patient presents with a large mass progressive course. The initial manifestations
on the jaw. It is now recognized that the include a nonproductive cough and low-grade
organisms colonize in the mouth, colon, and fever, subsequently followed by a productive
vagina. Infection results from mucosal disruption cough, which can be associated with hemopty-
and can occur at any site in the body. The sis.1 With chest wall involvement, pleuritic pain
pulmonary form of the disease is actually quite will develop in the patient. Rarely, a sinus tract
rare.1 Infection is characterized by a pyogenic may appear as a bronchocutaneous fistula. When
response and necrosis, followed by intense this occurs, it is highly suggestive of actinomy-
fibrosis. Actinomycosis is difficult to diagnose, cosis. Late in the disease, the patient may present
and is often confused with TB, lung abscess, or with weight loss, anemia, and clubbing of the
malignancy.1 digits.

Radiographic Manifestations: The usual pattern or open lung biopsy may be necessary to confirm
of acute pulmonary actinomycosis consists of the diagnosis. There is no reliable serologic test.1
airspace consolidation, commonly in the periph- Treatment: Untreated, actinomycosis is ulti-
ery of the lung and often in the lower lung fields. mately fatal, but early treatment can result in
The typical CT scan feature is a chronic segmen- cure rates of .90%.1 Prolonged treatment with
tal airspace consolidation containing necrotic high doses of antimicrobial agents is necessary.
low-attenuation areas with frequent cavity for- Penicillin is the drug of choice. Regimens include
mation. Other findings include hilar or medias- IV administration of 18 to 24 million units of
tinal adenopathy, bronchiectasis within the penicillin for 2 to 6 weeks, followed by oral
consolidation, and localized pleural thickening penicillin for an additional 6 to 12 months.
and/or effusion. If not treated with appropriate Tetracyclines, erythromycin, clindamycin, imi-
antibiotics, a lung abscess may develop, and the penem, and chloramphenicol are acceptable
infiltrate may extend into the pleura with an alternatives. The organisms are generally not
associated empyema. Subsequently, actinomyco- sensitive to the fluoroquinolones, metronidazole,
sis will extend into the chest wall with osteomy- or the aminogycosides.1 Whether patients should
elitis of the ribs, abscess formation, and draining be treated for the co-pathogens usually associat-
sinus formation. This is highly suggestive of ed with Actinomyces is not resolved, but most
actinomycosis.1 Chest CT scan may be a more experts do not recommend additional antibiotics.
sensitive imaging modality, especially if bone Patients with actinomycosis have a tendency to
windows are obtained (which might reveal early relapse, and prolonged therapy optimizes the
likelihood of a cure. However, small trials have
rib erosion). Actinomycosis is often mistaken for
shown success with relatively brief courses of
pulmonary carcinoma; the presence of an air
therapy (6 weeks).1 Some cases may require both
bronchogram in the mass lesion should suggest
medical and surgical therapies. Patients with
the possibility of a nonneoplastic process. Acti-
bulky disease should probably not receive short
nomycosis can also present as an endobronchial
courses of therapy unless surgical debulking is
infection, which is often associated with a
also performed. A comparison of the main
broncholith or other foreign body. Both actino-
features of actinomycosis and nocardiosis is
mycosis and nocardiosis are often confused with
shown in Table 1.
TB, cryptococcosis, anaerobic pulmonary infec-
tion, bronchogenic carcinoma, and lymphoma.1
Bronchiectasis
Diagnosis: A diagnosis of actinomycosis is
rarely suspected; in one series, it was suspected Bronchiectasis is a syndrome, with many under-
on hospital admission in ,7% of the patients in lying etiologies and associations, that has been
whom it was ultimately diagnosed.1 Because defined as an irreversible dilation and destruc-
actinomycosis often mimics malignancy, diagno- tion of one or more bronchi, and inadequate
sis may not be made until surgical resection. clearance and pooling of mucus in the airways.6
Because these organisms are normal oropharyn- Bronchiectasis results from the occurrence of one
geal flora, isolation in specimens of sputum or of three main pathologic mechanisms: bronchial
bronchial washings is not considered significant, wall injury, bronchial lumen obstruction, and
unless sulfa granules are found. Actinomyces are traction from adjacent fibrosis. Three important
fastidious bacteria that are difficult to culture, pathogenic components, infection, inflammation,
and thus correlation with the clinical and and enzymatic/lytic enzyme release, cause a
radiographic presentation is essential. Bronchos- chronic, self-perpetuating destruction to the
copy is usually not diagnostic unless endobron- airways.6 This leads to the unique progressive
chial disease is present, and samples must be airway dilation that is associated with the
obtained anaerobically with a protected speci- inflammation in bronchiectasis, as opposed to
men brush and delivered to the laboratory under the small airway narrowing seen in asthma and
anaerobic conditions. Histologic examination of COPD.6,7 Bronchiectasis is also characterized by
lung tissue by either transbronchial lung biopsy persistent microbial infection and inflammatory

Table 1—Distinguishing Features of Nocardiosis and Actinomycosis
Nocardiosis Actinomycosis
Gram-positive aerobica Gram-positive anaerobica

Incidence increasing Incidence decreasing
Male 3:1 predominance Male 3:1 predominance
Occurs primarily in immunocompromised hosts Occurs primarily in immunocompetent hosts; alcoholism and
poor dental hygiene are risks
Pulmonary manifestations predominate Pulmonary manifestations in a minority of patients
(approximately 15%)
Chest wall involvement is uncommon Chest wall involvement and bony erosion are common
Metastatic spread (especially to the brain) is common Metastatic spread is uncommon; spread by direct contiguous
invasion
Granuloma formation and fibrosis are rare Granuloma and intense fibrosis are common; form the
characteristic sulfur granule
Diagnosis can usually be made on sputum, BAL fluid, Diagnosis often requires cytologic or histologic examination
or pleural fluid cultures
Treatment with sulfonamides Treatment with penicillin
Surgical drainage often needed Often treated successfully with antibiotics alone
a
On Gram stain, the two organisms are indistinguishable as branching, gram-positive filamentous organisms. However,
Nocardia spp will stain weakly with modified acid-fast stain, whereas actinomycosis will not.
response with release of microbial toxins and follicles within thickened bronchial walls. Cystic,
immune mediators. It is estimated that the cylindrical, and varicose forms may coexist in the
prevalence in the United States ranges from 4 same patient. The fourth pattern, follicular
per 100,000 persons aged 18 to 34 to 271 per bronchiectasis, usually occurs following child-
100,000 among those over age 75. Prevalence in hood pneumonia, measles, pertussis, or adeno-
underdeveloped countries is likely higher.6 Bron- virus infection.
chiectasis is often divided into a form associated Although insightful, these definitions are not
with cystic fibrosis (CF) and a non-CF form. Non- particularly helpful from a clinical or therapeutic
CF bronchiectasis will be reviewed first. standpoint. Four clinical stereotypes have been
defined and are more useful. These are (1)
Classification rapidly progressive (early-onset and rapidly
progressive diffuse disease with frequent exacer-
A classification system has been devised that bations and copious sputum); (2) slowly progres-
classifies bronchiectasis according to anatomic sive (slow, insidious progression, with an
and morphologic patterns or airway dilatation as increase in sputum production and exacerbations
follows: (1) cylindrical bronchiectasis, in which over decades); (3) indolent disease (patients can
there is uniform dilatation of the bronchi, which be asymptomatic and do not show deterioration);
are thick walled and extend to the lung periphery and (4) predominant hemoptysis (recurrent
without normal tapering (on a high-resolution hemoptysis in the setting of very little sputum).7
CT [HRCT] scan, it has parallel ‘‘tram track’’ lines
or ‘‘signet ring’’ appearance); (2) varicose bron- Etiology
chiectasis, which has an irregular and beaded
outline of bronchi with alternating areas of The most common causes of non-CF bron-
constriction and dilatation similar in appearance chiectasis8–10 are listed in Table 2. In general the
to saphenous varicosities; (3) cystic bronchiecta- causes can be divided into idiopathic, postinfec-
sis, which is the most severe form and is common tious, or due to an underlying anatomic or
in patients with CF, characterized by bronchial systemic disease.11 The condition is most com-
dilatation and clusters of round air-filled and monly idiopathic in adults.6,8 The prevalence of
fluid-filled cysts, with a honeycomb appearance undiagnosed CF is not known, but studies have
in patients with CF; and (4) follicular bronchiec- suggested it is very low. Patients with focal
tasis, which has extensive lymphoid nodules and bronchiectasis, which is localized to a segment or

Table 2—Common Causes of Bronchiectasis abnormalities, but prolonged therapy for up to
18 months may be necessary.6
Cause Disease Example
There are an increasing number of immune
Localized Foreign-body aspiration deficiencies that have been associated with
Mechanical airway External compression bronchiectasis. Ciliary disorders are considered
obstruction Stenosis to be primary disorders of immune defense, as
Lung tumors
Necrotizing pneumonia
airway clearance mechanisms contribute an
Diffuse Intraluminal webs important component of barrier immunity. Ac-
Congenital Absent cartilage quired adult-onset hypogammaglobulinemia
Pulmonary sequestrations may involve one or more of the immunoglobulin
CF
Mucociliary clearance Kartagener syndrome classes. IgG subclass deficiencies may be present
defects Primary cilia dyskinesia even with normal total IgG levels. Patients with
Young syndrome HIV infection have been found to have a high
Immune disorders Hypogammaglobulinemia,
IgG subclass deficiency, HIV,
incidence of bronchiectasis, which may in part be
allergic bronchopulmonary due to recurrent bronchopulmonary infections
aspergillosis, post-lung (especially Pneumocystis-proved pneumonia and
transplant Mycobacterium intracellulare infection). The bron-
Postinfectious Bacteria
complications Mycobacterial infections chiectasis observed in HIV-infected patients is
Whooping cough particularly aggressive. Allergic bronchopulmo-
Viral (measles, adenovirus, nary aspergillosis (ABPA) predisposes patients to
influenza virus)
bronchiectasis as a consequence of a persistent
Rheumatologic Rheumatoid arthritis,
diseases Sjögren syndrome, complex immune response to airway coloniza-
inflammatory bowel disease tion by Aspergillus. This type of bronchiectasis
Sequelae of aspiration most commonly involves the central airways,
or toxic inhalation
COPD distinguishing it from other types of bronchiec-
Lung fibrosis Sarcoidosis tasis.6
After radiation therapy
TB Diagnosis
Miscellaneous a1-Antitrypsin deficiency,
yellow nail syndrome
Clinical Manifestations: Clinical findings from
a retrospective chart review of patients with
lobe, should undergo bronchoscopy to evaluate confirmed bronchiectasis included cough (90%),
for and eliminate an obstructing bronchial lesion. chronic daily sputum production (76%), dyspnea
Other indications for bronchoscopy are to obtain (72%), hemoptysis (56%), and pleuritic chest pain
a biopsy specimen to determine ciliary disorders (46%). Two symptoms that are also very common
and obtain specimens for the diagnosis of are rhinosinusitis and fatigue. The most common
mycobacterial disease.12 physical findings were crackles (70%) and
The factor most commonly associated with wheezing or rhonchi (,50%). Daily cough and
bronchiectasis in childhood is infection,6 al- sputum production have been reported in HIV-
though it is being seen more commonly in adults positive patients with bronchiectasis confirmed
now, especially with the increased use of HRCT by CT scan in ,39% of cases. The disease is more
scanning. Radiographic findings obtained with common in women and most commonly presents
an HRCT scan of the chest have been described in in the sixth decade of life.6
patients with Mycobacterium avium-intracellulare Pulmonary function study results may be
complex (MAC). The most notable finding in normal if the involvement of bronchiectasis is
bronchiectasis is the presence of small nodular localized and mild. With diffuse disease, pulmo-
opacities or the ‘‘tree-in-bud’’ appearance. Ab- nary function tests may reveal an obstructive
normalities most often occur in the lower lung ventilatory defect with hyperinflation and im-
fields. Treatment with multiple antimicrobial paired diffusing capacity of the lung for carbon
agents may lead to the resolution of these monoxide. Airway hyperresponsiveness has

been seen in up to 40% of patients with
bronchiectasis in some series. On the other hand,
some patients with diffuse disease may present
with a combined obstructive and restrictive
ventilatory defect. Pulmonary function tests are
not useful in distinguishing bronchiectasis from
other obstructive airway diseases.6 Laboratory
studies in patients with bronchiectasis include a
mild degree of leukocytosis, usually without a
left shift; an increase in the erythrocyte sedimen-
tation rate; mild anemia; and hypergammaglob-
ulinemia.
Radiographic Findings/Imaging: Routine chest
radiographs can be used but are insensitive to
Figure 1. Large internal diameter of the bronchi (greater
exclude the diagnosis, detecting abnormalities in than the accompanying vessel), which is diagnostic of
only 50% of patients. Findings are abnormal in bronchiectasis (large arrows). From the author’s personal
approximately 50% of patients with proven files.
bronchiectasis. The classic finding of tram tracks,
representing thickened dilated bronchial walls, is The pattern of distribution of the bronchiec-
best seen on radiographs obtained from a lateral tatic changes on HRCT can help narrow the
view. Other findings include hyperinflation and differential diagnosis.14 Focal changes suggest
air trapping, increased linear markings, rounded mechanical obstruction, congenital bronchial
opacities that represent areas of focal pneumonia, atresia, or a necrotizing pneumonia. Diffuse
and ring shadows that represent dilated airways changes that have a central predominance
seen en face. Although bronchography was the suggest ABPA or cartilage deficiency syndromes.
historical gold standard for confirming the More peripheral changes seen predominantly in
diagnosis, HRCT scanning has become the the upper lung regions suggest CF, sarcoidosis,
current diagnostic standard for the detection of or postradiation fibrosis. Peripheral middle lobe
bronchiectasis. It is both highly sensitive and changes are seen with atypical mycobacterial
specific for the diagnosis of bronchiectasis. infections and immotile cilia syndrome. Periph-
Today, HRCT scanning is the method used in eral changes in the lower lung fields should
nearly all cases of bronchiectasis. Given the high prompt consideration of aspiration, fibrotic lung
sensitivity of HRCT scanning, it has become disease (traction bronchiectasis), HIV, hypogam-
much easier to diagnose the disorder, which may maglobulinemia, transplant rejection, and prior
account for the increased awareness and preva- infection. Most cases of diffuse lower lobe
lence of the disease. Standard criteria for the bronchiectasis will be idiopathic.
diagnosis of bronchiectasis on HRCT scans have Differential Diagnosis/Additional Testing: Addi-
been established. The most specific criteria are an tional testing includes a workup to detect the
internal bronchus diameter that is wider than its underlying cause and microbiologic examination
adjacent artery (signet ring formation), the failure of the sputum. Additional tests include sweat
of the bronchi to taper as they move toward the chloride testing, ciliary structure and function
periphery of the lung parenchyma, and bronchi examination, immunoglobulin levels, HIV, a1-
visualized in the outer 1 to 2 cm of the lung antitrypsin, rheumatoid factor and ANA levels,
fields.13 Secondary criteria include excessive barium swallow, and Aspergillus antigen.12 The
bronchial wall thickening, impacted mucus, and choice of additional testing should be prompted
crowding of the bronchi. Figure 1 shows the by the history, associated symptoms, and radio-
characteristic large bronchi in a patient with graphic patterns.9,10 Studies have shown that a
Kartagener syndrome. MRI has similar sensitiv- specific cause can be identified in many cases,
ity and specificity and can be used in cases where and this has led to a modification in the
radiation must be avoided. treatment in up to 50% of patients.13 In some

cases, such as ABPA or immunodeficiencies, BRONCHODILATORS: Most patients with bronchi-
specific therapy may prevent disease progres- ectasis have significant airway hyperresponsive-
sion.15 Bronchiectasis should be distinguished ness, presumably as a result of transmural
from COPD (particularly chronic bronchitis).6 airway inflammation. The routine use of bron-
Both diseases present with cough, sputum chodilators has the added potential advantage of
production, wheezing, and dyspnea. Exacerba- the stimulation of mucociliary clearance, which is
tions are common in both disorders, although the associated with the use of p-adrenergic agents.
volume of sputum production is greater in Both aerosolized p-agonist therapy and aerosol-
patients with bronchiectasis. Recurrent fever ized anticholinergic therapy should be tried
and hemoptysis are less likely to be found in when there is evidence of reversible airway
patients with chronic bronchitis. The presence of obstruction.6,8
Pseudomonas in the sputum may be helpful to the ANTIBIOTICS: Antibiotics are the cornerstone
diagnosis. The incidence of Pseudomonas aerugi- for the treatment of exacerbations of bronchiec-
nosa is approximately 31% in patients with tasis. They are used to treat acute exacerbations,
bronchiectasis, but only 2% to 4% in patients to prevent exacerbations, or to reduce the
with COPD. bacterial burden.10 Early in the disease process,
Bronchiectasis can also be confused with patients are typically colonized with Haemophilus
interstitial fibrosis, especially in patients with influenzae. As the disease progresses, Psuedomonas
end-state fibrosis who have a honeycomb ap- spp predominate. Other pathogens include Mor-
pearance seen on a chest radiograph. This axella catarrhalis, Aspergillus, and MAC.7 Staphy-
parenchymal honeycomb appearance may mimic lococcus aureus is uncommon, and if repeatedly
the air-filled cysts of bronchiectasis. isolated, should prompt the consideration of
Therapy: The objectives of management for undiagnosed CF.11 Early, when the bacterial flora
bronchiectasis are the relief of symptoms, the include Streptococcus pneumoniae and H influenzae,
prevention of complications, the control of treatment with TMP-SMX, ampicillin-clavulanate
exacerbations, and a reduction in mortality. acid, or one of the newer macrolide agents is
Unfortunately, only a small number of well- effective. In patients who have been colonized
designed trials in small numbers of patients have with Pseudomonas, oral therapy requires the use
been performed in patients with non-CF bron- of a fluoroquinolone.10 In some cases, IV admin-
chiectasis. Many of the current recommendations istration of antipseudomonal antibiotics is re-
are extrapolated from those done in patients with quired.6 Whether prophylactic antibiotic therapy
CF.13 is necessary remains an unresolved question.
GENERAL SUPPORTIVE MEASURES: Vaccination Strategies that have been tried include a high oral
against influenza and pneumococcal pneumonia or IV dose for a prolonged period (4 weeks),
are also recommended, although they have not pulsed courses of antibiotics with on/off periods,
been proven to change important outcomes in and regular aerosolized therapy.6,11,16 Strategies
these patients.13 for prophylaxis with low-dose antibiotics range
AIRWAY CLEARANCE TECHNIQUES: Postural drain- from daily to 1 week of each month. Daily
age and chest physiotherapy are useful to inhaled antibiotic prophylaxis is now recom-
enhance the gravity-aided clearance of secre- mended in patients with CF who have been
tions. Alternative treatment includes the use of a colonized with P aeruginosa. In non-CF bronchi-
flutter device, a positive expiratory pressure ectasis, this approach is reserved for patients
mask, chest oscillation, and humidification of with severe disease, manifested by copious
inspired air.6,8 purulent sputum and frequent exacerbations,
EXERCISE TRAINING: The role of pulmonary who fail to respond to other approaches. Both
rehabilitation and inspiratory muscle training inhaled tobramycin and gentamicin have been
has been investigated in only one well-designed shown to decrease bacterial density, but the
trial, but it has been suggested that rehabilitation benefits seem to be less than those seen in
increases exercise tolerance in patients with patients with CF. In addition, adverse events
bronchiectasis.8 such as bronchospasm are more common.17

ANTIINFLAMMATORY AGENTS: Although intense ectasis who were in stable condition.18 Therapy
airway inflammation characterizes bronchiectasis, with inhaled mannitol may improve impaired
few studies have looked at the efficacy of mucociliary clearance by inducing an influx of
corticosteroids in the treatment of this disorder. fluid into the airways and has shown clinical
Inhaled steroids have been suggested as alterna- promise in patients with non-CF bronchiecta-
tive therapy and may be useful in some patients, sis.8,17 This is particularly exciting because it is
especially those with significant airway hyperre- easier to inhale a dry powder than to use a
activity. It has been shown that inhaled cortico- nebulizer. One small study has also shown
steroids can reduce the levels of inflammatory benefit with nebulized hypertonic saline.17
mediators and improve dyspnea and cough. SURGERY: In patients with localized bronchiec-
However, a systematic review found no signifi- tasis, surgical removal of the most affected
cant improvement in pulmonary function.8,13 segment or lobe may be considered. The major
Short courses of oral corticosteroid therapy are indications for surgery include the partial ob-
often used during acute exacerbations. Nonsteroi- struction of a segment or lobe due to a tumor or
dal antiinflammatory agents, such as indometha- the presence of a highly resistant organism in the
cin (not available in the United States), have been affected area, such as MAC or Aspergillus.
used in Europe, either orally or by inhalation.8 Patients require significant pulmonary function
Leukotriene receptor antagonists may be of
to withstand surgery. Surgery may also be
benefit in patients with bronchiectasis because
performed for massive hemoptysis in patients
they can inhibit neutrophil-mediated inflamma-
with adequate pulmonary reserve, although the
tion. However, there have been no randomized
increased success of bronchial artery emboliza-
controlled trials published concerning patients in
tion for hemoptysis makes surgery less desir-
this population.8 Macrolides suppress inflamma-
able.6,10,11
tion, independent of their antimicrobial action,
LUNG TRANSPLANTATION: Patients with bronchi-
and have improved the clinical status and lung
ectasis and CF were initially considered not to be
function of patients in a few small studies of
good transplant candidates because of concerns
bronchiectasis.16,17 Long-term use needs to be
about overwhelming infection after the use of
balanced against potential side effects, including
gastrointestinal, cardiac, and auditory. The possi- prolonged immunosuppression. However, dou-
bility of MAC infection must also be excluded as ble-lung transplantation has been successful in
macrolide monotherapy increases the likelihood patients with CF, and the St. Louis International
of resistance.17 Further study is needed before Transplant Registry lists .1,000 patients with CF
they can be recommended routinely. and .200 non-CF bronchiectasis patients who
MUCOLYTIC AGENTS AND HYDRATION: Adequate have undergone lung transplantation, with a 1-
oral hydration and the use of nebulized solutions year survival rate of 72% and a 4-year survival
may improve airway mucus clearance.6 Acetyl- rate of 49% in patients with CF.9,11
cysteine is beneficial in some patients. To date,
there have been no randomized, controlled Cystic Fibrosis
clinical trials showing mucolytics to be of benefit
in the treatment of non-CF bronchiectasis. Re- Genetics
combinant human DNase breaks down DNA
that is released from degenerating bacteria and CF is the most common genetic disease in the
neutrophils. DNA has a tendency to form thick, United States, with an incidence of 1 in 3,000
viscous gels. DNase improves the clearance of births in a white population. The incidence is
secretions and pulmonary function and reduces much lower in African Americans, Asians,
the number of hospitalizations in patients with Hispanics, and Native Americans. CF is an
CF, but has not been found to be useful in non-CF autosomal-recessive disorder with variable pen-
bronchiectasis. One study has suggested that etrance. Carriers of the CF gene are phenotypi-
DNase was ineffective and potentially harmful in cally normal. About 5% of persons in the white
.300 adult outpatients with idiopathic bronchi- US population are carriers of the CF gene, and

approximately 20,000 individuals are affected by individual’s sensitivity to the CFTR dysfunction,
this disorder.19,20 as well as the amount of functional CFTR, which
The CF gene, which was sequenced in 1989, is is influenced by the specific type of mutation. It is
located in the long arm of chromosome 7 and now recognized that some patients may present
encodes for the CF transmembrane regulator with only one characteristic feature of CF and a
(CFTR) protein.19 The CFTR is located at the cell borderline abnormal sweat test finding in the
surface and acts as an ion channel that regulates presence of either a known CFTR mutation or an
liquid volume on epithelial surfaces through abnormal nasal potential difference (PD), which
chloride secretion and the inhibition of sodium has led to use of the term atypical or nonclassic CF.
absorption. The CFTR protein may also regulate Nonclassic CF is often associated with Class IV or
the function of other epithelial cell proteins. The V mutations. These patients typically present
defective transport of ions across the epithelial later in life, and will display typical CF symp-
membrane leads to thick viscous secretions in toms in at least one organ, but often have a
many organs and to excessive chloride concen- normal or borderline sweat chloride test. They
tration in the sweat of patients with CF. This are typically pancreatic sufficient and have
abnormality is the basis for the laboratory test milder pulmonary disease and a better overall
that is most frequently performed to diagnose prognosis.21,22 Additionally, patients with only
this disorder. The CFTR protein is expressed in one mutation and mild symptoms with indeter-
all of the epithelial cells affected in patients with minate testing may have another CFTR-related
CF, including those in the lung, pancreas, sweat disease, such as chronic sinusitis, ABPA, or
glands, and liver. It is also found in the large asthma. It is now thought that other modifier
intestine and testes.19 genes and environmental exposures determine
More than 1,600 mutations of the CFTR gene the phenotypic expression of the underlying
have been described. The DF508 mutation is the genotypic mutation.22
most common and accounts for about 90% of CF
chromosomes in patients of northern European Pathogenesis
descent, but only 60% of CF chromosomes
worldwide. The mutation is due to the deletion CF is initiated by a defect in the gene that is
of a single phenylalanine residue at position 508. normally responsible for encoding CFTR protein,
The D508 mutation is a Class II mutation that which is necessary for the flow of electrolytes
results in improper folding and thus degradation and fluid across cell membranes. The resultant
of the protein (see below). CFTR mutations are abnormalities in salt and water transport lead to
categorized into six classes19: an alteration in the composition of secretions in
the respiratory tract, pancreas, GI tract, sweat
Class I: absent or defective protein synthesis
glands, and other exocrine tissues.23 In the lung,
Class II: abnormal processing or transport of the
these alterations change the properties of the
protein to the cell membrane
mucus layer lining the epithelia and the compo-
Class III: abnormal regulation of CFTR function,
sition of the airway surface fluid, ultimately
inhibiting chloride channel activation
resulting in the clinical features of CF. The net
Class IV: normal amount of CFTR but reduced
fluid loss on the airway surface leads to the
function (abnormal conductance)
collapse of cilia and impaired mucociliary clear-
Class V: reduced synthesis of fully active CFTR
ance, persistent bacterial infection, excessive host
Class VI: decreased stability of fully processed
inflammatory response (characterized by the
and functional CFTR
accumulation of leukocyte-derived DNA and
These multiple mutations lead to varying secretions rich in elastase), and airway obstruc-
phenotypic presentations of the disease. Even tion, leading to progressive lung destruction/
patients with similar genetic mutations may bronchiectasis. Although bacterial infection clear-
manifest different clinical manifestations of the ly leads to an intense inflammatory response,
disease. The degree of organ involvement and there is mounting evidence that patients with CF
perhaps the disease severity correlate with the have increased basal and inducible airway

inflammation independent of infection.19,20,24,25 and 59 mmol/L are indeterminate, and levels
Figure 2 is a nice summary of the interaction 60 mmol/L are indicative of CF. In patients
between airway obstruction, infection, inflamma- over 6 months of age, who will have higher
tion, and destruction. concentrations of chloride, levels 39 mmol/L
indicate that CF is unlikely, levels between 40
Diagnostic Tests and 59 mmol/L are indeterminate, and levels
60 mmol/L remain indicative of CF.26 About
Prior to the mid-1990s, most patients were 1% of patients with CF have normal sweat
diagnosed with CF after presenting with typical chloride test results. Abnormal sweat test results
symptoms. Since that time, newborn screening are seen in patients with other disorders (as
(NBS) has become much more widespread. listed in Table 3). Therefore, a diagnosis should
Newborns with CF will have elevated levels of only be made if the clinical history is suggestive
serum immunoreactive trypsinogen (IRT), which of CF.
can be detected via a radioimmunoassay or Molecular Diagnosis: Approximately 1,600
enzyme-linked immunosorbent assay performed mutations have been identified after sequencing
on samples of dried blood. After an abnormal the entire gene in a research laboratory. Geno-
IRT, most NBS programs perform DNA testing to typing at commercial laboratories usually can
identify the known CFTR mutations, although identify only 20 to 30 of the most common
some repeat the IRT after 2 weeks. NBS is not a mutations. This accounts for approximately 90%
diagnostic test, and thus only identifies new- of CF mutations in the general population. DNA
borns at risk for CF. An elevated IRT must be analysis can be particularly helpful in cases
followed by direct diagnostic testing (typically where the sweat chloride testing is indetermi-
with the sweat chloride test).26 nate. Two separate mutations on two separate
Sweat Test (Pilocarpine Iontophoresis):The sweat chromosomes are generally associated with
chloride test remains the gold standard diag- disease. A single mutation on one chromosome
nostic test, because genetic screening only or two mutations on a single chromosome may
identifies a small number of the most common be associated with atypical disease or with other
mutations. The results of this test are abnormal CFTR-related diseases, or may not manifest with
in the large majority of patients with CF. A level symptoms at all.26 It is important to note that the
of .60 mEq/dL is usually diagnostic for CF. phenotypes associated with CFTR gene muta-
However, the test must be repeated at least tions have expanded, and genotype analysis
twice, and an adequate sample containing at cannot predict prognosis in individual pa-
least 75 mg of sweat must be collected over a 30- tients.26
min period. The cutoff values are different in
PD Across the Respiratory Epithelium: This is a
infants and older patients. In infants, a level 29
research tool that may be available at few centers
mmol/L makes CF unlikely; levels between 30
to aid in the diagnosis of CF. The abnormal
transport of chloride leads to a very negative PD
across the nasal epithelium. The measurement of
this PD can establish a CF diagnosis. Nasal
perfusion with amiloride hydrochloride and with
chloride-free solutions leads to characteristic
changes in the PD.
Ancillary Tests: In cases where the diagnosis
may be elusive, ancillary testing may be helpful.
This might include genital evaluation in males,
pancreatic function testing or imaging, HRCT of
the chest to evaluate for bronchiectasis, and
Figure 2. Products of polymorphonuclear cells and their
effects on inflammation of the airways in patients with CF. lower airway sampling for classic pathogenic
Adapted from Ramsey.27 organisms.26

Table 3—False-Positive or False-Negative Sweat Test only one or no mutation is identified, these
Results
patients are at risk for CF or may have another
False positives
CFTR-related disease. In this situation, ancillary
Adrenal insufficiency testing may help confirm or exclude the diagno-
Anorexia nervosa sis. If a diagnosis cannot be made at the time of
Atopic dermatitis presentation, these patients should also be
Autonomic dysfunction
Celiac disease monitored periodically for the development of
Familial cholestasis symptoms.26
Fucosidosis
Glucose-6-phosphate dehydrogenase deficiency Nonpulmonary Clinical Manifestations
Glycogen storage disease, type I
Hypogammaglobulinemia
Hypoparathyroidism In the pancreas, dysfunction of the exocrine
Hypothyroidism (untreated) portion leads to fat malabsorption and malnutri-
Klinefelter syndrome
Mucopolysaccharidosis, type I
tion. Glucose intolerance is present in as many as
Malnutrition 50% to 70% of older patients with CF; diabetes
Nephrogenic diabetes insipidus mellitus occurs in about 15%. Malabsorption of
Nephrosis fat-soluble vitamins such as A, D, E, and K can
Prostaglandin E1 infusion, long-term
Pseudohypoaldosteronism lead to vitamin deficiency and coagulopathy. The
False negatives liver is affected by biliary cirrhosis as a result of
Dilution of sample thick secretions in the biliary ducts. This is
Malnutrition
manifested by abnormal liver function test
Peripheral edema
Low sweat quantity/rate results. Diffuse liver involvement can lead to
Dehydration portal hypertension. Meconium ileus is present
CFTR mutations with preserved sweat duct function in about 20% of infants with CF and is
pathognomonic for this disorder. A similar
syndrome occurs in older patients with CF
Clinical Diagnosis of CF
because of inspissated mucus in the GI tract.
This results in the distal intestinal obstruction
In infants with a positive NBS, with either a
syndrome, often requiring surgical treatment.
repeat positive NBS or DNA testing that reveals
About 95% of male patients with CF are
known mutations, the diagnosis of CF can be
infertile. Although sperm maturation is normal,
confirmed with sweat chloride testing. In infants
the Wolffian structures are often not developed.
with an indeterminate sweat chloride test, the
The vas deferens is often completely absent. This
diagnosis of CF can be made if two CF-causing
may indicate a role for the CFTR protein in the
mutations are identified. Infants with indetermi-
development of the male genital tract. In fact, in
nate sweat chloride testing and no or one CF-
subjects with congenital bilateral absence of the
causing mutation cannot be diagnosed defini- vas deferens but without any other abnormalities
tively. These infants are at risk for developing CF of CF, mutations in the CFTR gene have been
or a CFTR-related disease and should be fol- reported.19 Women with CF are not infertile,
lowed closely. although they may have difficulty conceiving
In patients presenting with symptoms of CF because of thick cervical mucus and/or anovu-
or a family history of CF, the following is used to latory cycles if their nutritional status is poor.
make a diagnosis: CF can be diagnosed if the Pregnancies can be successful, and pulmonary
sweat chloride value is greater than 60 mmol/L function has not been found to deteriorate after
(on two occasions, or once with two mutations pregnancy.
identified by DNA analysis) and excluded if the
value is 39 mmol/L. Patients with an indeter- Pulmonary Manifestations
minate level should undergo DNA analysis (if
not already done). As with infants, the presence The primary cause of morbidity and mortal-
of two known mutations is diagnostic of CF. If ity in patients with CF is bronchiectasis and

obstructive lung disease. Pulmonary disease is killing by alginate. Bacteria may have native or
present in 98% of patients with CF by the time acquired antibiotic resistance. In addition, phar-
they reach adulthood. Despite the great advances macokinetics differ in patients with CF, as the
in the management of this disorder, the majority volume of distribution of hydrophilic drugs (eg,
of the patients succumb to respiratory complica- penicillins, cephalosporins, and aminoglyco-
tions. A recurrent cough that becomes persistent sides) is increased because of decreased amounts
is often the first manifestation. Airway hyperre- of adipose tissue. The renal clearance of amino-
activity and wheezing are common in children. glycosides is increased, and therefore the dosage
Bronchodilator responsiveness tends to decrease has to be adjusted, usually at triple the normal
with age, perhaps as a result of the destruction of dose.19,23
the cartilage. Pansinusitis with opacification of
the paranasal sinuses is a universal finding in Management of Pulmonary Disease
patients with CF. Nasal polyps are present in up
to 30% of patients with CF.19,23 Although the focus of this section is on the
In patients with CF, the lungs are normal at treatment of pulmonary disease in patients with
birth, but infection occurs early in life and is CF, it should be kept in mind that management in
persistent. The abnormal ionic environment and general will be suboptimal unless all aspects of
chronic airway obstruction by thick secretions the disease are addressed (ie, exocrine pancreatic
promote colonization with pathogenic bacteria, supplementation, nutritional support, glucose
which leads to the accumulation of inflammatory control, psychosocial issues, and treatment com-
cells. These cells release inflammatory mediators pliance). Progress has been made in attempts at
that cause inflammation and damage to the addressing the underlying defect of CF with gene
airway wall, leading to the development of therapy, but current clinical treatment is aimed at
bronchiolitis and subsequently bronchiectasis treating the effects of the CFTR dysfunction—
(Figure 2). thickened airway mucus, infection, and inflam-
H influenzae, S aureus, and, later, P aeruginosa mation.
are the pathogens that are most commonly found Clearance of Airway Secretions: The chief non-
in the airways of patients with CF. The abnormal pharmacologic means of enhancing airway se-
CFTR may be partly responsible for colonization cretion clearance has been chest physiotherapy
with Pseudomonas, as the normal CFTR appears to (either manual or with use of an oscillatory vest)
be involved in the clearance of this organism and postural drainage. Other techniques include
from the airways. The high sodium content in CF forced expiratory techniques, positive expiratory
secretions may contribute to chronic infection, as pressure, and flutter valves. A Cochrane review
low sodium content is required for the effective in early 200927 noted that there is no high-level
killing of bacteria in airway epithelia. Coloniza- evidence that any of these techniques are
tion with P aeruginosa is not benign, as it has been superior to the others. All patients who produce
found to be an independent risk factor for the daily sputum should be instructed in clearance
accelerated loss of lung function and decreased techniques. All of the techniques require a great
survival. Colonization with Burkholderia cepacia deal of time, and treatment compliance can be an
denotes an even worse prognosis. Many Burkhol- issue. Therefore, several methods can be intro-
deria spp have innate antibiotic resistance, are duced to each patient.28
transmissible from person to person, and are Bronchodilator Therapy: As noted earlier, many
highly virulent. Occasionally infection with the patients with CF will demonstrate a degree of
complex can cause an invasive, fatal bacter- bronchial hyperactivity and reversibility. The
emia—the ‘‘cepacia syndrome.’’23 obstructive airway disease is typically only
The mucoid appearance of Pseudomonas is partially reversible, as the underlying causes
due to the production of alginate. This bacterium include the chronic infection, inflammation, and
is difficult to eradicate because of the poor resulting structural damage. Bronchodilator ther-
penetration of antibiotics into purulent airway apy should be considered in patients who have at
secretions and to the interference in phagocytic least a 10% increase in FEV1 in response to an

inhaled bronchodilator. In addition, bronchodi- the two, it is reasonable to assume that they may
lators are often used in all patients with CF prior be complementary.29
to chest physiotherapy and immediately prior to Antibiotic Therapy: Patients with CF have
the inhalation of hypertonic saline solution, frequent exacerbations of infection. Acute exac-
antibiotics, or dornase alfa (as these medications erbations are manifested by increased cough and
have the potential to induce nonspecific bronchi- sputum volumes, sometimes associated with
al constriction). The role of these medications in hemoptysis, and are often accompanied by
improving mucociliary clearance has not been systemic symptoms such as decreased energy,
well defined. Current guidelines recommend the anorexia, and weight loss. Spirometry demon-
use of b-adrenergic receptor antagonists over strates a decrease in lung function. In order to
anticholinergic agents.28,29 standardize the definition of acute exacerbations,
Reduction in the Viscosity of Secretions: The a mnemonic has been proposed: CF of the
increased viscosity of the sputum in patients PANCREAS (Cough, Fever, pulmonary function
with CF is due in part to the presence of many studies, Appetite, Nutrition, Complete blood
polymorphonuclear neutrophils and their degra- count, Radiograph, Examination, Activity, and
dation products, including DNA from dying Sputum).23 Chronic therapies should be contin-
cells. Recombinant DNase (recombinant human ued.30 Parenteral antibiotics are generally admin-
DNase or dornase alfa) digests extracellular istered for 14 to 21 days to reduce the burden of
DNA and can help to reduce the viscosity. A bacteria, to decrease symptoms, and to improve
lung function. The most recent respiratory tract
meta-analysis of randomized trials of dornase
cultures should be used to guide therapy.
alfa has concluded that treatment improves lung
Cephalothin and nafcillin are used for the
function and is well tolerated. There is some
treatment of infection with S aureus, and vanco-
controversy about when to initiate dornase alfa,
mycin is used for patients with a penicillin
but most clinicians will consider a trial in
allergy. For patients colonized with Pseudomonas,
patients with documented chronic infection and
an antipseudomonal penicillin is combined with
obstruction on spirometry. A guideline commit-
an aminoglycoside. Combination therapy reduc-
tee for the CF Foundation recommends chronic
es the risk of the development of resistance.
dornase alfa for all children with CF over the age
Intensified bronchodilator therapy and chest
of 6 years. The recommended dosage is 2.5 mg
physiotherapy are indicated during the treatment
daily.28,29
of exacerbations. Short-term corticosteroids may
Osmotic Therapy: A decreased amount of be added in patients with hyperreactive airways,
airway surface liquid is an important factor in but are not recommended for routine use in acute
the under lying pathophysiology of CF. There- exacerbations.28,30
fore, osmotically drawing water onto the airway Chronic infection with Pseudomonas is associ-
surface via inhalation of a hypertonic substance ated with a more rapid decline in pulmonary
might help to clear secretions and restore function and increased mortality; delaying the
mucociliary transport. Inhaled hypertonic saline onset of chronic infection is critical. When the
solution has been used for this purpose in organism is first isolated, a prolonged course of
patients with CF, and has been associated with antibiotics that eradicates the organism has been
increased mucus clearance and improvement in shown to delay the onset of chronic infection.
lung function, and, in one long-term study, with Repeated attempts to eradicate the organism may
fewer exacerbations requiring antibiotic therapy. also be successful and beneficial. A combination
Prescribing patterns vary, but twice-daily treat- therapy consisting of an oral quinolone and an
ments (4 mL of 7% saline solution) in patients inhaled aminoglycoside is typically used. Some
with chronic cough and sputum production patients with CF are given long-term antibiotic
should be considered. There have been no therapy in the hopes of suppressing bacterial
randomized controlled trials comparing dornase growth and recurrent infections, although this
alfa with hypertonic saline solution. As the practice is controversial. The most common
mechanism of action differs somewhat between current practice involves the use of nebulized

antipseudomonal antibiotics in patients with slow the progressive decline in lung function,
documented chronic infection. The inhaled route particularly in younger patients with more mild
is attractive as it allows the delivery of higher disease. The 2007 Cochrane review, which is
concentrations to the airways with low systemic based on four trials enrolling a total of 287
absorption, thus reducing the risk of ototoxicity patients, confirms this finding.19,35 The beneficial
and nephrotoxicity. A 2009 Cochrane review effects are dependent on achieving adequate
confirmed that long-term use is associated with serum levels, and thus the drug must be
improved lung function and a decreased number individually dosed based upon measured phar-
of hospitalizations.31 Inhaled tobramycin and macokinetics (desired peak plasma concentra-
inhaled aztreonam are currently approved for tions between 50 and 100 lg/mL). This therapy
use in the United States. Ongoing research in has not been used widely (only 6% based upon
inhaled therapy is focusing on other classes of current CF patient registry data) because of
antimicrobial agents, more rapid and efficient concerns about the logistics of dosing and fear
delivery methods, and liposomal formulations of gastrointestinal and renal toxicity. However,
that may allow more effective penetration of the several clinical trials have suggested that renal
mucoid biofilm.32 impairment does not occur at an increased rate,
Antiinflammatory Agents: There is a neutro- and most gastrointestinal complaints are related
phil-predominant inflammation in the airways of to the underlying disease. There is a statistically
patients with CF. These neutrophils perpetuate the significant increase in GI bleeding, but the event
inflammatory cycle through the release of cyto- rates remain very low. The CF Foundation
kines, chemotactants, and proteolytic enzymes currently recommends high-dose ibuprofen ther-
(Figure 2). As noted earlier, patients with CF have apy for children 6 to 12 years of age with
abnormal basal and inducible airway inflamma- moderate to severe lung disease.29,34,36
tion. This inflammation is not entirely indepen- Macrolide therapy was found to be beneficial
dent from infectious stimulation, as neutrophils in patients with panbronchiolitis, which led to
and inflammatory mediators increase significantly empiric use by some physicians in patients with
during infectious exacerbations. When consider- CF. Several well-conducted clinical trials have
ing potential antiinflammatory strategies, several now shown that the long-term use of azithromy-
key concepts must be kept in mind: the inflam- cin (which appears to act primarily as an
matory process is primarily endobronchial; it is antiinflammatory agent by inhibiting neutrophil
characterized by persistent neutrophil influx; migration and elastase production and reducing
intracellular signaling pathways are a key com- the production of proinflammatory cytokines) is
ponent; and the inflammatory response is pro- associated with improved lung function and a
longed and involves heightened oxidative and reduction in the number of exacerbations. The CF
proteolytic stress. Foundation currently recommends azithromycin
Several early studies evaluated the effects of (500 mg orally 3 d/wk) for patients chronically
systemic glucocorticoids in patients with CF. infected with Pseudomonas. Prior to the initiation
Although a beneficial effect on lung function of therapy, some experts have recommended that
was seen in some patients, the adverse effects sputum be examined for nontuberculous myco-
(glucose intolerance, growth retardation, cata- bacteria (as macrolide antibiotics are a vital in the
racts) limit widespread use. Therefore, therapy treatment of nontuberculous mycobacteria).29,34
with systemic glucocorticoids is recommended Other antiinflammatory agents are being
only for patients with asthma or ABPA compli- investigated in patients with CF. Increased
cating their disease. There is a lack of good oxidative stress and reduced levels of glutathione
clinical trials of inhaled corticosteroids in pain the lungs of patients with CF have led to trials
tients with CF, and these also are only recom- of the antioxidant N-acetylcysteine, aerosolized
mended in patients with asthma or ABPA.29,33,34 glutathione, and oral supplementation with
Ibuprofen has also been studied because of its antioxidant vitamins. Evidence suggests that
ability to inhibit the migration and activation of these agents might attenuate lung inflammation,
neutrophils. In high doses, ibuprofen appears to but further study is needed. Pharmacologic

therapies that target proinflammatory and regu- Pulmonary Complications
latory cytokines have been developed for other
diseases (rheumatoid arthritis, psoriasis, inflam- Hemoptysis: Hemoptysis occurs frequently
matory bowel disease). No published data on during bronchitic exacerbations and usually is
their use in CF is available. In addition, there is self-limited. Conservative measures such as bed
some concern that these agents might overly rest, cough suppression, antibiotics, and correc-
suppress the inflammatory response, leading to tion of coagulopathy, if present, are adequate
secondary infectious complications. Finding treatment for most patients. Massive hemoptysis
ways to interrupt intracellular signaling path- is associated with a high mortality rate but may
ways that lead to increased inflammation may respond favorably to bronchial artery emboliza-
also be an effective strategy, but more under- tion. It is successful in as many as 90% of cases,
standing of the complex roles these play in other but recurrences can occur in about 20% of cases.
important cellular mechanisms is needed. The Repeated procedures can be performed if neces-
increased levels of neutrophils in the lung lead to sary. If this proves unsuccessful, lung resection of
massive amounts of proteases that overwhelm the involved lobe may be the only alternative, but
native antiproteases. Several trials have exam- it is often difficult to ascertain with certainty
ined the use of inhaled a1-antitrypsin in patients which lobe or segment is responsible for the
with CF. Although it appears to be well tolerated, hemorrhage.39
no clear benefit on important outcomes have yet Pneumothorax: Spontaneous pneumothorax
been demonstrated. In addition, this therapy is occurs in about 16% of patients with CF. The
limited by expense, supply, and the risks of using vast majority of these patients have severe
plasma-derived products. Some of this may be pulmonary involvement antecedent to the pneu-
overcome in the future with recombinant a1-
mothorax, with an FEV1 of ,50% predicted. The
antitrypsin.33,34
average recurrence rate is nearly 50%, and,
New Therapies in Development: Because CFTR
despite treatment, the mortality rate is high at
mutations lead to defective or absent CFTR
30% to 60%. This high mortality rate relates more
protein, the most logical way of treating CF
to the severe underlying parenchymal involve-
would be to replace the CFTR gene to restore
ment than to the pneumothorax itself. Chemical
normal production. There are multiple steps to
pleurodesis may be necessary for treating recur-
achieving this goal: sufficient gene product must
rences and does not necessarily preclude future
be delivered to the primary target cells and it
lung transplantation.39
must be incorporated so as to allow normal gene
expression. Although progress has been made, Nontuberculous Mycobacterial Infections: Re-
gene therapy is still some years away from cently, there has been a marked increase in the
clinical practice. Other approaches in develop- isolation of nontuberculous Mycobacterium spp
ment include correction of the abnormal protein (primarily MAC and Mycobacterium chelonei) in
folding of the CFTR, improvement in the ion adult patients with CF. Several centers have
channel function, and induction of alternative ion reported positive culture findings from up to
channels.23,37 A recently completed randomized 18% of patients studied. Distinguishing airway
trial of ivacaftor, a CFTR potentiator, showed colonization from infection can be difficult.
statistically and clinically important improve- HRCT scanning may be useful in the evaluation.
ments in lung function, quality of life, and weight Nodular opacities or a tree-in-bud appearance
gain along with a reduction in pulmonary suggests the presence of infection rather than
exacerbations and sweat chloride concentrations colonization. Transbronchial lung biopsies may
over a 48-month period (with no increase in be required to demonstrate the presence of
adverse events or side effects). This study is an infection. If pulmonary function declines and
important milestone in the development of atypical Mycobacterium spp are found in cultures
therapies that address the underlying CFTR from at least three sputum samples, treatment
dysfunction rather than just the downstream with antimycobacterial agents is recommend-
effects of infection and inflammation.38 ed.19

ABPA: ABPA develops in a small portion of would receive the most benefit. Traditionally
patients in the United States (1.8% in a 1995 pediatric patients were not included in the lung
report). ABPA should be suspected if there is allocation system, so patients less than 12 years
evidence of bronchospasm, peripheral eosino- of age continue to be transplanted on the basis of
philia, sputum cultures positive for Aspergillus time on the waiting list. Patients between 12 and
fumigatus, and an immediate skin test response to 17 years of age have a lung allocation score, but
A fumigatus. Diagnosis is confirmed by total receive preference for pediatric donors. The
serum IgE levels of .1,000 ng/mL and IgE or system appears to be beneficial as the average
IgG specific to A fumigatus.19 wait for patients with CF has decreased from an
Respiratory Failure and Cor Pulmonale: Respi- average of 900 to 300 days and fewer patients are
ratory insufficiency develops as lung disease dying while awaiting transplant.40
progresses, initially with hypoxemia on exercise, Contraindications to transplantation include
then at rest, and eventually with carbon dioxide other organ failures, noncompliance with ther-
retention. Right ventricular failure represents the apy, psychosocial instability, or profound mal-
culmination of the pathologic sequence of lung nutrition. An increased risk for transplantation
disease with progressive respiratory failure. In is associated with colonization with resistant
most cases, this process heralds the terminal organisms (particularly B cepacia complex), but
stage in a patient’s course with only limited
only colonization with Burkholderia cenocepacia is
survival beyond a few months.
considered an absolute contraindication to
Transplantation: Patients with CF are generally
transplantation. Patients who have undergone
good transplant candidates, as they are young
previous thoracic surgery or pleurodesis, an
and otherwise healthy, and are used to undergo-
illness requiring mechanical ventilation, or who
ing complex medical regimens. The transplanted
have concomitant diabetes mellitus are at
lung does not develop the CF defect. However,
increased risk for complications but are consid-
transplantation in CF is not without controversy,
ered viable candidates for transplantation at
especially because some prediction models sug-
most centers.40
gest that transplantation rarely improves surviv-
al in patients less than 18 years of age with CF.
Prognosis
Others have found that only those patients with a
predicted 5-year survival of ,50% and without B
Most patients still die of respiratory compli-
cepacia are likely to have increased survival.
cations. The degree of pulmonary impairment is
These patients require bilateral lung transplanta-
tion using a clamshell incision.40 predictive of survival. In 1992, Kerem et al41
Indications for transplantation include dete- published the results of a study that demonstrat-
riorating respiratory status despite aggressive ed that when the FEV1 decreased to ,30%
medical therapy, and an FEV1 of ,30% predicted predicted, the 2-year survival rate was ,50%.
in compliant patients with good nutritional Women appear to experience a greater deterio-
status and no other organ impairments. Patients ration of lung function with age. When the first
can also be considered if they have an exacerba- accurate description of CF was published by
tion requiring an intensive care unit admission or Andersen in 1939, .80% of patients died within 1
manifest major life-threatening pulmonary com- year of birth. Since then, advances in diagnosis
plications (eg, massive hemoptysis), pulmonary and therapy have been accompanied by a
hypertension, or increasing antibiotic resistance gradual improvement in prognosis and increased
of bacterial infecting the lungs. Female patients survival time. According to data from the CF
and those under 18 years of age have a worse Patient Registry, the median survival time in the
prognosis and should be considered for earlier United States was approximately 20 years in 1970
listing. In May 2005 the United Network for and had increased to 37.4 years by 2007. Recent
Organ Sharing began using a lung-allocation estimates have projected that children born with
score rather than simply time on the waiting list CF in the United States today will survive into
in order to better distribute organs to those who their sixth decade of life.42

Nothing to Disclose 15. Bilton D. Update on non-cystic fibrosis bronchi-
ectasis. Curr Opin Pulm Med. 2008;14(6):595–599.
The author has disclosed that no relation- 16. Zoumot Z, Wilson R. Respiratory infection in
ships exist with any companies/organizations noncystic fibrosis bronchiectasis. Curr Opin Infect
whose products or services may be discussed in Dis. 2010;23(2):165–170.
this chapter. 17. Metersky ML. New treatment options for bron-
chiectasis. Ther Adv Respir Dis. 2010;4(2):93–99.
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Notes

Chapter 2. Pulmonary Vascular Diseases
Objectives: As many as 3 million people die each year in the

Describe the risk factors and epidemiology of VTE. United States from acute PE.1–3
Provide approaches to the diagnosis and treatment of
VTE. Risk Factors
List recommendations for the prevention of VTE.
Describe the epidemiology and pathophysiology of
pulmonary hypertension (PH). Risk factors associated with VTE are often
Describe the steps in the diagnosis of pulmonary arterial divided into acquired and genetic, and these can
hypertension (PAH).

overlap in an individual patient. Acquired risks
List the recommended treatment regimens for PAH.
include prolonged immobility or paralysis; can-
cer; major surgery (particularly operations in-
Key words: anticoagulation; hypercoagulable state; pulmo-
nary arterial hypertension; pulmonary embolism; pulmo- volving the abdomen, pelvis, and lower
nary hypertension; thrombolytic therapy; venous thrombosis extremities); trauma; obesity; high estrogen states
(ie, pregnancy, taking birth control pills, and
Synopsis: hormone replacement therapy); varicose veins;
VTE is a common and potentially fatal disease. Prevention is congestive heart failure; cor pulmonale; myocar-
paramount, yet remains underutilized. Diagnostic algo- dial infarction; stroke; fractures of the pelvis, hip,
rithms that use clinical prediction scores, D-dimer testing,
or leg; indwelling large-vein catheters; inflam-
and noninvasive imaging have been developed and vali-
dated. Treatment is centered on prevention of clot extension matory bowel disease; heparin-induced throm-
and embolization in the acute phase and prevention of bocytopenia (HIT); and myeloproliferative
recurrence and chronic complications long-term. The main- disorders such as polycythemia vera and hyper-
stay of therapy is heparin and the vitamin K antagonists,
although newer agents are now in the final phases of testing viscosity syndromes. Patients with a history of
and will soon be available for both prevention and treatment VTE are at increased risk for recurrence. Con-
of VTE. Pulmonary arterial hypertension is a syndrome genital or hereditary hypercoagulable states
characterized by increased pulmonary artery pressures and
include the following: activated protein C resis-
resistance. There are multiple underlying causes and
associated diseases. Clinical features include dyspnea and tance (factor V Leiden mutation); prothrombin
signs of right heart failure. Diagnosis is reliant on clinical G20210A mutation; increased factor VIII activity;
suspicion, echocardiography, and right heart catheteriza- antithrombin III deficiency (can also be acquired
tion. We have learned much in the past 20 years about the
underlying pathophysiology, which involves several path-
with the nephrotic syndrome); protein C defi-
ways involving vasoconstrictors, mitogens, and procoagu- ciency; protein S deficiency; dysfibrinogenemia;
lants. Treatment is based on functional limitations and disorders of plasminogen and plasminogen
degree of right ventricular dysfunction, and often involves a activation; the presence of antiphospholipid
combination of medications.
antibodies and lupus anticoagulant; and hyper-
homocysteinemia.2,4 Many patients may present
with multiple risk factors for VTE that can
VTE further increase their likelihood of developing
this complication. Examples include the elderly
Pulmonary embolism (PE) and DVT constitute patient with congestive heart failure who sus-
the spectrum of one disease: VTE. About 79% of tains a hip fracture, and the patient with a
patients who present with PE also will have myeloproliferative disorder who is undergoing
concomitant DVT; conversely, only approximate- major surgery. Whether patients with VTE
ly 50% of patients presenting with DVT will have should be routinely screened for an underlying
PE. The estimated annual incidence of VTE in the thrombotic state is a controversial issue. Such
United States is one episode per 1,000 patients. testing would be warranted if identification of

abnormalities could help determine the type or proximal veins without prior calf involvement.
duration of anticoagulation. At the current time, Iliofemoral thromboses appear to be the source of
the evidence does not support this.4 most clinically apparent PEs. The occurrence of
DVT can be self-limited with resolution of the clot
Pathogenesis in most cases; the clot can embolize, resulting in
PE; and/or the postthrombotic syndrome of
The Virchow triad of venous stasis, endothe- venous insufficiency and the accompanying
lial vascular injury, and hypercoagulability ex- stasis changes can occur. The postthrombotic
plains how various processes can interact to syndrome can occur in up to one-half of patients
overcome antithrombotic defenses, resulting in with acute DVT. Its frequency is likely reduced
VTE. Vascular stasis predisposes the patient to by the use of compression stockings for 2 years
VTE by allowing activated coagulation factors to after the initial event, but the underlying predis-
remain undiluted and in contact with the position for the disorder is very poorly under-
vascular endothelium. Vascular trauma or injury, stood. Therefore, the prevention of DVT will
to include the presence of indwelling catheters, prevent these complications.2,5
presumably initiates thrombosis through the
release of tissue factors that activate coagulation Detection of DVT
proteins. The term hypercoagulability refers to
abnormal fibrinolytic system pathways or ac- The clinical diagnosis of DVT of the lower
quired and congenital deficiencies of functional extremity is insensitive and nonspecific, with
abnormalities that predispose the patient to VTE. DVT rates ranging from 10% to 25% of those
The incidence of cancer is slightly increased suspected of having the disease. Even when the
in a first episode of DVT (11% VS 9%, respective- classic signs and symptoms of thrombophlebitis
ly) or PE (6% VS 5%, respectively) compared to are present, only 45% of patients are found to
control subjects. Cancers of the pancreas, liver, have DVT by venography. Therefore, patients
ovary and brain and metastatic disease account presenting with suspected DVT should first have
for most of these. This hypercoagulability relates the pretest probability of disease determined.
to the effects of tumor cells on thrombin The Wells clinical prediction rule (Table 1) has
generation and fibrinolysis, as well as to tumor- been assessed and validated in multiple studies
derived activators of factor X. Because these and can accurately categorize patients into low,
tumors are most commonly incurable, an ex- moderate or high probability of having the
haustive evaluation for underlying malignancy, disease. Obtaining a D-dimer level at this point
apart from routinely obtaining a medical history in the evaluation further simplifies the approach
and conducting a physical examination, is not and may obviate the need for further testing.
recommended.5 Sensitive D-dimer assays (ie, enzyme-linked
immunosorbent assay or semiquantitative rapid
DVT enzyme-linked immunosorbent assay) have suf-
ficient sensitivity and predictive value to rule out
PE usually arises from the deep venous DVT in patients with a low or moderate clinical
system of the body as a complication of DVT. probability. The false-negative result rate is too
DVT usually begins in the lower extremities, high to be useful in patients with a high clinical
although occasional thrombi form in pelvic veins, probability. In those patients and in any patients
renal veins, upper extremity veins and the right in the low-risk or moderate-risk group who have
heart. Most thrombi originate in the soleal veins an abnormal D-dimer level, imaging of the
of the calf, often at sites of decreased blood flow extremity is necessary.6–8
such as the valve cusps or bifurcations. The The gold standard imaging test for DVT
majority of calf thrombi resolve spontaneously, currently is compression ultrasound. The diag-
and PE is uncommon. About 20% to 30% of DVTs nosis of DVT using compression ultrasonogra-
propagate to the popliteal, femoral or iliac veins. phy is made by findings such as abnormal
An additional 10% to 20% of all DVTs occur in compressibility or lack of compressibility of the
22 Chapter 2. Pulmonary Vascular Diseases (Moores)

Table 1—Simplified Clinical Model for Assessment of DVT (Wells Rule)
Clinical Variable Score
Active cancer (treatment ongoing or within previous 6 months or palliative) 1

Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or 1
regional anesthesia
Localized tenderness along the distribution of the deep venous system 1
Entire leg swelling 1
Calf swelling at least 3 cm larger than that on the symptomatic leg (measured 10 cm below the tibial tuberosity) 1
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
Previously documented DVT 1
Alternative diagnosis at least as likely as DVT 2
High probability if score is 3 or greater; moderate if score is 1–2; and low if score is 0 or less. Adapted from Wells et al.60
vein and abnormal Doppler color flow study as a single diagnostic test. However, compression
results. Studies have demonstrated that a lack of ultrasound alone as a first test may establish the
compressibility of a vein is highly sensitive diagnosis in a percentage of patients without the
(.95%) and specific (.95%) for proximal vein need for contrast dye or radiation exposure.
thrombosis.6,9 Ultrasound imaging is limited in
that it does not detect isolated calf vein thrombi, PE
and serial studies may need to be performed if
the initial test result is negative and the clinical Natural History of PE
probability is high. A repeat study finding that is
negative 5 to 7 days later is associated with a
The resolution of PE with the reestablishment
,1% incidence of subsequent VTE over the next
of vascular patency begins almost immediately
3 months. Other tests used in the evaluation of
following the event. The National Institutes of
suspected DVT are shown in Table 2. The
Prospective Investigation of Pulmonary Embo- Health trials demonstrated that with heparin
lism Diagnosis (PIOPED) II data as well as meta- therapy alone, the resolution of PEs occurred
analyses of published trials have shown that CT during the first several weeks after the event,
venography is diagnostically equivalent to com- with 36% of the vascular defects resolving by day
pression sonography.1,10 In patients who also have 5, 52% resolving by day 14, 73% resolving by 3
symptoms suggestive of PE, some favor CT months, and 76% resolving by 1 year for patients
pulmonary angiography (CTPA) with venography who survive the initial event. Untreated PE has a
Table 2—Diagnostic Tests for DVT of the Lower Extremities
Test Invasiveness Complications Comments
Contrast venography Most invasive Phlebitis, allergic Reference or gold standard

reactions,
renal failure
Radionuclide venography Less invasive Minimal Sensitive for proximal DVT; not commonly
used in clinical practice
Impedance plethysmography Noninvasive Minimal Sensitive/specific for proximal DVT; limited in
CHF setting and previous DVT
Fibrinogen scanning Less invasive Minimal Sensitive for calf vein thrombosis; not
commonly used in clinical practice
Real-time Doppler ultrasound Noninvasive Minimal Sensitive/specific for proximal DVT, operator
dependent; clinical gold standard
CT venography Noninvasive Allergic reactions Diagnostically equivalent
CHF = congestive heart failure.

mortality rate of nearly 30%. If treatment is congestive heart failure). No individual risk
initiated, the mortality rate is ,8%.2 factor or clinical symptom or sign is sensitive
enough to rule in or out the diagnosis of VTE.12,13
Chronic Thromboembolic Pulmonary Thus, as with DVT, prediction rules that combine
Hypertension (CTEPH) these factors have been developed. The two most
widely used and validated rules are shown in
CTEPH will develop in approximately 3% to Table 3.14 It should be emphasized that the tool or
4% of patients with acute PE. It is important to approach used is less important than the idea
detect this complication, as it is the only poten- that the clinical pretest probability of disease
tially curable form of severe PH without the need
must be determined in each patient prior to
for lung transplantation. A gradual increase in
further testing.
pulmonary vascular resistance occurs in the
As noted in the section on DVT, moderately
absence of documented recurrent PE and is
to highly sensitive D-dimer assays have a
thought to be related to an increased resistance
sensitivity of 96% to 98% in patients with
to flow through the pulmonary arteries that
results from the initial obstruction and subse- suspected PE, which is sufficient to rule out the
quently from vascular remodeling in small, disease in those patients with an unlikely pretest
unobstructed vessels. Risk factors for CTEPH probability.15,16 In patients with a high pretest
have been identified and include ventriculoatrial probability, however, imaging studies should be
shunts, infected pacemakers, splenectomy, previ- performed instead of the D-dimer assay.7,8 One
ous VTE, recurrent VTE, malignancy, thyroid
Table 3—Clinical Prediction Rules for Acute PE
replacement therapy, and the antiphospholipid
antibody syndrome. Patients who experience a Canadian (Wells) clinical prediction score
major central thromboembolic event or have Variable and score
significant hemodynamic compromise on presen- Signs and symptoms of DVT—3.0
PE as likely as or more likely than an alternative
tation, a documented thrombophilia, or persistent
diagnosis—3.0
abnormalities seen on lung perfusion studies on Heart rate .100/min—1.5
follow-up may also need to be monitored more Immobilization or surgery in previous 4 wk—1.5
closely. Ventilation-perfusion (V̇/Q̇) scanning is Previous DVT or PE—1.5
Hemoptysis—1.0
the screening investigation of choice, as many Cancer—1.0
chest radiologists are not familiar with the Total score
distinguishing features of CTEPH seen on CT ,2.0—Low pretest probability
2.0–6.0—Moderate pretest probability
angiography. Patients who are surgical candi-
.6.0—High pretest probability
dates should be referred to a specialty center for Dichotomized Wells score
the consideration of pulmonary endarterectomy. 4.0—PE unlikely
All patients should receive lifelong anticoagula- .4.0—PE likely
Revised Geneva score
tion therapy.11 Variable and score
Age .65 y—1.0
Diagnosis of PE Previous DVT or PE—3.0
Surgery or lower limb fracture in previous week—2.0
Active cancer—2.0
Clinical Suspicion: The clinical suspicion of PE
Unilateral lower limb pain—3.0
is often arrived at using an unstructured ap- Hemoptysis—2.0
proach based on a combination of factors Heart rate
including the presence or absence of identifiable 75–94/min—3.0
95/min—5.0
risk factors (eg, surgery in the past, obesity, prior Pain on leg palpation or unilateral edema—4.0
VTE), symptoms (eg, dyspnea, pleuritic chest Total score
pain, hemoptysis), physical examination findings 0–3—Low pretest probability
4–10—Moderate pretest probability
(eg, tachypnea), the results of basic laboratory
11—High pretest probability
studies (eg, hypoxemia), and the likely presence
of alternative diagnoses (eg, asthma, pneumonia, Adapted from Tapson.2

issue that often arises is the usefulness of D- clinically useful.1,20,21 However, its use in detect-
dimer testing in specific populations known to ing small peripheral PEs is unproven (6% of
have other reasons for an increase in the D-dimer cases in the PIOPED study). Such small clots may
level (hospitalized or postoperative patients, not be important physiologically, but their
patients with malignancy, pregnant patients, detection may be an important marker for future
and elderly patients). Although the specificity VTE.22 Several analyses have suggested that CT
(and thus clinical utility) of testing in these scanning may be a more cost-effective initial test
populations is lower, the sensitivity remains for suspected PE, compared with the V̇/Q _ lung
high. Thus a normal D-dimer level is still useful scan because of its greater sensitivity for PE and
in the exclusion of VTE.17 There are a few clinical its ability to identify alternative diagnoses to PE.
situations in which the sensitivity of the test CT scanning can also be used to estimate clot
drops and it becomes unreliable to exclude the burden and right ventricular function and is
presence of disease. These include patients who emerging as a useful prognostic measure in
have had symptoms for more than 14 days and patients with documented acute PE. There are
patients already on therapeutic anticoagulation.17 two notes of caution in regard to CTPA. First,
there are occasional nondiagnostic scans. Review
Diagnostic Imaging Studies for PE of patients who had anticoagulation withheld
after a nondiagnostic scan reveals an unaccept-
Many studies have been used in diagnosing ably high recurrence rate in the ensuing 3
acute PE. Until the mid-1990s, the first-line months.9 Most importantly, CT scanning is
imaging study was the V̇/Q̇ scan. A normal V̇/Q̇ associated with significant radiation exposure
scan finding provides compelling evidence and has been linked to an increased risk of breast
against the diagnosis of PE. In one study of 515 and lung carcinomas. This has led to the
consecutive patients with clinically suspected PE recommendation that other testing be considered
who had anticoagulation therapy withheld on the for initial imaging in patients with suspected PE.9
basis of a normal perfusion scan finding, only Thus, V̇/Q̇ scanning might be considered as the
three patients had symptomatic VTE (PE, one initial test of choice in young patients (especially
patient) during a 3-month follow-up period. Using women) with a normal baseline chest radio-
the PIOPED criteria, a high-probability V̇/Q̇ lung graph, as well as in other patients who may have
scan finding accompanied with a high prescan a contraindication to CT scanning (renal function,
clinical suspicion is associated with confirmed PE contrast dye allergy).19 In patients with signs or
in .96% of cases. V̇/Q̇ scan patterns other than symptoms of concomitant DVT, compression
normal or high-probability patterns may require ultrasound may be a reasonable first choice.
additional diagnostic evaluation, although a re- The use of magnetic resonance angiography
cent management study utilizing compression for the detection of PE was investigated in the
ultrasound of the leg and stratification based upon PIOPED III study. Although the sensitivity
pretest probability suggested a very high diagnos- appears to be similar to that of CTPA, there are
tic utility of V̇/Q̇ scanning.18 A prospective many more nondiagnostic studies with MRI,
randomized trial also confirmed that patients reducing the clinical utility. This may be related
who underwent V̇/Q̇ scanning vs CT scanning as to the need for an experienced radiologist to
the main diagnostic imaging test had similar interpret the study. In addition, breath holds of
outcomes.1,19,20 20 to 30 s are required for lung imaging, which
Spiral CTPA of the pulmonary circulation has limits the efficacy of the test in patients with
emerged as the primary diagnostic method for acute PE. Newer scanners may reduce the need
the evaluation of PE. As a minimally invasive for breath holds beyond 10 to 15 s.9,23
examination, this technique is widely available Pulmonary angiography was considered to
and has replaced the use of conventional be the reference gold standard, especially with
pulmonary angiography in most centers. The the subselective injection of contrast media and
overall sensitivity, specificity, and predictive the use of magnified views. A negative finding
values as established in the PIOPED II trial are for a pulmonary angiogram with magnification

appears to exclude clinically relevant PE, based on the current evidence, the suggested approach
on data from two follow-up studies. The mortal- for the diagnosis of suspected acute PE is shown
ity rate for patients undergoing the procedure is in Figure 1.9
,0.5%, and the morbidity rate is about 5%
(usually due to catheter insertion and contrast Treatment of VTE (DVT and PE)
reactions). Because of the expense and invasive-
ness of pulmonary angiography, alternative The goals of treatment of VTE are to reduce
diagnostic algorithms have been sought. Despite the short-term and long-term complications such
the lack of an independent gold standard, as extension of the thrombus, fatal PE, early or
outcome studies have suggested that spiral CTPA late recurrence, postthrombotic syndrome, and
is as accurate as pulmonary angiography. Based CTEPH. When patients present with acute VTE,
Figure 1. Diagnostic algorithm for acute PE. From Moores et al.9

they should be started on parenteral anticoagu- help us to accurately identify low-risk pa-
lation therapy with IV unfractionated heparin tients.25,26 Current guidelines recommend early
(UFH) or subcutaneous low-molecular-weight discharge for low-risk patients.24
heparin or the pentasaccharide fondaparinux. Patients with acute VTE require prolonged
Oral warfarin therapy can be initiated on the first anticoagulation to prevent extension and recur-
day of treatment. Treatment using both agents rence. The current guidelines recommend 3
should be continued for at least 5 days and until months of therapy for patients in whom throm-
the international normalized ratio stays in the bosis develops in the setting of documented
therapeutic range of 2.0 to 3.0 for 2 consecutive transient risk factors. In patients who experience
days (at which time the heparin or fondaparinux idiopathic (unprovoked) events, treatment
therapy can be discontinued). Compared to should be given for at least 3 months. At that
treatment with warfarin alone, overlap therapy point, patients should be evaluated for the risk-
with heparin reduces the risk of recurrence. A benefit ratio of continuing therapy indefinitely.
validated weight-based IV nomogram achieves a Studies suggest that D-dimer levels, persistent
therapeutic response more effectively than em- thrombus on ultrasound imaging, thrombin
piric heparin dosing; thus, it is recommended levels, and perhaps other markers of chronic
that such a nomogram be utilized if UFH therapy inflammation may help to identify those patients
is used.2,24 The most widely used test for who are at the highest risk of recurrence after
monitoring heparin therapy is the activated stopping anticoagulation therapy, but we are not
partial thromboplastin time, which is a global yet able to use these in a systematic fashion that
anticoagulation test and does not measure allows us to individualize the duration of
heparin levels. Failure to achieve an adequate therapy.24,27–29 Therefore, in the absence of a
anticoagulation response with heparin therapy high bleeding risk, most patients with an
(ie, activated partial thromboplastin time, .1.5 unprovoked event should receive indefinite
times control) is associated with the increased therapy. There is no evidence that longer (but
recurrence of VTE. finite) initial courses of therapy (such as 6, 12, or
The low-molecular-weight heparin prepara- 18 months) are more effective than 3 months, as
tions and pentasaccharides share advantages the recurrence rates upon discontinuation of
over UFH as follows: greater bioavailability, therapy are identical.24 In patients with continu-
more predictable dosing, and a lower risk of ing risk factors (such as active malignancy) and
HIT. This negates the need for monitoring in patients who have had a documented recurrent
most instances, although measuring the anti- event, long-term (perhaps lifelong) therapy is
factor Xa level in morbidly obese patients or in recommended.24 Considerable progress has been
those with significantly impaired renal function made in recent years on the development of
can be considered. In patients with suspected or newer anticoagulants. These include oral direct
documented HIT, treatment with a direct throm- thrombin inhibitors (dabigatran) and oral direct
bin inhibitor such as argatroban or lepirudin factor Xa inhibitors (rivaroxaban, apixaban).30–33
should be considered. Treatment with warfarin These may eventually replace heparin and
should not be initiated until the platelet count vitamin K antagonists for both prevention and
has returned to normal, especially in those with treatment of VTE. All have been studied in phase
active thrombosis, as there is the potential for III trials but are not yet licensed in the US for
worsening thrombotic complications. treatment of VTE. The current guidelines do not
Bed rest is not recommended for the treatment recommend use of these agents over warfarin or
of acute DVT unless there is significant pain and other vitamin K antagonists secondary to the lack
swelling.24 Many patients with DVT can be treated of long-term safety data.24
entirely as outpatients. Although some patients
with PE likely can also be treated as outpatients, Thrombolytic Therapy
the data for this population are less robust.
Recently, prognostic scores in patients with acute Thrombolytic therapy is approved for the
PE have been developed and validated, and may treatment of proximal DVT and massive PE.

These agents dissolve thrombi by activating Prevention of VTE
plasminogen into plasmin. Plasmin degrades
fibrin to soluble peptides in the presence of a The rationale for DVT and PE prophylaxis is
thrombus or hemostatic plug. Streptokinase, based on the clinically silent nature of the disease
urokinase, and tissue plasminogen activator are and the high prevalence of DVT among hospital-
approved for use in the United States. Throm- ized patients. There is added importance for
bolytic treatment of DVT has been associated prophylaxis when one considers that most pa-
with decreased pain and swelling and a reduced tients who die of PE do so within 30 minutes of
incidence of postphlebitic syndrome. For the the acute event. The eighth edition of the
treatment of PE, thrombolytic agents produce American College of Chest Physicians Consensus
more rapid resolution of intravascular abnor- Conference on Antithrombotic Therapy recom-
malities than have been demonstrated by either mended preventive strategies based upon the
V̇/Q̇ lung scans or pulmonary angiography. level of risk for VTE. The approach recommended
However, no proven effect on mortality has yet involved assessing of patient risk predominantly
been demonstrated. Thrombolytic therapy is as the primary reason for hospitalization.35
currently recommended for patients with acute The recently released ninth edition of the
PE who show signs of hemodynamic instability guidelines is much more complex and attempts to
unless there are major contraindications related balance both risk for VTE and risk for major
to the bleeding risk.24,34 bleeding. Separate chapters are devoted to non-
surgical, nonorthopedic surgical, and major or-
Inferior Vena Cava Interruption thopedic surgical patients.36–38 It is beyond the
scope of this review to list all of these recommen-
Inferior vena cava interruption is most dations. In general, however, high-risk patients
commonly achieved with the use of an intravas- without a significant bleeding risk should receive
pharmacologic prophylaxis. High-risk patients
cular filter. A randomized trial found that the use
who are also at risk for major bleeding should
of an inferior vena cava filter reduced the rate of
receive mechanical prophylaxis, with initiation of
PE, had no effect on mortality, and was associ-
pharmacologic agents if the bleeding risk changes
ated with a greater risk of recurrent DVT. These
to an acceptable level.36–38 Hospitalization for an
devices are being utilized more frequently,
acute medical illness is independently associated
especially now that many can be safely retrieved
with a relative risk for VTE of about 8. Thus, the
after several months. However, the approved
appropriate prophylaxis of medical inpatients is
indications remain few, as follows: absolute
clearly as important as that in surgical patients.
contraindication to anticoagulation, life-threaten- Several risk factors for VTE have been identified
ing bleeding while receiving anticoagulation, and in hospitalized medical patients. Major risk
documented recurrent VTE while receiving ther- factors include New York Heart Association
apeutic anticoagulation.24 (NYHA) class III and IV heart failure, COPD
exacerbations, and sepsis. Additional risk factors
Surgical Embolectomy include advanced age, history of VTE, cancer,
stroke with lower extremity weakness, end-stage
This procedure should be reserved for pa- renal disease, and bed rest. Many medical
tients with confirmed massive PE who are patients have multiple risk factors. Unfortunately,
hemodynamically unstable and not candidates no systematic way of combining these in order to
for thrombolysis. The high mortality rates asso- identify risk categories in medical patients has
ciated with this procedure, especially if cardio- been accepted and validated.38
pulmonary arrest has occurred, have resulted in
a limited enthusiasm for its use. Interventional PH
catheter extraction or fragmentation may become
viable options for these patients in the near PH is a syndrome resulting from restricted
future.24 flow through the pulmonary circulation, which

leads to increased pulmonary vascular resis- Table 4—Revised Nomenclature and Classification of
tance, and ultimately to right heart dysfunction Pulmonary Hypertension (2003) From the Third World
Conference on Pulmonary Hypertension
and right heart failure. It is defined by a mean
pulmonary artery pressure (PAP) of .25 mm Hg WHO group I
at rest or .30 mm Hg during exercise, which is PAH
shared by many conditions. An important IPAH
FPAH
distinction is that both the PAP and the Associated with:
pulmonary vascular resistance should be elevat- Collagen vascular disease
ed. An elevated cardiac index can cause an Congenital systemic to pulmonary shunts
(large, small, repaired or nonrepaired)
increase in PAP without an increase in pulmo-
Portal hypertension
nary vascular resistance.39 PH was previously HIV infection drugs and toxins
categorized into primary or secondary PH, Other (glycogen storage disease, Gaucher disease,
based on the absence or presence of identifiable hereditary hemorrhagic telangiectasia,
hemoglobinopathies, myeloproliferative disorders,
causes or associated conditions. A revised splenectomy)
classification system that acknowledged the Associated with significant venous or capillary
separation of disorders directly affecting the involvement
arterial tree from disorders affecting the venous Pulmonary veno-occlusive disease
Pulmonary capillary hemangiomatosis
circulation or those affecting the circulation by WHO group II
altering respiratory function was proposed in Pulmonary venous hypertension
1998. A revision of this classification was Left-sided atrial or ventricular heart disease
Left-sided valvular heart disease
proposed at the Third World Conference on
WHO group III
Pulmonary Hypertension, held in Venice, Italy, PH associated with hypoxemia
in 2003 (see Table 4). The major changes noted in COPD
these revisions were as follows: (1) abandonment Interstitial lung disease
Sleep-disordered breathing
of the term secondary PH; and (2) the replace- Alveolar hypoventilation disorders
ment of the term primary PH with idiopathic Chronic exposure to high altitude
pulmonary arterial hypertension (IPAH), or, when WHO group IV
PH due to chronic thrombotic and/or embolic disease
supported by genetic testing, familial pulmonary
Thromboembolic obstruction of proximal pulmonary
arterial hypertension (FPAH).40–42 arteries
Pulmonary arterial hypertension (PAH) is a Thromboembolic obstruction of distal pulmonary
subset of PH (the two terms are not synonymous) arteries
Pulmonary embolism (tumor, parasites, foreign material)
that is defined as a mean PAP of .25 mm Hg at WHO group V
rest or .30 mm Hg during exercise with a Miscellaneous
normal pulmonary capillary wedge pressure Sarcoidosis, histiocytosis X, lymphangiomatosis,
(,15 mm Hg) and a lesion localized to the compression of pulmonary vessels (adenopathy,
tumor, fibrosing mediastinitis)
pulmonary arteriole. IPAH is an uncommon
disorder that affects women more commonly WHO = World Health Organization. Adapted from Rubin
than men among persons 20 to 40 years of age. In et al.61
approximately 6% of patients, there is a family
history of PAH (ie, FPAH), which has been found cases. Thus, genetic testing and counseling
to be related to one of .70 identified mutations should be offered to patients with either IPAH
in the gene-encoding bone morphogenetic pro- or FPAH and their families. The lack of a single
tein receptor type II (BMPR2), which is localized genetic mutation, the low penetrance of overt
to chromosome 2q33. Sporadic mutations in this PAH in BMPR2 mutation carriers, and the lack of
gene are seen in up to 25% of patients with IPAH. a single environmental stimulus have led to the
Asymptomatic carriers of the BMPR2 gene often development of the multiple-hit hypothesis in
have an abnormal increase in PAP in response to the etiology of PAH (Fig 2).40,42,43
exercise and given additional environmental or PAH related to risk factors or associated
genetic stimuli may develop overt disease. Actin- conditions is a heterogeneous group of disorders,
like kinase 1 has also been implicated in familial including connective tissue disease, congenital

(Fig 3).45 These changes lead to progressive
obstruction of flow, increased pulmonary vascular
resistance, and eventual right heart failure and
death. As the number of patients who respond
significantly to acute vasodilator challenge is very
low, the contribution of vasoconstriction relative
to vascular remodeling is minimal. Endothelial
injury may also expose the underlying smooth
muscle to circulating mitogens and growth factors
that stimulate cell growth and proliferation. The
Figure 2. Multiple-hit hypothesis of pathogenesis of PAH. main cellular changes involve smooth muscle
Adapted from Gabbay et al.43
cells, fibroblasts, endothelial cells, and platelets.
The following three pathways are important:
systemic pulmonary shunt, portal hypertension, prostacyclin (prostaglandin 12); nitric oxide
HIV infection, drugs and toxin exposure, and (NO)-cyclic guanosine monophosphate-phospho-
hemoglobinopathies and myeloproliferative dis- diesterase 5; and endothelin. An imbalance
orders. The use of appetite-suppressant drugs for between the up-regulated vasoconstrictive/pro-
.3 months has been associated with an increase proliferative endothelin system and the down-
in the risk of development of PH of .30 times.
regulated vasodilatory/antiproliferative/anti-
Hepatosplenic schistosomiasis may account for
thrombotic NO and prostaglandin 12 systems is
one of the most prevalent forms of PAH
a key contributor. Platelets likely play an impor-
worldwide. The World Health Organization
tant role as procoagulants by increasing the
(WHO) also suggests that other appetite stimu-
platelet release of serotonin, vascular endothelial
lants such as amphetamines may have a very
likely causative role in PH.42 The Registry to growth factor, and platelet-derived growth factor.
Evaluate Early and Long-term Pulmonary Arte- Reduced levels of tissue plasminogen activator
rial Hypertension was established in 2006 to may also contribute to the procoagulant state.
provide characteristics of patients with PAH and Finally, pulmonary arterial smooth muscle cells
information about diagnosis, treatment, and are abnormal and appear to favor a decreased
management of these patients. Forty-six percent apoptosis/proliferation ratio.42,46
of the patients in the registry have IPAH, and
approximately 3% have FPAH. Fifty percent have
PAH associated with another condition, with the
majority of these being secondary to collagen
vascular disease.44
Pathogenesis
The current understanding of PAH is as a

vasoproliferative disease invoked by mitogenic
stimuli. The pathogenesis of PAH is complex and
poorly understood, and, as mentioned earlier,
includes both genetic and environmental factors
that alter vascular structure and function. The
vascular changes involve the pulmonary arteriole, Figure 3. Typical micrograph of a lung from a patient with
and are characterized by vasoconstriction, vascu- PAH showing the classic plexiform lesion (intimal prolif-
eration and interruption of the media by a glomeruloid
lar remodeling with intimal and medial prolifer-
proliferation of small vascular channels). Reprinted with
ation, varying degrees of inflammation, the permission from http://en.wikipedia.org/wi ki/
formation of plexiform lesions, and thrombosis Pulmonary_hypertension.

Clinical Features considered. Risk groups thought to benefit from
screening include patients with known genetic
PH frequently presents with nonspecific mutations; first-degree relatives of patients with
symptoms (Table 5). The most common symp- PAH; patients with scleroderma, HIV, sickle cell
toms are dyspnea on exertion, fatigue, and disease, or recent acute PE; patients with portal
syncope, resulting from reduced cardiac output hypertension prior to liver transplantation; pa-
during activity. Patients may also occasionally tients who have previously used appetite sup-
present with angina-like chest pain with normal pressant medications; and patients with
coronary arteries. This chest pain may reflect congenital systemic to pulmonary shunts.40,42,46
right ventricular ischemia. Hemoptysis as a The best screening test for the detection of PAH is
consequence of pulmonary vascular rupture is a transthoracic echocardiogram (TTE). TTE is
rare but may be a catastrophic event. The also a valuable tool to detect features of left-sided
Raynaud phenomenon is seen in approximately heart disease or intracardiac shunts. Increased
2% of patients with IPAH but is a frequent pulmonary artery (PA) systolic pressure raises
finding in cases of PAH associated with connec- the possibility but is clearly not specific for PAH.
tive tissue diseases such as scleroderma. The If the TTE confirms elevated PAP, further testing
physical examination findings are nonspecific to identify the underlying cause is warranted.
but may give clues to a secondary cause of PAH. Echocardiography is imprecise in the measure-
With more advanced disease, the physical exam- ment of PAP. In addition, because echo cannot
ination reveals signs of right ventricular dys- determine the pulmonary capillary wedge pres-
function. The ECG most often reveals right atrial sure and cardiac output, it should not be used
or right ventricular hypertrophy and right-axis alone to diagnose or initiate or monitor thera-
deviation. The chest radiograph shows an en- py.39,47 As some patients only develop symptoms
larged cardiac silhouette consistent with right with exercise, there is some interest in exercise
ventricular hypertrophy, with enlarged pulmo- echocardiography to detect exercise-induced
nary arteries.40,42,46 PAH. However, the current consensus is that no
treatment decisions should be made based on the
Diagnostic Approach presence of exercise-induced PAH alone.42,46
Spirometry, diffusing capacity, arterial blood
The most important step in the diagnosis of gas measurement, and CT scan of the lung can
PAH is to suspect its presence. As noted, the be performed to exclude underlying respiratory
symptoms are vague and nonspecific, and PAH disease and/or hypoxemia. CT scan and MRI
should be considered in any patient with are also being explored to assess RV mass,
unexplained dyspnea on exertion (and perhaps volumes, and function. When suggested by
in all those patients with an unexplained isolated history, an overnight polysomnogram can be
reduction in diffusing capacity). There are no performed to assess for severe sleep apnea. The
early symptoms of PAH, and thus annual tests for underlying liver disease, HIV, and
screening in high-risk populations should be autoimmune diseases are noninvasive and
should be performed in most patients with
unexplained PAH. A V̇/Q̇ scan should be
Table 5—Signs and Symptoms of Pulmonary Hypertension
performed to evaluate for potential CTEPH, as
Signs Symptoms patients who qualify for thromboendarterecto-
my can have a dramatic improvement with this
Jugular vein distention Dyspnea or exertion procedure. Patients with a prior history of VTE
Prominent right ventricular heave Fatigue
Accentuated pulmonic valve
(particularly a large central clot), malignancy,
component (P2) Syncope and the lupus anticoagulant are at increased risk
Right-sided third heart sound (S3) Anginal chest pain of developing CTEPH.41,42,46,48
Tricuspid insufficiency murmur Hemoptysis Right heart catheterization is the gold stan-
Hepatomegaly Raynaud phenomenon
Peripheral edema dard for diagnosis and should be performed in
all patients with suspected PH, especially if

specific treatment is planned.49 Cardiac catheter- second line of treatment is screening of high-risk
ization is indicated to establish severity and patients (as previously discussed), as it is
prognosis, measure wedge pressure, exclude generally believed that earlier diagnosis and
congenital heart disease, and test the response treatment may improve outcomes. The third line
to selective pulmonary vasodilators (eg, inhaled is to optimize the therapy for any related diseases
NO, or IV adenosine or epoprostenol). Most such as heart failure, hypoxemia, sleep disorders,
authors recommend heart catheterization of both or collagen vascular diseases. The fourth line of
the right and left sides. Left-sided heart cathe- therapy is supportive—directed at the conse-
terization can evaluate for coronary artery quences of PAH. General measures include
disease as well as measure left ventricular end- pneumococcal and influenza vaccinations and
diastolic pressure. Right heart catheterization the avoidance of pregnancy; high-altitude expo-
measurements should include sequential oxygen sure; tobacco; and medications such as appetite
saturation for the presence of an intracardiac suppressants, decongestants, and nonsteroidal
shunt; pulmonary angiography for thromboem- antiinflammatory agents. In addition, the follow-
bolic PH; and hemodynamic measurements ing should be considered:
including PAP, PA occlusion pressure, and
1. Anticoagulation: Patients with PAH should
cardiac index. A positive response to therapy
receive long-term anticoagulation therapy.
with vasodilators is defined as a fall in mean PAP
Patients with this condition are prone to
of .10 mm Hg to reach a mean PAP of ,40 mm
thromboembolism in part because of reduced
Hg, with an increased or unchanged cardiac
PA blood flow, right ventricular dilatation,
output. Very few patients show a short-term
venous insufficiency, and inactivity. The range
response, but a negative challenge result will
of anticoagulation recommended is an inter-
obviate a trial of calcium channel blockers.42,49
national normalized ratio of 1.5 to 2.5.
2. Oxygen: All patients with PAH and docu-
Measurement of Exercise Capacity
mented hypoxemia should receive supple-
mental oxygen to maintain an oxygen
Formal assessment of exercise capacity is an
saturation of .90%.
integral part of the evaluation. A 6-min walk test
3. Diuretics: Careful diuresis is indicated in
is usually performed to determine the degree of
patients with evidence of right ventricular
exercise limitation, as it has proven to be
failure.
reproducible and to correlate well with other
4. Inotropic agents: There are no data on the
measures of functional status. This test has been
long-term use of inotropic therapy for PAH.
very useful in monitoring the response to
Some authors have suggested using digitalis
therapy, and has often been used as a primary
because it may improve right ventricular
endpoint in clinical trials. Importantly, it has
function. The use of cardiac glycosides is
been found to be an independent predictor of
controversial because of the lack of well-
survival in patients with PAH.42,49
designed randomized controlled trials in this
population.40,42,46,50
Treatment of PAH
The fifth line of treatment is vascular-targeted
No current treatment of PAH achieves a cure therapy aimed at reversing or reducing vasocon-
for this devastating disease. It is important to striction, endothelial cell proliferation, and
note that the clinical data upon which treatment smooth muscle cell proliferation. In patients who
recommendations are made were conducted exhibit evidence of an acute hemodynamic re-
primarily in patients with IPAH and PAH related sponse to vasodilator challenge testing, long-term
to connective tissue disease and anorexigen treatment with orally administered calcium chan-
use.41,42 There are six main lines of treatment nel blockers in relatively high doses can occasion-
for PAH.46 The first is prevention. As some forms ally produce a sustained hemodynamic response
of PAH have clear causal mechanisms, these with a reduction in PAP and an increased cardiac
factors should be eliminated where possible. The output. This group of responders not only has

Table 6—WHO Classification of Functional Status of Patients With PH
Class 1 Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical
activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
Class 2 Patients with pulmonary hypertension resulting in slight limitation of physical activity. These patients are
comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class 3 Patients with pulmonary hypertension resulting in marked limitation of physical activity. These patients are
comfortable at rest, but less than ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near
syncope.
Class 4 Patients with pulmonary hypertension resulting in inability to perform any physical activity without symptoms.
These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present at rest, and
discomfort is increased by any physical activity.
Modified for the NYHA classification of patients with cardiac disease. From McGoon et al.49
improvement in symptoms in exercise tolerance, many of the trials utilizing these classes of
but also has increased survival. Unfortunately, medications were not powered to detect an
calcium channel blockers have no antiprolifera- improvement in survival, a recent meta-analysis
tive effect, and thus only a small subset of patients suggests that mortality is lower in patients treated
will benefit from long-term use. Long-acting with targeted therapies.42,46,50,52
nifedipine, diltiazem, or amlodipine can be used. The approach to the use of these agents in
Verapamil should be avoided because of its PAH is typically based on the patient’s functional
negative inotropic effects. In patients who do not class, as defined by the WHO classification
show a reduction in PAP (with the administration system, which is a modification of the NYHA
of vasodilators) during right heart catheterization, system for heart failure (Table 6). In general,
it is not beneficial and is potentially dangerous to patients in functional class I receive general care
initiate therapy with calcium channel blockers. only although trials with early use of specific
Significant adverse effects include systemic hypo- therapy are currently underway. Oral therapies
tension, pulmonary edema, and right ventricular are considered to be first-line agents for patients
failure.40,42,46,50 in functional class II and class III, whereas
Current US Food and Drug Administration parenteral therapies are generally reserved for
(FDA)-approved and investigational therapies patients in class IV. There is no clear consensus as
aimed at reducing endothelial and smooth muscle to which agent to start first, nor is there any
cell proliferation target the following three major current consensus as to the role of combination
pathways involved in the pathogenesis of PAH: therapy.53 Few studies have been published
prostacyclin, NO, and endothelin. Continuous IV directly comparing individual medications or
epoprostenol, subcutaneous and IV treprostinil, classes of medications. Multidrug treatment is
and inhaled iloprost are prostanoids that have appealing because the three classes of FDA-
been shown to improve exercise capacity, func- approved medications exert their effects by
tional capacity, hemodynamics, and, in the case of different mechanisms. Using two or more drugs
epoprostenol, survival. In the NO pathway, may allow for dosing below the levels that cause
sildenafil (which inhibits phosphodiesterase 5) important side effects. It is not clear whether the
has demonstrated improvement in exercise capac- sequential addition of agents is preferable to
ity, functional status, and hemodynamics.51 Bo- upfront combination approaches. It is also not
sentan is an oral nonselective endothelin receptor clear which of several possible combinations of
antagonist; sitaxsentan and ambrisentan are se- agents is most efficacious. At this time it is
lective endothelin A receptor antagonists. These recommended that patients with class III–IV
therapies have been shown to improve exercise PAH who fail to improve after 3 months on
capacity, functional status, and time to clinical targeted therapy should be considered for com-
worsening. Bosentan has also been shown to bination therapy54,55 Authors of the American
improve hemodynamics. Two studies have shown College of Chest Physicians evidence-based
improved survival with bosentan therapy com- guideline published updated guidance for med-
pared with historical control subjects. Although ical therapy for PH in June 2007. Their overall

Figure 4. Treatment algorithm for PAH. The recommended therapies presented in this algorithm have been evaluated mainly
in those patients with IPAH, or PAH associated with connective tissue disease or anorexigen use. Extrapolation to other forms
of PAH should be made with caution. Country-specific regulatory agency approval status and functional class indications for
PAH medications vary. From Badesch et al.50
recommended approach is shown in Figure 4.50 Responders to calcium channel blockers have a
A variety of other substances may play roles as 95% 5-year survival rate. Patients in NYHA
mediators and thus may be therapeutic targets, classes II and IV who have been treated with
including vasoactive intestinal peptide, platelet- epoprostenol have a 5-year survival rate that is
derived growth factor, serotonin, and Rho twice that of matched control subjects. Patients
kinase inhibitors. In addition, stem cell therapy with evidence of right heart failure have a much
to rebuild the damaged circulation is being lower survival rate.40 Prognosis is influenced by
explored.40 If pharmacologic treatment fails, the underlying etiology. Patients with PAH
surgical (the sixth line of) treatment (lung related to congenital heart disease have the best
transplantation or atrial septostomy) should be prognosis. Patients with HIV and PAH associat-
considered.56 ed with connective tissue disease (particularly
those with scleroderma) have the worst progno-
Prognosis sis.42 Posttreatment markers of poor prognosis
include persistent elevations in right atrial
Median duration of survival of patients pressure, low cardiac index, low mixed venous
diagnosed with PAH between 1980 and 1985 oxygen saturation, continued functional class III
was 2.8 years. Since that time, survival has or IV symptoms, poor exercise capacity (6-min
improved. Patients without evidence of right walk test ,380 m), and elevated serum B-type
ventricular failure may survive .10 years.40 natriuretic peptide levels.42,57–59 Patients with

persistent poor functional class or exercise 8. Stein PD, Hull RD, Patel KC, et al. D-dimer for the
capacity, severely reduced right heart function, exclusion of acute venous thrombosis and pul-
a right atrial pressure .15 mm Hg, or cardiac monary embolism: a systematic review. Ann Intern
index ,2 L/min/m2 should be considered for Med. 2004;140(8):589–602.
lung transplantation.40 Either single or double 9. Moores LK, King CS, Holley AB. Current ap-
lung transplantation is an option, but most proach to the diagnosis of acute nonmassive
centers prefer double transplantation because of pulmonary embolism. Chest. 2011;140(2):509–518.
concerns about postoperative reperfusion injury 10. Stein PD, Woodard PK, Weg JG, et al. Diagnostic
after a single lung transplant. Experience has pathways in acute pulmonary embolism: recom-
shown that lung transplant recipients with mendations of the PIOPED II Investigators.
primary PAH have survival rates of 73% at 1 Radiology. 2007;242(1):15–21.
year, 55% at 3 years, and 45% at 5 years. 11. Lang IM, Klepetko W. Update on chronic throm-
Obliterative bronchiolitis is a common compli- boembolic pulmonary hypertension, a frequently
cation in transplant patients with PAH. The undiagnosed condition. Rev Esp Cardiol. 2009;
recurrence of PAH after lung transplantation 62(2):120–125.
has not been reported in the transplanted lung.40 12. Le Gal G, Perrier A. Contemporary approach to
the diagnosis of non-massive pulmonary embo-
Nothing to Disclose lism. Curr Opin Pulm Med. 2006;12(5):291–298.
13. Le Gal G, Righini M, Roy PM, et al. Differential
The author has disclosed that no relation- value of risk factors and clinical signs for
ships exist with any companies/organizations diagnosing pulmonary embolism according to
whose products or services may be discussed in age. J Thromb Haemost. 2005;3(11):2457–2464.
this chapter. 14. Ceriani E, Combescure C, Le Gal G, et al. Clinical
prediction rules for pulmonary embolism: a
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Notes

Chapter 3. Asthma
Objectives: clinical and physiologic features appeared to

Understand the epidemiology of asthma and the contribu- overlap with other diseases of the airways. The
tions of genetic predisposition and environmental factors. definition emphasized the clinical and physio-
Learn the pathology and pathophysiology of asthma and logic consequences of reversible bronchospasm
the importance of inflammatory mechanisms of this disease.
Appreciate the risk factors for asthma and the causes of and bronchial hyperresponsiveness (BHR). This
exacerbation of symptoms. resulted in controversy because these two major
Be able to objectively and accurately diagnose this disease. features of asthma are seen in other common
Learn the strategies of treating asthma based on the pulmonary conditions, such as COPD and acute
National Institutes of Health guidelines.
viral tracheobronchitis. To this date there is no
blood test or other technologic assessment that
Key words: asthma; atopy; diagnosis; epidemiology; path-
ophysiology; treatment
provides simple criteria for the diagnosis of
asthma, and there is growing consensus that
Synopsis: asthma is not a disease at all, but rather a
composite of multiple separate, but overlapping,
Asthma is an episodic disease that is caused by widespread
inflammation of the airways resulting from a complex syndromes. Over the past two decades, the
interaction of cells, mediators, and cytokines. The typical recognition that asthma is an inflammatory
symptoms—wheezing, shortness of breath and cough—may disease of the airways with distinct features has
be provoked by environmental irritants and respiratory
viruses. The acute symptoms of asthma are caused by airway
allowed for a more precise description.
contraction. Persistent inflammation can result in hypertrophy An expert panel of the National Institutes of
and hyperplasia of smooth muscle, microvascular leakage, Health (NIH) was first to provide us with a
activation of airway neurons, stimulation of mucus-secreting widely accepted definition of asthma. The first
cells, disruption of the ciliated epithelium, and collagen
deposition. There are three cardinal physiologic features of report of this group was published in 1991. It is
asthma: (1) diffuse airflow obstruction in both large and small often referred to as the NIH Asthma Guidelines.
airways; (2) reversibility of the airflow obstruction, either It has been updated a number of times, is
spontaneously or in response to therapy; and (3) bronchial
evidence-based, and is available online for easy
hyperresponsiveness that can be described as an exaggerated
bronchoconstrictive response by the airways to a variety of access as the Expert Panel Report 3.1 In 1993, the
stimuli. Spirometry is most useful for diagnosis and monitor- National Heart, Lung, and Blood Institute col-
ing the disease. Reversing airway obstruction with an inhaled laborated with the World Health Organization to
short-acting bronchodilator is helpful in confirming the
diagnosis. Bronchoprovocation testing to induce airflow
develop a global strategy to improve asthma
obstruction also is helpful in the diagnosis of asthma. A recognition and care. This led to the Global
negative test rules out asthma and a positive test is supportive. Initiative for Asthma (GINA), and another Web-
There are both short-term and long-term therapeutic objectives based guideline report to disseminate knowledge
for every asthmatic patient. The short-term objective is the
reversal of immediate symptoms. Long-term objectives are about asthma. This report was updated in 2011.
those directed at improving asthma control, including GINA offers an operational description of asth-
symptoms, effects on the quality of daily living, and use of ma, and, like the US guideline, emphasizes the
rescue medication, and also preventing future exacerbations.
Treatment protocols use step-care pharmacologic therapy
presence of inflammation.2
based on asthma symptoms and the clinical response.
Asthma is a chronic inflammatory disor-
der of the airways in which many cells and
cellular elements play a role. The chronic
Definition of Asthma inflammation is associated with airway hy-
perresponsiveness that leads to recurrent
A universally accepted definition of asthma was episodes of wheezing, breathlessness, chest
elusive for most of the past century. Many of the tightness, and coughing, particularly at night

or in the early morning. These episodes are number of local activated eosinophils and the
usually associated with widespread, but severity of asthma.
variable, airflow obstruction within the lung Specific cytokines, most of which are prod-
that is often reversible either spontaneously ucts of lymphocytes and macrophages, appear to
or with treatment.2 direct the movement of cells to the site of airway
inflammation. They also activate the cells, caus-
ing them to release their mediators. For example,
Pathophysiology IL-3, IL-5, and granulocyte-macrophage colony-
stimulating factor direct eosinophils to release a
Asthma is caused by a complex interaction of number of mediators from their preformed
cells, mediators, and cytokines that results in granules. These mediators are major basic pro-
inflammation. This causes the following impor- tein, eosinophil cationic protein, eosinophil-de-
tant pathophysiologic changes in asthma pa- rived neurotoxin, and eosinophil peroxidase. All
tients: airway smooth muscle contraction and have inflammatory effects that contribute to the
over time hypertrophy and hyperplasia, micro- pathogenesis of asthma.
vascular leakage, activation of airway neurons, Mast cells, usually as a result of IgE-mediated
stimulation of mucus-secreting cells, disruption stimulation, also release preformed mediators,
of the ciliated epithelium, and the laying down of such as histamine and proteases (eg, tryptase,
collagen in the lamina reticularis of the basement chymotryptase, carboxypeptidase, and kininoge-
membrane layer. The characteristic cellular nase), and further act as a regulator of inflam-
changes involve (1) constitutive cells such as mation by producing cytokines that promote
epithelial cells, dendritic cells, mucous glands, eosinophil infiltration and activation. Several
endothelial cells, and myofibroblasts; (2) resident mast cell products (histamine, LTC4, and PGD2)
cells such as bone marrow-derived mast cells and are smooth muscle constrictors and hence induce
macrophages; and (3) infiltrating cells such as bronchoconstriction.
eosinophils, CD4 (helper cell) T lymphocytes, LTs also cause increased mucus secretion.
neutrophils, basophils, and platelets. These in- Increased vascular permeability is caused by
flammatory cells are capable of generating a wide histamine, LTC4, platelet-activating factor, and
variety of mediators that can induce broncho- bradykinin.
constriction. These include histamine, platelet-
activating factor, and a number of derivatives of Structural Changes of the Airway
the arachidonic cascade such as prostaglandin
(PG) D2 and the cysteinyl leukotriene (LT) C4, Denudation of the airway epithelium can lead
LTD4, and LTE4. A number of typical histopath- to airway edema and the loss of substances in the
ologic findings can be found in the airways of mucosa that protect the airway. Epithelial dam-
asthma patients. age promotes BHR because access by irritating
substances to sensory nerve endings is increased.
Cellular Infiltration Similarly, aeroallergens can more readily pene-
trate the airways. It is believed that eosinophil-
Infiltration of the airways by inflammatory derived basic proteins, together with partial
cells such as mast cells, eosinophils, activated T reductive products of oxygen and proteases,
lymphocytes, and neutrophils can be demon- contribute to epithelial fragility. Regeneration
strated by bronchial biopsies and inferred by first appears as simple or stratified squamous
demonstrating increased numbers of these cells epithelium before differentiation and maturation
in BAL fluid. The extensive bronchial wall to new ciliated and mucus (goblet) cells.
infiltration by eosinophils may be accompanied One of the characteristic findings in patients
in severe cases by eosinophilic infiltration of the with severe asthma is the presence of tenacious
alveolar septa and adjacent arteries. The number mucus plugs in the airways. Death from asthma
of activated lymphocytes found in bronchial usually occurs from blockage of the airways by
biopsy specimens has been correlated with the diffuse mucus plugging. The presence of mucus is
40 Chapter 3. Asthma (Braman)

associated with the hyperplasia and metaplasia of been traditionally thought of only as a passive
goblet cells; it may cause lung hyperinflation due effector cell of asthma, responsible for broncho-
to air trapping, or, when more severe and located motor tone, may also contribute to the inflam-
in central airways, it may cause atelectasis. mation of asthma. This immunomodulatory
Edema of the airway mucosa is due to function of the smooth muscle is similar to that
increased capillary permeability with leakage of seen with epithelial cells. There is also evidence
serum proteins into the interstitium. A number of that smooth muscle cells in the airways are
cell-derived mediators are capable of inducing capable of producing growth factors that can
edema formation, including histamine, PGE, themselves promote proliferation in an autocrine
LTC4, LTD4, LTE4, platelet-activating factor, manner. The airway architecture is changed by
and bradykinin. The intense mucosal thickening the deposition of type III and V collagen and
in asthma contributes to the airway wall thick- fibronectin beneath the basement membrane.
ness and, therefore, to airway wall narrowing. This has been referred to as subepithelial fibrosis.
Growing evidence points to asthma as a Increased numbers of myofibroblasts are also
disease of airway wall restructuring that involves seen in the reticular layer in biopsy material
the activation of the epithelial3 trophic unit. obtained from asthmatic patients.
Inflammatory cells and mediators interact with The structural changes that occur in the
the epithelial trophic unit to cause the changes airways of asthmatic patients are likely to be
we refer to as airway remodeling.4 The airway detrimental and contribute to fixed airway
epithelium becomes an important source of narrowing. Thickening the inner airway wall
mediators, growth factors, and chemokines that may also amplify the degree of luminal narrow-
perpetuate the inflammatory and repair re- ing for a given degree of smooth muscle
sponse. Biopsy studies in patients with chronic shortening, and this might result in an exagger-
asthma have shown a number of pathologic ated narrowing of the airway after a broncho-
changes that support the thought that there is constricting stimulus. It has been argued that
increased release of fibroproliferative and fibro- some aspects of remodeling have beneficial
genic growth factors that are seen with in vivo effects, as follows: stiffening the airway may
models studying asthma. Growth factors that are result in decreased compressibility, allowing the
thought to be important in asthma include airways to better resist dynamic compression;
fibroblast growth factor 2, insulin-like growth and extra connective tissue surrounding the
factor 1, platelet-derived growth factor, endothe- smooth muscle cells may provide a radial
lin-1, and transforming growth factor b. constraint to maximal shortening.6
Thickening of the reticular basement mem-
brane, the laminar reticularis, is observed with Physiologic Mechanisms
light microscopy, is a constant feature of asthma,
and is diagnostic of the disease. In other chronic Neurogenic Influences
respiratory diseases such as COPD, bronchiecta-
sis, and tuberculosis, basement membrane thick- There is evidence that the neural control of the
ening appears to be more focal and variable. airways is abnormal in asthma patients, and that
There is evidence of increased bronchial neurogenic mechanisms may augment or modu-
smooth muscle mass that contributes consider- late the inflammatory response. The autonomic
ably to the thickness of the airway wall. The nervous system regulates many aspects of airway
smooth muscle of asthmatic patients does not function, such as airway tone, airway secretions,
behave abnormally after isolation; there is no blood flow, microvascular permeability, and the
correlation between airway hyperresponsiveness release of inflammatory cells. A primary defect in
in vivo and increased airway muscle sensitivity autonomic control, the b-adrenergic receptor the-
measures in vitro. There is evidence that the ory, has been postulated for asthma. It is more
smooth muscle cell may secrete cytokines and likely, however, that autonomic dysfunction is a
chemokines and express cellular adhesion mole- secondary defect caused by inflammation or by the
cules.5 Therefore, the smooth muscle that has effects of treatment. For instance, inflammatory

Table 1—Causes of Airflow Limitation in Asthma may be induced by a number of inciting events.
These include viral respiratory infections, an IgE-
Acute bronchoconstriction
Mucus plugging of airways
mediated allergic reaction, and the inhalation of
Bronchial wall edema noxious agents such as ozone or sulfur dioxide.
Inflammatory cell infiltration Antiinflammatory agents such as inhaled corti-
Airway wall remodeling (fibrosis) costeroids (ICSs) are effective in reducing BHR.
Smooth muscle hypertrophy
Uncoupling of elastic recoil forces Measuring bronchial hyperresponsiveness has
been successfully used as a guide for asthma
Reprinted with permission from ACCP Pulmonary Medicine treatment, but this is not a practical approach for
Board Review. 25th ed. Northbrook, IL: American College of
Chest Physicians; 2009. most patients.9
The degree of BHR can be determined in the
mediators can modulate the release of neurotrans- pulmonary function laboratory by standard inha-
mitters from airway nerves such as irritant lation challenge testing. The methacholine and
receptors and C-fiber endings. They can also histamine inhalation challenges are the most
directly act on autonomic receptors such as those frequently used clinical tools to determine the
that cause reflex bronchoconstriction from gastro- presence and degree of BHR. Cold air and
esophageal reflux. hypotonic saline solution challenges are also
There is also evidence that the nonadrenergic, performed. Although the end result of this testing,
noncholinergic (NANC) nervous system is im- airway narrowing, is the same for these provoca-
portant in the pathogenesis of asthma. As the tive agents, the mechanisms that cause the airways
to constrict vary. Methacholine and histamine act
airway epithelium becomes denuded, sensory
directly on airway smooth muscle. Exercise and
nerve endings may become exposed, causing a
hyperosmolar or hypoosmolar solutions act indi-
release of potent neuropeptides such as sub-
rectly by releasing pharmacologically active sub-
stance P, neurokinin A, and calcitonin gene-
stances from mediator-secreting cells such as mast
related protein. These neuromediators can lead
cells. Sulfur dioxide and bradykinin act by directly
to bronchoconstriction, microvascular leakage,
stimulating airway sensory nerve endings.
and mucus hypersecretion.
The inhalation of hypertonic saline solution
This neurogenic inflammation of the airways,
or mannitol and adenosine 5 0 -monophosphate
triggered by sensitized sensory nerve endings,
have been advocated as producing more diag-
has been postulated to cause airway hyperalgesia nostic provocation for asthma than histamine or
and result in symptoms such as cough and chest methacholine but have not attained widespread
tightness. Nitric oxide (NO) also appears to be use clinically. The degree of BHR usually
one of the neurotransmitters of the NANC correlates with the clinical severity of asthma
system and is an important braking mechanism and the medication needs of the patient. In
that can initiate bronchodilatation. addition, fluctuations of diurnal peak flow
measurements correlate with the degree of BHR.
BHR
Airway Obstruction
Airway inflammation is thought to be a key
factor in producing BHR, which is a cardinal This is another cardinal feature of asthma. The
feature of asthma.7,8 This can be described as an causes of airflow limitation in patients with asthma
exaggerated bronchoconstrictive response by the are listed in Table 1. During an acute asthma attack,
airways to a variety of stimuli such as aeroaller- lung hyperinflation occurs, protecting airway
gens, histamine, methacholine, cold air, and narrowing. This happens because of the interde-
environmental irritants. It is not clear whether pendence of lung volume and airway caliber,
bronchial hyperreactivity is acquired or is pres- because parenchymal attachments cause greater
ent at birth and genetically determined to appear tethering of the airways at higher lung volumes.
with the appropriate stimulus. It is thought that Inflammation of the bronchial wall, however,
airway inflammation is a stimulus for BHR, as it may uncouple the mechanical linkage between

the parenchyma and the airway. This may There is a key role for naive CD4þ T
contribute to airway narrowing and also to thymocytes (called TH0 cells). As they come in
BHR. During an acute attack of asthma, airway contact with the antigen on the antigen-present-
resistance increases, and all measures of airflow ing cells, these lymphocytes become differentiat-
(eg, peak expiratory flow rate [PEFR], FEV1, ed and activated (CD4þ/CD25þ state). The
FEV1/FVC ratio, and specific conductance) are specific subclass of TH0 cells that become
abnormal. During remission, the results of these differentiated during this allergic reaction are
tests may be normal, and yet considerable called TH2 cells and are to be distinguished from
dysfunction may be present in peripheral air- the TH1 subclass that is associated with the
ways. Studies using a wedged bronchoscope delayed hypersensitivity reaction. The TH2 sub-
technique have shown that peripheral resistance class is associated with the release of specific
can be 10-fold higher than in healthy subjects. interleukins and other cytokines that are respon-
There is evidence that this is linked to BHR. In sible for episodic and chronic allergic reactions.
many asthmatic patients, particularly children For example, in the sensitization stage, the
and younger adults with milder disease, airflow release of IL-4 enhances the synthesis of IgEs by
obstruction is completely reversible. In most antigen-stimulated B lymphocytes and plasma
elderly asthmatic patients and those of any age cells. IgE infiltrates the airways and becomes
group with more severe and persistent symp- fixed to mast cells, basophils, and dendritic cells
toms, airflow obstruction is only partially revers- through high-affinity cell surface receptors. This
ible despite continuous intense antiinflammatory sets the stage for the acute allergic response with
and bronchodilator therapy, including large the inhalation of more antigens.
doses of oral corticosteroids. The reasons for The allergic reaction can be divided into an
these permanent physiologic changes remain early (minutes) bronchospastic response and a
obscure. It is suspected that airway remodeling late (hours after exposure) inflammatory re-
is at least in part responsible. sponse. First, the antigen bridges to at least two
IgE antibodies. Then, mast cell degranulation
Atopic Asthma and synthesis of proinflammatory molecules
occurs. The synthesized mediators are IL-3, IL-
Atopy may be defined as the largely genetic 4, IL-5, tumor necrosis factor (TNF)-a, granulo-
susceptibility for developing IgE directed to cyte-macrophage colony-stimulating factor, and
epitopes expressed on common environmental arachidonic acid derivatives LTs, PGD2, and
allergens such as dust mites, animal proteins, thromboxane A2. The late-phase response is
pollens, and fungi. Atopic (allergic) reactions in initiated by mast cell mediators as follows: IL-5
the upper airways (eg, nose and sinuses) and is a chemoattractant for eosinophils, IL-3 and IL-5
lower airways are both important in the patho- are chemoattractants for basophils, LTB4 appears
genesis of asthma. The term extrinsic asthma has to attract neutrophils, and TNF-a increases the
been used to describe asthma that is triggered by number of adhesion molecules on endothelial
exposure to inhaled aeroallergens. Cellular re- cells that enhance the adhesion of leukocytes.
sponses may occur with the first exposure to a The formation of antigen-specific IgE antibody
specific antigen in such genetically predisposed usually does not occur until the second or third
individuals. The antigen is trapped in airway year of life. The prevalence of allergic asthma is,
mucus and is exposed to underlying epithelial therefore, less common during infancy. It in-
cells and resident dendritic cells. As the antigen creases in later childhood and adolescence, and
penetrates beneath the mucosa, it is likely peaks in the second decade of life.
exposed to granulocytes and tissue macrophages, In developing regions of the world (Africa,
and eventually enters the lymphatic system after Central and South America, Asia, and the
enzymatic degradation. In performing these Pacific), asthma prevalence has been rising
functions, antigen-presenting cells are setting sharply with increasing urbanization and West-
the stage for subsequent lymphocyte activation ernization.10 The reasons for this increased
to occur. prevalence remain largely unknown, but it has

been noted to be associated with a parallel rise in Outdoor allergens include pollens (mainly
atopic sensitization and increase in other allergic from trees, weeds, and grasses), fungi, molds,
conditions (eg, eczema and rhinitis). Although and yeasts but these agents carry less risk for
there is unquestionably a genetic component to asthma and ragweed pollens have been especial-
asthma, it is possible that changing patterns of ly associated with seasonal asthma symptoms.
environmental influences, such as exposure to Food allergens, although an important cause of
microorganisms, pollutants, and indoor and anaphylaxis, are not a common precipitant of
outdoor allergens, exert a strong influence on asthma symptoms.
the development of the disease in susceptible Sensitization to indoor aeroallergens (eg, dust
individuals. mites, cockroaches, molds, and animals) and
Several epidemiologic studies have shown a outdoor aeroallergens (eg, pollens and molds)
correlation between allergen exposure and the may be an important cause of acute and chronic
risk of developing asthma.11,12 For example, there recurrent symptoms. Often, allergic asthma has a
is a dose-response relationship between levels of well-defined seasonal variation; avoidance of the
house dust mite allergen found in the beds of offending antigen may result in a dramatic
infants of atopic parents at age 2 to 3 months and improvement of symptoms and in pulmonary
asthma at school age.13 Symptoms and need for function and BHR.
medication correlate with the level of household
exposure of known allergens in susceptible Nonatopic Asthma
individuals. Improvement of asthma symptoms
occurs when allergen exposure is reduced.14 The term intrinsic asthma is used to describe
patients who have none of the typical features of
The important allergens for children and
atopy, including a positive family history of
adults appear to be those that are inhaled.
allergy and asthma, positive immediate hyper-
Important indoor allergens include domestic
sensitivity reactions to skin-prick tests following
(house dust) mites, cockroach allergen, and fungi
exposure to a variety of aeroallergens, and an
(Alternaria, Aspergillus, Cladosporium, and Candi-
elevated serum IgE level. Usually, such patients
da). Warm-blooded animals such as pets (cats
are older than atopic asthmatic patients and have
and dogs) and rodents are problematic as they
a later onset of asthma. Bronchial biopsy studies
excrete urine, feces, saliva, and dander that can
in patients with intrinsic asthma have been
be highly allergenic. Removal of a pet from the
compared with a group of patients with extrinsic
home of a sensitized patient is encouraged, but it
asthma with a comparable severity of symptoms.
may require several months before allergen
There is a more intense inflammatory cell
levels decrease.15 These antigens have also been infiltrate in the bronchial mucosa of the intrinsic
identified in locations where there are no pets asthmatic patients with leukocytes, macrophag-
residing, including homes, schools, day-care es, and CD3 and CD4 cells. Patients with intrinsic
centers, and work environments. Successful asthma have an exaggerated T-cell response to
controlled trials of animal dander avoidance maintain the same degree of symptoms and BHR.
have now been reported for schools and for This may mean that intrinsic asthma may involve
homes without an animal.16 House dust has been activation by an as-yet-unidentified antigen.
shown to be composed of several organic and Putative nonallergic antigens that may cause
inorganic compounds including insects and such reactions include viral antigens or inappro-
insect feces, mold spores, mammalian danders, priately recognized ‘‘self-antigens.’’
pollen grains, fibers, mites, and mite feces. In
poor and inner-city locations, mouse and rat Risk Factors for Asthma
allergen exposure and sensitization are also
common in children who have asthma. Rodent Genetics of Asthma
exposure is also common in underdeveloped
areas and must be considered in asthma control Although it is generally agreed that there is a
in these populations. major hereditary contribution to the etiology of

asthma, the inheritance patterns are complex, the receptor more resistant to b-agonist down-
and asthma cannot be simply classified as having regulation and has been associated with less
an autosomal-dominant, autosomal-recessive, or intense BHR in asthmatic patients.
sex-linked mode of inheritance. This may be in Genes determining the specificity of the
large part because of the marked heterogeneity of immune response may also be important to the
the asthma phenotype. For example, the roles of pathogenesis of asthma. Genes located on the
contributing factors such as atopy, viruses, human leukocyte antigen complex may govern
aspirin sensitivity, exercise, and occupational the response to aeroallergens in some individu-
exposure differ greatly among asthmatic patients. als. Genes on chromosomes 11, 12, and 13 may
Variability in clinical symptoms, severity of direct the control of proinflammatory cytokines.
disease, degree of BHR, and response to therapy Chromosome 12, for example, contains genes
are other examples of disease heterogeneity. that encode for interferon-7, mast cell growth
However, genetic studies have discovered factor, insulin-like growth factor, and NO syn-
multiple chromosomal regions that may contain thase. Certain genes are involved in the devel-
genes that contribute to asthma. High serum IgE opment and function of regulatory T cells, and
levels have been linked to chromosomes 5q, 11q, are associated with atopy and asthma by gene-
and 12q. Clinically, there is a strong correlation gene interaction.
between BHR and elevated IgE levels, and It should be noted that despite many
evidence shows there is coinheritance of genes encouraging reports, most studies on the genet-
for atopy and BHR found on these same ics of asthma that show an association between
chromosomes. Population studies that have asthma-related phenotypes and alleles within a
conducted genome-wide screens have contribut- specific gene have generally lacked statistical
ed to our understanding of the inheritance of power.
asthma. They have shown the linkage of asthma,
BHR, total IgE levels, and elevated eosinophil Gender and Race
counts to multiple chromosomal regions. Chro-
mosomes 2q, 3p, 5q, 6p, 12q, 13q, 19q, and 21q Childhood asthma is more prevalent in boys,
are likely to contain genes for allergy and asthma. but this is reversed in puberty and adulthood.
These genome screens have also found numerous The overall prevalence, therefore, is greater in
loci that contain potential candidate genes that female individuals. Black race/ethnicity is asso-
can regulate the immune response of asthma. For ciated with a higher risk of asthma death,
example, genes that regulate IgE production, b2- independent of socioeconomic status and educa-
adrenergic and glucocorticoid receptor function, tion. The higher incidence of asthma that has
and the inflammatory mediator response have been seen with urbanization suggests that envi-
been found. They may be important in deter- ronmental factors may be as important as genetic
mining genetic susceptibility, responses to envi- and racial factors. In fact, subjects of different
ronmental stimuli, and responses to treatment. races acquire the risk of the population they
Following the identification and characteriza- move to. A controlled trial of environmental
tion of the b-receptor gene, variants of the gene intervention in an inner-city population of
were evaluated to see whether they could be children to reduce allergies and environmental
responsible for the expression of asthma. One smoke that included the reduction of exposure to
mutation (the substitution of glycine for arginine indoor allergens including cockroach and dust
at position 16) was associated with more severe mite allergens has resulted in reduced asthma-
asthma and especially with more severe noctur- associated morbidity.14
nal symptoms. This mutation causes an increase
in the degree of agonist-promoted down-regula- Air Pollution
tion of receptor expression. The increased risk for
the development of asthma in homozygotes for Both outdoor and indoor pollutants contrib-
this allele is profoundly affected by cigarette ute to worsening asthma symptoms by trigger-
smoking. Another mutant at position 27 renders ing bronchoconstriction, increasing BHR, and

enhancing responses to inhaled aeroallergens. appearing for the first time after an active
The two main outdoor pollutants are industrial infection with both of these organisms, as well
smog (sulfur dioxide particulate complex) and as significant improvement in lung function and
photochemical smog (ozone and nitrogen ox- symptoms with antimicrobial therapy directed to
ides). Whether long-term exposure is further these organisms. In one prospective study, M
injurious is not clear. pneumoniae or C pneumoniae was found in the
Modern construction techniques have been airways of .60% of a group of stable patients
suspected of causing greater indoor air pollution. with chronic asthma. Therapy with the macrolide
In energy-efficient buildings, there is 50% less antibiotic clarithromycin improved lung function
turnover of fresh air. Indoor pollutants include and decreased tissue expression of IL-5 in those
cooking insulating products, paints, and varnish- patients who were polymerase chain reaction
es that contain formaldehyde and isocyanates. positive to these organisms. This suggests that
The use of poorly vented gas stoves and antibiotic use in some patients with persistent
appliances results in increased indoor levels of asthma may help to control the disease.
NO2 and has been associated with increased
respiratory symptoms.17,18 Installing nonpollut- Other Factors
ing, more effective heating in the homes of
children with asthma does not significantly A number of interesting epidemiologic asso-
improve lung function but can significantly ciations have come to light concerning the risk of
reduce symptoms of asthma, days off school, the development of asthma. For instance, being
health-care utilization, and visits to a pharma- underweight and being overweight are both
cist.19 Also, fumes from wood-burning applianc- associated with an increased risk of the develop-
es or fireplaces, commonly used for heating and ment of asthma. Several hypotheses have been
cooking in poor, underserved regions of the proposed to explain the epidemiologic associa-
world, can precipitate symptoms in persons tions of obesity and asthma.23 These include
who have asthma.20 Long-term passive cigarette airway mechanics, influences on immune re-
smoke exposure has been linked to new-onset sponses, and hormonal influences. Particularly,
asthma in children and adults as well as the diminished tidal lung expansion in over-
worsening asthma symptoms in those with weight individuals may partially account for the
preexisting asthma. Sprays and strong odors, findings. Studies in animal models have indicat-
particularly perfumes, can also irritate the lungs ed that elevations of IL-6 levels may contribute to
and precipitate asthma symptoms. and up-regulate inflammation in the airways.
The levels of the hormone leptin, a member of the
Respiratory Infections IL-6 family, are elevated in obese persons. Leptin
may have an effect on inflammation by promot-
The role of respiratory infections in the ing the release of IL-6 from macrophages in
pathogenesis of asthma has been under intense lymphocytes. There is some evidence that weight
investigation.21 It has been established that viral loss in obese asthmatic patients is associated with
respiratory infections are common precipitators improved symptoms and lung function, espe-
of asthma.22 Whether they can initiate the disease cially PEFR variability.
de novo is suspected but has not been strongly Growing up on a farm decreases the risk of
suggested. There are strong data to suggest that atopy and allergic rhinitis in adulthood, suggest-
some of the atypical bacteria, such as Chlamydia ing that environmental factors may have a
pneumoniae and Mycoplasma pneumoniae, may also lifelong protective effect against the development
be involved. These organisms are temporally of allergy. In developing countries, the move to
related to exacerbations of asthma and can be cities is associated with a switch from biomass
found by polymerase chain reaction techniques fuels such as wood, charcoal, and animal wastes
to be present in bronchial biopsy specimens to gas and electricity. The use of modern fuels has
obtained from patients with chronic stable been associated with an increased rate of allergic
asthma. There have also been reports of asthma sensitization and symptoms. Studies indicate a

reverse relationship between family size and exposure and asthma also strongly implicate
asthma. This and other evidence suggests that atopy in the pathogenesis of asthma. One
the exposure of young children to older children alternative theory is that there is one common
at home or to children at day-care centers mechanism involved in the development of both
protects against the development of asthma. IgE-mediated hypersensitivity and bronchial
There has been some suggestion that the use of hyperreactivity or that the two may be related
dietary antioxidants may protect against the by genetic linkage. This would suggest that there
development of asthma. In one study, for is not a causal relation between atopy and
example, the severity of asthma was negatively asthma, and would explain why certain patients
associated with the consumption of red wine. (intrinsic asthmatic patients) have no allergic
This is another bit of evidence to suggest that basis for their asthma.
flavonoids and other dietary antioxidants may It has been stated that most asthmatic
protect against asthma. patients in whom asthma develops during
Vitamin D deficiency has been associated childhood will outgrow it by early adulthood.
with higher rates of asthma. It is associated with Statistics show that this is true in only 30% to
BHR, poorer asthma control, and lower pulmo- 50% of children with asthma and is more likely in
nary function. Vitamin D has been associated male patients than in female patients. Lung
with a number of biologic effects that are growth appears to be relatively normal in
important to the key inflammatory events of children with asthma, but can be reduced in
asthma smooth muscle cells, epithelium, and some with more severe and persistent symptoms.
inflammatory cells.24 Vitamin D supplementation Even in those who become asymptomatic at
trials are needed. puberty, lung function frequently remains abnor-
mal, and cough and BHR persist. The following
The Natural History of Asthma three features of childhood asthma may predict
those who are more likely to have persistent
The most reliable information on the natural symptoms into adulthood: severe atopy deter-
history of asthma comes from large community mined by skin testing, a marked degree of
surveys. Comparisons from country to country bronchial reactivity, and difficult-to-control asth-
and even within the same country are difficult to ma. This is particularly evident in young girls.
make because of the varying criteria used to Elevations in serum IgE levels, eosinophilia, and
make the diagnosis and the inclusion of cigarette skin test reactivity to aeroallergens are seen in
smokers who might also have underlying COPD. children with persistent wheezing from early
The peak prevalence of asthma in all studies is in childhood to later childhood, but not in those
childhood and is about 10% of the population. who wheeze in the first 6 years of life but
This declines to about 5% to 6% in adolescence outgrow their wheezing by age 6 years (ie,
and early adulthood, when remission rates are transient wheezers).25
quite high. The prevalence rises again during Fixed airflow obstruction develops in some
later adulthood to 7% to 9%. The relationship of asthmatic patients over time. One study evaluat-
atopy and asthma has been carefully studied. In ed patients after a 20- to 30-year follow-up. They
both children and adults, the presence of were reexamined to assess the risk factors for the
bronchial hyperreactivity correlates with the development of irreversible airway obstruction
presence and number of positive immediate and low diffusing capacity. In this study, irre-
hypersensitivity skin test results to inhalant versible airflow obstruction developed in 16% of
allergens. The presence of positive skin test patients. This was associated with a lower FEV1
results in infants of allergic parents correlates (percentage predicted), a lower level of BHR, less
with the onset of asthma in later childhood, and reversibility at initial testing, and less use of
the number of positive skin test results shows a corticosteroids at follow-up.26
correlation with the severity of asthma in In adulthood, there is a steady incidence of
childhood and early adulthood. Studies correlat- new-onset asthma through patients of all ages,
ing skin test reactivity to house dust mite even in elderly patients.27 Many patients begin

with recurrent wheezing following respiratory caused by emphysema and chronic bronchitis
viral infections. This pattern may gradually or can also cause typical asthma symptoms, and the
abruptly develop into persistent wheezing and distinction between these conditions can become
often severe, poorly responsive disease. At other quite difficult, especially when COPD is compli-
times, asthma develops explosively, with no cated by acute viral or irritant-induced broncho-
previous respiratory symptoms, immediately spasm. In general, the symptoms of asthma are
following the onset of a typical viral respiratory considerably more episodic and of more sudden
infection. Longitudinal studies of asthmatic onset than those of COPD, and periods of
patient populations have shown that although prolonged remission are typical.
remission from asthma is common in the second Attacks of asthma are likely to be provoked
decade, it is much less common in older age by known aeroallergens, especially in the youn-
groups, but may still be as high as 20% to 30%. ger atopic population. It is not unusual for an
Asthmatic subjects who have severe symptoms, asthmatic patient to give a history of wheezing
reduced ventilatory function, and a concomitant and shortness of breath following exposure to
diagnosis of COPD are much less likely to have a household pets such as cats and dogs. Sensitivity
remission. Not infrequently, heavy cigarette to rats, guinea pigs, and other small animals may
smokers in whom COPD has developed may similarly develop in animal handlers and labo-
also manifest acute bronchospasm that is respon- ratory workers. Asthma may occur seasonally,
sive to therapy with inhaled bronchodilators. such as during ragweed season in the fall or
This pattern is similar to that seen with asthma. during flower and tree blooming in the spring. It
Because of the underlying emphysema and is believed that exposure to household mites that
chronic bronchitis, they have an element of live in bedding, in floor rugs, and on other fabrics
irreversible airflow obstruction. These patients found in the house is also a major cause of
are often labeled as having asthmatic bronchitis asthma symptoms, especially in warmer climates
in order to distinguish them from those with that favor their growth. Similarly, in areas of the
pure asthma and to identify the irreversible inner city, especially where poverty is found,
component of their disease. Unlike some adult cockroach exposure is an important inciting
asthmatic patients, these patients will not ever agent of atopic asthma.
have a complete remission of their disease. The immediate hypersensitivity reaction
Asthma may also result from exposure to (atopic reaction) has two phases: an immediate
occupational hazards. Remission usually occurs bronchospastic reaction that causes symptoms
when the patient is removed from the offending within minutes after exposure and a delayed
environment, but unfortunately this is not always reaction that occurs up to 6 h after exposure.
the case. Sometimes exposure to an aeroallergen results in
a predominantly delayed allergic reaction. The
Clinical Features of Asthma patient may not recognize the offending agent,
because the exposure has occurred many hours
Symptoms of Asthma before.
Typically, all symptoms of the asthma triad
The typical triad of symptoms of asthma is present simultaneously, but this is not always the
wheezing, shortness of breath, and cough with or case. There is evidence that some patients with
without sputum production. These symptoms asthma perceive their symptoms poorly. In studies
are not specific for asthma and can be seen in of acutely ill asthmatic patients, up to 10% of them
other acute and chronic airway diseases. For have no shortness of breath and complain only of
example, an acute viral tracheobronchitis associ- wheezing and cough. The reasons for the lack of
ated with or following typical upper respiratory
dyspnea remain obscure, but the following several
infection symptoms can cause the asthma triad of
observations are relevant:
symptoms and can be associated with BHR for
up to 6 weeks. Unlike asthma, these symptoms 1. Asthmatic subjects have a higher threshold for
usually resolve completely over time. COPD tolerating resistive loads than normal subjects.

2. Asthmatic subjects with greater resting base- are chest tightness, substernal pressure, chest
line airflow obstruction are less likely to pain, and nocturnal awakenings. These symp-
perceive worsening lung function following toms are more likely to be confused with cardiac
a cholinergic inhalation challenge. disease, especially ischemic heart disease, in the
3. Symptoms caused by a precipitous drop in older individual. Gastroesophageal reflux also
lung function due to the immediate hyper- causes a feeling of chest tightness in addition to
sensitivity reaction are better perceived than heartburn. Reflux can exacerbate asthma, espe-
those that may occur as a result of a slower cially in children, and sometimes the treatment of
equal decline in lung function caused by the reflux can result in improvement of asthma. In
late-onset reaction. patients with symptomatic reflux, upper respira-
4. Abnormalities in the perception of asthma tory symptoms are very common, and they can
symptoms have important therapeutic impli- be confused with the symptoms of asthma. For
cations. An asthmatic patient who is not able example, cough may be the sole presenting
to detect increased airway resistance will not manifestation of gastroesophageal reflux. Symp-
reach for appropriate medication when nec- toms of nasal and laryngeal irritation are com-
essary. mon to both gastroesophageal reflux and asthma,
5. It has been postulated that poor perception of and objective measures of airway disease can be
asthma in some patients may be responsible helpful in distinguishing the two.
for fatal and near-fatal attacks, especially in
the elderly, as impaired perception of bron- Physical Signs of Asthma
chospasm is also a feature of aging. Objective
monitoring of airway function by means of The physical findings associated with acute
spirometry and peak flowmeters is essential bronchospasm of asthma are (1) the direct result
for asthma prevention. of diffuse airway narrowing and hypersecretion
of mucus and (2) the indirect result of reflex
Other variant manifestations of asthma also influences from an increase in the work of
occur. Patients with asthma may present with breathing, increased metabolic demands on the
only cough or dyspnea as isolated symptoms. A body, and diffuse sympathetic nervous dis-
nonproductive cough may be present for years as charge. Tachypnea and tachycardia are universal
a sign of asthma before the full triad of features of acute asthma. The average respiratory
symptoms begins. Cough is probably caused by rate is between 25 and 28 breaths/min, and the
the stimulation of airway sensory nerves by average pulse rate is 100 beats/min. Respiratory
inflammatory mediators. The asthmatic cough is rates of .30 breaths/min and heart rates of .120
often provoked by respiratory irritants such as beats/min are not uncommon and may be seen
cigarette smoke and by cold air, laughter, and in as many as 25% to 30% of patients. Sinus
cough itself. Many times, a single cough will tachycardia is also a known complication of
begin a series of violent coughing paroxysms that asthma therapy with the use of such drugs as
may last for many minutes and lead to exhaus- sympathomimetics and theophylline. Usually,
tion. Cough may be provoked also by deep however, as airway function improves with
inhalation and by forced exhalation. This may be sympathomimetic treatment, sinus tachycardia
useful as a bedside test because a coughing actually improves rather than worsens. In pa-
paroxysm induced by a deep-breathing maneu- tients with acute asthma, premature ventricular
ver suggests hyperreactive asthmatic airways. contractions occur occasionally, whereas atrial
Because patients with isolated cough or dyspnea arrhythmias are extremely uncommon. Other
may have normal findings on pulmonary func- ECG abnormalities seen in acute severe asthma
tion studies, reversible airflow obstruction may include P pulmonale, right axis shift, right
not be possible to document. In such cases, bundle-branch block, and right ventricular strain.
bronchoprovocation testing with histamine or Diffuse musical wheezes are characteristic of
methacholine may be useful in making the asthma, but their presence or intensity does not
proper diagnosis. Other symptoms of asthma reliably predict the severity of asthma. By the

time wheezing can be detected by stethoscope, treatment with a short-acting inhaled p-agonist
peak flow rates may be decreased by as much as is generally accepted as a significant change.
25%. In general, wheezing during inspiration Alternatively, after outpatient treatment, a .15%
and expiration, loud wheezing, and high-pitched improvement in the FEV1 between office visits
wheezing are associated with greater airway proves the presence of reversible airway disease
obstruction. In very severe cases, wheezing may and supports a diagnosis of asthma.
be absent. This suggests very poor air movement Short-term home monitoring with the PEFR
and impending respiratory failure. meter can be useful in diagnosing asthma and
A prolonged phase of exhalation is typically identifying environmental triggers of asthma,
seen, as is chest hyperinflation. These are due to and can detect early signs of deterioration when
airflow obstruction and airtrapping, respectively. symptoms change. Long-term monitoring is
Accessory muscle use, pulsus paradoxus, and useful for those with severe brittle asthma and
diaphoresis are associated with severe airflow for those who have a poor perception of asthma
obstruction, although their absence does not rule symptoms. Peak flow measurements ideally
out a severe attack. Cyanosis and signs of acute should be done early in the morning (when
hypercarbic acidosis, such as mental obtunda- measurements tend to be lowest) and in the
tion, are absent in all but extreme cases. evening (when they should be highest), 5 to 10
Accessory muscle use and pulsus paradoxus min after inhaling a b-agonist. Each patient
are due to large negative swings in intrapleural should establish a personal best PEFR after a
pressure, and they may not be manifest in the period of maximal therapy. The severity of
patient with rapid, shallow breathing. They are asthma is reflected not only by the level of
reported to be present in 30% to 40% of patients
baseline obstruction, but also by its variability
with acute asthma.
over a 24-h period. A zone system has been
provided by the NIH guidelines for patient ease,
Objective Measures of Asthma and Asthma
as follows: green is 80% to 100% of the personal
Severity
best and shows good control; yellow is 50% to
80% of the personal best and signals caution that
The use of objective measurements of pul-
asthma is not under sufficient control; and red is
monary function is important in patients with
,50% of personal best and signifies danger and
asthma because the perception of asthma symp-
toms is often poor and the physician’s findings the need for immediate physician intervention.
on physical examination may either overestimate A diurnal variation in PEFR of 20% is
or underestimate the severity of the airflow diagnostic of asthma. The magnitude of peak
obstruction. The following tests of pulmonary flow variability is in general proportional to the
function can be useful for establishing the severity of the disease. A high degree of
diagnosis of asthma and/or for following the variability signals unstable asthma that demands
clinical course of the patient once the diagnosis increased medication.
has been made: (1) spirometry, (2) PEFR mea- Virtually all asthmatic patients have hypox-
surements with a peak flowmeter, (3) arterial emia during an acute exacerbation; the more
blood gas analysis, (4) bronchoprovocation test- severe the attack, the lower the arterial oxygen
ing, (5) exhaled NO, and (6) CT scanning. tension. Arterial blood gas analysis is helpful
During an acute attack of asthma, on average during a severe attack. During an acute attack,
the FEV1 is reduced to about 30% to 35% an assessment of oxygen saturation by transcu-
predicted, and the FVC to about 50% predicted. taneous oximetry is helpful to ensure adequate
The FEV1 in absolute terms is reduced to about oxygenation. The mechanism of arterial hypox-
1L. The PEFR is reduced to about 150 L/min. emia is ventilation-perfusion mismatch. Areas
Reversible airflow obstruction is characteristic of with low ventilation/perfusion ratios cause
asthma and can be demonstrated by spirometry; hypoxemia and are due to bronchospasm,
a .15% improvement in the FEV1 (and an mucus plugging, and mucosal swelling from
absolute value .200 mL) 5 to 10 min after inflammation.

Hypocarbia and respiratory alkalosis are challenge result is typical of asthma, but it is not
present in about 75% of patients with acute specific because it can be seen in a number of
asthma. When the obstruction worsens and the other inflammatory airway diseases and in
FEV1 approaches about 15% to 20% predicted, patients who have allergic rhinitis without
the PCO2 normalizes. Carbon dioxide retention asthma. A normal response to methacholine or
occurs when the FEV1 reaches ,15% predicted histamine is incompatible with asthma, and an
and the absolute FEV1 is very severely reduced to alternative diagnosis should be considered.
,0.5 L. Acute respiratory acidosis results. This Exercise testing is a form of bronchoprovo-
occurs in about 10% of asthmatic patients who cation testing that is especially useful in children.
seek emergency care. The mechanism of carbon Using a standard 6-min protocol, a 15% fall in
dioxide retention in patients with severe asthma FEV1 or a 20% fall in PEFR from baseline 5 to 15
is severe ventilation-perfusion mismatch. High min after exercise is considered to be diagnostic.
ventilation/perfusion ratios result in dead space Although the presence and quantification of
or wasted ventilation. As the work of breathing various inflammatory cells and mediators in
increases and carbon dioxide production rises, sputum and body fluids have been used to
the lungs become incapable of removing the reflect the activity of inflammation in asthma,
carbon dioxide that is produced, and respiratory there is no universally accepted method to apply
acidosis occurs. It is believed that respiratory this clinically. NO is a reactive gas that is formed
muscle fatigue also contributes to respiratory from arginine through the action of NO synthase.
failure, and in extreme cases sudden respiratory In asthma, there is some evidence that this
muscle failure can result in acute cardiopulmo- enzyme is upregulated, and elevated levels of
nary arrest. NO have been detected in the exhaled air of
Superimposed metabolic acidosis is seen on asthmatic subjects. NO is a potent vasodilator
blood gas analysis in severe cases. This may be and bronchodilator, and most likely serves as a
due to lactic acidosis caused by vigorous muscle neuroregulator of NANC nerves. Exhaled NO is
contraction or to inadequate cardiac output, and well established as a marker of eosinophilic
may possibly be seen as a complication of inflammation and has been shown to correlate
excessive sympathomimetics. with sputum eosinophil counts, BHR, serum IgE
Inhalation challenge testing is useful in some levels, asthma symptoms, and lung function
patients when the diagnosis of asthma is not tests. It has been shown to be a fairly effective
secure. This occurs when the patient has normal screening tool, with a sensitivity of 88% when
peak flow rates and spirometry findings yet there are levels of 20 parts per billion or greater in
typical asthma symptoms are present. In such patients with asthma symptoms. Unfortunately,
cases, an FEV1 response to an inhaled broncho- exhaled NO levels do not always correlate with
dilator cannot be used as a criterion for asthma. If disease severity. Serial measurement may aid in
the fluctuation in diurnal PEFR is also not useful, monitoring disease activity. It has shown prom-
methacholine or histamine bronchoprovocation ise, for example, in identifying pending exacer-
testing can be helpful. Low concentrations of the bations of asthma. A standardized method of
agonist are inhaled after baseline spirometry measurement must be carefully followed to
ensures normal or nearly normal airway func- prevent spurious results.
tion. Gradually increasing doses are given, either Chronic inflammation in asthma can lead to
by tidal volume breathing or by single deep airway remodeling and airway narrowing. This
breaths from a dosimeter, and the forced spiro- can be quantified by the use of CT scanning.
gram is repeated after each dose. A calculation of High-resolution CT scanning is a useful tool for
the FEV1 at the administration of each dose imaging the airways of asthmatic patients. Asth-
produces a dose-response curve. If the FEV1 matic patients have thicker airways compared
drops 20% below baseline at any standard dose, with control subjects. The thickness is related to
the test result is positive. An inhaled b-agonist is disease severity, airflow obstruction, and airway
administered, which promptly returns lung reactivity. This is a new tool for assessing asthma
function to baseline. A positive methacholine severity and is not clinically applicable.28

The Treatment of Asthma Table 2—When to Consider Allergen Immunotherapy
When maximum therapy with inhaled bronchodilators

There are both short-term and long-term and corticosteroids is not effective
therapeutic objectives for every asthmatic patient. Other triggers treated or ruled out
Exposure avoidance to aeroallergens is not possible
The short-term objectives are the control of
Atopy is confirmed by
immediate symptoms and the response to falling * Exposure provokes symptoms for a narrow spectrum
peak flow rate measurements. Long-term objec- of allergens

tives are those directed at disease prevention, * Confirmation by skin tests or serum-specific IgE
because there are now well-proven strategies to (RAST testing)

Relative contraindications:
avoid serious exacerbations of acute broncho- Severe asthma with abnormal PFTs
spasm that often lead to emergency department Patients not able to comply with therapy
visits or hospitalization.29 In order to meet these Patients taking b-blockers

Patients with immune deficiency, immunologic
therapeutic objectives, four components of asthma
disease, or malignancy
care should be addressed. First, the optimal Pregnancy (maintenance injections may be continued
treatment of asthma depends on a careful assess- during pregnancy)
Young children (,5 y)
ment of the patient’s symptoms as well as objective
monitoring by office spirometry and home PEFR
measurements. Second, the treatment of asthma bronchial hyperreactivity, reducing symp-
with bronchodilator and antiinflammatory medi- toms, and improving the overall quality of life.
cations is tailored to the patient’s needs and relies Corticosteroids are the most useful antiinflamma-
on a staging system that is based on the symptoms tory agents. They suppress a number of pathways
and objective measures of lung function. These of chronic inflammation in asthma.32 Inflammato-
medications have proven quite safe for asthmat- ry genes are regulated by proinflammatory
ics.30 Third, measures should be taken to avoid transcription factors such as nuclear factor kB
exposure to respiratory allergens and irritants that and activator protein 1. These factors can switch
can cause the worsening of symptoms. This on gene transcription. Corticosteroids act to
includes the avoidance of outdoor allergens such
suppress the action of these factors. They act by
as ragweed, grass, pollens, and molds, and indoor
preventing the migration and activation of in-
allergens such as animal dander, house dust mites,
flammatory cells, interfering with the production
and cockroach antigen. When exposure cannot be
of PGs and LTs, reducing microvascular leakage,
avoided, allergen immunotherapy should be con-
and enhancing the action of b2-adrenergic recep-
sidered (see Table 2), although this modality is
tors on airway smooth muscle.32
somewhat controversial. Indoor irritants such as
Corticosteroids are available for oral, paren-
smoke from cigarettes and wood-burning stoves,
teral, and inhaled use. Oral preparations such as
strong odors, and cleaning solutions are particu-
prednisone are useful for the treatment of acute
larly troublesome. Fourth, patient education can be
exacerbations of asthma that are unresponsive to
a powerful tool in asthma control.31 Family
bronchodilator therapy. Doses of 40 to 60 mg/d
members also can be helpful, especially with
are given until the patient responds, and then the
children and elderly adults. Active participation
by a patient in monitoring lung function, the dosage can be slowly tapered down. Often, poorly
avoidance of provocative agents, and decisions controlled asthma requires daily or every-other-
regarding medications provide asthma manage- day maintenance therapy with prednisone in
ment skills that give that patient the confidence to dosages of 10 to 15 mg. IV corticosteroids, usually
control his or her own disease. given as methylprednisolone 60 to 80 mg every 6
to 8 h for 1 or 2 days, are effective within 4 to 6 h
Medications for Asthma of administration in preventing further progres-
sion of the severe asthma exacerbation that
Antiinflammatory Agents: Antiinflammatory requires hospitalization. A massive bolus of
agents are capable of reducing airway inflamma- corticosteroid (methylprednisolone 500 mg) is no
tion and thus improving lung function, decreasing more effective than a large dose (60–80 mg).

ICSs: ICSs are safe and effective treatment for exacerbation rates and the need for steroid
moderate-to-severe asthma and have been in use bursts. The LPMs are generally very safe. The
for .20 years.33 Active cigarette smoking, how- rare cases of Churg-Strauss vasculitis have
ever has been shown to impair the efficacy of ICS occurred in patients with severe steroid-depen-
treatment in patients with mild asthma.34 For- dent asthma who have had a recent steroid taper.
mulations of beclomethasone, triamcinolone, Because this form of vasculitis has been seen in
flunisolide, fluticasone, and budesonide can patients in whom inhaled steroids have been
reduce airway inflammation with one to several substituted when oral steroids have been ta-
months of treatment. The dose-response curve pered, the reaction may not be specific to the LT-
for ICSs in asthma is flat. Effects are seen below modifying agents.36
or at the lower end of the recommended range. Omalizumab: Omalizumab, a humanized mu-
High doses only contribute marginally to effica- rine monoclonal antibody that inhibits the
cy. The long-term use of ICSs has been associated binding of IgE to mast cells by forming complex-
with a good safety profile. High doses of inhaled es with circulating free IgE, has been shown to be
steroids (eg, .1,000 lg/d) are capable of causing effective in the treatment of patients with atopic
hypophyseal-pituitary-adrenal axis suppression. asthma. The reduction of free IgE in the
Local adverse effects such as hoarseness, dys- circulation leads to a down-regulation of baso-
phonia, cough, and oral candidiasis do occur, but phil and mast cell receptors. This further reduces
can usually be avoided by the use of a spacer or the potential for mast cell/basophil activation
holding chamber and by rinsing the mouth after and the subsequent release of inflammatory
each use. Oral and parenteral corticosteroids are mediators. Randomized, controlled trials have
associated with many side effects, such as the been conducted in patients with moderate-to-
risk of osteoporosis, cataracts, diabetes mellitus, severe asthma.37 The agent has been shown to
and, rarely, depression of immunity to infection. reduce the asthma exacerbation rate and the use
Attempts to reduce dependence on oral cortico- of ICSs, especially in poorly controlled patients.38
steroids should be made, especially by the use of Many patients are able to completely eliminate
inhaled agents. the need for corticosteroid therapy. Symptom
Cromolyn Sodium: Cromolyn sodium is an scores and quality-of-life indexes also improve.
inhaled antiinflammatory agent capable of pre- The drug is well tolerated with no serious reports
venting allergen-induced bronchospasm with an of adverse events. The medication must be given
extremely good safety profile. This agent was not by injection two times a month, and many
converted to non-CFC products and is no longer patients can be taught self-administration.
available. Bronchodilators: Inhaled short-acting b-adren-
LT Pathway Modifiers (LPMs): LPMs are also ergic agonists are the treatment of choice for the
medications that are considered to be asthma acute exacerbation of asthma symptoms. Inhaled
controllers.35 There are two subclasses, as fol- agents can be delivered by metered-dose inhaler,
lows: the 5-lipoxygenase inhibitors, which inhibit dry-powder capsules, and compressor-driven
the cysteinyl LTs and also LTB4; and the LTD4 nebulizers.
receptor antagonists of the cysteinyl LTs LTC4, Long-Acting b-Agonists (LABAs): LABAs may
LTD4, and LTE4. These agents have been shown be helpful for long-term maintenance therapy
to be effective in preventing allergen-induced and also used to control nocturnal symptoms;
asthma, exercise-induced asthma (EIA), and however, as they are not an antiinflammatory
aspirin-induced bronchospasm and allergic rhi- treatment, a LABA should not be used as a single
nitis. The use of antihistamines with the LPMs agent to treat asthma, as this has been associated
provides a more complete protection to allergen with asthma mortality, especially in the African
challenge. Studies comparing the LPMs with American population.39 Studies of inadequately
low-dose ICSs have favored the latter with controlled asthmatic patients have shown a
respect to FEV1; however, symptom scores, daily benefit to adding a LABA to a moderate-dose
b2-agonist use, and patient preferences are ICS regimen rather than doubling the dose of the
similar. The LPMs may also reduce asthma ICS, adding theophylline, or adding an LPM. The

need for regularly scheduled doses should alert action of 30 to 60 min until the maximal effect is
the physician to the need for more intense produced.
antiinflammatory medication. A new strategy, Magnesium Sulfate: A Cochrane Database
known as single inhaler maintenance and reliev- review concluded that nebulized inhaled mag-
er therapy, has been used in patients with nesium sulfate in addition to a b-agonist for the
moderate-to-severe asthma.40 When a budeso- treatment of an acute asthma exacerbation
nide/formoterol combination inhaler is used as a appears to have benefits with respect to im-
reliever instead of a short-acting b2-agonist, proved pulmonary function. In patients with
while continuing maintenance therapy with severe asthma, there is a trend toward benefit in
budesonide/formoterol twice daily, there is an terms of hospital admissions.43
improvement in asthma control and significant IV therapy has also been shown to be
reduction in severe exacerbations.41 This strategy effective in severe exacerbations.44
is now known as single inhaler maintenance and Bronchial Thermoplasty: Bronchial thermo-
reliever therapy. It is not possible with salmeterol plasty is a procedure performed by fiber-optic
or indacaterol because of cumulative side effects. bronchoscopy.45 Segmental and subsegmental
Regularly scheduled doses of short-acting b- bronchi are warmed at 658C, causing a 50%
agonists have been associated with diminished reduction of the smooth muscle area. In severe
control of asthma and heightened bronchial asthma, airway smooth muscle is hypertrophic
reactivity. In addition, epidemiologic evidence and hyperplastic, and this is thought to cause
has linked excessive b-agonist use to increased excessive bronchoconstriction. Reducing this
mortality. Ideally, short-acting b-adrenergic ago- muscle mass, likely through denaturation of
nists should be prescribed for acute symptom motor protein, and disrupting the actin-myosin
relief on an as-needed basis. interaction, is felt to be therapeutic. Several
Theophylline: Theophylline is an effective studies have shown an improvement in symp-
bronchodilator and has antiinflammatory proper- toms, severe exacerbation rate, and quality of life
ties. It is available as a sustained-release prepara- assessment. Although the safety of this proce-
tion and can be taken once or twice daily. The dure has been acceptable, the future of this
monitoring of theophylline blood levels is impor- procedure will be determined by additional
tant to avoid toxicity, especially in the elderly, who studies that are designed to assess the long-term
are more prone to adverse effects. GI side effects effects of this procedure.
are seen with mild toxicity and blood levels in the Allergen Immunotherapy: The most recent
range of 20 to 30 lg/mL. Serious cardiac recommendations by allergy experts are present-
arrhythmias and seizures may occur with blood ed in Table 2.
Future Therapeutic Approaches: A number of
levels in excess of this range. A range of 8 to 15
new biologic agents46 that may be particularly
lg/mL is generally considered to be therapeutic.
applicable in a subpopulation of asthmatics with
Inhaled Anticholinergics: Inhaled anticholiner-
poor response to current treatment have been
gics, such as ipratropium, produce bronchodi-
tested. To date none have been approved for
latation by reducing vagal tone and are widely
clinical use. Some highlights of recent trials include:
used in patients with COPD. They may be
useful in combination with b-agonists for a A human anti-TNF-a antibody, golimumab,
severe acute exacerbation of asthma. The role has been studied. Overall, treatment with
of the long-acting anticholinergic tiotropium has golimumab has not demonstrated a favorable
been evaluated for long-term maintenance ther- risk-benefit profile in this population of pa-
apy when coupled with an ICS. Its effects tients with severe persistent asthma. Although
appear to be equivalent to those of the long- a subgroup analysis indicates that there may be
acting b-agonist salmeterol.42 They may be tried a stratified group of patients who could benefit
as a substitute bronchodilator when side effects from anti-TNF-a therapy, this must be bal-
preclude the use of b-agonists, although it must anced by a higher risk of neoplasm found with
be remembered that they have a slower onset of this agent.

A humanized anti-IL-4 monoclonal antibody, Table 3—Levels of Asthma Control
pascolizumab, was evaluated in a phase 2
Controlled
study. It was not efficacious and therefore its All of the following:
progression was discontinued. 1) No daytime symptoms or ,13/wk
Overexpression of IL-13 is observed in severe 2) Limitations of activities: none
3) Nocturnal awakening: none
asthma patients in sputum and bronchial
4) Need for reliever (rescue) medication: 23/wk
biopsy specimens. The anti-IL-13 monoclonal 5) FEV1 or peak flow: normal
antibody lebrikizumab significantly attenuates 6) Exacerbations: none
the allergen-induced early and late allergic Partly controlled
Any measure present, in any week:
responses 14 days after the first dose. Lebriki- 1) Symptoms .23/wk
zumab treatment is associated with improved 2) Limitations of activities: any
lung function. Patients with high pretreatment 3) Nocturnal awakening: any
4) Need for reliever (rescue) medication: .23/wk
levels of serum periostin have greater improve- 5) FEV1 or peak flow: ,80% predicted or of personal
ment in lung function with lebrikizumab than best (if known)
those with low periostin levels. 6) Exacerbations: one or more a year
Uncontrolled
Two humanized monoclonal antibodies, me- Three or more features of partly controlled asthma
polizumab and reslizumab, have been devel- present in any week
oped that bind to human IL-5. The IV infusion An exacerbation in any 1 week makes a poorly
controlled asthma week
of anti-IL-5 (mepolizumab) causes pronounced
and long-term suppression of circulating eo-
sinophils and greatly reduced sputum eosino-
phil numbers. Patients selected on the basis Currently, there are phase II trials of anti-IL-17
that they were frequent exacerbators with in patients with inadequately controlled asthma.
elevated sputum eosinophils despite high
doses of corticosteroids experienced signifi- Treatment Protocols for Asthma
cantly fewer exacerbations.
There has been considerable interest in thymic A global strategy for asthma management
stromal lymphopoietin (TSLP), an IL-7-related and prevention has been offered in the NIH
cytokine that is secreted by airway epithelial guidelines. Treatment protocols use step-care
cells and promotes T cell proliferation and Th2 pharmacologic therapy based on the intensity of
cytokine production. This role is exerted both asthma symptoms and the clinical response to
at the induction phase of the Th2 response, via these interventions (Table 3). As symptoms and
polarization of DCs to drive Th2 cell differen- lung function worsen (partly controlled or
tiation, and at the effector phase of the uncontrolled asthma), step-up or add-on therapy
response, by promoting the expansion of is given. As symptoms improve, therapy can be
activated T cells and their secretion of Th2 ‘‘stepped down.’’ Studies have confirmed that
cytokines. TSLP is a good therapeutic target in guideline-derived asthma control can be
the treatment of allergic diseases, but its achieved in a majority of patients.47
protective role in IBD sounds a note of caution The classification of asthma by severity has
because neutralization of TSLP could poten- proven useful when decisions are being made
tially unmask or aggravate Th17- and/or Th2- about management at the time of the initial
dominated inflammatory disease. assessment of a patient (Table 4). Asthma
IL-17, a cytokine produced by TH17 cells, may severity, however, involves both the severity of
play a role in the neutrophil response in the the underlying disease and its responsiveness to
airways. In severe asthma, which encompasses treatment. This classification of severity is no
a population of asthmatics who are poorly longer recommended as the basis for ongoing
controlled by steroids, patients may show a treatment decisions in the new GINA guidelines.
neutrophilic component to the airway inflam- Instead, the concept of asthma control has been
mation, rather than simply an eosinophilic. suggested as a basis for treatment decisions. The

Table 4—Initial Asthma Treatment by Severity of Diseases Use of short-acting rescue inhaler greater than
2 days a week.
Mild intermittent asthma
Reliever medication needed more than two
Severity: Symptoms ,23/wk; nocturnal symptoms
,23/mo; FEV1 and PEFR .80% predicted; PEFR times a week.
variability ,20%. Nocturnal awakenings one to three times a
Treatment: Inhaled short-acting b-agonist prn.
week.
Mild persistent asthma
Severity: Symptoms .23/wk and ,13/d; nighttime FEV1 or peak flow at 60% to 80% predicted/
symptoms .23/mo; FEV1 and PEFR .80% predicted; personal best.
PEFR variability between 20% and 30%. Limited participation in normal activities.
Treatment: Begin anti-inflammatory therapy; ICSs (low
Needing urgent care, including hospitalization.
dose) are preferred, or consider an LT pathway
modifier. Use short-acting b-agonist prn for quick
relief, but increased use means need for additional
There is considerable interpatient variability
controller therapy. in attaining asthma control. It is recommended
Moderate persistent asthma that periodic assessments be made every 1 to 6
Severity: Daily symptoms and daily use of rescue b- months for each asthmatic to assess control and
agonist; .2 exacerbations/wk and 1 nighttime
exacerbation/mo; FEV1 and PEFR between 60% and assure that the goals of asthma care are being
80% predicted; PEFR variability .30%. met. The classification of asthma control is seen
Treatment: Increase ICS dose or add long-acting b- in Table 3.
agonist; if symptoms still persist, may increase dose
of ICS, add LT pathway modifier, or consider
theophylline; continue short-acting b-agonist for acute Adherence to Asthma Management Advice
relief.
Severe persistent asthma A significant number of people continue to
Severity: continuous symptoms; limited physical
activity; frequent exacerbations; frequent nighttime have poor outcomes with their asthma despite
symptoms; FEV1 and PEFR ,60% predicted; PEFR effective treatments and management guidelines.
variability .30%. One important reason is poor adherence to
Treatment: ICSs, long-acting b-agonist, theophylline, and
recommended therapy. Patients with poor ad-
oral corticosteroids.
herence to their recommended management have
Reprinted with permission from ACCP Pulmonary Medicine certain characteristics that are likely to be
Chest Physicians; 2009.
associated with poor outcomes.49 Poorly compli-
ant patients have poorer self-reported asthma
term control refers to control of the manifesta- control in terms of medication use, symptoms,
tions of disease, including symptoms, effects on time off work, asthma-specific quality of life,
the quality of daily living, and use of rescue primary care visits, emergency attendances, and
hospital admissions. They also have higher levels
medication. A periodic assessment of asthma
of physical and psychological comorbidities, are
control is useful and strongly recommended. One
younger, and face more difficult social and
simple office-based approach is offering patients
economic circumstances. Significant psychologi-
the asthma control test.48 It presents a scoring
cal (anxiety) and social factors are independently
system for asthma control that includes five associated with patients being identified as
items for gauging the status of current asthma. poorly compliant. As significant psychological
These include asthma symptoms, the use of and social problems are identified in more than
rescue medications, and questions regarding the 70% of patients dying from asthma and experi-
impact of asthma on everyday functioning. This encing near-fatal attacks, the physician’s explor-
is a brief, easy-to-administer, patient-centered ing this aspect of asthma care is extremely
index of asthma control. important. One especially vulnerable group of
Signs of lack of control may include any of asthma patients is pregnant women. Exacerba-
the following: tions of asthma during pregnancy occur primar-
ily in the late second trimester. The major triggers
Two or more exacerbations per year requiring a are viral infection and nonadherence to ICS
corticosteroid burst. therapy. Women who have an exacerbation

during pregnancy are at a significantly increased as 50% in athletes. Airway hyperresponsiveness
risk of having a low-birth-weight baby compared to exercise at a young age has been shown to be a
with women without asthma.50 strong predictor of persistent asthma.
Although nearly all asthmatic patients report
Asthma Phenotypes having increased bronchospasm following vigor-
ous exercise at some point in their history,
A phenotype is defined as the observable, objective testing is at times essential for a
visible characteristics of an organism resulting diagnosis. This may occur when treating the
from the interaction between its genetic makeup symptoms of EIB/EIA is not successful and
and the environment. It is apparent that asthma objective confirmation is required. In addition,
is not a single disease and that many common often for preemployment assessment (military,
features of asthma (such as exercise-induced deep-sea diving required), a valid diagnosis of
bronchospasm) are not seen in some patients, EIA/EIB may be required. The most direct way
and there are uncommon expressions of asthma to establish a diagnosis of EIA/EIB is to perform
(aspirin sensitivity) that are not seen in the an exercise challenge and not rely on symp-
majority. Asthma is therefore perceived to be a toms.53 The American Thoracic Society has
conglomerate of syndromes with distinct pheno- published guidelines on exercise challenge test-
typic expressions, all associated with reversible ing (ECT) for the diagnosis of EIA/EIB.54 The
airflow obstruction and BHR.51 There are many standardized ECT requires the patient to exercise
ways to differentiate asthma phenotypes, but on a treadmill or cycle ergometer for 4 to 6 min at
substantial overlap exists. Asthma phenotypes a heart rate or minute ventilation equivalent to
can be defined by clinical, physiologic, biochem- 80% to 90% or 40% to 60% of age-predicted
ical, and cellular features. For example, clinical maximum, respectively. The FEV1 is measured
phenotypic features may include time of onset of before and at set intervals after exercise, and a
disease, duration of disease, response to treat- positive response occurs if the FEV1 decreases by
ment, triggers of symptoms, allergic or nonaller- more than 10% after exercise.
gic, and many more. Some of the major asthma During exercise, patients seem to be protect-
phenotypes are presented below. ed, as the airways actually dilate, possibly
because of the presence of circulating catechol-
Exercise-Induced Asthma/Exercise-Induced amines. Symptoms of cough and shortness of
Bronchospasm breath parallel the drop in lung function that
usually reaches its peak response 5 to 10 min
The term exercise-induced asthma has been after exercise. Often, patients hear no wheezing
widely used but has also created controversy during the attack, and in some patients atypical
because exercise does not cause asthma and not presentations of chest tightness or chest pain
all individuals who develop bronchospasm fol- alone will occur. A cardiac workup may often
lowing exercise are asthmatics. In 2007 the precede pulmonary testing in such patients. The
American Academy of Allergy, Asthma & Im- symptoms usually abate without treatment,
munology Work Group on EIA developed these although administration of a short-acting p-
definitions52: Exercise-induced bronchoconstric- agonist immediately returns lung function to
tion (EIB) is defined as ‘‘the airway obstruction normal. Occasionally, the attack following exer-
that occurs in association with exercise without cise can be very severe and may require
regard to the presence of chronic asthma,’’ and emergency treatment.
EIA is defined as ‘‘the condition in which Despite standardization of the ECT protocol,
exercise induces symptoms of asthma in patients the airway response to exercise testing has been
who have asthma.’’ An estimated 7% of Amer- shown to be variable. Unlike the methacholine or
icans have asthma. Up to 90% of people with histamine challenge, the exercise challenge is an
asthma demonstrate EIA. The prevalence of EIB indirect airway challenge and it has been
has been documented to be 6% to 13% in people suggested that surrogate indirect tests such
with no history of asthma or allergy and as high eucapnic voluntary hyperpnea and mannitol

provocation may be more sensitive to detect relative to asthmatic patients without EIB
EIA/EIB than the standard ECT. However, have a reduction in the levels of the protective
insufficient evidence is available to conclude that eicosanoid lipoxin A4.
either of these tests is suitable.55 7. There is some evidence that a low-salt diet
The mechanisms that cause EIB/EIA in may protect patients from EIB/EIA and that
susceptible patients have been intensely studied. high salt intake may accentuate the condition.
As ventilation increases with exercise, cooler, This would support the evidence that osmotic
dryer air is drawn into the airways in greater changes in the airways from the exercise
quantities. This causes heat and water loss from challenge may initiate the bronchospastic
the airways into the airstream. The epithelial response.
surface is stressed and there is shedding of
Bronchoconstriction becomes less intense
epithelial cells into the airway lumen. There is a
during a second challenge if performed an hour
transfer of water from the osmotically sensitive
or so after the first. About 50% of individuals will
epithelial cells as well as creation of a thermal
have less than half the severity of response when
gradient. Osmotic stimuli are known to directly
the exercise is repeated within the hour. An
activate inflammatory cells such as mast cells.
intense warm-up period 30 to 60 min before
Airway cooling and mucosal drying are therefore
competitive sports therefore can be helpful, and a
thought to trigger mast cells and eosinophils to
strenuous warm-up in conjunction with a bron-
release their mediators (LTs, PGD2) and that this
chodilator can be more effective than either
mediator release is the predominant cause of EIB/
intervention alone. The use of masks and
EIA. It is believed that the greater the heat and
mouthpieces that trap expired water and allow
water loss, the greater the degree of broncho-
rebreathing has also been a successful strategy.
spasm. There is also evidence that the mechanism
Pretreatment can effectively block exercise-
of bronchoconstriction is mediated through the
induced bronchospasm in greater than 90% of
sensory nerve activation with retrograde axonal
patients. b-agonists are the first choice for
transmission via the release of neurokinins.
treatment, and cromolyn has shown to be an
A number of factors may enhance or reduce
alternative. Montelukast has been an effective
the risk of exercise-induced bronchospasm, in-
agent for prevention of EIB/EIA, as have ICSs
cluding the following:
when given over time to provide better overall
1. Patients with poorly controlled asthma are asthma control.
more likely to have EIA.
2. Exercise in cold, dry air is more likely to cause Severe Asthma
EIB/EIA.
3. Running, especially outdoors, is more likely to One group of patients with asthma that
cause EIB/EIA than other activities such as seems to require a more targeted approach is
swimming. one with high medication requirements and
4. The greater the intensity of the exercise, the persistent symptoms and exacerbations.56,57 This
more likely the bronchospasm. has been referred to as refractory asthma or severe
5. Patients with a large bronchodilator response asthma and comprises approximately 10% of all
to a short-acting b-agonist are more likely to asthmatics. A more recent definition used the
have asthma symptoms during exercise. This term severe refractory asthma, and includes pa-
suggests that patients with more variability in tients who remain difficult to control despite an
airway tone (bronchial lability) may be more extensive reevaluation and an observational
susceptible to EIB/EIA. period of at least 6 months by an asthma
6. The intensity of cellular airway inflammation specialist.58 Before confirming the diagnosis of
with eosinophils and mast cells and the severe asthma, however, other phenotypic factors
generation of inflammatory mediators such that contribute to refractory asthma should be
as the LTs have been associated with suscep- recognized and adequately treated. These in-
tibility to EIB/EIA. Patients with EIB/EIA clude acid reflux, sinusitis, atopy, and poor

adherence to therapy. Unfortunately, biomarkers these patients, leading to the concept that
that can be detected by noninvasive tests to adventitial inflammation in the peripheral air-
distinguish severe asthma or that can predict ways leads to excessive airway narrowing. This
disease progression have not been identified. leads to an altered airway-parenchymal interde-
However, a BAL biomarker study identified a pendence and the loss of the normal elastic recoil
pattern or molecular phenotype, raising the forces that normally keep the airways open. It
possibility that protein expression patterns could has been observed that lung function has a
be used clinically to recognize phenotypes of definite circadian rhythm and that PEFRs are
asthma, including severe asthma, that could highest at 4:00 PM and lowest at 4:00 AM. Healthy
predict prognosis and response to therapy.59 individuals show a fluctuation of only about 8%,
The American Thoracic Society has proposed whereas many asthmatic patients can, during
a clinical description of such patients to include60 periods of unstable symptoms, show as much as
(1) major criteria: treatment with continuous or a 50% variation in peak expiratory rates in a 24-h
near-continuous (.50% of year) oral corticoste- period. This can result in frequent nocturnal
roids or requirements for treatment with high- awakenings and the need for frequent rescue
dose ICSs; and (2) several minor criteria: require- therapy. Sustained-release theophylline has prov-
ment for additional daily treatment with a en to be a valuable tool in the control of nocturnal
controller medication, eg, long-acting b-agonist asthma, and LABAs such as oral extended-
theophylline or LT antagonist; asthma symptoms release albuterol and inhaled salmeterol are also
requiring short-acting b-agonist use on a daily or helpful. Because research with transbronchial
near-daily basis; persistent airway obstruction biopsy specimens has shown that the levels of
(FEV1 ,80% predicted; diurnal peak expiratory inflammatory cells are highest at 4:00 AM, the key
flow variability .20%); one or more urgent care to controlling nocturnal asthma is the control of
visits for asthma per year; three or more oral the inflammatory response with ICSs or, if
steroid bursts per year; prompt deterioration necessary, oral corticosteroids.
with .25% reduction in oral or ICS dose; near-
fatal asthma event in the past. Severe asthma Aspirin-Induced Asthma
requires one or both major criteria and at least
two minor criteria. Acute idiosyncratic reactions to aspirin may
result in either acute bronchospasm or urticaria/
Nocturnal Asthma angioedema, rarely both together.62 Aspirin-
induced asthma is a syndrome that predomi-
Exacerbations of wheezing and shortness of nantly affects adults, rather than children, and
breath are a common cause of sleep deprivation nonatopic individuals. A third of patients,
in asthma patients, and tend to be underreported however, may manifest positive immediate
by patients and overlooked by physicians.61 Even skin-test hypersensitivity to inhaled aeroaller-
patients who have mild disease that is apparently gens. The disease usually evolves over decades
controlled by medication may awake at least one and first begins as chronic nonallergic perennial
time during the night because of their asthma. rhinitis, often complicated by nasal polyposis
Deaths from asthma have been rising in many and recurrent bacterial sinusitis. Asthma then
countries over the past few decades, and most of appears, is often severe and unremitting, and
these deaths from asthma occur at night between requires treatment with systemic steroids. The
midnight and 8:00 AM. The mechanisms of symptoms of rhinosinusitis, however, may con-
nocturnal asthma are not completely understood. tinue to be more troubling to the patient than
Bronchial biopsy specimens have not shown asthma. Although aspirin may have previously
increases in T cells, eosinophils, or mast cells at been tolerated, suddenly acute bronchospasm
4:00 AM in asthmatic patients with nocturnal develops in the patient 30 min to several hours
asthma. Transbronchial biopsy specimens have after ingesting a standard dose of oral aspirin.
shown accumulations of eosinophils and macro- This may also be associated with flushing of the
phages in alveolar and peribronchial tissue in face and ocular and nasal congestion. Cross-

sensitivity occurs with the use of other nonste- the agents have been shown to block aspirin-
roidal antiinflammatory drugs (NSAIDs) such as induced bronchospasm in sensitive patients.
indomethacin, naproxen, ibuprofen, sulindac,
and piroxicam, all of which are inhibitors of PG Occupational Asthma
synthesis from the cyclooxygenase pathway of
arachidonic acid metabolism. Noninhibitors such Asthma that is precipitated by a particular
as sodium salicylate, salicylamide, propoxy- occupational environment and not to stimuli
phene, and acetaminophen do not cause the outside of the workplace is called occupational
reaction. asthma.63 The following two types have been
It is believed that by blocking the cyclooxy- described: (1) asthma that follows a latent period
genase pathway, arachidonic acid metabolism is of exposure to either a high-molecular-weight or
preferentially shifted to the 5-lipoxygenase path- a low-molecular-weight sensitizing antigen; and
way to produce LTs, including the cysteinyl LTs (2) asthma that follows exposure to workplace
LTC4, LTD4, and LTE4. They are potent inflam- irritants. One form of irritant-induced asthma is
matory mediators that can induce bronchocon- called reactive airways dysfunction syndrome, a
striction, mucous secretion, bronchial wall condition that usually results from the sudden
edema, and swelling of the nasal mucosa. They inhalation of a large dose of a highly irritating
are also potent chemokines for eosinophils. There substance. Occupational asthma associated with
is a fourfold increase in urinary LTE4 levels after a latency period causes asthma by immunologic
aspirin provocation in the aspirin-sensitive pa- events that affect only a small proportion of
tient. It has also been shown that aspirin- exposed subjects. Although some compounds
sensitive patients have increased expression of induce asthma through the production of specific
the cysteinyl LT receptor CysLT1 on leukocytes IgE antibodies, the immunologic mechanisms
from nasal mucosal biopsy specimens compared responsible for other agents have not been
with those who do not have this syndrome. The identified. The reaction between specific IgE
precise mechanism for this syndrome is not antibodies and antigens may cause an isolated
known. The overexpression of the enzyme LTC4 early asthmatic reaction that occurs within a few
synthase has been reported, and some studies minutes after the occupational exposure. It
have described polymorphisms of the LTC4 typically reaches a maximum within 30 min,
synthase promoter region. and subsides within 1 to 1.5 h. Also, a biphasic
reaction may occur, and the spontaneous recov-
The prevalence of aspirin-induced broncho-
ery may be followed by a late bronchospastic
spasm in the population of asthmatic patients
reaction 4 to 6 h after exposure. This reaches
depends on the population studied. Approxi-
maximal intensity within 8 to 10 h, and subsides
mately 3% to 5% of hospitalized asthmatic
after 24 to 48 h. When an isolated late reaction
patients report a history of a reaction to aspirin.
occurs, the affected individual may be away from
This number is higher at highly specialized
the workplace, making the diagnosis less obvi-
referral centers where patients with the most
ous. The presence of sensitization to occupational
severe asthma are cared for. The treatment is, of
agents can be detected by skin tests, radioaller-
course, the avoidance of aspirin and NSAIDs with
gosorbent tests, or enzyme-linked immunosor-
known cross-reactivity. For the occasional patient
bent assay, and this can strongly support the
who needs these drugs, oral desensitization
diagnosis. Unfortunately, there are very few
protocols using gradually increasing doses of
standardized commercially available materials
aspirin are effective. Using aspirin desensitiza-
for skin tests or for radioallergosorbent tests in
tion, about two thirds of the patients report a
patients with this disorder.
significant improvement in their rhinosinusitis,
The following six major categories of agents
and about half have improvement in their asthma.
have been described in the pathogenesis of
The addition of LT inhibitors (eg, zileuton) and
occupational asthma:
receptor antagonists (eg, montelukast) as thera-
peutic options for asthma is important because 1. Exposure to animals, shellfish, fish, and

arthropods can cause asthma in farmers, 4. Increased lower airway exposure to airborne
laboratory workers, grain handlers, and poul- contaminants from mouth breathing.
try workers. 5. Increased need for conditioning the inspired
2. Exposure to wood, plants, and vegetables can air.
cause asthma in woodworkers, carpenters, There has been some evidence that treating
grain handlers, bakers, and tobacco workers. the upper airways improves asthma disease
3. Enzymes and pharmaceuticals are known to control and quality of life and that immunother-
cause asthma in pharmaceutical workers, apy in patients with allergic rhinitis may prevent
pharmacists, and detergent industry workers. subsequent asthma.
4. Low-molecular-weight chemicals cause asth-
ma in solderers, spray painters, chemical Cough-Variant Asthma (CVA)
manufacturers, polyurethane manufacturers,
and electronics workers. At times, cough may be the sole presenting
5. Metals and metal salts such as aluminum, manifestation of asthma, and the characteristic
chromium, cobalt, nickel, and platinum fumes findings of variable airflow obstruction may not
can cause asthma in electroplaters, hard-metal be present. Such patients represent a subgroup of
workers, polishers, and solderers. patients with asthma, rather than being asthmatic
6. Dusts, fumes, and gases may cause asthma via patients who cough.65 As a result, CVA is
a sudden, high-concentration exposure, usu- significantly underdiagnosed. Prospective stud-
ally due to an accident in the workplace, or via ies have shown that asthma is among the most
less severe repetitive exposures. common causes of chronic cough (24% to 29%) in
adult nonsmokers.
Estimates of the prevalence of occupational
There is evidence that cough receptors in the
asthma vary, but it is estimated that 2% to 15% of
airways are separate from bronchoconstrictive
all cases of adult-onset asthma arise from
receptors, and this may explain why such
workplace exposure. Seeking the occupational
patients do not wheeze. Cough receptors are
causes of asthma in the patient’s history can be
more abundant in the central airways. Patients
very rewarding and can lead to primary preven-
with CVA have demonstrated heightened sensi-
tion by the avoidance of the offending environ-
tivity of their cough reflexes, whereas those with
ment.
the typical form of asthma do not differ from
healthy volunteers when cough reflex sensitivity
Rhinitis/Rhinosinusitis and Asthma
is experimentally measured. Methacholine sensi-
Upper airway disorders, such as allergic tivity, on the other hand, occurs less often in
rhinitis, nonallergic rhinitis, and sinusitis, are patients with CVA when compared with those
common in allergic and not-allergic asthma and with typical asthma. In addition, inhalation
may influence asthma outcomes. The number of challenge tests suggests that preservation of the
atopic asthma patients who also have rhinitis bronchodilating and bronchoprotective effects of
may be as high as 95%, and approximately 90% deep inspirations is a distinguishing feature of
of patients with mild to moderate asthma and cough variant asthma.66 The cough receptors are
almost 100% of those with severe asthma have presumably stimulated by inflammatory cell
radiologic abnormalities of the sinuses. The mediators that are released by airway inflamma-
upper airways may influence asthma in a tion. Subepithelial layer thickening, which is a
number of ways:64 pathologic feature of airway remodeling that is
thought to be caused by chronic inflammation, is
1. The release of mediators into the airways or present in CVA.
peripheral circulation. The diagnosis of CVA should be suspected in
2. Neural reflexes. a patient who has a chronic cough, usually
3. Increased production of bone marrow pro- present for months and even years, and no
genitors of inflammatory cells. obvious cause seen on the chest radiograph.

The history is often suggestive in that the patient regarding causality.64 It has been discovered in as
coughs vigorously after exposure to fumes, many as 30% to 90% of patients. In patients with
cigarette smoke, and other irritants, and often reflux symptoms, 24-h pH monitoring has
after laughter and exercise. The diagnosis is proven reflux to be present in .80% of patients.
supported by a positive response to bronchial Even when reflux symptoms are not present,
inhalation challenge with methacholine, hista- reflux can be demonstrated with this study
mine, or exercise, and is confirmed by a clinical nearly 30% of the time. Asthmatic patients have
response to bronchodilators and/or antiinflam- been shown to have decreased lower esophageal
matory agents. Most patients will respond to sphincter pressures when compared with healthy
treatment with inhaled bronchodilators and ICSs. individuals. Medications such as theophylline
A subgroup of patients will require the addition and b-agonists can reduce pressure in the lower
of LT receptor antagonists and/or a short course esophagus, as can certain foods, such as those
of oral corticosteroids. A negative methacholine with a high fat content, chocolate, caffeinated
inhalation challenge test result essentially ex- beverages, alcohol, and peppermint. In addition,
cludes asthma from the differential diagnosis of oral prednisone has been shown to increase
chronic cough. esophageal acid contact time. A large study of
veterans showed that patients with significant
Allergic Bronchopulmonary Aspergillosis (ABPA) esophageal disease, such as erosive esophagitis
and/or esophageal stricture, had a 1.5 odds ratio
ABPA is a syndrome most commonly seen in of having asthma compared with healthy sub-
patients with asthma and cystic fibrosis. Patients jects. In patients with difficult-to-control asthma,
present with wheezing, fleeting, pulmonary reflux should be considered as a possible
infiltrates, and expectoration of brown mucus triggering agent. A favorable asthma response
plugs. ABPA is suspected on clinical grounds, to antireflux medical therapy has been shown to
and the diagnosis is confirmed by radiologic and occur, especially in patients with reflux symp-
serologic testing. In the United States, the toms, but also in as many as 24% of patients with
accepted criteria for diagnosis are (1) asthma; no reflux symptoms. Unfortunately, such studies
(2) immediate cutaneous reactivity to Aspergillus have not shown consistent results. A trial of
fumigatus; (3) precipitating (IgG) antibodies to A therapy with a proton pump inhibitor used in
fumigatus; (4) elevated total serum IgE levels high doses (eg, omeprazole, 20 mg bid) may be
(.1,000 ng/mL); (5) elevated serum IgE antibod- necessary and has been shown to be more
ies to A fumigatus; (6) proximal bronchiectasis; (7) effective than the use of H2 blocker therapy.
infiltrates seen on the chest radiograph; and (8) Consensus has not been reached on the role of
peripheral eosinophilia with radiographic infil- surgery when medical therapy fails. The follow-
trates.67 ing two possible mechanisms of gastroesophage-
The mainstay of treatment for ABPA is oral al reflux-induced asthma exacerbation have been
corticosteroids to control the asthma symptoms proposed: (1) a vagally mediated reflex caused by
as well as the immunologic response to the acid in the esophagus, which stimulates sensory
Aspergillus antigens. Usually, 40 to 60 mg of mucosal receptors; and (2) microaspiration into
prednisone is required for complete clearing. The the upper airway, which stimulates other vagally
IgE concentration should decrease in 1 to 2 mediated reflexes. With either mechanism,
months, and a subsequent increase suggests heightened cholinergic tone could result in
recurrence of the disease. Azoles such as itracon- significant bronchoconstriction.
azole have also shown effectiveness in the
treatment of this condition.68 Corticosteroid-Resistant Asthma
Gastroesophageal Reflux and Asthma Patients with severe unremitting asthma

symptoms despite the use of high doses of
The prevalence of gastroesophageal reflux in corticosteroids have been termed corticosteroid-
asthma is quite high, but there is still controversy resistant asthmatic patients when no confounding

factors have been discovered.69 These factors lower lung function and has been described at
include poor adherence to recommended thera- autopsy in patients with ‘‘acute asphyxic asth-
py, uncontrolled gastroesophageal reflux, unrec- ma,’’ those who die from an asthma exacerbation
ognized food or environmental antigen exposure, that comes on in hours when the patient was
aspirin-sensitive asthma, ABPA, systemic vascu- previously stable. The cause of the neutrophilic
litis, and fixed airway disease secondary to inflammation is not well established, but viral
COPD. infection, cigarette smoke exposure, and occupa-
Five to ten percent of asthmatics fall into a tional irritants have all been suggested. Increases
category of relative glucocorticoid insensitivity. in the chemotactic factor IL-8 that attract neutro-
By definition, such patients have an FEV1 of phils have been found in these patients. Patients
,75% predicted, with a failure to improve by with neutrophilic predominant asthma have
15% after an adequate dose and duration of been shown to have signs of systemic inflamma-
glucocorticoid therapy (eg, 40 mg/d prednisone tion and this is associated with worse clinical
for 1 to 2 weeks); are clinically resistant to outcomes.70
corticosteroid therapy; and have a longer dura-
tion of asthma, lower morning lung function, and Fatal and Near-Fatal Asthma
a greater degree of bronchial reactivity than
corticosteroid-sensitive asthmatic patients. Al- Despite our better understanding of the
though some abnormalities have been demon- pathogenesis of asthma and more effective
strated in other tissues, such as the cutaneous treatment programs,71,72 morbidity and mortality
vasoconstrictor responses to beclomethasone associated with this condition still remain a
dipropionate, metabolic effects suggesting gluco- problem in most countries in the industrialized
corticoid resistance in other tissues such as bone world.73 Many factors have been proposed to
have not been seen, and the hypothalamic- explain this dilemma. These factors include poor
pituitary-adrenal axis response in such patients compliance with medication and asthma moni-
has been shown to be normal. toring, an underestimation by the patient and
Glucocorticoid resistance probably is pro- physician alike of the severity of the asthma,
duced by a number of heterogeneous mecha- poor long-term access to medical care, especially
nisms, ranging from an inherited genetic basis to for the poor, and overreliance on inhaled b-
exposure to environmental stressors such as agonist therapy. Near-fatal and fatal attacks of
cigarette smoking or infection. Abnormalities in asthma are the result of acute hypercarbic
histone deacetylation pathways, overexpression respiratory acidosis; fatalities are not often due
of a nonfunctional glucocorticoid receptor b, or to serious cardiac arrhythmias. Despite severe
transcription-factor interference with corticoste- degrees of acidosis, even to pH levels of ,7.0,
roid binding to the functional glucocorticoid recovery can be rapid and complete. In fact, there
receptor a are possible mechanisms. It is possible is evidence that when the asthma attack is
that other patients with asthma do not respond sudden and respiratory failure occurs within a
because the type of inflammation in the airways few hours, recovery too is rapid. Improvement
is not eosinophilic but rather neutrophilic, and occurs more rapidly than when the asthma attack
thus is not steroid responsive. has been slowly progressive over days. The term
Although the underlying mechanisms are sudden asphyxic asthma has been given to such
becoming better understood, there remains a explosive attacks. There is evidence that such
lack of effective novel therapies. patients are immunohistologically different in
that their airways have a relative paucity of
Neutrophilic Asthma eosinophils and a larger number of neutrophils
compared with the classic asthma picture.
Some asthmatics have a preponderance of Typically, in patients who die of asthma, the
neutrophils in the sputum rather than eosino- lungs are overinflated, and both large and small
phils. This phenotype of asthma is more com- airways are filled with plugs consisting of a
monly seen in patients with severe disease and mixture of mucus, serum proteins, inflammatory

Table 5—Identified Causes of a Near-Fatal Asthma Attack GSK. The ACCP Education Committee has
reviewed these relationships and resolved any
Environmental allergen exposure
Upper respiratory viral infection
potential conflict of interest.
Aspirin and NSAID ingestion
Profound emotional upsets References
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Notes

Chapter 4. Chronic Obstructive Pulmonary Disease
Objectives: COPD: Definition and Epidemiology

Review the current definition of COPD that incorporates
concepts of airway and systemic inflammation associat- In the 20th century, the definition of COPD as a
ed with this disease.
Explore the impact of COPD, including morbidity and disease state characterized by chronic airflow
mortality. limitation due to chronic bronchitis and emphy-
Review the risk factors for COPD. sema was internationally accepted. Chronic
Explore the natural history of COPD from its earlier
bronchitis has been defined in clinical terms:
asymptomatic stages to the late stages associated with
high morbidity and mortality. the presence of chronic productive cough for at
Explore the current understanding of the pathophysiol- least 3 consecutive months in 2 consecutive
ogy of COPD: the pathologic consequences of airway years. Other causes of chronic productive cough
inflammation and parenchymal lung destruction.
Explore the systemic consequences of the disease and the must have been ruled out. Emphysema, on the
comorbidities associated with COPD. other hand, has been defined by its pathologic
Review the current state of pharmacologic and non- description: an abnormal enlargement of the
pharmacologic therapy for COPD, including preventive
measures such as smoking cessation and an integrated
airspaces distal to the terminal bronchioles
disease management approach. accompanied by destruction of their walls and
without obvious fibrosis. Contrary to this tradi-
Key words: chronic bronchitis; COPD; emphysema; natural tional view, recent data have shown that this
history; risk factors; treatment destructive process is accompanied by a net
increase in the amount of collagen, suggesting
Synopsis: there is indeed active fibrosis associated with the
COPD, like asthma, is inflammatory disease of the lungs. breakdown of the elastic framework of the lung.
The number of patients with COPD has grown dramatically Over the past decade there has been increas-
and it now ranks as the third leading cause of death in the
United States. In the developed world, cigarette smoking is ing interest in the pathogenesis and management
the leading cause of this disease. In underdeveloped areas of of COPD as it became recognized that the disease
the world, indoor burning of fossil fuels for cooking and was having a major worldwide impact. An
heating is another important cause. Lung damage is caused
by (1) proinflammatory mediators, (2) oxidative stress, and
estimated 210 million people worldwide have
(3) proteolytic digestion of lung tissue. The cumulative COPD. The World Health Organization antici-
effect of this injury occurs slowly and silently over decades pates that total deaths from COPD will increase
and causes progressive obstruction to airflow. When lung
by 30% over the next 10 years. It has been
function reaches a critical level (approximately FEV1 of 50%
predicted), shortness of breath impacts activities of daily calculated that COPD ranks as the 12th largest
living. Chronic bronchitis, daily cough, and sputum disease burden in the world, with projections
production are common among cigarette smokers and that it will rank No. 5 by the year 2020. In the
portend a worse prognosis. An acute worsening of COPD
symptoms is called acute exacerbation of COPD. It is most United States at present, estimates from national
commonly caused by a viral or bacterial infection. Frequent interviews taken by the National Centers for
exacerbations are associated with a more rapid decline in Disease Control and Prevention reveal that more
lung function, poor quality of life, more frequent hospital-
than 13.1 million people are afflicted with COPD.
izations, and mortality. Evidence-based interventions prov-
en effective include influenza and pneumococcal It is likely that these statistics underestimate the
immunizations, short- and long-acting b-agonists, long- prevalence of COPD by nearly 50%, as close to 24
acting anticholinergics, patient education, and, for severely million US adults have impaired lung function.
affected patients, inhaled corticosteroids and phosphodies-
terase inhibitors and pulmonary rehabilitation. Proinflam- Many patients therefore underreport their symp-
matory mediators are found in the blood of COPD patients. toms and remain undiagnosed. In the National
Health and Nutrition Examination Survey
(NHANES) III, using surveys, physical exams,

and pulmonary function testing, prevalence for COPD beneficiaries were nearly 2.5 times
estimates using World Health Organization those of the expenditures for all other patients.
definitions show that 23.6 million adults (13.9% The cost per patient in other countries around the
of the adult population) have COPD.1 These world varies depending on how health care is
NHANES III data suggest that 12.5% of current provided and paid for. There is a striking direct
smokers and 9.4% of former smokers have relationship between the severity of COPD and
evidence of obstructive lung disease. Sixty-three the cost of care.
percent of patients with low lung function had no As a result of the impact of COPD on
prior or current reported diagnosis of any morbidity, mortality, and health-care utilization
obstructive lung disease. and finances, a number of thoracic and respira-
The average number of days of restricted tory disease societies offered consensus state-
activities reported by patients with COPD is very ments regarding the assessment and management
high, ranking this condition among the highest of COPD. The dawn of the 21st century brought
chronic conditions for this measure of morbidity another guideline, the Global Initiative on Chron-
in the nation. In 1996, COPD was listed as the ic Obstructive Lung Disease (GOLD), sponsored
eighth leading cause of disability-adjusted life by the World Health Organization and the
years in men and the seventh leading cause of National Heart, Lung, and Blood Institute. The
disability-adjusted life years among women. A GOLD presents an evidence-based approach that
Lung Association survey revealed that half of all can be followed by all health-care systems
COPD patients (51%) say their condition limits throughout the world. It has been updated as
their ability to work.2 It also limits them in recently as 2011.3
normal physical exertion (70%), household The term COPD defined by GOLD differs
chores (56%), social activities (53%), sleeping from previous consensus statements. It does not
(50%), and family activities (46%). COPD is a incorporate the terms chronic bronchitis and
leading cause of hospitalizations in the United emphysema into the definition. Instead, it defines
States. An estimated 672,000 hospital discharges COPD as a disease state characterized by airflow
were reported in 2006, a discharge rate of 22.5 per obstruction that is no longer fully reversible and
100,000 population. COPD is an important cause is usually progressive. The disease is caused by
of hospitalization in our aged population. Ap- an interaction between noxious inhaled agents
proximately 64% of discharges were in the 65 such as cigarette smoke, industrial and other
years and older population in 2006. environmental pollutants, and host factors (ge-
Perhaps even more striking and ominous are netic, respiratory infections, etc) that results in
the magnitude and trend of the mortality rates chronic inflammation in the walls and lumen of
for COPD. Over the past few decades, the the airways. The pathology of COPD, as well as
mortality rates associated with other common the symptoms, the pulmonary function abnor-
diseases such as cardiovascular disease and malities, and complications all can be explained
stroke were declining. During the same time on the basis of the underlying inflammation.4
period, the mortality rate for COPD was rising at In the 2006 GOLD definition of COPD, the
an alarming rate. COPD is the third leading cause phrase ‘‘preventable and treatable’’ was added,
of death in America, claiming the lives of 124,477 similar to recent American Thoracic Society
Americans in 2007. This is the eighth consecutive (ATS)/European Respiratory Society (ERS) rec-
year in which women have exceeded men in the ommendations.5 This was done to encourage a
number of deaths attributable to COPD. In 2007, positive outlook for patients and the health-care
almost 64,000 women died compared with community toward COPD and to stimulate
almost 60,000 men. The cost of COPD has also effective management programs to treat those
increased dramatically. In 2010 it was estimated with the disease.
to be $49.9 billion. Direct medical services Although the GOLD document does not
accounted for $29.5 billion, and the indirect cost specifically include chronic bronchitis and em-
of morbidity was $8.0 billion and of premature physema in the definition of COPD, it is clear
mortality was $12.4 billion. Medicare expenses that they are considered the predominant causes
70 Chapter 4. Chronic Obstructive Pulmonary Disease (Braman)

of COPD, as the guidelines describe the mecha- in those who continue to smoke. In asthma,
nisms of airflow limitation, driven by the bronchial hyperresponsiveness is not related to
inflammation, as ‘‘small airway disease’’ (chronic baseline airway caliber, whereas in COPD the
bronchitis) and ‘‘parenchymal destruction’’ (em- increased responsiveness to bronchoconstric-
physema). In the past, asthma was also included tors can be explained entirely by the geometric
under the umbrella term COPD. As asthma effect of fixed airway narrowing.
became recognized as an inflammatory disease Unfortunately, many adult patients with asth-
with a different cellular and inflammatory ma are current or former smokers. It is likely
mediator profile compared with smoking-in- that such patients have more than one patho-
duced chronic bronchitis and emphysema, it logic process with several pathways of inflam-
was no longer considered under the term COPD. mation. Although studies on the effects of
This was also justified by the fact that asthma is smoking on the rate of decline of FEV1 in
felt to be distinct: airflow obstruction is predom- asthma have given conflicting results, most
inantly reversible and the airways of asthmatics smoking asthmatics will present with some
are markedly hyperresponsive to a variety of degree of fixed airflow obstruction. This has
specific (aeroallergens) and nonspecific (metha- raised a complexity of semantic issues that
choline, histamine, cold air) inhaled substances. have not been solved. One attempt has been to
Although it is still clinically useful to distinguish combine two of the major pathologic processes
asthma from COPD (chronic bronchitis and and describe such patients using the term
emphysema), it is important to recognize three asthmatic bronchitis, but this does not have
problems with this nosology: widespread acceptance.
Remission rates for adults with asthma are
much less than those seen in children, and if Risk Factors for COPD
remission does occur, the probability of relapse
increases with increasing age. As a result, most The major risk factors for the development of
asthmatics, even those who have never COPD are listed in Table 1. All of these factors
smoked, who are at the age when COPD is have one thing in common: they are associated
most often recognized (over age 60) have with an accelerated decline in FEV1 over time.
evidence of poorly reversible airflow obstruc- Cigarette smoking leads the list and in most
tion on pulmonary function testing. This is countries is the responsible agent in at least 85%
supported by data from longitudinal studies to 90% of cases. Because the basic cellular and
indicating that the average FEV1 in asthmatics molecular mechanisms of disease are still poorly
declines over a period of years. Despite these understood, the reasons why only certain indi-
findings, there are many patients who show no viduals with a positive exposure history become
correlation between their FEV1 and the dura- affected are not known. For example, it is
tion of their disease. common to see pulmonary function abnormali-
Bronchial hyperresponsiveness—the exagger- ties reflecting obstruction in the small airways,
ated bronchoconstrictive response to nonspe- and nonuniform distribution of ventilation in
cific agonists such as methacholine—is a young adults who smoke. These changes are not
constant feature in asthmatics that is so predictive, because only 15% to 20% of these
important to its pathogenesis that it has been heavy smokers will develop an accelerated
incorporated into the definition of asthma. On decline of their FEV1 over time and clinically
the other hand, increased responsiveness to evident COPD. The differences in susceptibility
constrictors such as methacholine and hista- to tobacco smoke injury are likely to be related to
mine (but not indirect bronchoconstrictors genetic factors.
such as cold air and bradykinin) is seen in Approximately 15% of both asthma and
the majority of middle-aged smokers with COPD is likely to be work-related, and a
COPD and has even been shown to be a strong conservative estimate of the annual costs of this
predictor of progression of airway obstruction occupational asthma and COPD is nearly $7

Table 1—Risk Factors for COPD
Risk Comment
External factors
Cigarette smoking Most important risk factor: 85%–90% of cases; 15%–20% of 1-PPD smokers and 25%
of 2-PPD smokers develop COPD
Pipe and cigars High risk, but lower than cigarette smokers
Passive smoking Children of smoking parents have more respiratory symptoms and lower airway
function; unknown significance for adult COPD
Occupational exposure Risk in coal miners, gold miners, grain handlers, cement and cotton workers, etc;
interacts with smoking
Environmental pollution Indoor use of biomass fuels for cooking and heating in underdeveloped countries;
particulate matter from urban pollution
Host factors
Genetic factor a1-antitrypsin deficiency, .90% caused by homozygous ZZ phenotype
Gender Men more at risk than women
Socioeconomic More common with low socioeconomic status
Bronchial hyperresponsiveness A strong predictor of progressive airway obstruction in smokers
Atopy and asthma Many adult nonsmoking asthmatics develop fixed airway obstruction; atopy alone
not a factor
Childhood illnesses Low birth weight, respiratory infections, and symptomatic childhood asthma
Dietary influences Vitamin C, D, and E (tocopherol) deficiencies have been suggested
Adapted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest
Physicians; 2009. PPD ¼ packs per day.
billion in the United States alone.6,7 It has been This exposes a large population, especially women
more difficult to demonstrate the association and children, to high levels of indoor air pollution.
between COPD and occupational exposures than The burning of biomass occurs in a variety of
the association between COPD and cigarette settings, including domestic heating and cooking,
smoking. There have been several reasons offered, regeneration and clearing of agricultural lands,
but perhaps the most compelling is that many and intentional and unintentional forest fires.
exposed workers are also cigarette smokers or Smoke from biomass combustion, which contains
have been exposed to secondhand smoke. An ambient particulate matter and a wide variety of
increasing body of literature is providing longitu- volatile organic compounds, produces significant
dinal evidence that coal workers, hard rock levels of pollutants. They have significant harmful
miners, tunnel workers, concrete manufacturing effects and are a major contributor to morbidity
workers, and other nonmining industrial workers and mortality. Children, women, and the elderly
(with exposures to dusts, gases, and/or fumes) are most affected. Apart from poor lung growth
have an excess annual loss of FEV1 of 8 mL/y, seen in growing children, the risk of developing
compared with 9 to 11 mL/y attributable to respiratory tract infections (both upper and lower)
smoking. Recent findings have linked occupation- is greatly increased in children living in homes
al diesel exposures to an increased risk of COPD. using biomass fuel. Women who spend many
Some workers have been shown to have acute hours cooking food in poorly ventilated homes are
airflow obstruction when exposed to organic and at increased risk of developing COPD. Overall,
inorganic dusts, isocyanates, and irritant gases. people exposed to biomass smoke have an odds
Such events appear to predict later findings of ratio of 2.44 (95% confidence interval [CI], 1.9–3.33)
chronic, fixed obstructive lung disease. Recent for developing COPD relative to those not exposed
estimates by the ATS suggest that for COPD, a to biomass smoke.8
population-attributable risk of approximately 15%
to 20% is caused by occupational exposures. Genetic Risk Factors for COPD
Approximately half the world’s population
burn biomass fuel (wood, crop residues, animal One genetic abnormality that has been
dung, and coal) for cooking and heating purposes. known and well studied is a1-antitrypsin (AAT)

deficiency. Also called a1 antiprotease deficiency, Table 2—Diagnosis of AAT Deficiency
this disorder accounts for less than 1% of COPD
Features that prompt suspicion for screening
in the United States. AAT is a serum protein 1. Onset of COPD before age 50
made in the liver that is capable of inhibiting the 2. COPD without a smoking history or other risk factor
activity of specific proteolytic enzymes such as 3. Family history of AAT deficiency
trypsin, chymotrypsin, and neutrophil elastase. If 4. Family history: COPD, bronchiectasis, panniculitis
5. Young adult asthmatic unresponsive to therapy
not inactivated by AAT, neutrophil elastase 6. Patient with predominant lower lobe emphysema
destroys lung connective tissue, particularly 7. Necrotizing panniculitis
elastin, and this leads to the development of 8. C-ANCA vasculitis
9. Unexplained liver disease
emphysema.9
Laboratory testing for diagnosis
AAT is coded for by a single gene on 1. Protein electrophoresis reveals absence of a1 peak
chromosome 14. The serum protease inhibitor 2. Serum AAT levels 2.5 to 7 lM (normal 20–48 lM)
phenotype (Pi type) is determined by the 3. Phenotyping by isoelectric focus .90% Pi ZZ
independent expression of two independent Adapted with permission from ACCP Pulmonary Medicine
alleles. More than 90% of severely deficient Board Review. 25th ed. Northbrook, IL: American College of
patients are homozygous for the Z allele. Such Chest Physicians; 2009. C-ANCA ¼ cytoplasmic antineutro-
phil cytoplasmic antibodies.
patients are designated Pi ZZ and have a reduced
serum AAT level to about 20% of the normal
level. Other rarely observed phenotypes associ- decreased mortality.11,12 In addition, those who
ated with very low levels of AAT are Pi SZ, Pi were treated who had an FEV1 percentage
null-null, and Pi null-Z. The normal M allele predicted between 35% and 49% had a slowing
phenotype is designated Pi MM. Individuals in their decline in lung function compared with
with this phenotype have AAT levels of 150 to an untreated group. Weekly intravenous infusion
350 mg/dL reported from most commercial labs. of AAT preparations maintains serum AAT levels
Often the true laboratory standard values are above the putative protective threshold and is
reported. Normal levels are 20 to 48 lM. generally well tolerated. In addition to develop-
Most patients homozygous with the Z allele ing advanced emphysema, hepatitis, and cirrho-
are of northern European descent. Asian and sis, AAT deficiency patients are at a 70% to 100%
African Americans are rarely affected. Cigarette increased risk of developing lung cancer. Despite
smoking is the most important risk factor for the some positive studies on augmentation therapy, a
development of COPD in patients with AAT Cochrane review concluded that there was
deficiency. Symptoms begin early in adult life insufficient evidence to recommend it consider-
(usually by age 40), and COPD leads to an early ing the high cost.13
death. On the other hand, it is rare that Pi ZZ
lifetime nonsmokers ever develop COPD, and if Other Genetic Factors
they do, it is in later life.10 Most never develop
any pulmonary symptoms, have a normal life Most of the genetic effects on COPD have
expectancy, and remain undetected unless they yet to be identified.14 It is likely that a number
are found through family screening. Heterozy- of genetically determined abnormal protective
gotes who are Pi MZ have intermediate levels of mechanisms against protease, oxidant, and
AAT deficiency. Epidemiologic evidence sug- toxic peptide injury are important in the
gests that they are not at increased risk for pathogenesis of COPD.15 Our understanding
developing COPD when compared with Pi MM of disease susceptibility has been increased by
phenotypes. It is important to screen patients for results of several genome-wide association
AAT deficiency (Table 2) for family counseling studies. The CHRNA3/5, HHIP, and FAM13A
and because multivariate analyses from the loci all appear to be associated with disease
National Institutes of Health Registry suggest susceptibility. Multiple other association studies
that severely deficient patients who receive have been performed for COPD using case-
augmentation therapy (IV infusions of human control and population- and family-based stud-
AAT) have fewer exacerbations of COPD and ies. Unfortunately, these studies have often

yielded inconsistent results. Candidate genes disease can expect to lose 25 to 30 mL/y of lung
that have been studied in COPD are those function after age 35. The rate of decline appears
regulating proteases and antiproteases. For to accelerate slightly with aging, but sudden,
example, polymorphisms of the AAT gene not large, irreversible falls are very rare. Although
associated with deficiency of the protein pre- nonsmokers lose FEV1 slowly, they never develop
dispose to the development of COPD. These significant airflow obstruction; this is also true of
abnormalities are located at the Taq I and Hind most smokers. Susceptible smokers, on the other
III sites of the AAT gene. There is speculation hand, develop varying degrees of airflow ob-
that abnormalities at these sites of the gene may struction, as they often demonstrate a decline in
not be normally responsive to inflammatory lung function of 60 mL/y and more. This
cytokines. This may lead to inappropriate ultimately causes exertional dyspnea when the
synthesis and hence a relative deficiency of FEV1 is between 40% and 59% of its predicted
the protein during times of stress. Antioxidant value and becomes disabling when the FEV1
genes have also been of interest. Polymor- declines by about 70%. Such an inexorable decline
phisms in the gene that control subjects gluta- may lead to fatality; when the FEV1 falls below 1
thione S-transferases have also recently been L, the 5-year mortality is approximately 50%.
linked to the development of COPD. This Smoking cessation in the susceptible smoker will
family of metabolic enzymes may play an not result in recovery of lost FEV1, but will slow
important part in cellular defense by detoxify- the rate of decline to normal (Fig 1). Smoking
ing various substances in tobacco smoke. There
cessation in the patient with early changes of
is recent evidence that genetic polymorphisms
COPD at age 45 can make the difference between
of cytochrome p450 and microsomal epoxide
a normal life span and premature death. A
hydrolase may also be associated with the
prospective multicenter longitudinal study of
development of COPD, and also variants in
the effects of smoking cessation in patients
the gene ADAM33 have been significantly
identified with mild to moderate airflow obstruc-
associated with COPD. Variation of the b-
tion has been conducted in this country and
defensin gene has been demonstrated to influ-
supported by the National Heart, Lung, and
ence b-defensin expression in airway epithelial
Blood Institute.17 This lung health study showed
cells and increase the risk for COPD. And genes
that smokers who stopped smoking with the help
regulating mucociliary clearance (eg, cystic
of an aggressive smoking intervention program,
fibrosis transmembrane regulator and mucins)
and genes that regulate inflammatory mediators including nicotine replacement, significantly re-
(tumor necrosis factor a [TNF-a], vitamin D- duced the decline in their FEV1 over a 5-year
binding protein, transforming growth factor study period when compared with those who
[TGF]-b1, etc) have been of interest. continued to smoke. In this study, even with
intense smoking intervention, only about 20% of
Natural History of COPD the group were sustained nonsmokers over the 5-
year study, showing the significant challenge of
The natural history of COPD includes a cigarette smoking cessation in this group. The
prolonged preclinical period of approximately inhaled bronchodilator ipratropium did not slow
20 to 40 years. During this asymptomatic period the decline of lung function when given over the
there is deterioration of lung function in marked same time period, and more recent studies have
excess of the normal age-related decline. The failed to show convincingly that other currently
decline in FEV1 has been accepted as a key marker available pharmacologic agents (bronchodilators,
for progression of COPD. The natural history of inhaled corticosteroids [ICSs]) can affect lung
COPD was first shown in population studies on function decline.
London workingmen and reported in the 1970s.16 The slowly progressive course of COPD is
It was discovered that the FEV1 declines contin- often interrupted by a sudden change in symp-
uously and smoothly over a nonsmoking indi- toms and lung function. These acute respiratory
vidual’s life. Nonsmokers without respiratory illnesses or exacerbations are usually caused by

Figure 1. Accelerated decline in lung function (FEV1) in smoker and ‘‘susceptible’’ smoker in whom the progressive disability
of COPD develops. Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
American College of Chest Physicians; 2009.
viral or bacterial infections and are heralded by exacerbations cause a decrease in lung function
an increase in symptoms. Patients with milder for up to 90 days. There is evidence that more
stages of COPD will often develop one to two frequent exacerbations play a causal role in
exacerbations per year; those with more severe accelerating the development of chronic airflow
disease are likely to have many more. The obstruction.
Figure 2. Inflammation caused by cigarette smoke and other irritants causes inflammation in the large and mainly small
airways (chronic bronchitis) and parenchymal destruction (emphysema). Reprinted with permission from ACCP Pulmonary
Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.

Pathology and Pathophysiology The antigens are transported to the bronchial
associated lymphatic tissue layer and to regional
The pathologic changes in COPD are found lymph nodes, where B and T lymphocytes
in the large and small (,2 mm) airways and in initiate the cellular and humoral components of
the lung parenchyma18,19 (Fig 2). In advanced the adaptive immune response. This response
stages, there are also changes in the pulmonary assists in the destruction of microbes that may
circulation, the heart, and the respiratory mus- penetrate the airway as the innate immune
cles. Alveolar hypoxia causes medial hypertro- system is overwhelmed and in the neutralization
phy of vascular smooth muscle with extension of of extracellular microbial toxins that are released
the muscularis layer into distal vessels that do by these microorganisms.
not ordinarily contain smooth muscle. Intimal BAL studies in cigarette smokers have shown
hyperplasia also occurs in advanced stages. an increase in the number of neutrophils and
These latter changes are associated with the macrophages. Macrophages likely play an im-
development of pulmonary hypertension and portant role in perpetuating the inflammatory
its consequences—right ventricular hypertrophy process of COPD and are increased fivefold to 10-
and dilation. Loss of vascular bed also occurs fold in the BAL when the disease is present. They
with emphysema in association with the destruc- may release neutrophil chemotactic factors as
tive alveolar processes. In some patients with well as proteolytic enzymes, such as matrix
advanced COPD there is atrophy of diaphrag- metalloproteinases (MMPs), that damage the
matic muscle, loss of skeletal muscle, and epithelial barrier. Neutrophils are also thought
wasting of limb muscles. to be important in causing the tissue damage of
COPD. They release a number of mediators,
Changes in the Airways of Smokers including proteases such as neutrophil elastase
and MMPs, oxidants such as the oxygen free
Early structural changes have been described radical H2O2, and toxic peptides such as defen-
in otherwise healthy smokers even as young as sins. Proteases and free radicals can damage the
20 to 30 years old. These changes are attributed to epithelium as well as the basement membrane.
the toxic effects of cigarette smoke and possibly The repair process that ensues includes the
the added effects of environmental pollution. secretion of antiproteases, such as secretory
Cigarettes contain a complex mixture of particles leukocyte protease inhibitor and tissue inhibitor
and gases and thousands of chemicals. The of metalloproteinases, by epithelial cells in order
smoke that is inhaled contains many free radicals to regulate the proteolytic process.
and reactive oxygen species that are injurious to The process of repair may be impaired in
the lungs. The burden of gases and particles that patients with COPD. In patients with more
are inhaled into the lungs results in inflam- advanced airflow obstruction, T lymphocytes
matory and immune responses, both innate and and neutrophils are found in the epithelium
adaptive.18 The innate respiratory defense sys- and T lymphocytes and macrophages are found
tem includes an epithelial cell barrier and in the subepithelium of centriacinar airways
mucociliary transport system. When they are where emphysema is most marked. Although
overwhelmed, foreign particles may penetrate CD4þ lymphocytes are found in the airways of
the airway, and the epithelial disruption initiates atopic asthmatics, the T lymphocytes of patients
an immune response. Inflammatory cells migrate with cigarette-induced COPD are mainly CD8þ
into the epithelial layer, including polymorpho- cells. These cells are also thought to cause cell
nuclear cells, eosinophils, macrophages, natural damage. Eosinophilic inflammation of the air-
killer cells, and mast cells. Uncommitted B cells ways is also a hallmark of asthma and not
and CD4þ and CD8þ lymphocytes also partici- usually seen in chronic bronchitis, although there
pate in the response. Antigens that are deposited is an increase in eosinophilic basic proteins
on the epithelium are transported within the (eosinophil cationic proteins and eosinophil
airway by antigen-presenting cells, the special- peroxidase) in induced sputum. This may indi-
ized epithelial M cells, and the dendritic cells. cate that eosinophils had been present in the

sputum but were destroyed, possibly by neutro- Table 3—The Inflammatory Cells of COPD
phil elastase. During attacks of acute bronchitis,
Neutrophils
to the contrary, the number of tissue and sputum Potent chemokines (IL-8) and LTB4 attract neutrophils
eosinophils is markedly increased. to airways
Tissue from surgically resected lung speci- Increased numbers in sputum and BAL fluid, few in
mens from patients with COPD have been airways

Neutrophil numbers correlate with degree of airflow
evaluated for signs of inflammation. Patients obstruction
were categorized into GOLD stages of COPD.19 Secrete proteases: neutrophil elastase, cathepsin, and
The progression of COPD from GOLD stage 0 to proteinase-3

A causative link to mucus hypersecretion
GOLD stage 4 was strongly associated with an Phagocytic ability of neutrophils impaired by cigarette
increase in the volume of the tissue in the wall smoke (by suppression of caspase-3-like activity)
and the accumulation of inflammatory mucus predisposing to respiratory infection
exudates in the lumen of the small airways. As Macrophages
Activated by cigarette smoke
COPD severity progressed, the percentages of the Increased numbers found in sputum, BAL, and
airways that contained polymorphonuclear neu- bronchial submucosa
trophils, macrophages, CD4þ cells, CD8þ cells, B Release inflammatory mediators: TNF-a, LTB4, IL-8,
ROS
cells, and lymphoid aggregate increased. Bron- Release increased amounts of MMP-1 and -9
chial biopsies from former smokers show similar Have defective phagocytic function against apoptotic
inflammatory changes to those of active smokers, epithelial cells
Numbers of macrophages increase with increasing
suggesting that inflammation may persist in the
COPD severity
airway once established. The inflammatory cells T lymphocytes
involved in the pathogenesis of COPD are listed Increased numbers in lung parenchyma and airways
in Table 3. Greatest number are CD8þ cells
T-cell numbers correlate with amount of alveolar
destruction
Cytokines and COPD T-cell numbers also correlate with severity of airflow
obstruction
A number of extracellular signaling proteins CD8þ cells shown to cause cytolysis and apoptosis of
alveolar epithelial cells
called cytokines are important in the pathogen-
Eosinophils
esis of COPD, as they are thought to mediate the Usually not in sputum in COPD but eosinophil basic
tissue damage and repair induced by cigarette protein found
smoking.20 Increased quantities of certain proin- Hence, they may have been present and degranulated
by sputum elastase
flammatory cytokines, including IL-8, IL-1, IL-6, Increased numbers predict corticosteroid
and TNF-a, and the antiinflammatory cytokine responsiveness and also possibly asthma
IL-10 have been found in the sputum of smokers Increased in BAL and airway biopsy in acute
and even further increased during an acute exacerbation of COPD

Epithelial cells
exacerbation. Exposure of bronchial epithelial Likely an important source of inflammatory mediators
cells to cigarette smoke causes a release of as in asthma
Activated by cigarette smoke to produce IL-1 and IL-
neutrophilic and monocytic chemotactic factors,
8, TNF-a, and G-CSF
with IL-8 and granulocyte colony-stimulating Airway epithelial cells important source of TGF-b
factor accounting for increased neutrophilic TGF-b may be the cause of airway fibrosis in COPD
activity and monocyte chemotactic protein-1 VEGF important
VEGF receptor blockade causes alveolar cell
causing increased monocytic activity.
destruction (emphysema)
Cytokines may also be involved with tissue Dendritic cells and B cells
remodeling in COPD. There are distinct patho- Found in increased numbers in lymphoid follicles in
logic features of airway remodeling seen with bronchial wall
May reflect an adaptive immune response to infection
COPD, including inflammatory cell proliferation, May reflect a role for autoimmunity in COPD
epithelial damage, subepithelial fibrosis, myofi-
broblast proliferation, increased collagen deposi- Reprinted with permission from ACCP Pulmonary Medicine
tion in the lung parenchyma, smooth muscle Chest Physicians; 2009. G-CSF ¼ granulocyte colony-stimu-
hypertrophy, and neovascularization. Increased lating factor; ROS ¼ reactive oxygen species.

expression of TGF-b and epidermal growth factor smoker’s cough get COPD. Progression from
may activate fibroblastic proliferation in the GOLD stages 0 to 4 has been correlated with (1)
airways of patients with COPD. Patients with the thickness of the airway walls, (2) the degree
COPD have increased levels of total collagen and to which the airway lumen is filled with mucous
collagens I, III, and IV in the lungs, and levels of exudates, and (3) the extent of the inflammatory
collagens I and III, fibronectin, and laminin have response measured by the number of airways
been inversely related to FEV1, suggesting that containing polymorphonuclear leukocytes, mac-
the deposition of extracellular matrix proteins rophages, and lymphocytes (CD8þ cells, CD4þ
contribute to the airflow obstruction seen with cells, and B cells).
COPD. Vascular endothelial growth factor In addition to the structural abnormalities
(VEGF), which is expressed in airway smooth seen in the small airways, there is also a loss of
muscle cells, plays a key role in neovasculariza- alveolar attachments to the airway perimeter.
tion and vascular permeability and in the This impairs elastic recoil and favors increased
expression of fibroblast growth factors. Vascular tortuosity and early closure of the small airways
remodeling changes have also been inversely during expiration. Several tests, such as frequen-
related to measures of lung function (FEV1).21 cy dependence of compliance, nitrogen slope of
the alveolar plateau, closing volume, and Vmax
Structural Changes of COPD at low lung volume (eg, Vmax 75) are thought to
reflect small airway narrowing. These patho-
Other structural changes in the airways of physiologic abnormalities in 2-mm and smaller
smokers include mucus hyperplasia, bronchiolar airways have been referred to as ‘‘small airway
edema and smooth muscle hypertrophy, and disease,’’ implying that this is a distinct clinical
peribronchiolar fibrosis. These changes result in entity. It is more important instead to think of the
narrowing of the small airways (,2 mm). Studies early inflammatory changes in the small airways
suggest that the inflammatory cellular infiltrate, as the first stage in a protracted process that
fibrosis, and muscle in the airway wall show a eventually leads to persistent airflow obstruction
progressive worsening of pathologic changes and progressive decline in the FEV1. The path-
when nonsmokers, smokers with mild COPD, ogenesis of COPD that targets the airways
and smokers with more severe disease are (chronic bronchitis) and lung parenchyma (em-
compared, and there is a progression of the physema) is thought to occur because of a
number of airways ,400 lm in diameter as the complex interaction between extracellular signal-
disease worsens. Because the total cross-sectional ing proteins, oxidative stress, and proteolytic
area of these small airways is so much larger than digestion of connective tissue (Fig 3).
the cross-sectional area of the central conducting
airways (and hence they contribute so little to Oxidative Stress
total airway resistance), dyspnea and changes in
the FEV1 are usually absent until the disease is There is considerable evidence that an in-
quite advanced. This zone of the lungs is often creased oxidative burden plays a role in the
referred to as the ‘‘silent zone’’ because these pathogenesis of COPD.22 Macrophages generate
pathologic abnormalities usually go undetected reactive oxygen species as a result of exposure to
by symptom assessment and routine spirometry. cigarette smoke and through nicotinamide ade-
In some smokers, the inflammation and peri- nine dinucleotide phosphate-oxidase oxidase
bronchiolar fibrosis progress, and the pulmonary generate superoxide anions (O 2 ). This is con-
functional abnormalities associated with the verted to hydrogen peroxide (H2O2). Direct
small airway changes and the symptoms of measurement of the oxidative burden in airspac-
COPD become progressively worse. The pres- es can actually be performed by quantifying
ence of chronic bronchitis (cough and sputum H2O2 in BAL fluid. Cigarette smoke also contains
production) in cigarette smokers, however, is not oxidants, around 1017 oxidant molecules per
useful in predicting the future development of puff, and has been linked to alterations in the
airflow obstruction; that is, not all smokers with a antioxidant defenses. An imbalance between

Figure 3. COPD is caused by oxidative stress and proteolytic breakdown of connective tissue seen in this schema. Reprinted
with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest Physicians;
2009.
oxidants and antioxidants can be linked to direct is associated with a deficiency of antiproteolytic
injury to lung cells from free-radical protein activity, AAT deficiency, and by several animal
damage, mucus hypersecretion, inactivation of models that induce emphysema by instillation of
antiproteases, and enhanced inflammation elastolytic enzymes into the lungs. The main
through activation of transcription factors. Reac- sources of proteases in COPD are from neutro-
tive nitrogen species, found in cigarette smoke phils and macrophages including neutrophil
and produced endogenously, have also been protease, proteinase-3, matrix metalloproteases,
implicated in COPD pathogenesis. The free- and various cathepsins.
radical theory of aging suggests that reactive Bilirubin has been suggested as a possible
oxygen species, modifiable by genetic and biomarker for COPD, as there has been discov-
environmental factors (eg, smoking, pollutants), ered a 6% decrease in COPD incidence in men
mediate aging and apoptosis of cells, and these per 0.1 mg/dL increase in serum bilirubin
changes have been seen in emphysematous levels.24 Because serum bilirubin levels are
lungs. Oxidative stress of the lungs is thought regulated in part by the antioxidant enzyme
to contribute to several of the systemic manifes- heme oxygenase, serum bilirubin may reflect
tations of COPD such as weight loss and skeletal overall oxidant-antioxidant balance and serve as
muscle wasting. a surrogate marker of oxidative stress.
Protease-Antiprotease Imbalance Pathology of Chronic Bronchitis
There is a delicate balance between factors The presence of a gellike mucus in the
that cause proteolytic breakdown of lung tissue airways of healthy people is essential for normal
and those that resist it.23 A prevailing hypothesis mucociliary clearance. This is swallowed and
is that emphysema is caused by a protease- rarely noticed. Smokers with chronic bronchitis
antiprotease imbalance that results in increased produce larger amounts of sputum each day,
destruction and inappropriate repair of the averaging about 20 to 30 mL/d and even as high
lungs. This theory is supported by a disease that as 100 mL/d. This occurs as a result of an

Table 4—Pathologic Types of Emphysema because these glands are known to produce
deterrents such as lactoferrin, antiproteases, and
Centriacinar (centrilobular)
Focal destruction of respiratory bronchioles; surrounded
lysozyme. Other epithelial alterations seen in
by normal lung parenchyma chronic bronchitis are decreases in the number
More severe in upper lobes and length of the cilia and squamous metaplasia.
Type most frequently associated with smoking The mucociliary abnormalities of chronic bron-
Panacinar (panlobular)
Uniform destruction of all airspaces beyond the chitis cause a continuous sheet or blanket of
respiratory bronchioles mucus lining the airways instead of the discreet
More lower lobe distribution deposits of mucus seen on normal airways.
Occurs in smokers earlier in life
Pooling of secretions also may occur. This
Associated with ATT deficiency
Paraseptal emphysema provides additional cause for bacterial growth,
Involves the alveolar ducts and alveoli at the lung which in turn causes a release of toxins that are
periphery further damaging to the cilia and epithelial cells.
Emphysematous areas are often surrounded by
interlobular septa
Bacterial exoproducts are known to stimulate
May be associated with spontaneous pneumothorax in mucus production, slow ciliary beating, impair
young adults immune effector cell function, and destroy local
Both centrilobular and paraseptal emphysema may
immunoglobulins. This cycle is especially seen in
progress to bulla formation (at least 1 cm in diameter
and wall ,1 mm thick) current as opposed to former smokers.
The Pathology of Emphysema

increase in the size and number of the submu-
Emphysema is a destructive process that
cosal glands and an increase in the number of
occurs in the gas-exchanging airspaces—the
goblet cells on the surface epithelium. Mucous
respiratory bronchioles, alveolar ducts, and
gland enlargement and hyperplasia of the goblet
alveoli. It results in perforations (fenestrae),
cells are therefore the hallmark of chronic
obliteration of airspace walls, and coalescence
bronchitis. Goblet cells are normally absent in of small distinct airspaces into much larger ones.
the small airways, and their presence there (often There is permanent enlargement of the gas-
referred to as mucous metaplasia) is important to exchanging units of the lungs (acini). These
the development of COPD. In the larger airways pathologic changes cause loss of elastic recoil of
in chronic bronchitis there is a reduction in the lungs and abnormal gas exchange. Recent
serous acini of the submucosal glands. This studies have shown good correlation between
depresses local defenses to bacterial adherence, physiologic measurements of lung elastic recoil
and diffusing capacity and microscopic measures
Table 5—Mechanisms of Airflow Obstruction in COPD of airspace wall per unit of alveolar volume and
alveolar surface area.
Emphysema
Loss of elastic recoil
Three morphologic forms of emphysema
1. Less driving pressure from alveoli to proximal have been described (Table 4). It should be
airways recognized that most smoking-related emphyse-
2. As patency in smaller airways depends on elastic ma has features of both and the clinical relevance
recoil, intraluminal pressure is reduced and
airways collapse during forced expiration is limited. The mechanisms by which emphyse-
Chronic bronchitis ma and chronic bronchitis cause airflow obstruc-
Airway inflammation and hypersecretion of mucus tion are shown in Table 5.
1. Peribronchiolar fibrosis results in narrowing of
The release of large amounts of neutrophil
peripheral airways, loss of alveolar attachments,
and loss of elastic recoil elastase and metalloproteinases from inflamma-
2. Intraluminal mucus may contribute to airflow tory cells that overwhelm the antiprotease
obstruction defenses of the lung is the most likely cause of
Reprinted with permission from ACCP Pulmonary Medicine the alveolar destruction of emphysema. In
Board Review. 25th ed. Northbrook, IL: American College of addition, lung repair is inhibited by cigarette
Chest Physicians; 2009. smoke.

Pathophysiology Table 6—Systemic Consequences of COPD
Cardiovascular disease
The physiologic hallmark of COPD is the Osteoporosis
limitation of expiratory flow with relative pres- Metabolic disease (diabetes mellitus)
ervation of inspiratory flow. Reductions in the Gastrointestinal disease
Anorexia
FEV1 and FEV1/FVC percentage are characteris- Weight loss
tic, whereas the maximal inspiratory flow rate is Skeletal muscle dysfunction
normal or near normal. The degree of reversibil- Anemia of chronic disease
Generalized fatigue
ity in COPD is seldom brisk as it is in asthma. Depression
Differences in the degree of reversibility in COPD Altered sleep
and asthma may be explained by the fact that in Cor pulmonale
the latter disease, many inflammatory mediators Reprinted with permission from ACCP Pulmonary Medicine
have been implicated, including potent broncho- Board Review. 25th ed. Northbrook, IL: American College of
constrictors such as histamine, kinins, and Chest Physicians; 2009.
prostaglandins. In contrast, there are few bron-
choconstrictor mediators released in COPD. One predominant abnormalities detected by this test
important inflammatory mediator found in the are low-V̇/Q̇ regions. This type of mismatch
sputum of patients with COPD is leukotriene B4 causes arterial hypoxemia. There is little right-to-
(LTB4). It is a potent chemoattractant for neutro- left shunting in COPD. Lung and thoracic wall
phils. The term partial reversibility has been used hyperinflation are another consequence of the
in COPD, although this term has not been loss of elastic recoil. This favors expiratory flow.
adequately defined. Reversibility in COPD pa- As lung volume increases, elastic recoil pressure
tients can be acute, in response to bronchodilator also increases, and this causes the airways to
drugs, mainly because of release of cholinergic enlarge. This reduces the airway resistance. The
tone. It also may be in response to oral steroids or hyperinflation may also have a deleterious effect.
ICSs, presumably as a result of decreased As the chest wall volume expands, the thoracic
inflammation. Studies have shown that the cage and diaphragm are put at a mechanical
majority of COPD patients will have a small disadvantage. This increases the work of breath-
but significant degree of reversibility of airflow ing and contributes to the sensation of dyspnea.
obstruction (defined as 12% and at least 200 mL
improvement in the FEV1). Some longitudinal Systemic Inflammation and COPD
studies have suggested that increased reversibil-
ity is associated with a higher risk of dying from There is growing evidence that the inflam-
COPD, whereas others have suggested that the matory response of COPD is not limited to the
presence of reversibility coupled with close lungs.25 There are a number of systemic conse-
clinical treatment and follow-up is associated quences of the disease that are considered related
with better survival rates. to systemic inflammation. They are listed in Table
Early in the course of COPD, the expiratory 6. Individuals with stable COPD have signifi-
flow-volume curve shows a scooped-out lower cantly raised blood levels of C-reactive protein
part of the expiratory limb as a result of (CRP), fibrinogen, TNF-a, endothelin-1, IL-6, and
abnormal flow at low lung volume. In later circulating leukocytes compared with normal
stages, there is decreased expiratory flow at all subjects. Recently, levels of VEGF, known to be
lung volumes. Nonuniform ventilation of the involved in angiogenesis and inflammation, also
lungs is seen even in the earlier stages of COPD have been shown to be elevated in COPD.
and can be demonstrated with the N2 washout Elevated levels of inflammatory cytokines in the
test. The multiple inert gas test has been used to blood of COPD patients suggests that there is a
quantify the V̇/Q̇ mismatch in the lungs of persistent level of systemic inflammation, possi-
COPD patients and has also shown these bly caused by a ‘‘spillover’’ of inflammation from
abnormalities in early stages of COPD. The the inflammation that is occurring in the airways,

the lung parenchyma, and the pulmonary vas- clinical outcomes with a variety of conditions.
culature. This latter theory, however, has not There is some evidence that treatment with an
been proven. There is some evidence that ICS and long-acting b-agonist can reduce sys-
individuals with elevated inflammatory markers temic SP-D levels. Attenuating lung inflamma-
such as fibrinogen and CRP are at risk for an tion may result in less leakage of SP-D into the
accelerated decline in FEV1, a greater hospital- systemic circulation. Further research on this
ization rate, and death. mechanism of inflammation is needed.
An analysis of the relative risk for systemic Noninvasive biomarkers to help manage
disease in patients with COPD followed by COPD, predict prognosis, and provide new
general practitioners has shown that COPD therapeutic targets are needed. Proteomic analy-
patients are at increased risk for glaucoma, sis of induced sputum has identified two
angina, fractures, myocardial infarction, osteopo- additional potential biomarkers, apolipoprotein
rosis, and respiratory infection when compared AI and lipocalin-1. The former is known to have
with control subjects without COPD. Anemia a systemic origin, playing a role in cholesterol
may occur in 10% to 15% of patients with severe transport to the liver. Lipocalin-1 is an innate
COPD. A reduced hemoglobin in patients on defense molecule with a putative role in antibac-
long-term oxygen therapy has proven to be a terial defense. These biomarkers are significantly
strong predictor of survival and is associated reduced in patients with COPD when compared
with a greater hospitalization rate and a longer with healthy smokers. Their levels correlate with
cumulative duration of hospitalization. In a FEV1/FVC, indicating their relationship to dis-
nationally representative sample of 47 million ease severity. This finding possibly indicates a
hospitalizations from 1979 to 2001, hospital deficiency in the innate defense system that
discharges with a diagnosis of COPD were more could explain increased susceptibility to infec-
likely to be hospitalized with pneumonia, hyper- tious exacerbations.
tension, heart failure, ischemic heart disease, Natriuretic peptides are the major hormones
pulmonary vascular disease, thoracic malignan- of the natriuretic peptide system that is highly
cies, and ventilatory failure when compared with activated in patients with both left and right
age-adjusted discharges without COPD. Further, heart failure. In a study that evaluated circulating
having a diagnosis of COPD was associated with brain natriuretic peptide (BNP) levels as a
higher age-adjusted in-hospital mortality for parameter for the presence and severity of
pneumonia, hypertension, heart failure, ventila- pulmonary hypertension in patients with chronic
tory failure, and thoracic malignancies when lung disease, patients with significant pulmonary
compared with hospital discharges with these hypertension had elevated BNP levels and a
comorbidities who did not have a diagnosis of lower 6-min walk distance.27 An elevated BNP is
COPD. These results suggest that the burden of a risk factor for death, independently of lung
disease associated with COPD is largely under- functional impairment or hypoxemia, in patients
estimated because having a diagnosis of COPD is with COPD. Serum BNP can be used as a
associated with increased risk for hospitalization prognostic marker as well as a screening tool
and in-hospital mortality from other common for significant pulmonary hypertension in pa-
diagnoses. tients with COPD.
Another marker of inflammation, surfactant
protein D (SP-D), has been studied.26 SP-D is a Systemic Comorbidities
glycoprotein produced in the lungs. In addition
to regulating surfactant homeostasis, SP-D also The relationship between COPD, systemic
has a role in innate immunity and host defense inflammation, and cardiovascular disease has
responses to microorganisms and inhaled parti- gained a great deal of attention, as the presence
cles. Lung injury has been shown to increase of airflow obstruction doubles the risk of
levels of lung and systemic SP-D, and systemic cardiovascular mortality irrespective of current
SP-D may be harmful. It has been associated with smoking status.28,29 When the rates of comorbid-
an increased risk of atherosclerosis and poor ities in COPD patients are compared with those

in the general population, it has been shown that Patients with COPD have an increased risk
COPD patients are at increased risk for glauco- for osteoporosis.34 This may be because of
ma, angina, fractures, myocardial infarction, lifestyle, genetics, treatment with corticosteroids,
osteoporosis, and respiratory infection when endocrine abnormalities, or the impairment of
compared with control subjects without COPD.30 the body composition and peripheral skeletal
Ischemic heart disease, stroke, and sudden muscles. Some specifically identified risk factors
cardiac death rates can each be increased by the for osteoporosis in patients with COPD are
presence of COPD.31,32 Because systemic low- smoking, increased alchohol intake, reduced
grade inflammation is implicated in effecting clot vitamin D levels, genetic factors, treatment with
formation and subsequent cardiovascular events, corticosteroids, reduced skeletal muscle mass
the findings of systemic inflammation in COPD and strength, low BMI and changes in body
has a putative link. The direct effects of inflam- composition, hypogonadism, reduced levels of
matory markers of inflammation, such as the insulinlike growth factors, and chronic systemic
CRP on the pathogenesis of clot formation and inflammation. Vertebral fractures are common in
discovery of elevated CRP levels in the blood of older men with COPD as well as women.35 The
patients with COPD, have provided a possible likelihood of these fractures is greatest in men
mechanism. Using the NHANES III population using continuous systemic steroids.
data, investigators have found that an elevated Many studies have shown that middle-aged
CRP score coupled with moderate to severe and elderly COPD patients may develop hypo-
airflow obstruction was associated with an
gonadism. Prevalence of hypogonadism in men
increased occurrence of ischemic changes on the
with COPD can range from 22% to 69% and has
electrocardiograms of participants. The effects of
been associated with several other systemic
ICSs, newer antiinflammatory agents such as
manifestations, including osteoporosis, depres-
PDE-4 inhibitors, statins, and angiotensin-con-
sion, and muscle weakness. Testosterone replace-
verting enzyme inhibitors are being studied to
ment therapy may result in modest improvements
determine the effects on the cardiovascular and
in fat-free mass and limb muscle strength, but its
overall mortality of COPD patients.
therapeutic efficacy in COPD patients still re-
The prevalence of the metabolic syndrome
mains controversial.
has also been investigated in patients with
Sleep disturbance is common in COPD
COPD. Nearly half of all COPD patients in a
pulmonary rehabilitation program have been patients, occurring in as many as 43% of patients.
shown to have three or more features of the It has been shown to correlate with the presence
metabolic syndrome, including abdominal obe- of cough, sputum production, and wheeze. The
sity, elevated triglyceride levels, elevated high- coexistence of COPD and obstructive sleep apnea
density lipoprotein cholesterol levels, elevated has been labeled the overlap syndrome.36 It is
blood pressure, and high fasting blood glucose important to recognize, as the combination of
levels. Increasing evidence points toward a role these two conditions causes more severe noctur-
of inflammation in the pathogenesis of type 2 nal hypoxemia and a greater risk of morbidity,
diabetes similar to its role in COPD. The such as decreased quality of life (QOL), and
incidence of type 2 diabetes in patients with mortality than either disease alone. Long-term
COPD has been investigated using data from the follow-up studies of more than 9 years showed
Nurses’ Health Study.33 The risk of type 2 that the mortality of those with the overlap
diabetes was significantly higher for patients syndrome was 42%, compared with 24% in those
with COPD than for those without (multivariate with COPD alone. Although the exact mecha-
relative risk 1.8, 95% CI 1.1–2.8). By contrast, the nism is not known, both diseases are associated
risk of type 2 diabetes among asthmatic patients with increased oxidative stress and the presence
was not increased. COPD patients with diabetes of proinflammatory mediators, and systemic
who have been hospitalized for an acute exacer- consequences, such as cardiovascular disease,
bation have a higher mortality than those may be responsible for these disturbing statistics.
without diabetes mellitus. CPAP therapy with nocturnal oxygen as needed

is the treatment of choice and offers a marked are the major hormones of the natriuretic peptide
improvement with morbidity and mortality. system, which is highly activated in patients with
Weight loss is a common occurrence in both left and right heart failure. BNP is predom-
COPD, and when severe it is labeled the inantly secreted by the cardiac ventricles, and in
pulmonary cachexia syndrome.37 It is a prognos- both acute and chronic left heart failure serum
tic indicator of poor outcome.38 The mechanism levels are elevated. BNP levels can be elevated in
is not entirely understood, but loss of skeletal patients with COPD, but the levels are not nearly
muscle mass is the main cause of weight loss. as high as seen with congestive heart failure.
Loss of fat is also contributory. Poor nutritional BNP has a negative predictive value of 97.7% at a
intake, high metabolic rate, sedentary lifestyle, cutoff of 100 pg/mL. BNP levels have been
tissue hypoxia, and a systemic inflammatory shown to be associated with diminished exercise
response from high levels of TNF have all been tolerance and a poor prognosis in patients with
proposed as causative. It is likely that oxidative chronic left heart disease. In addition, BNP levels
stress also enhances muscle proteolysis. Inter- have been found to be elevated in patients with
ventional studies that have studied growth pulmonary arterial hypertension and reflect the
hormone and anabolic steroids have been disap- clinical and hemodynamic status in this patient
pointing. Early identification of patients at risk, population. Elevated BNP levels resulting from
aggressive nutritional supplementation, and a pulmonary hypertension secondary to end-stage
vigorous exercise program have demonstrated lung disease have been reported in the absence of
the greatest benefit. left ventricular failure. They have been shown to
be a risk factor for death, independent of lung
COPD—Clinical Aspects functional impairment or hypoxemia. Serum
BNP can be used as a prognostic marker as well
Symptoms of COPD
as a screening tool for significant pulmonary
hypertension in patients with chronic obstructive
The symptoms that are associated with
lung disease.
COPD are usually not present until the patient
The diagnosis of acute pulmonary embolism
has been smoking a pack of cigarettes a day for at
(PE)40 in patients with COPD is also often
least 20 years. The patient usually presents in the
fifth decade with a chronic cough, often wors- difficult to make. This is especially true during
ened after a viral respiratory infection. The an acute exacerbation of COPD, when symptoms
second major symptom is dyspnea. It usually of the two conditions may be indistinguishable.
does not present until the sixth or seventh In fact, the diagnosis may not be possible on
decade. Dynamic hyperinflation during exercise clinical grounds. The prevalence of PE in
is recognized as an important factor in exercise postmortem series of patients with COPD is
limitation in COPD. The extent of dynamic extremely high, ranging from 28% to 51%. In the
hyperinflation during exercise in COPD corre- PIOPED study, a subgroup of patients with
lates with a reduced resting inspiratory ca- COPD and suspected PE, 19% received a
pacity.39 This limits the tidal volume response diagnosis of PE on pulmonary angiography. Risk
to exercise. This inability to expand the tidal factors and symptoms were similar to those with
volume in response to increasing metabolic and without pulmonary embolus. Recent studies
demand is an important contributor to exercise have reported a 25% prevalence of PE in a group
intolerance in COPD. of patients admitted to the hospital for a severe
Dyspnea is a common symptom in the older exacerbation of COPD, but the study results may
population, and often it is difficult to distinguish not be generalized to most COPD, as some
whether heart disease or pulmonary disease is patients in this study were excluded if they had
the cause when both are present. High levels of evidence of a potential infection. More recent
BNP in the blood have been very helpful in evidence, which excluded the diagnosis of PE on
differentiating cardiac and pulmonary causes of the basis of a normal (,500 lg/mL) D-dimer test
dyspnea in the acute setting. Natriuretic peptides and negative diagnostic imaging studies, showed

a much lower prevalence of PE. Only 6.2% of Table 7—GOLD Guidelines: Classification of Severity of
patients who had a clinical suspicion of PE and COPD Based on Postbronchodilator FEV1
only 1.3% who had no clinical suspicion, as Stage Characteristics

judged by emergency department physicians,
were discovered to have PE. This study showed I: Mild COPD FEV1/FVC ,70%
FEV1 80% predicted
that the prevalence of suspected PE in patients
With or without chronic
presenting with a COPD exacerbation is very low symptoms (cough, sputum
and routine investigation for PE in this group is production)
not warranted. There are some important lessons II: Moderate COPD FEV1/FVC ,70%
50% FEV1 , 80% predicted
from these recent studies. When there is no
Dyspnea worsens; þ/ cough
suspicion of infection, either viral or bacterial, sputum
suspicion for PE in patients with a COPD III: Severe COPD FEV1/FVC ,70%
30% FEV1 ,50% predicted
exacerbation should be higher, especially in those
Dyspnea worsens; þ/ cough
patients who are sick enough to require hospi-
sputum
talization, as they may have more severe and IV: Very severe COPD FEV1/FVC ,70%
debilitating disease that predisposes them to PE. FEV1 ,30% predicted or
Other clues that should increase clinical suspi- respiratory/heart failure
Weight loss and anorexia
cion of PE in COPD patients are a previous Hemoptysis
history of malignancy and a decrease in the PaCO2 Cough syncope
compared with baseline values. PE is a serious Coughing spells
Depression and or anxiety
comorbid condition in patients with COPD, and Cor pulmonale
a high clinical suspicion should be maintained in
the appropriate clinical setting Reprinted with permission from ACCP Pulmonary Medicine
Over the last 2 decades, as a result of an Board Review. 25th ed. Northbrook, IL: American College of
intense antismoking campaign, the rate of smok-
ing in the United States has been reduced from
about one-third of the adult population to its retrosternal airspace, and a teardrop-shaped
current level of about 20%. In many susceptible heart. Pruning of the pulmonary arterial vessels
smokers who stopped smoking in midlife, the and bullae are seen in emphysema. The high-
onset of COPD symptoms is delayed until late in resolution CT scan has a much better sensitivity
life. It is not unusual to see a patient with COPD and specificity, but is not recommended for
present for the first time with symptoms at age 75 routine use. It may be helpful when surgery for
and beyond. The main symptoms and various large bullae is contemplated or during the
stages of disease severity are presented in Table 7. evaluation for eligibility for lung volume reduc-
tion surgery (LVRS).
The Physical Exam and Laboratory Tests
Pulmonary function studies are important for
the diagnosis and staging of COPD. Because the
The signs of COPD are well known: slow and
best correlate with morbidity and mortality is the
prolonged expiration, wheezing, chest wall hy-
perinflation, limited diaphragmatic motion on FEV1, proposals for staging have used this test.
auscultation, distant breath sounds, and heart The 1995 ATS standards suggested a severity
sounds and often coarse early inspiratory crack- scoring on the basis of the severity of airflow
les. The accessory muscles of respiration may be obstruction: stage I is an FEV1 of 50% or greater;
in use and the patient may be using pursed-lip stage II is an FEV1 of 35% to 49% predicted, and
breathing. Signs of cor pulmonale include pedal stage III is an FEV1 of less than 35% predicted.
edema; a tender, congested liver; and neck vein This classification was helpful as it offered
distention. Cyanosis may be present as well as patients with stage I disease have little impair-
asterixis, which is associated with severe hyper- ment in their QOL. Patients with stage II COPD
capnia. The roentgenographic signs of COPD have a significant impairment in QOL, and this
include a low, flat diaphragm, an increased results in a large per capita health-care cost.

Table 8—Distinguishing Features of COPD and Asthma conclusion not to recommend spirometry screen-
ing was reached through a systematic review of
COPD Asthma
the evidence by a task force of the Agency for
Onset in midlife Onset early in life (often Healthcare Research and Quality. The Agency for
childhood) Healthcare Research and Quality’s conclusion
Symptoms slowly Symptoms vary from day was that the evidence does not justify recom-
progressive to day
Long history of Allergic rhinitis and/or eczema mending spirometry as a routine tool in the
tobacco smoking history practice of primary care.
Dyspnea during Sudden dyspnea after acute
exercise exposure
Largely irreversible Largely reversible airflow
Differentiation From Asthma
airflow limitation limitation
Table 8 lists the most common distinguishing
Reprinted with permission from ACCP Pulmonary Medicine
features between asthma and COPD. Epidemio-
Chest Physicians; 2009. logic studies have shown that as many as 30% of
patients with fixed airflow obstruction have a
Patients with stage III disease are profoundly history of asthma. Differentiating asthma from
impaired, are often hospitalized with severe COPD may be difficult and at times not possible,
exacerbations of disease, and therefore are high especially in older patients, as they may develop
utilizers of health-care resources. A new severity fixed airway obstruction.41,42 The most useful
scoring system was introduced by the GOLD discriminator, the response to an inhaled short-
guidelines2 (Table 8). It began staging with an acting b-agonist bronchodilator, may not differ-
‘‘at-risk’’ group, stage 0, to emphasize the point entiate asthma from COPD. When the postbron-
that patients with risk factors (cigarette smoking, chodilator FEV1 returns to normal, the diagnosis
occupations) who have symptoms of cough and is asthma (no fixed airflow obstruction). But
sputum need to be counseled about COPD even many asthmatics, especially those with long-
though their screening spirometry is normal. The standing disease,41 may not show any response,
GOLD guidelines were updated in 2006. The and some patients with COPD will show a brisk
spirometry classification of severity of COPD bronchodilator response. On the other hand,
now includes only four stages: stage I, mild; asthmatics with fixed airflow obstruction show
stage II, moderate; stage III, severe; and stage IV, other features that are distinct from COPD
very severe. The category stage 0, at risk, is no caused by cigarette smoking. When compared
longer included as a stage of COPD. The GOLD with patients with COPD of comparable age,
committee felt that there was incomplete evi- they have significantly more eosinophils in the
dence that the individuals who meet the criteria peripheral blood, sputum, and BAL, and, on
for this stage (chronic cough and sputum bronchial biopsy, have higher ratios of CD4þ/
production, normal spirometry) necessarily pro- CD8þ T cells infiltrating the airway and have
gress on to stage I. Other GOLD stages are greater thickness of the airway basement mem-
modifications of the previous (1995) ATS criteria, brane than patients with COPD.43 Other distin-
now adopted in the new ATS/ERS guidelines.5 guishing features include higher levels of
Although the measurement of lung function exhaled nitric oxide, lower emphysema scores
remains the best way to diagnose COPD, the on high-resolution CT scans, and higher diffusing
routine use of spirometry for case finding in capacities. Because many of these tests are
adults with exposure to risk factors (such as impractical, not available for widespread use, or
cigarette smoking) or for those with persistent not discriminatory enough for clinical use, the
respiratory symptoms remains controversial. most recent ATS/ERS statement on COPD stated:
This controversy is, in part, because no random- ‘‘Some patients with asthma cannot be distin-
ized clinical trial has demonstrated that early guished from COPD with the current diagnostic
detection of COPD changes the course of disease tests. The management of these patients should
or increases the rate of smoking cessation. A be similar to that of asthma.’’5

COPD—Outpatient Management
Once the diagnosis of COPD is established,

pulmonary function testing can be helpful by
staging the disease. Pharmacologic44 and non-
pharmacologic45 intervention is offered accord-
ing to disease severity and the patient’s tolerance
for specific drugs (Fig 4). The goals of therapy are
to induce bronchodilatation, decrease airway
inflammation, and improve mucociliary trans-
port. Because COPD is basically an irreversible
condition, disease management of daily symp-
toms and other impacts on QOL are most
essential. The patient who still smokes should
be encouraged to quit. Preventive therapy with a
yearly influenza vaccine is recommended.46
Vaccination with the flu shot has been shown to Figure 4. Treatment plan from the GOLD guidelines.
result in 52% fewer hospitalizations for pneumo- Reprinted with permission from ACCP Pulmonary Medicine
nia and influenza in patients with COPD. Board Review. 25th ed. Northbrook, IL: American College of
Vaccinated patients also have fewer outpatient Chest Physicians; 2009.
visits for respiratory symptoms. Evidence of the
effectiveness for the pneumococcal vaccine is less clinics, and (3) pharmacologic therapy with
impressive, but nevertheless it is still recom- nicotine replacement, which is needed in
mended.47 highly dependent smokers. Highly dependent
smokers can be identified as those who smoke
Smoking Cessation a pack a day or more, require their first
cigarette within 30 min of arising in the
Cigarette smoking compromises airway func-
morning, and find it difficult refraining from
tion by damaging airway epithelial cells,
smoking in places where it is forbidden.
increasing mucus viscosity, and slowing mu-
Therapy with the antidepressant bupropion
cociliary clearance. There is a greater bacterial
hydrochloride has also been shown to be
adherence to oropharyngeal epithelial cells in
effective.
smokers compared with nonsmokers. Smokers
The Lung Health Study showed that despite
are prone to attacks of acute bronchitis. As a
intensive antismoking efforts, middle-aged
result, they show increased rates of acute
smokers with COPD are not likely to quit.
exacerbations, ED visits, work absences, and
Only 22% were sustained quitters after a 5-year
frequency of medication use.

follow-up.17
Smokers also show greater decline in lung
function, worsening of respiratory symptoms,
and lower QOL scores than a comparable Pharmacologic Therapy
group of nonsmoking patients.
The presence of respiratory illness such as Short-Acting b2-Agonists:
COPD is not a motivator for smoking cessa- Achieve variable degrees of bronchodilatation:
tion. rapid onset of action with duration of 4 to 6 h.
Physician-delivered smoking cessation inter- Improve symptoms and, in most studies,
ventions can significantly increase smoking exercise capacity.
abstinence rates. Metered-dose inhaler use of b2-selective agents
Smoking cessation interventions for COPD is safe three or four times a day; higher doses
should include (1) physician intervention (set may cause hypokalemia, cardiac arrhythmias,
a quit date), (2) group smoking cessation and reduced arterial oxygen tension.

Long-Acting b2-Agonists: diesterase inhibitor), drugs like roflumilast are
Maximal effect comparable to short-acting b2- selective PDE4 inhibitors. PDE4 is a member of
agonists with longer duration of action (12 h) the phosphodiesterase family and is expressed
for agents such as salmeterol and formoterol. in airway smooth muscle and in inflammatory
Improved symptoms and QOL measures; no cells such as neutrophils, monocytes, and
tachyphylaxis found. eosinophils.
Good safety profile with recommended doses; Inhibition of PDE4 prevents the breakdown of
occasional tremor that improves after several intracellular cyclic adenosine monophosphate,
days of use.48 which has important antiinflammatory effects.
b-agonists have important effects in addition to Roflumilast is currently approved by the US
their bronchodilating properties. These include Food and Drug Administration for the treat-
decreasing bacterial adherence to the epitheli- ment of severe COPD associated with chronic
um, capillary leak, and inflammatory mediator bronchitis and a history of exacerbations.52
release, and improving mucociliary clearance.49 Side effects are mainly gastrointestinal, al-
though patients need to be monitored closely
Anticholinergic Therapy:
for weight loss and new psychiatric symptoms.
Short-acting agents (ipratropium) afford bron-
chodilatation and relief of symptoms for 4 to 6 Systemic Corticosteroids:
h. The long-acting anticholinergic tiotropium Twenty percent to 30% of patients with chronic
(TIO) offers improved bronchodilatation for 24 COPD symptoms improve if given oral steroid
h and therefore can be given once a day. therapy. Responders have more eosinophils in
No tachyphylaxis with these agents. induced sputum and bronchial biopsies and
Effects on long-term prognosis of COPD are likely have concomitant asthma.
being studied; TIO has been shown to reduce Long-term treatment with oral corticosteroids
exacerbation rates and hospitalizations due to is not recommended for patients with COPD.
exacerbations.50 Treatment of hospitalized patients with high
Side effects mild (occasional dry mouth). doses results in fewer treatment failures and
shorter stays; 2 weeks of therapy is sufficient
b2-Agonists Plus Anticholinergic Drugs:
after hospital discharge.53
Combining both agents provides a small Complications include cataracts, osteoporosis,
additional benefit to either drug alone.
secondary infection, diabetes, and skin dam-
No additional side effects from combination
age.
therapy.
ICSs:
Theophylline: Patients with COPD are less corticosteroid-
There are small changes in FEV1 with chronic
responsive than those with asthma. The ex-
use. Other positive effects are improvements in
pression of the inflammatory genes responsible
trapped gas volumes, vital capacity, distance
for COPD is regulated by acetylation of core
walked, breathlessness in everyday activities,
histones. Histone deacetylase 2 (HDAC2)
and fatigue.51
suppresses inflammatory gene expression.
Owing to a narrow therapeutic index, adverse
HDAC2 activity and expression are reduced
effects, limited efficacy, and multiple drug
in COPD, and this causes amplification of the
interactions, its use has declined.
inflammatory response. Corticosteroid resis-
Frequent adverse effects occur with therapeu-
tance in COPD is thought to occur because
tic blood levels of 5 to 15 lg/mL (nausea,
corticosteroids use HDAC2 to switch off
diarrhea, headache, and irritability). Seizures
activated inflammatory genes.54
and cardiac arrhythmias are considerably (10– ICSs have not been shown conclusively to
15 times) more common in elderly with toxic
benefit the long-term decline in FEV1.
blood levels (.20 lg/mL). Use may provide small but significant im-
Phosphodiesterase 4 (PDE4) Inhibitors: provements in lung function and 6-min walk
Unlike theophylline (a nonselective phospho- test. Studies have also demonstrated fewer

exacerbations of COPD and improved QOL higher pneumonia rate. However, exacerba-
indices. A systematic review of nine random- tions requiring antibiotics occurred more fre-
ized trials concludes that ICSs do reduce the quently in patients treated with SFC, but those
exacerbation rate in COPD.55 It reminds us that requiring systemic corticosteroids were less
side-effect profiles are also increased. Oropha- frequent than in the TIO-treated patients.
ryngeal candidiasis and skin bruising were
Mucolytic Drugs:
more likely to occur. No effects on overall
Have a variable effect in patients with COPD.
mortality were seen in these trials.
RCTs suggest that they are ineffective at
There is an association between pneumonia
shortening the course or improving outcomes
and the use of ICSs.56 Randomized controlled
of patients with acute exacerbations.
trials (RCTs) of any ICS with at least 24 weeks
of follow-up have shown a significantly in- Antibiotics:
creased risk of serious pneumonia, without a The results of multiple trials favor the use of
significantly increased risk of death. antibiotics for acute exacerbations of COPD
ICSs alone are not approved for COPD in the that include worsening dyspnea, increased
United States. Only ICS products combined sputum volume, and sputum purulence.
with a long-acting b-agonist are approved. There is some evidence supporting macrolide
Benefits are enhanced when coupled with prophylactic use.
long-acting b-agonist treatment.57,58 In the well The risk of a subsequent exacerbation after
known TORCH trial,57 combination therapy vs treatment of an exacerbation with oral cortico-
placebo did not reach statistical significance in steroids without or with antibiotics was eval-
reduction of death from all causes (the primary uated in a historical population-based cohort
outcome) among patients with COPD. There study comprising patients using maintenance
were significant benefits in other outcomes medication for obstructive lung disease. Treat-
among these patients, such as a decrease in the ment with antibiotics in addition to oral
annual rate of exacerbations from 1.13 to 0.85 corticosteroids is associated with a longer time
and improved health status and spirometric to the next exacerbation and a decreased risk of
values. There was no difference in the inci- developing a new exacerbation.60
dence of ocular or bone side effects.
Maintenance of airway patency, reduction in Future Therapies:
Several new targets have been identified to
hyperinflation, improvements in mucociliary
clearance, and/or decreases in airway inflam- treat COPD.61 Although mediator antagonists
mation may contribute singly or together to tested in COPD patients have so far been
produce the observed functional changes of disappointing, CXC receptor 2 antagonists that
combined long-acting b-agonist/ICS. block pulmonary neutrophil and monocyte
Guidelines recommend adding ICS to a long- recruitment may be more promising.
acting bronchodilator when the FEV1 is ,50% Broad-spectrum antiinflammatory drugs, in-
predicted and there is a history of frequent cluding inhibitors of the enzymes PDE4, p38
exacerbations in the last several years. mitogen-activated protein kinase, nuclear fac-
The Investigating New Standards for Prophy- tor-jB, and phosphoinositide-3-kinase-c, may
laxis in Reducing Exacerbations study made a be more effective.
comparison over a 2-year treatment period in a Another approach is the reversal of corticoste-
multicenter study of patients receiving TIO vs roid resistance through increasing histone
those receiving salmeterol/fluticasone (SFC).59 deacetylase-2 activity. This might be achieved
There was no difference between the two study by theophyllinelike drugs, more effective anti-
groups in exacerbation rates. More patients oxidants, and nonantibiotic macrolide agents.
failed to complete the study with TIO. SFC- Statins have diverse antiinflammatory effects
treated patients had a small, statistically in addition to their lipid-lowering ability.62 A
significant benefit with QOL scores, an unex- 1-year retrospective cohort study of patients
pectedly lower death rate (3% vs 6%), and a with COPD showed that subjects receiving

statins had fewer episodes of exacerbation and Nonpharmacologic Therapy
required intubation fewer times than subjects
not receiving statins.63 A multicenter prospec- Pulmonary Rehabilitation:
tive study is underway in the United States to Pulmonary rehabilitation is a multidisciplinary
confirm this retrospective study. Similarly, program that attempts to return the COPD
patients taking angiotensin-converting enzyme patient to the highest functional capacity
inhibitors have shown improved outcomes. possible.65
Pulmonary rehabilitation addresses decondi-
Oxygen Therapy: tioning, social isolation, anxiety and depres-
Several controlled studies have been complet- sion, muscle wasting, and weight loss.
ed: oxygen vs no oxygen (Medical Research Evidence supports the use of lower-extremity
Council [MRC]) and continuous vs nocturnal exercise training, as it improves exercise
oxygen (Nocturnal Oxygen Therapy Trial). tolerance.
In patients with hypoxemia and congestive Upper-extremity strength and endurance train-
heart failure, death rates are significantly lower ing is recommended.
and QOL indices are improved when oxygen is Pulmonary rehabilitation improves dyspnea,
in chronic use. improves QOL scores, and reduces the number
Patients who used oxygen for at least 15 h/d of hospitalizations and days in the hospital; the
had a significant fall in their pulmonary artery effects on survival are not definite.66
pressures and an increase in cardiac output. Pulmonary rehabilitation has been shown to
Oxygen should be prescribed when (1) the help patients requiring long-term mechanical
arterial PaO2 is ,55 mm Hg or SaO2 ,88%; (2) ventilation by improving overall strength,
PaO2 is 56 to 59 mm Hg with ECG evidence of p weaning outcomes, and functional status.
pulmonale, pedal edema, and/or secondary There is not enough evidence to support or
erythrocytosis. refute the use of bronchial hygiene physical
Long-term oxygen therapy does not improve therapy in people with COPD.67 Chest physio-
survival in patients with moderate hypoxemia therapy has no role in the acute exacerbation of
(PaO2 56–65 mm Hg) or in patients with only COPD.
nocturnal hypoxemia. Nutrition and COPD:
Long-term oxygen has been shown to be Malnutrition occurs in one-quarter to one-third
beneficial in patients with COPD and resting of patients with moderate to severe COPD and
hypoxemia, and it is now the standard of care. is an independent risk factor for mortality.
Short-term ambulatory oxygen for COPD Both fat mass and fat-free mass are depleted,
patients who meet the hypoxemia criteria only the latter because of depressed protein synthe-
during exercise has offered some improvement sis. It is believed that weight loss, and
in exercise performance, but it is not clear particularly skeletal muscle mass loss, is
whether long-term oxygen in such patients associated with a systemic inflammatory re-
would be clinically beneficial and worth the sponse in malnourished patients with COPD,
expense. Previous RCTs to answer this ques- as the proinflammatory cytokines IL-6 and
tion have given mixed results. In one study,64 TNF-a have been shown to be elevated.
the use of oxygen improved the 6-min walk Skeletal muscle loss in COPD is probably
test (427 vs 412 steps, P ¼ .04) but a QOL multifactorial in origin. There is a link to
questionnaire did not show any difference systemic inflammation even without weight
between the oxygen and placebo. Only two of loss.
27 patients showed consistent improvement of Studies have shown that leptin, an adipocyte-
dyspnea measured on the Chronic Respiratory derived hormone involved in the control of
Questionnaire. These are compelling reasons, body weight, is decreased in patients with
including cost, why this practice should be COPD. Serum leptin levels have been correlat-
discouraged for most patients. ed with TNF-a levels, thus creating a link

between nutritional status and systemic in- Surgery for COPD
flammation in COPD.
LVRS has emerged as a treatment for far
Resting energy expenditure is elevated and
advanced COPD due to emphysema.70
contributes to the negative energy balance.
LVRS involves resection of functionless areas
Nutritional supplements alone do not reverse
of emphysematous lung in order to improve
the loss; results with anabolic steroids, growth
lung elastic recoil and lung and chest wall
hormone, and the progestational agent meges-
hyperinflation.
terol acetate show some effect on appetite and
Overall mortality with the procedure ranges
body weight; however, improved exercise
between 0% and 6% within 30 days of surgery
tolerance and respiratory muscle function do
and between 0% and 8% at 6 months, although
not always follow.
in patients with very severe degrees of ob-
A combination of nutritional support and
struction the rates are much higher.
exercise as an anabolic stimulus appears to be
The range of FEV1 improvement presurgery and
the best approach to obtaining marked func-
postsurgery is approximately 250 to 350 mL.
tional improvement.
Borg scale dyspnea scores on the 6-min walk test
Depression and COPD: show improvement, as do the distances walked.
Psychological comorbidities such as anxiety Sixteen percent to 42% of patients no longer
and depression are common in COPD. require oxygen following surgery.
There is evidence that pharmacological treat- The National Emphysema Treatment Trial
ments, cognitive behavioral therapy, pulmo- defined a subgroup of patients with a very high
nary rehabilitation, relaxation therapy, and risk for mortality.71 Interim analysis showed
palliative care can be effective in relieving that if the FEV1 was ,20% predicted and the
these symptoms.68 computed tomography scan of the lungs
Noninvasive Positive-Pressure Ventilation showed homogeneous or the carbon monoxide
(NPPV): diffusing capacity was ,20%, there was a high
Theoretical advantage to resting chronically risk of death after surgery and little chance of
fatigued muscles at night. functional improvement. Among those not in
COPD patients have a high prevalence of sleep the high-risk group, there was 2.2% mortality
apnea and hypoxemia and hypercarbia at with surgery at 30 days, compared with 0.2%
night. They have less REM sleep and shorter mortality in the medically treated group. After 1
sleep times than normal subjects. It has been month, 28% of the surgery group were hospi-
theorized that noninvasive ventilation would talized, living in a nursing home or rehabilita-
help. tion facility, or unavailable for interview.
Trials have shown conflicting conclusions: Changes in exercise capacity, pulmonary func-
patients without CO2 retention show little tion, QOL measures, and dyspnea at 6 to 24
gain; patients with severe CO2 retention, months all favored surgery. Further subgroup
especially those that have severe nocturnal O2 analysis showed that those with upper lobe
desaturation, appear to respond most favor- emphysema on computed tomography scans
ably. and with low exercise capacity at the beginning
A systematic review of the effectiveness of of the trial had the most favorable outcomes.
bilevel NPPV in the management of chronic Given the potential risks of median sternotomy
respiratory failure due to severe stable COPD and thoracoscopy, the usual surgical approach-
has been reported.69 RCTs did not find im- es to LVRS, less invasive procedures are being
proved gas exchange; lung hyperinflation and studied. They include bronchoscopic LVRS that
diaphragmatic work of breathing were re- is done with the placement of endobronchial
duced in a nonrandomized subset of patients. one-way valves. Preliminary studies have
There is little evidence to support the use of shown improvement in lung function, exercise
NPPV in the management of stable hypercarbic capacity, and dynamic hyperinflation with this
COPD patients. procedure.

Resection of large bullae is occasionally neces- model.74 Management by a primary care provid-
sary for dyspnea, chest pain, or recurrent er who is backed by an electronic medical record
pneumothorax.72 Other complications that can that is integrated into a networked information
occur with large bullae are bleeding and system is needed. The electronic medical record
infection. The best results occur when the would offer prompts to assure adherence to
bullae occupy more than one-third of the evidence-based guidelines. The clinician would
hemithorax. Factors that do not favor surgical have access to multidisciplinary skilled health
resection are the presence of multiple small professionals who could offer assistance with
bullae and diffuse emphysema in the remain- case management, establishing patient-centered
der of the lungs. No prospective clinical trials goals, and referral to pulmonary rehabilitation
have been performed. Case series have shown services. Nurse case managers, respiratory ther-
improvement in dyspnea and even reversal of apists, and physical therapists can be instrumen-
respiratory failure after bullectomy. However, tal in providing patient and family education
in those with underlying emphysema, there is regarding self-management, including an action
a progressive decline in the FEV1 over time and plan for sudden changes in symptoms. Nurse-led
return of crippling dyspnea in many. Bullec- home care programs for COPD patients using
tomy can be performed by thoracoscopic telephone contacts and home and hospital
surgery in selected patients. visitations by a member of the health-care team
Lung transplantation can be lifesaving for can offer improved outcomes. Clinical trials of
patients with very advanced disease compli- disease management programs in patients with
cated by respiratory failure and secondary severe COPD have been associated with 42%
pulmonary hypertension.73 Patients are con- reduction in COPD-related hospitalization and
sidered for single or double lung transplanta- emergency department visits. The disease man-
tion when the FEV1 is less than 25% and/or the agement programs are also associated with a
PaCO2 is greater than 55 mm Hg. The procedure reduction in all-cause hospitalizations and emer-
is costly, is limited by lack of organs, and gency department visits and improved respira-
requires prolonged immunosuppression. Re- tory health status as measured by the St. George’s
cent studies have suggested that, unlike pa- Respiratory Questionnaire. However, these im-
tients with cystic fibrosis and idiopathic provements may be associated with an increase
pulmonary fibrosis, patients with COPD do in respiratory medication use and associated
not fare well after transplantation, with limited costs.
exercise capacity due to skeletal muscle dys-
function. In January 2008, the International
Acute Exacerbation of COPD
Society for Heart and Lung Transplantation
Over the years, many definitions of the acute
reported survival figures for COPD of 85% at 1
exacerbation or ‘‘flare’’ of COPD have existed,
year and 68% at 3 years. The 2011 report
and many authors have employed substantially
revealed that the half-life survival among
different criteria. The most recent and practical
patients surviving at least 1 year with COPD
definition comes from the GOLD Guidelines. It
was 6.8 years, and for AAT-deficiency emphy-
states, ‘‘An exacerbation of COPD is an acute
sema, 8.7 years. This compares with figures for
event characterized by a worsening of the
cystic fibrosis of 10.4 years, for idiopathic
patient’s respiratory symptoms that is beyond
pulmonary artery hypertension of 9.5 years,
normal day-to-day variations and leads to a
for sarcoidosis of 8.0 years, and for idiopathic
change in medication.’’2
pulmonary fibrosis of 6.9 years.
A widely quoted description of a COPD
exacerbation includes the Winnipeg criteria,
Disease Management Programs which have also included a staging proposal.
Patients with COPD exacerbation have three
In an ideal system of health care, a patient changes in their clinical condition: (1) worsening
would have all elements of a chronic care of dyspnea, (2) an increase in sputum volume,

and (3) sputum purulence. Patients with type I although if a patient is not responding to initial
exacerbations have all of the above symptoms. antibiotic coverage they may be useful.
Patients with type II exacerbations have two of Techniques that potentially preclude contam-
the three symptoms. Type III exacerbations are ination include transtracheal aspirates, broncho-
characterized by at least one of these symptoms alveolar lavage, and protected brush sampling
and also one of the following clinical criteria: during bronchoscopy. Studies using these tech-
upper respiratory infection in the past 5 days, niques have shown that patients requiring
fever without another apparent cause, increased hospitalization compared with those treated as
wheezing, increased cough, and increased respi- outpatients for an exacerbation of COPD and
ratory rate or heart rate by 20% above baseline. those outpatients with the most severe degree of
The severity assessment of an exacerbation is airflow obstruction are more likely to harbor
based on the patient’s medical history and gram-negative enteric organisms. The presence
clinical outcomes. The ATS/ERS classification of of bacterial colonization in the stable state is
severity of a COPD exacerbation ranks the associated with an increased exacerbation fre-
clinical relevance of the episode and its out- quency, and patients colonized with H influenzae
comes: level I, treated at home; level II, requires have an increased total symptom count and more
hospitalization; and level III, leads to respiratory sputum purulence at the time of exacerbation.77
failure.5 Using molecular typing, it has also been shown
Before the onset of an exacerbation of COPD, that the acquisition of new strains of bacteria
there is usually a prodromal period of up to 7 such as H influenzae, M catarrhalis, and S pneumo-
days when symptoms of increased dyspnea, niae is associated with an exacerbation of COPD
cough, sore throat, and the common cold occur.75 in as many as one-third of cases.
This is not accompanied with a drop in lung The role of viral infection has been investi-
function. On the day of the exacerbation, there is gated using sophisticated methods such as PCR
a small but significant drop in lung function viral detection as well as more standard methods
including peak flow rates, FEV1, and FVC. Peak such as serologic testing and culture.78 Viruses
flow rate recovery to baseline values is complete may be detected in nearly 40% of COPD
in 75% of patients by 1 month. Approximately exacerbations using these techniques. These
7% of patients with a COPD exacerbation do not include rhinovirus, respiratory syncytial virus,
return their peak flow rates to baseline by 3 coronavirus, influenza, and parainfluenza. Evi-
months. This suggests that a substantial propor- dence for Mycoplasma infection has been found in
tion of exacerbations of COPD are associated up to one-third of the acute exacerbations of
with a permanent loss of lung function. This is chronic bronchitis in some studies; however, in
consistent with the finding that patients with most studies Mycoplasma and Chlamydia pneu-
more frequent exacerbations of COPD have a monia are seen in less than 10% of cases. A
more rapid decline of lung function over time.76 COPD exacerbation associated with a virus is
The most frequent cause of an acute exacer- likely to produce more severe symptoms, and the
bation of COPD is respiratory infection. Sputum exacerbation is likely to last longer (13 days).
cultures in patients with mild to moderately There is also more laboratory evidence of an
severe COPD often show nonpathogenic bacteria acute-phase response (eg, elevated levels of IL-6
(gram-negative and gram-positive, such as Strep- and fibrinogen) with an associated viral infec-
tococcus viridans, Neisseria spp, or Corynebacterium tion. Clearly, environmental factors are also
spp). Pathogenic bacteria include Haemophilus important. Hospital admissions for COPD ap-
influenzae (22%), Pseudomonas aeruginosa (15%), pear to be high when air pollution levels in the
Streptococcus pneumoniae (10%), and Moraxella ambient environment are high. Small increases in
catarrhalis (9%). Sputum samples may have SO2 and airborne particles have been shown to
limited validity considering the possible contam- cause increases in emergency room visits for
ination from oropharyngeal secretions. They are COPD during winter and summer seasons by 6%
generally not recommended for routine use, and 9%, respectively.

Table 9—Factors Associated With Increased Risk for COPD the procalcitonin level to predict the need for
Exacerbations antibiotics has also been studied. A level ,0.1
Increased age
lg/L does not suggest the need for antibiotics,
Severity of airway obstruction (FEV1 impairment) whereas a level .0.25 lg/L does. Between these
Longer duration of COPD levels, one needs to use clinical judgment.
Chronic bronchial mucous hypersecretion Although an additional study did not support
Productive cough and wheeze
Elevated cough and sputum this recommendation, methodologic issues were
Antibiotic or systemic corticosteroid use in the past year raised, and the use of procalcitonin may help
Prior use of medications for COPD reduce the use of antibiotics without adversely
Bacterial colonization
impacting outcomes.
Comorbid conditions (eg, cardiovascular disease)
Poor health-related QOL Risk factors associated with COPD exacerba-
Hypercapnea and hypoxia tions are seen in Table 9. The presence of chronic
Low serum albumin bronchitis (daily cough and sputum production)
Single-nucleotide polymorphism in CCL1 gene
is a marker of poor outcomes in COPD and
Reprinted with permission from ACCP Pulmonary Medicine especially is a risk for future exacerbation, and a
Board Review. 25th ed. Northbrook, IL: American College of history of exacerbation within the prior year is
the best predictor of a subsequent exacerbation.80
Low FEV1, underprescription of oxygen therapy,
Whatever the cause of an acute exacerbation
and current smoking were all factors that would
of COPD, it is clear that bronchial inflammation
predict frequent exacerbation rates.81
is enhanced during this event.79 Sputum neutro-
phils and eosinophils are seen in increased Diagnostic and Therapeutic Approaches
numbers in the sputum. Increased levels of
myeloperoxidase have also been found in the Often, patients present to a local ED or
sputum, indicating neutrophilic activity, and hospital with an acute exacerbation of COPD. It
high levels of IL-8 and LTB4, well known is useful to do a chest radiograph. The chest
neutrophil chemoattractants, are also seen. Air- radiograph may be positive in approximately
way bacterial load correlates with sputum MPO 15% of cases, and in 25% of such patients there is
level, IL-8 level, LTB4 level, and sputum leuko- a change of management prompted by the chest
cyte elastase activity. This suggests that bacterial radiograph result. Spirometry, on the other hand,
load contributes to airway inflammation in has not been helpful in decision making for
patients with stable COPD. patients with an acute exacerbation of COPD.
During recovery, levels of sputum chemo- There is poor correlation between arterial blood
attractants and inflammatory markers rapidly gases and the FEV1 at the time of presentation.
fall with improvement. However, patients who The FEV1 has not been helpful in predicting need
do not clinically recover to baseline by day 35 for hospital admission. Although severe abnor-
show persistently higher levels of serum CRP malities of arterial blood gases and history of
postexacerbation. And a high level of CRP at 14 prior relapses are helpful, there are no predictive
days postexacerbation has been shown to be models of adequate sensitivity and specificity to
associated with a shorter time to the next rely on. The best indicators for the need for
exacerbation. It is also related to a recurrence of mechanical ventilation include the blood gas
an exacerbation within 50 days. Failure to resolve values on admission and the degree of change
the symptoms of an exacerbation appears to be in pH after initial oxygen therapy. Significant
associated with persistently heightened systemic predictors of hospital mortality include older
inflammation, evidenced by the CRP level. Other age, lower body mass index, poor functional
markers reported to be higher in blood during an status prior to admission, lower PO2/FIO2 ratio,
exacerbation compared with the baseline include history of congestive heart failure, low serum
IL-8, TNF-a, leptin, endothelin-1, eosinophil albumin, and presence of cor pulmonale.
cationic protein, myeloperoxidase, fibrinogen, Most therapeutic interventions for the treat-
IL-6, AAT, leukotriene E4, and LTB4. The use of ment of the acute exacerbation of COPD have been

studied through RCTs.82 In general, mucolytic In a study of RCTs83 investigating the clinical
agents are ineffective in shortening the course and benefit of antibiotics for COPD exacerbation,
improving the outcome of patients. Chest physio- antibiotics were not seen to reduce treatment
therapy and mechanical percussion of the chest failures in outpatients with mild to moderate
are also ineffective and may be potentially exacerbations. In patients with severe exacerba-
harmful. b2-agonists and anticholinergic agents tions, antibiotics had a substantial benefit on
appear to be equivalent in their usefulness and are treatment failure rates (pooled odds ratio of 0.25,
superior to all parenterally administered broncho- 95% CI 0.16–0.39, I2 ¼ 0%; number needed to treat
dilators, including methylxanthines. The addition of 4, 95% CI 3–5) and on mortality (pooled odds
of a methylxanthine to an inhaled bronchodilator ratio of 0.20, 95% CI 0.06–0.62; number needed to
has also been carefully examined. One study treat of 14, 95% CI 12–30). Hence, antibiotics
showed a statistical trend toward lower hospital- effectively reduce treatment failure and mortality
ization rates for patients given IVaminophylline in rates in COPD patients with severe exacerbations.
the ED, whereas two other studies showed no For patients with mild to moderate exacerbations,
significant advantage. The effect of adding two antibiotics may not be generally indicated. In
inhaled bronchodilators has also been carefully mechanically ventilated patients, not giving anti-
studied. There appears to be only marginal biotics has been associated with increased mor-
improvement to the use of both agents. The side tality and nosocomial pneumonia. The most
effects of anticholinergic therapy are generally consistently measured endpoint with a positive
fewer and mild. The adverse effects of albuterol in result is an improvement in peak expiratory flow
the acute setting include tremors, headache, and rate of a mean of 11 L/min, more in patients with
palpitations. Changes in heart rate, blood pres- the antibiotic treatment.
sure, and ECG tracings are also possible. To prevent tissue hypoxia, oxygen therapy is
The use of systemic steroids for patients with given to maintain arterial PaO2 greater than 60
an acute exacerbation of COPD who require mm Hg and O2 saturation above 90%. Values
hospitalization is helpful. If a patient is able to greater than this raise the risk of CO2 retention
take oral medication, prednisone 30 to 40 mg per and respiratory acidosis. Arterial blood gas
day is recommended. IV therapy may be neces- measurements should be done if a patient does
sary but a changeover to po therapy when not show prompt improvement with initial
possible is recommended and given for only 2 measures. The initiation of mechanical ventilation
wks posthospitalization. The most common should be considered when, despite optimal
adverse effect is hyperglycemia. medical therapy and oxygen administration,
Antibiotic therapy has been a controversial there is acidosis (pH ,7.35) and hypercapnia
issue.83 Patients with more severe exacerbations (PaCO2 45–60 mm Hg) and a persistently elevated
are more likely to benefit, and some studies have respiratory rate .24/min. Also, clinical signs of
suggested the presence of sputum purulence also respiratory muscle fatigue such as use of respira-
predicts the need for antibiotics. A 5- to 10-day tory accessory muscles, paradoxical motion of the
course has been recommended based on local abdomen, or retraction of the intercostal spaces
resistance patterns. Antibiotics appear to be are indications for ventilator support.
effective when two or three symptoms of in- Mechanical ventilation can be administered
creased dyspnea, sputum volume, and purulence via invasive ventilation (use of an endotracheal
are present (Winnipeg type 2, 3). However, there is tube) or noninvasive (nasal or face masks). NPPV
still some controversy concerning the role of is beneficial for patients who have a high
antibiotics for COPD exacerbations, especially in likelihood of respiratory failure and may require
studies performed in the primary care setting, invasive mechanical ventilation.84 In the first
where generally patients with milder disease are hours, NPPV requires the same level of supervi-
treated. Treatment with antibiotics in addition to sion as conventional mechanical ventilation. The
oral corticosteroids has been associated with a use of NPPV provides a statistically significant
longer time to the next exacerbation and a difference in the need for intubation reported in
decreased risk of developing a new exacerbation. several clinical trials. Arterial blood gases improve

because of an increase in alveolar ventilation Prevention of Exacerbations
without significant modifications in the alveolar
ventilation/perfusion mismatching and gas ex- There is a significant decrease in functional
change in the lungs. The addition of NPPV to status, lung function, and QOL and increase in
standard care in patients with an acute exacerba- mortality in those with frequent COPD exacer-
tion of COPD has decreased the rate of endotra- bations, as well as high socioeconomic costs.
cheal intubation 28%, length of hospital stay 4.57 Therefore, prevention of exacerbation is most
days, and in-hospital mortality rate 10%.85 Some important.86
analyses have shown that these beneficial effects Influenza vaccinations are currently recom-
occurred only in patients with severe exacerba- mended in the care of people with COPD, but
tions (pH ,7.30), not in those with milder these recommendations are based largely on
exacerbations. Other RCTs have shown that the evidence from observational studies, with very
NPPV success was especially high in patients with few RCTs reported. Meta-analysis of the results
mild acidosis (pH .7.30), whereas patients with from these trials indicates that inactivated influ-
more severe acidosis did not fare equally well and enza vaccine reduces exacerbations in COPD
were more likely to require intubation. A recent patients. The magnitude of this benefit is similar
prospective study conducted in the UK on 9,716 to that seen in large observational studies, and
inpatients with COPD exacerbation and acute was due to a reduction in exacerbations occur-
respiratory failure managed in general clinical ring 3 or more weeks after vaccination, and due
practice showed an overall mortality of 25% in to influenza. There is a mild increase in transient
patients receiving NIV, significantly higher than local adverse effects with vaccination, but no
the figures reported in the RCTs. evidence of an increase in early exacerbations.
Optimal NPPV delivery methods, optimal The clinical efficacy of the 23-valent pneu-
duration of treatment, and appropriate delivery mococcal polysaccharide vaccine in immuno-
pressures are additional questions that need to be competent patients with COPD has been
addressed in the literature. In general, a bilevel studied. Kaplan-Meier survival curves for com-
ventilatory support with CPAP (eg, 4–8 cm H2O) munity acquired pneumonia did not show
and pressure support ventilation (eg, 10–15 cm significant differences between those who did
H2O) provides the most effective mode of NPPV. and did not receive the vaccine. Pneumococcal
Contraindications for NPPV include the polysaccharide vaccine was shown to be effective
following: respiratory arrest, cardiovascular in- in preventing community acquired pneumonia in
stability (hypotension, arrhythmias, myocardial patients with COPD aged less than 65 years and
infarction), impaired mental status causing an in those with severe airflow obstruction. The
inability to cooperate, copious and/or viscous effect of adding pneumococcal vaccination to
secretions with high aspiration risk, recent facial influenza vaccination on exacerbation rates of
or gastroesophageal surgery, craniofacial trauma COPD is not settled. A decrease in the risk of
and/or fixed nasopharyngeal abnormality, hospital admission for COPD has been observed
burns, and extreme obesity. Patients meeting in retrospective studies in vaccinated compared
these exclusion criteria should be considered for with nonvaccinated subjects.
immediate intubation. The use of long-term antibiotics for the
Patients who are hospitalized with an acute prevention of COPD exacerbations has received
exacerbation of COPD have a mortality rate of considerable attention.87 A large multicenter
about 3%. Almost half of all patients admitted randomized trial in the United States studied
with hypercarbic respiratory failure will be whether 250 mg of daily azithromycin could
readmitted to the hospital within the next 6 decrease the frequency of exacerbations of COPD
months, and Medicare statistics in the United in those who had an increased risk of exacerba-
States have shown readmission rates for a COPD tions.88 Azithromycin taken daily for 1 year, when
exacerbation are 21%. Mortality for those who added to usual treatment, decreased the frequen-
require treatment in an intensive care unit may cy of exacerbations and improved QOL but
be close to 50%. caused hearing decrements in a small percentage

of subjects. The impact of long-term antibiotics on of physical activities is likely to be a key
microbial resistance patterns is not known. underlying mechanism and increases the risk of
The use of long-term bronchodilators such as new exacerbations. Comprehensive pulmonary
b-agonists and anticholinergics (UPLIFT Trial) rehabilitation, including general exercise train-
has been associated with significant reductions in ing, has been shown to decrease exacerbation
COPD exacerbations. The TORCH trial showed rates for COPD. It can be implemented immedi-
that adding ICS to a long-acting b-agonist was ately after an exacerbation, and can lead to a
more effective in reducing exacerbations that reduction in hospital admissions and an increase
either agent given alone. in exercise tolerance and QOL.89
There is a strong scientific rationale for the
use of PDE4 inhibitors for COPD. They are potent Outcomes of COPD
antiinflammatory agents, effective against the key
inflammatory processes involved in COPD and At present COPD is the only major cause of
asthma. The inflammation in COPD is different mortality with a rising incidence worldwide and
from asthma, with a predominance of alveolar has become the third leading cause of death in the
macrophages that leads to neutrophilic inflam- United States. Traditionally, clinical staging of
mation and the involvement of CD8þ leukocytes. severity and risk of mortality has relied on the
These cells all predominantly express PDE4, and measurement of FEV1. Staging criteria for COPD
so PDE4 inhibitors are a logical treatment for the using percentage of predicted FEV1 can be useful
specific pattern of inflammation found in COPD. in predicting impairment in health-related QOL.
PDE4 inhibitors perpetuate the antiinflammatory
Even patients with milder disease show substan-
effects of cyclic adenosine monophosphate ele-
tially compromised health-related QOL and
vation. PDE4 inhibitors have a different spectrum
elevated mortality rates. Patients who have
of activity than corticosteroids, which do not
presented to the ED with an acute exacerbation
inhibit neutrophilic inflammation.
have been evaluated for mortality over time after
One PDE4 inhibitor, roflumilast, has been
the index event. Mortality has been found to be
approved in the United States and Europe for the
5% at 30 days, 9% at 60 days, 11% at 90 days, 16%
prevention of COPD exacerbations in patients
at 180 days, 23% at 1 year, 32% at 2 years, and 39%
with severe COPD following 6 clinical trials with
at 3 years. At the end of the follow-up of this
the drug.52 Overall, these trials have shown a 17%
study, 46% of patients had died. On multivariate
reduction in COPD exacerbations over 1 year (in
patients with chronic cough and a history of analysis, independent predictors of mortality
exacerbations) and a small but significant im- were increasing age, having congestive heart
provement in FEV1 (increase in FEV1 of 36–88 failure, having a metastatic solid tumor, and
mL) when compared with placebo. The thera- hospital utilization for COPD exacerbation dur-
peutic ratio for PDE4 inhibitors is determined by ing the past year.
selectivity of receptor subtypes including the Another landmark study came from the Study
relative effects on PDE4B (antiinflammatory) to Understand Prognoses and Preferences for
and PDE4D (emesis). The main side effects for Outcomes and Risks of Treatments.90 This five-
these agents are gastrointestinal (nausea, vomit- center study described the outcomes of patients
ing, and diarrhea). Tolerance to these side effects hospitalized with an acute exacerbation of hyper-
develops quickly, and is usually seen in clinical carbic (.55 mm Hg) COPD. The report shows that
trials in the first few weeks of therapy. Weight loss only 11% of the patients died during their hospital
has been observed, especially in overweight stay; however, the 60-day, 180-day, 1-year, and 2-
subjects, and reports of suicide have been year mortality was extremely high (20%, 33%,
included in the labeling. 43%, and 49%, respectively). After discharge there
Acute exacerbations of COPD can worsen the was a considerably high readmission rate. Over
muscle dysfunction seen with COPD. This results the next 6 months, almost half the patients were
in a decrease in exercise tolerance, enhanced readmitted at least once. Some of the patients
symptoms of depression, and fatigue. Avoidance were readmitted several times. At 6 months only

Table 10—Measures Used for COPD Outcomes 3. Stops for breath after walking about 100 m or
after a few minutes on the level.
FEV1
Dyspnea (MRC scale) 4. Too breathless to leave the house or breathless
BMI when dressing or undressing.
Exercise capacity
BODE index A simple grading index, the BODE index, has
Arterial blood gases been proposed as a useful tool to grade COPD
COPD exacerbations
severity and predict outcomes.93 The system uses
QOL health status
COPD Assessment Test score the body mass index (B), the degree of airflow
obstruction measured as the FEV1 as percentage
predicted (O), dyspnea measured by the MRC
Chest Physicians; 2009. dyspnea scale (D), and exercise capacity mea-
sured by the 6-min walk test (E). Patients with
26% were both alive and well and able to report a higher BODE scores were at higher risk for death.
good, very good, or excellent QOL. The score proved to be a better discriminator
Another 5-year study undertaken to investi- than lung function alone.
gate whether severe acute exacerbations of In 2011, the GOLD Guidelines proposed a
COPD exert a direct effect on mortality showed new assessment tool to provide a better under-
that only older age, arterial carbon dioxide standing of the impact of COPD on an individual
tension, and acute exacerbations of COPD were patient. It combines the symptomatic assessment
found to be independent indicators of a poor using the MRC scale with the patient’s risk of
prognosis.91 The patients with the greatest exacerbations. Four categories—A, low risk, less
mortality risk were those with three or more symptoms, through D, high risk, more symp-
acute COPD exacerbations. toms—are proposed that allow an assessment not
A validated short, simple instrument to relying on lung function assessment. This may be
quantify COPD impact on health status has been especially helpful for communities where spi-
proposed for routine practice. The COPD As- rometry is not easily accessible.
sessment Test is an eight-item measure of health A list of indices used for COPD outcomes is
status impairment for COPD patients.92 The listed in Table 10.
score ranges from 0 to 40; it correlates very
closely with health status measured using the St. Conclusion
George’s Respiratory Questionnaire.
Comorbid conditions are common and they In the United States, over 13 million adults
also negatively influence health-related QOL. have been identified with COPD, and this
Other measures of COPD, such as BMI and number is likely much higher. As the US
dyspnea scores, have proved useful in predicting
population ages, the prevalence will likely climb
outcomes such as survival. BMI is easily obtained
even more. COPD currently accounts for approx-
by dividing weight (in kilograms) over height (in
imately 125,000 US deaths per year, and world-
meters squared). Values ,21 kgm2 are associat-
wide this number is approaching 3 million
ed with increased mortality. Functional dyspnea
people a year. There are over 672,000 hospital-
can be assessed by the MRC dyspnea scale as
izations in this country for COPD and over 16.3
follows:
million office visits to physicians. The total health
0. Not troubled with breathlessness except with costs are $49.9 billion per year ($29.5 billion in
strenuous exercise. direct costs), and 50% to 75% of these costs are
1. Troubled by shortness of breath when hurry- associated with COPD exacerbations. It is likely
ing or walking up a slight hill. that the care of patients with COPD will consume
2. Walks slower than people of the same age a growing proportion of the pulmonologist’s
because of breathlessness or has to stop for time in the years to come. Differentiation from
breath when walking at own pace on the level. another chronic airway disease, asthma, may be

difficult, especially when the latter is long 10. Seersholm N, Kok-Jensen A. Clinical features and
standing or complicated by cigarette smoking. prognosis of lifetime non-smokers with severe
a1 -antitrypsin deficiency. Thorax. 1998;53(4):
Relationships Disclosed 265–268.
11. American Thoracic Society/European Respiratory
The author has disclosed the following Society Statement: standards for the diagnosis and
relationships: consultant fee: Sunovion, Forest management of individuals with alpha-1 antitryp-
sin deficiency. Am J Respir Crit Care Med. 2003;
Labs; lecturer; nonpromotional, Genentech, GSK.
168(7):818–900.
The ACCP Education Committee has reviewed
12. Kueppers F. The role of augmentation therapy in
these relationships and resolved any potential
alpha-1 antitrypsin deficiency. Curr Med Res Opin.
conflict of interest. 2011;27(3):579–88.
13. Gtzsche PC, Johansen HK. Intravenous alpha-1
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erbations. Proc Am Thorac Soc. 2007;4(8):626–634. Outcomes following acute exacerbation of severe
80. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility chronic obstructive lung disease. Am J Respir Crit
to exacerbation in chronic obstructive pulmonary Care Med. 1996;154(4 Pt 1):959–967.
disease. N Engl J Med. 2010;363(12):1128–1138. 91. Soler-Cataluña JJ, Martı́nez-Garcı́a MA, Román
81. Garcia-Aymerich J, Monso E, Marrades RM, et al. Sánchez P, Salcedo E, Navarro M, Ochando R.
Risk factors for hospitalization for a chronic Severe acute exacerbations and mortality in
obstructive pulmonary disease exacerbation. Am patients with chronic obstructive pulmonary
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82. Quon BS, Gan WQ, Sin DD. Contemporary 92. Jones PW, Harding G, Berry P, Wiklund I, Chen
management of acute exacerbations of COPD: a WH, Kline Leidy N. Development and first
systematic review and meta-analysis. Chest. 2008; validation of the COPD Assessment Test. Eur
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83. Puhan MA, Vollenweider D, Latshang T, Steurer J, 93. Celli BR, Cote CG, Marin JM, et al. The body--
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8:30. 1005–1012.

Chapter 5. Cardiopulmonary Exercise Testing
Objectives: summarized, a comprehensive review of this

Provide a brief overview of normal exercise physiology subject topic is beyond the intent of this course
and responses. and syllabus. The reader is encouraged to consult
Outline the clinical indications, utility, conduct, and
interpretation of cardiopulmonary exercise testing.
more detailed appropriate source literature and
Highlight characteristic responses commonly demon- documents on this topic (see ‘‘References’’).
strated by patients with various symptoms and disorders To meet the expected metabolic demands of
frequently assessed by the pulmonologist.
exercise, the respiratory and cardiovascular
systems must be able to augment oxygen (O2)
Key words: cardiopulmonary exercise testing; exercise;
interpretation; pulmonary function laboratory; pulmonary
delivery to the working skeletal muscles. Oxygen
function testing transport in the body depends on a series of
linked mechanisms that can be schematically
Synopsis: expressed as follows (and potential factors that
Physical activity in the healthy human involves the active may affect these mechanisms are shown in
and effective integration of respiratory, cardiovascular, brackets, but these are not inclusive):
neuromuscular, and metabolic functions. Organs involved
in these varied and important roles have sizeable reserve, Inspired O2
with the consequence that clinical manifestations of a ðaltitudeÞ
disease state or abnormality may not become readily
apparent until the functional capacity of the organ(s) is
markedly impaired. When this occurs, patients commonly Respiratory Ventilation
experience the distressing, and often disabling, symptoms
ðalveolar ventilation; distributionÞ
of shortness of breath with activity and exercise limita-
tion. Cardiopulmonary exercise testing (CPET) allows the
clinician to objectively evaluate these important functions Respiratory Gas Exchange
and symptoms. Objective assessment and measurement of
various parameters during exercise, which strategically ðdiffusion; ventilation perfusionÞ
places an increased physiologic demand on the functional
reserve capacity of these organs, can also provide a Arterial O2
sensitive method for the early detection of abnormal
function and response(s). Exercise testing results parallel ðoxygen capacity saturationÞ
functional capacity and quality of life more closely than
measurements obtained only at rest, and accurately
predict important outcomes, such as mortality, in a
Cardiac Output
variety of patients and clinical circumstances. While ðstroke volume; cardiac frequencyÞ
CPET has been previously viewed as being merely
interesting (in the hands of a few individuals), it is now
cemented into mainstream clinical practice. In view of Circulation and Muscle Blood Flow
these meaningful benefits, the conduct and interpretation ðperipheral vascular resistanceÞ
of CPET is now an essential competency for practicing
pulmonologists.
O2 Extraction
ðcapillary-tissue diffusionÞ

Normal Exercise Physiology Muscle O2 Utilization O2 Stores
ðrespiratory enzymesÞ
Normal exercise physiology must be appreciated

for the appropriate interpretation of exercise
Venous O2
responses in disease. While relevant principles
of normal exercise physiology will be briefly Adapted from Jones.1

Figure 1. Respiratory system responses during exercise. Figure 2. Cardiovascular system responses during exercise.
Similarly, the removal of CO2, which is a _ TðCaO 2 C

V_ O2 ¼ Q vO 2 Þ ð1Þ
byproduct of metabolism, can be expressed as:
or
CO2 Production ðaerobic; anaerobicÞ
V_ O2 ¼ ðHR SVÞðCaO 2 C

vO 2 Þ ð2Þ
CO2 Stores
Muscle Blood Flow and Circulation where Q _ T is cardiac output, the product of stroke
volume (SV) and heart rate (HR), and CaO2 –
Venous CO2 CvO2 is the oxygen content difference between
systemic arterial and mixed venous blood.
Venous Return Meanwhile, when the inspired CO2 concen-
tration is negligible, the respiratory response to
ðcardiac outputÞ
exercise can be represented by:

Respiratory Gas Exchange k V_ CO 2

V_ A ¼ ð3Þ
ðventilation-perfusionÞ PaCO 2
or
Respiratory Ventilation
k V_ CO 2

ðalveolar ventilation; distributionÞ V_ E ¼ ð1 VDS=VTÞ ð4Þ

PaCO 2

Expired CO2 where V_ E is minute ventilation, the sum of
alveolar ventilation (V_ A) and dead space ventila-
Adapted from Jones.1 tion (V_ DS). PaCO2 is arterial PCO2 and VDS/VT is
Understanding the cardiorespiratory and the ratio of physiologic dead space to tidal
metabolic responses to exercise is facilitated by volume. These relationships are used to under-
close examination of the direct physiologic stand the ventilatory response during exercise,
determinants of oxygen uptake (V_ O2) and carbon because V_ E and V_ A are associated more closely to
dioxide output (V_ CO2), as depicted in the follow- V_ CO2 than to V_ O2.
ing equations. The cardiovascular responses are The normal respiratory and cardiovascular
represented by rearrangement of the Fick system responses during exercise are shown in
equation: Figures 1 and 2.
104 Chapter 5. Cardiopulmonary Exercise Testing (Marciniuk)

Figure 3. Relationship between resting and maximal exercise values in healthy humans. Adapted from Gallager.2
These relationships and equations also serve production continues, further fueled by anaero-
to illustrate and emphasize the integrative bic respiration and progressive increases in
aspects of exercise, which result in the cumula- lactate production later in exercise, the respira-
tive response being significantly greater than any tory exchange ratio rises in the healthy human.
individual contribution alone. For instance, oxy- The peak oxygen uptake is usually determined
gen supply in a fit athlete may increase to more by the capacity of the cardiovascular system to
than 20 times the resting oxygen consumption deliver oxygen to the working muscles. Except in
(ie, from 0.25 L/min at rest to more than 5.0 L/ well-trained athletes and perhaps the fit elderly,
min at peak exercise). This net increase is not gas exchange remains well preserved during
brought about by a 20-fold increase in any one exercise, although the hyperventilation induced
mechanism, but rather is shared between mech- by lactic acid production typically results in a
anisms. For example, the increase in V_ E during slight fall in the PaCO2 and a rise in PaO2 near the
exercise occurs not only because of the typical end of exercise.
hyperventilation (due to metabolic acidosis) at
end-exercise, but also because of a fall in VDS/VT Clinical Indications and Utility of CPET
during exercise.
The fractional changes in various compo- The indications for CPET depend on the
nents of the cardiovascular and respiratory clinical setting and question(s) to be addressed.
systems during exercise are summarized in Shortness of breath with exercise and activity
Figure 3 (representative data from a population limitation are cardinal and common symptoms of
of healthy middle-aged men2). dysfunction, and are, therefore, some of the most
These data illustrate the major demands frequent reasons for testing in the clinical
placed on cardiorespiratory function during laboratory. CPET also has significant utility in
exercise and exemplify the significant reserve distinguishing normal from abnormal responses,
that exists to meet these increased demands of and in establishing cardiovascular from respira-
exercise. The demands are met by increases in tory causes for activity limitation, or for symp-
ventilation (breathing frequency and tidal vol- toms.
ume) and cardiac output (heart rate and stroke Our understanding of the clinical utility of
volume), as well as by redistribution of blood to CPET is also increasing as further work is
the exercising muscles. In addition, dead space published demonstrating the prognostic value
ventilation decreases as alveolar ventilation of exercise testing in various clinical settings.1,3–5
becomes more efficient. The oxygen uptake rises Results from exercise testing have been shown to
with increasing exercise, and in some fit and correlate with important clinical outcomes in-
motivated individuals, reaches a plateau near cluding mortality in normal humans, COPD,
end-exercise. Meanwhile, as carbon dioxide interstitial lung disease (ILD), cystic fibrosis,

Table 1—Clinical Indications for Cardiopulmonary Exercise Equipment, Conduct, and
Testing
Measurements
Objective assessment of symptoms
Evaluation of severity of impairment A stationary cycle ergometer or a motorized
Appraisal of contributors to exercise limitation

treadmill is most commonly used for clinical
Early detection of disease or impairment
Assessment of response to therapy testing. Both cycle ergometer and treadmill
Disability assessment testing are appropriate, although the cycle
Assessment/titration of supplemental O2 therapy ergometer is more frequently used. The cycle
Identification of exercise-associated bronchoconstriction
Preoperative risk and transplantation assessment ergometer allows for a direct measurement of
work rate, has less potential for artifact, and
Adapted from Palange et al4 and Weisman et al.5 seems to be better tolerated by patients, partic-
ularly those with significant lower limb joint
pulmonary hypertension, solid organ transplant, problems. Alternatively, the treadmill yields
ischemic heart disease, and chronic heart failure higher values for the peak V_ O2 (approximately
(CHF). 8%–12%), and is better accepted by fit normal
Generally accepted clinical indications for subjects.
Specialized equipment is used for CPET.
CPET are listed in Table 1.
Similar to pulmonary function testing equip-
CPET has been found to be particularly
ment, exercise testing equipment systems,
useful in the setting of preoperative assessment
whether mixing chamber or breath-by-breath,
for major surgery and/or lung resection. The risk
require meticulous calibration procedures to
of death and complications associated with
ensure measurements are and remain accurate
surgery in these instances tends to be higher in
and precise. In addition to daily calibration,
patients with a lower peak V_ O2. For lung cancer
routine physiologic calibration should be per-
resection, patients with a peak V_ O2 . 15 mL/kg/
formed. This is best undertaken by a healthy staff
min may undergo surgery with an acceptably
member who exercises at several constant work
low mortality risk.6 However, reported operative
rates for a specified duration while V_ E, V_ O2, and
mortality for patients with a peak V_ O2 of 10 to 15
V_ CO2 are measured. This might entail measure-
mL/kg/min is approximately 8.3% (range, 0%– ments after 4 to 6 min each at rest, at 50 W, and at
33%), and in patients with a peak V_ O2 , 10 mL/ 100 W. Values should remain consistent (less than
kg/min, the operative mortality is approximately 5% variation) with measurements collected pre-
26% (range, 0%–50%).6 A suggested algorithm viously under identical circumstances. If not, the
for the determination of operative suitability and cause of any discrepancy must be investigated
risk in the setting of lung resection surgery is and corrected.
shown in Figure 4. Ventilatory measurements unique to CPET, as
CPET has also recently evolved into one of well as other commonly performed measure-
the most important tools for evaluating out- ments, assessments, and derived variables are
comes in chronic heart failure.7,8 Compared to illustrated in Figure 5.
the healthy human, excessive ventilation during As evident in Figure 5, PaO2 (arterial sam-
exercise is characteristic of patients with CHF. pling) or arterial oxygen saturation (SaO2) (pulse
These abnormalities can be assessed during oximetry), work rate (cycle ergometer), blood
exercise by using various measurements, in- pressure (cuff sphygmomanometer), heart rate/
cluding the V_ E/V_ CO2 at the anaerobic threshold rhythm (electrocardiogram), and symptoms of
or at end-exercise, the slope of V_ E vs V_ CO2, and shortness of breath and leg fatigue (modified
with other derived variables between V_ E and Borg scale or visual analogue scale) are also
V_ CO2.7 The information garnered from CPET has measured. The reason(s) for stopping exercise
been demonstrated to highly correlate with risks should always be noted. Together these measure-
of hospitalization and mortality in this popula- ments allow for a comprehensive evaluation of
tion. behaviors during exercise, and for the determi-

Figure 4. Preoperative assessment of perioperative risk for lung resection surgery.6
nation of various derived variables that provide The choice of which test to perform largely
additional information in the interpretation depends on the clinical question being ad-
process. dressed. Maximal symptom-limited incremental
The patient should wear comfortable clothes protocols are most commonly performed. Endur-
and shoes, and refrain from heavy activity or ance exercise protocols are often carried out in
meals for 2 h before testing. All testing proce- research trials to determine a treatment effect and
dures should be explained, and informed consent may have clinical utility in the individual patient
obtained. A brief review of the clinical history in assessing a response to an intervention. They
and a physical examination should be per- are often completed at a constant work rate
formed. Baseline spirometry is measured, and (typically approximately 75% of the maximal
the patient should be familiarized with the work rate) and continued until the patient is no
equipment before testing. If a cycle will be used, longer able to exercise. Exercise challenge testing
the seat and handlebars should be adjusted for is frequently done to objectively assess for the
comfort. In the case of a treadmill, the patient presence of exercise-induced bronchoconstric-
should be shown how to get on and off the tion. The test is performed to illicit approximate-
moving belt comfortably and safely. ly 6 min of very intense exercise associated with

Figure 5. Measurements, assessments, and derived variables from CPET. Measured variables are denoted by solid lines,
derived variables by dashed lines. Adapted with permission from photograph by Marco Quezada.
high levels of V_ E. Spirometry is then performed ing physiologic contributors and mechanisms of
after exercise at frequent intervals (1, 5, 10, 15, 20, exercise limitation, and may demonstrate a
30 min), with a drop in the FEV1 of 10% to 12% ceiling effect because of a smaller magnitude of
indicating possible, and 15% probable, exercise- change in the healthy. Nonetheless, they have
induced bronchoconstriction.9 Readers are asked become embedded in our field because of the
to consult referenced guideline statements for meaningful information they yield.12,13
further information and detail regarding the Shuttle walk tests are emerging as another
conduct of this specialized testing.5,9 option in this setting, and recent reports14,15 have
When assessing activity, the clinician has a validated their usefulness in detecting a treat-
number of varied options, including self-report- ment effect. The exercise intensity during testing
ed questionnaires, activity motion sensors, stair is comparable to maximal tests on a cycle
climbing or step-testing, timed walk tests, shuttle ergometer or treadmill, and the results correlate
walk tests beyond CPET. The results obtained well with peak V_ O2. The obstacle to more
from pedometers and accelerometers correlate widespread use at this time relates to a lack of
with disease severity.10 The performance and familiarity. However, as further reports validat-
conduct of the six-minute walk distance test will ing their utility are published, our understanding
not be addressed in this chapter, but is discussed of the role of both incremental and endurance
in more detail elsewhere.11 However, timed walk shuttle walk test protocols will mature.
tests (typically 6 or 12 min) are the standard While these tests do evaluate activity, CPET is
‘‘simple’’ test for assessing activity limitation. the current gold standard for assessing exercise
They are safe and practical, and tend to mimic performance. It allows determination of mecha-
activities of daily living. Their utility has been nistic insights, recognition of coexistent and
confirmed to improve with standardization, multiple exercise-limiting factors, and provides
although they are susceptible to a training effect a thorough evaluation of respiratory responses
(similar to other tests). Their major limitation is and constraint. Both incremental and endurance
that they provide restricted information regard- protocols may be used, and the results from

Table 2—Contraindications to Cardiopulmonary Exercise Table 3—Indications for Terminating CPET in the Clinical
Testing Laboratory
Unstable angina or recent acute coronary syndrome Unstable angina or chest pain suggestive of myocardial
Uncontrolled arrhythmias causing symptoms or ischemia
hemodynamic compromise ECG changes suggestive of ischemia, complex ectopy, or
Active endocarditis, myocarditis, or pericarditis 28/38 heart block
Symptomatic, severe aortic stenosis Systolic blood pressure fall .20 mm Hg from highest
Poorly or uncontrolled heart failure value
Acute pulmonary embolism or infarction Systolic blood pressure .250 mm Hg, diastolic .120
Thrombosis of the lower limbs mm Hg
Suspected dissecting aortic aneurysm Desaturation to below 80%
Uncontrolled asthma Sudden pallor or dizziness
Pulmonary edema Mental confusion
Significant hypoxemia Signs of respiratory failure
Adapted from Weisman et al.5

endurance exercise testing have been found to be
more responsive to a treatment effect than either addressed and in part, by responses demonstrat-
incremental exercise or six-minute walk testing. ed by the patient during testing.
If a thorough evaluation of exercise performance .
is required, particularly in patients with multiple VO2
comorbidities, CPET remains the testing method
of choice. Oxygen uptake is determined by cellular O2
CPET is safe, with the risk of death for demand and maximal O2 transport (see ‘‘Normal
patients approximating 2 to 5 per 100,000 Exercise Physiology’’). It is typically presented
exercise tests performed.5 These risks can be together with work rate and increases nearly
minimized by a number of practical and common linearly as external work increases. The slope of
sense precautions: this relationship reflects the efficiency of meta-
bolic conversion of energy to work, and the
1. Direct physician supervision (the importance mechanical efficiency of the musculoskeletal
cannot be overemphasized), and a thorough system. Values of 8.5 to 11.0 mL/min/W are
understanding of the contraindications to normal for the DV_ O2/Dwork rate relationship,
testing, as well as the indications for termi- and are unaffected by age, height, or sex. While
nating exercise testing. obese individuals may have an elevated ratio, the
2. Appropriate cardiac and blood pressure mon- slope of that relationship remains normal.
itoring. As exercise progresses, V_ O2 increases until
3. Resuscitation equipment and expertise. one or more of its determinants approach
4. Accurate SaO2 monitoring and availability of limitation (HR, SV, or tissue extraction), and the
supplemental O2. V_ O2/work rate may begin to plateau. This
Specific contraindications for testing are plateau has been used as the best evidence of
listed in Table 2. Indications for prematurely V_ O2max, which is the gold standard used for
terminating CPET are listed in Table 3. assessing cardiorespiratory fitness. However, in
the clinical setting, a plateau may not be reached,
Variables Assessed During Exercise and the peak V_ O2 is often used for this purpose.
The peak V_ O2 is often normalized for body size
While a discussion of individual measure- by dividing it by weight in kilograms. Unfortu-
ments is presented, it is important to recognize nately, normalization by body weight in obese
that CPET involves their collective integration for individuals may provide a falsely low value.
interpretation. In many instances, specific indi- While using the lean body mass or height may be
vidual measurements are of lesser importance— more desirable, there is no consensus on how
this is dictated by the clinical question being best to account for body size.

Figure 6. Noninvasive estimations of the anaerobic threshold.
A reduced peak V_ O2 is the starting point for Respiratory Exchange Ratio (RER)
interpretation, and underlying causes responsi-
ble for reduced exercise capacity are determined The RER is the ratio of V_ CO2/V_ O2, which,
by inspecting the pattern of responses in other under steady state conditions, approximates the
variables. The peak V_ O2 should be expressed as respiratory quotient. An RER of 1.0 indicates
both an absolute value and also as a percentage metabolism by primarily carbohydrates; 0.7, by
of the predicted value. primarily fat; and 0.8, by primarily protein.
. Values above 1.0 may indicate carbohydrate
VCO2 metabolism, but also CO2 derived from lactic
acidosis or importantly, hyperventilation. The
CO2 output is determined by factors similar RER should be reported as a function of the V_ O2.
_
to VO2, but because CO2 is more soluble, CO2
output is more closely related to V_ E than to V_ O2. Anaerobic Threshold (AT)
Importantly, the body uses CO2 to compensate
for acute metabolic acidosis, which contributes to The AT (often referred to as the lactate
the V_ CO2 vs work intensity relationship above the threshold, lactate anaerobic threshold, or gas
point of anaerobic metabolism. exchange threshold) is considered an indicator of
Accurate measurement of the CO2 output is the onset of metabolic acidosis caused predom-
important, as it serves in the calculation of inantly by increased arterial lactate during
several meaningful derived variables. Moreover, exercise. The AT should be expressed as a
because V_ E is so closely related to V_ CO2, it is percentage of the peak V_ O2. In healthy individ-
helpful to analyze V_ E in relation to V_ CO2. uals, the AT occurs at 50% to 60% peak V_ O2, with

the range of normal being 40% to 80%. The AT is
affected by the type of exercise (lower for arm vs
leg exercise) and method of testing (lower for
cycle vs treadmill testing). From a practical point
of view, the AT denotes the upper limit of
exercise intensity that can be accomplished
aerobically, and exercise above the AT is associ-
ated with a progressive decrease in exercise
tolerance.
Invasive methods for measuring the AT
include arterial blood sampling of lactate or
bicarbonate. There are various methods for
estimating the AT noninvasively (Fig 6), includ-
ing the ventilatory equivalents method (V_ E/V_ O2,
V_ E/V_ CO2, PETO2, PETCO2), and the V-slope method
(V_ CO2 vs V_ O2). Confirmatory evidence is provid-
ed by noting the change in slope of the V_ E vs V_ O2
relationship, and when the RER approximates 1.
Like the peak V_ O2, a reduced AT is nonspe- Figure 7. Cardiovascular responses during exercise in
different clinical situations.
cific and requires inspection of other variables to
determine the underlying etiology of the reduc- The slope of the HR-V_ O2 relationship is a
tion. Values below 40% may be witnessed with a function of SV, with the higher the SV, the lower
wide variety of cardiovascular, respiratory, and the HR (Figs 2, 7). In patients with significant
musculoskeletal conditions. In some patients lung disease, the opposite may be seen, often
with severe respiratory limitation (for example, reflecting deconditioning, mechanical ventilatory
severe COPD), the AT cannot be determined limitation, or potentially the hemodynamic con-
noninvasively. sequences of dynamic hyperinflation.
.
HR and HR-VO2 Oxygen Pulse
In healthy individuals, HR increases linearly The ratio of V_ O2 to HR is referred to as the O2

with increasing exercise and V_ O2. Predicted pulse, and is often used as a correlate of stroke
maximal HR is often estimated by 220 age, volume during exercise. While under ideal
but this equation may underestimate maximal conditions this relationship generally holds true
heart rate in the elderly. The difference between (Equations 1 and 2), in many settings the variable
predicted maximal HR and the observed maxi- must be used with caution. The assumptions in
mal HR is called the heart rate reserve. In healthy the equations are not valid in the presence of
individuals, there is little or no heart rate reserve significant desaturation, or with impaired skele-
at end-exercise, and this suggests a maximal or tal muscle O2 extraction. A low O2 pulse may
near-maximal patient effort. Peak HR may be therefore not only reflect cardiovascular disease,
reduced in a variety of cardiovascular conditions but also deconditioning, early exercise termina-
(including with pharmacologic agents) or in a tion due to respiratory factors, symptoms or
submaximal study, but if a patient achieves submaximal effort, and/or the presence of
predicted maximal HR, it suggests that cardio- arterial O2 desaturation.
vascular function contributed to exercise limita-
tion. In this instance, examination of other Blood Pressure
variables (ie, V_ O2, AT) will assist in the determi-
nation of whether this observation was normal or Systolic blood pressure typically rises pro-
abnormal. gressively during exercise as V_ O2 increases, while

There are various methods used to estimate
peak V_ E, including actual measurement of the
maximal voluntary ventilation. Predicted maxi-
mal V_ E may also be estimated with various
equations, most commonly the FEV1 3 37–40.
Unfortunately, none of these methods are perfect
and there is a pressing need for enhancements in
this area. The use of the maximal voluntary
ventilation is limited by concerns about patient
effort and repeatability, and with the unique
breathing strategy adopted during the maneuver
that does not parallel the strategy used during
exercise. Equations are therefore most commonly
used, but may be less suited for patients with
neuromuscular disorders or respiratory muscle
weakness. Despite these limitations and regard-
less of the method used, estimating the peak V_ E
has significant clinical utility and has withstood
Figure 8. Respiratory responses during exercise in different the test of time.
clinical situations. The terms breathing or ventilatory reserve are
used to denote the relationship between predict-
diastolic blood pressure typically increases only ed peak V_ E and the actual measured peak V_ E,
slightly or remains relatively unchanged. Abnor- displayed both as an absolute value (in L) and as
mal patterns of response during exercise include a percentage of the predicted peak V_ E. Patients
an exaggerated rise, a reduced rise, or a fall. with respiratory disease characteristically have
Exaggerated increases are seen with resting reduced ventilatory capacity and increased ven-
hypertension, but in those without a known tilatory demand, resulting in reduced ventilatory
diagnosis, may also predict the future onset of reserve. Ventilatory demand is usually increased
resting hypertension. A reduced rise may suggest both at rest and during exercise in patients with
underlying cardiovascular or sympathetic con- COPD, ILD, and pulmonary vascular disease, for
trol abnormalities. A falling blood pressure example due to ventilation-perfusion inequality
during exercise is very serious, and an indication and increased dead space ventilation, hypox-
for immediate termination of the test. If this emia, and/or increased stimulation of lung
receptors (which serves to increase ventilation).
occurs, serious efforts to exclude heart failure,
It is also dependent on other factors such as
ischemia, or outflow tract obstruction should be
metabolic requirements, lactic acidosis, behavior-
undertaken.
al factors, deconditioning, body weight, and
mode of testing. In most healthy adults, peak
Breathing Pattern and Ventilatory Responses
V_ E at end-exercise approaches 70% of the
During Exercise
maximal V_ E, although this percentage may be
higher with increased fitness and with aging (Fig
The increase in V_ E with exercise is accompa- 8). In patients with significant respiratory disease
nied by increases in both the depth and frequen- and mechanical abnormalities, the patient’s end-
cy of breathing (Fig 1). Increases in VT are exercise V_ E may reach or even exceed the
primarily responsible for the increase in V_ E at predicted maximal peak V_ E. A plot of V_ E vs
low levels of exercise, but as exercise progresses, either V_ CO2 or V_ O2 (see below) is acceptable for
both VT and respiratory rate increase. At 70% to the graphical representation of ventilatory data.
80% of peak exercise, increases in V_ E are An oscillatory breathing response during
achieved primarily by increases in respiratory exercise may be seen in patients with CHF, and
rate. appears to be predictive of a poor outcome.16,17

Figure 9. Behavior of operational lung volumes during exercise.
This pattern of cyclical fluctuations in V_ E of more potentially reflects insensitivity to the stimulus
than 30%, lasting between 40 and 140 s, is noted of metabolic acidosis, an inability of the respira-
in as many as 50% of patients with significant tory system to respond to that stimulus (ie,
CHF. Invasive hemodynamic monitoring has significant COPD), or physiologically submaxi-
revealed that exercise oscillatory ventilation is mal exercise.
related to reduced cardiac index and elevated
filling pressures during exercise, and appears to End-Tidal PO2 (PETO2) and PCO2 (PETCO2)
reflect exercise-associated hemodynamic impair-
ment in patients with CHF.18 The characteristic response of these variables
. . during exercise is shown in Figure 6 (bottom
Ventilatory Equivalents for VO2 and VCO2 right). The period of increasing PETO2 with
relatively stable PETCO2 has been termed isocapnic
The ratio of V_ E to V_ O2 is called the ventilatory buffering. A high V_ E/V_ CO2 without a correspond-
equivalent for O2, and the ratio of V_ E to V_ CO2 is ing fall in PETCO2 suggests increased dead space
called ventilatory equivalent for CO2. They are ventilation, whereas a fall in PETCO2 when the
both related to VDS/VT, and are higher as VDS/VT V_ E/V_ CO2 is high suggests hyperventilation.
increases. They also both increase with hyper-
ventilation. Normal responses for these variables Flow-Volume Curves
are shown in Figure 6 (bottom left). The initial
increase in the V_ E/V_ O2 (while the V_ E/V_ CO2 has While first reported in 1961, flow-volume
still not increased) that typically occurs in concert curves during exercise were not adopted nor well
with metabolic acidosis is different from the studied until the 1990s. Since that time, our
pattern demonstrated with hyperventilation (at- insight of their usefulness to better understand
tributable to anxiety, pain, or hypoxemia), respiratory responses and symptoms during
whereby both the V_ E/V_ O2 and the V_ E/V_ CO2 exercise has grown.19 This greater understand-
increase together. The subsequent increase in ing, coupled with advances in technology, has
the V_ E/V_ CO2 represents the respiratory compen- led to the routine analysis of flow-volume curves
sation associated with a fall in the PaCO2 and the during exercise. The added value garnered from
PETCO2. their use relates to their ability to provide
The V_ E/V_ CO2 is usually ,34 at the AT, and information about the overall breathing strategy
usually ,37–40 at end-exercise. Similarly, a peak adopted by patients during exercise. They also
V_ E/V_ CO2 slope greater than 34 is also considered enable an appreciation of the behavior of
abnormal. Elevated values reflect either an operational lung volumes, including the end-
increased VDS/VT or a low PaCO2 from varied expiratory lung volume (derived from total lung
causes. A lack of an increase with exercise capacity and the inspiratory capacity) and the

Figure 10. Maximal and tidal flow-volume curves at rest and during exercise.
end-inspiratory lung volume. Additionally, anal- acteristic. The value of flow-volume curves
ysis of flow-volume curves provides an objective during exercise is being further studied, and it
assessment of the presence and degree of flow is likely that additional indications and applica-
limitation during exercise. tions, such as using them to better estimate
In patients with significant disease, there are maximal ventilatory capacity, may be adopted.
a number of characteristic patterns of response in
lung volumes that differ from healthy individu- PaO2, SaO2, and PAO2 PaO2
als (Fig 9, volume vs V_ E; Fig 10, flow vs volume).
In addition to COPD and ILD, patients with Normal exercise responses are enabled by
significant obesity (see Fig 11 below) and central efficient gas exchange. Arterial hypoxemia is
airway obstruction also demonstrate distinguish- uncommon during exercise in healthy humans,
ing responses.20 Analysis of flow-volume curves but may occur in some elite or aging athletes during
during exercise is also useful in helping to assess high-intensity exercise. Inefficient gas exchange is
demonstrated by the alveolar-arterial PO2 (PAO2
a therapeutic response.21,22
PaO2) gradient and by the PaO2. A significant
In these examples, the end-expiratory lung
widening of the gradient and fall in the PaO2 are
volume, the inspiratory reserve volume, and the
abnormal, and most characteristic of ILD and
presence/absence of flow limitation serve to
significant right-to-left shunts, and in some patients
distinguish the various disease states from
with COPD and pulmonary vascular disease. A
normal—these changes being unique and char-
reduced PaO2 with a normal PAO2 PaO2 may be
seen in processes associated with abnormal respi-
ratory control and in a hypoxic environment (ie,
altitude), although the latter is rarely reproduced in
the clinical laboratory. A reduced PaO2 with an
abnormally widened PAO2 PaO2 would suggest
worsening V/ _ Q_ inequalities, right-to-left shunt,
and/or diffusion limitation, potentially accompa-
nied by a fall in the mixed venous PO2.
The PAO2 PaO2 is normally ,10 mm Hg at rest,
but may normally increase to .20 mm Hg during
exercise. Values .35 mm Hg are abnormal and
indicate possible gas-exchange abnormalities.
While occasionally a less-than-optimal substitute,
Figure 11. Operational lung volumes during exercise in
oxygen saturation (SaO2) determined by pulse
obese and normal-weight patients with COPD. Adapted oximetry is frequently used as an alternative to
from Ora et al.29 arterial blood gas sampling. In the healthy individ-

ual, both the PaO2 and the SaO2 are not appreciably a visual analogue scale23 or a modified Borg scale24
different during exercise when compared to rest. is recommended. These have shown to be repeat-
able and responsive, and are commonly used in
Ratio of VDS/VT clinical laboratories. The reproducibility of results
obtained from these scales can be enhanced by
The ratio of physiologic dead space to tidal providing a consistent set of written instructions to
volume is another index of gas exchange effi- the patient before testing. As noted, the reason(s)
ciency. An increase in VDS/VT represents an for discontinuing exercise should be recorded. The
increased inefficiency of ventilation, which re- value of these ratings is further enhanced when
quires an increase in V_ E to maintain PaCO2. VDS/ relationships such as V_ E or work rate vs dyspnea
VT is highly dependent on the breathing pattern, or leg fatigue are examined, particularly in serial
as a rapid shallow breathing pattern increases studies or after interventions.
VDS/VT without any other abnormalities.
The VDS/VT is calculated from the PaCO2 and Reference Values
the PECO2 by using the following equation:
ðPaCO2 PECO2 Þ The selection of appropriate reference values
VDS=VT ¼ ð5Þ for use in interpreting CPET is essential. The
PaCO2
reader is advised to consult source references1,5,25
where the PECO2 is the mixed expired CO2 value
for guidance in selecting which reference values
of alveolar and dead space gas. It is obtained
may be most appropriate for his or her specific
directly by collecting expired gas and measuring
clinical laboratory.
the CO2 concentration. This can easily be done
from a mixing chamber, or for breath-by-breath
systems after determining the V_ E/V_ CO2 ratio.
Reproducibility of CPET Results
Approaches that substitute end-tidal PCO2 for
Whenever serial testing is undertaken, for
PaCO2 yield unreliable results, particularly in
example to assess the response to therapy, the
disease, because pulmonary gas-exchange abnor-
variability of the measurements during cardio-
malities in themselves affect the difference
between PaCO2 and PETCO2. pulmonary exercise testing must be considered
At rest, the VDS/VT may normally be approx- before a beneficial, detrimental, or no effect can
imately 0.30, and fall to approximately 0.10 to be concluded. The coefficient of variation (ratio
0.15 at end-exercise. Patients with respiratory of the standard deviation to the mean, expressed
disease may have at rest either normal or as a %) reported for serial measurements during
elevated values that fail to decrease normally maximal testing in the same subject are as
during exercise. In some instances, the VDS/VT follows (range of reported values listed):
will increase during exercise in patients with
V_ O2 3.0%–8.4% V_ CO2 5.0%–9.6%
significant disease. However, the VDS/VT is HR 1.4%–8.6% V_ E 5.0%–12.3%
neither sensitive nor specific for lung disease, AT 9.2%–13.0% Systolic BP 2.2%–6.7%
and thus an isolated abnormality should be SaO2 2.5% Duration (work rate) 3.6%–13.8%
interpreted with caution. This also emphasizes
the importance of evaluating the patterns of It should be understood that the variability
response from a collection of variables rather depends on a number of factors, such as the
than reacting to just a single measurement. population studied, the type of testing per-
formed, and the specific variable examined.
Symptoms During Exercise However, it appears reasonable to assume that
differences in most measurements obtained
Patients often report that breathlessness and/ during cardiopulmonary exercise testing should
or leg fatigue limits their exercise, although other exceed approximately 12% to 20% in order to be
reasons such as musculoskeletal complaints and considered clinically significant (ie, twice the
exhaustion are also reported. Objective evaluation coefficient of variation), and not due to inherent
of these endpoints is valuable, and the use of either variability alone.

Table 4—Suggested Normal Values for Selected CPET 3. HR or V_ E reaches predicted maximum
Variables
4. Respiratory exchange ratio .1.15
Variable Normal Value
5. Blood lactate concentration .4 mM
6. Patient exhaustion
Peak V_ O2 .85% predicted
AT .40% predicted peak V_ O2
The clinician must also decide upon contrib-
Peak HR .90% predicted peak HR utors to exercise limitation, and whether they are
HR reserve ,15 beats/min normal (ie, appropriate) or abnormal. Potential
BP ,200/90 mm Hg
factors that may contribute to limit exercise
O2 pulse (V_ O2/HR) .80% predicted
Peak V_ E ,85% (peak V_ E/predicted peak V_ E) include the following:
Ventilatory reserve .11 L (predicted peak V_ E – peak V_ E)
Respiratory rate ,60/min 1. Cardiovascular function
V_ E/V_ CO2 ,34 at AT; ,37–40 at end-exercise 2. Respiratory mechanics (and/or respiratory
VDS/VT ,0.30 muscle function)
PaO2 .80 mm Hg
SaO2 desaturation ,5% 3. Arterial hypoxemia
PAO2 - PaO2 ,35 mm Hg 4. Dyspnea
Exercise-induced ,10% fall in FEV1 5. Unfitness/deconditioning
bronchoconstriction
6. Musculoskeletal disorders, peripheral vascu-
Adapted from Weisman et al.5 lar disease
7. Other factors, for example, motivation, sec-
Interpretation and Reporting of CPET ondary gain, technical factors
While responses during exercise may vary in
Interpretation of CPET begins with the
healthy individuals and the range of normal is
requisition form. Requisition forms should be
quite broad, an understanding of ‘‘normalcy’’
designed to encourage the requesting physician
and normal exercise physiology is essential for
to provide as much clinical information as is
the recognition of disease. This understanding is
reasonable to enable the interpretation to be
essential for the appropriate interpretation of
valuable. This will enhance the ability of the
CPET. Suggested normal values for various
reporting physician to provide the most mean-
measurements obtained during CPET are listed
ingful interpretation possible from the available
in Table 4.
measured data.
In interpreting CPET, it is important to focus
There are a number of important fundamen-
on what is most important, on patterns of
tal questions that the reporting physician must
responses during exercise, and the reason(s) for
address when interpreting cardiopulmonary ex-
testing. This focus will ensure that a correct and
ercise testing.26 These include the following:
meaningful interpretation will result. Current
1. Are the results normal or abnormal? systems almost robotically produce a multitude
2. How limited is the patient? of both graphical and numerical results. This
3. What factors are responsible for the limita- abundance of ‘‘results,’’ and an overreliance and
tion? overdependence on complicated algorithms,
4. What abnormal patterns of response are have contributed to confusion. They undermine
demonstrated? the cardinal measurements and relationships, the
5. What clinical disorders may result in these fundamental importance of patient’s symptoms
patterns of response? during exercise, and the basic physiologic prin-
ciples that help us to better understand and
Determining whether a test is physiologically
appreciate the role and benefit (as well as the
maximal is necessary in excluding potential
limitations) of exercise testing in clinical practice.
underlying diseases or abnormalities. Useful
They also detract from the practical reality that,
indicators may include the following:
unlike in textbooks, guideline statements and/or
1. Plateau of peak V_ O2, or peak V_ O2 is achieved the lecture hall, CPET is never ordered nor
2. Maximum work rate is achieved interpreted in isolation. It should be requested,

Table 5—Characteristic Patterns of Response During Exercise in Various Settings
Variable CHF COPD ILD PVD Deconditioned
Peak V_ O2
AT V or indeterminate or
Peak HR V or or or
O2 Pulse or or
Peak V_ E/MVV or or
V_ E/V_ CO2
VDS/VT
PaO2 V
PAO2 - PaO2 V
MVV ¼ maximal voluntary ventilation; PVD ¼ pulmonary vascular disease; V ¼ variable; ¼ decreased; ¼ unchanged from
normal; ¼ increased. Adapted from Palange et al,4 Weisman et al,5 Wasserman et al,25 and Marciniuk and Gallagher.27,28
and its results translated within the context of all depression (25%), ischemic heart disease (10%–
available clinical information from the patient, 23%), anemia (17%), diabetes (12%–13%), cere-
with the specific goal of addressing the ques- brovascular disease (10%–14%), chronic renal
tion(s) being asked. CPET does not replace failure (6%-11%), and chronic heart failure (5%–
common sense—starting with the clinical assess- 7%).31 In these instances, interpretation should be
ment of the patient. For example, there are more partnered closely with the clinical setting and
appropriate methods than CPET to differentiate recognition of all potential comorbid conditions
COPD from ILD. To aid in achieving this goal, that could either alone or collectively affect
the characteristic patterns of response during exercise performance.
exercise, demonstrated in various disease states,
are noted in Table 5. These values highlight the Summary
importance of understanding that no single
measurement is diagnostic of any specific disease CPET typically involves the measurement of
entity. respiratory gas exchange (oxygen uptake [V_ O2],
Some special clinical circumstances require carbon dioxide output [V_ CO2], minute ventilation
comment. While obese individuals have well- [V_ E], and other variables) while monitoring the
documented impairments in respiratory func- ECG, blood pressure, pulse oximetry (SaO2), and
tion, obese patients with COPD may paradoxi- perceived exertion (Borg Scale) during a maximal
cally have similar or better dyspnea scores symptom-limited incremental exercise test on a
during exercise and comparatively preserved cycle ergometer or on a treadmill. In some
(or improved) exercise capacity and peak V_ O2. circumstances, a constant workload exercise test
These observations may be attributable to the (based on maximal test results) may be per-
finding that obese patients with COPD have formed. Measurement of arterial blood gases
lower operating lung volumes at rest and during provides more detailed information on pulmo-
exercise (Fig 11),29 although further study is nary gas exchange. Resting and exercise tidal
required to better understand these observations. flow-volume loops should also be monitored to
Another unique setting becoming increasingly accurately assess/understand the degree of
realized is when multiple comorbid conditions ventilatory constraint.
coexist, which may together act to further impair CPET provides a global assessment of the
exercise capacity. For example, subjects with integrative exercise responses, which are not
heart failure and coexistent COPD demonstrated adequately reflected by measurement of individ-
a significantly lower maximal V_ O2, and a signif- ual organ system function at rest—resting values
icantly higher V_ E/V_ CO2 slope, as compared to cannot reliably predict exercise performance and
otherwise comparable patients with heart fail- functional capacity. CPET is safe, and comorbid-
ure.30 Comorbidities in COPD are common and ities can be identified, while enhanced under-
include osteoporosis and arthritis (50%–70%), standing and insight into various responses,

including exercise limiting factors, is possible. 2. Gallagher CG. Exercise and chronic obstructive
Importantly, CPET promotes an integrative ap- pulmonary disease. Med Clin N Am. 1990;74(3):
proach to assessing metabolic, ventilatory, and 619–641.
cardiac function and reserve. While technically 3. Palange P. The prognostic value of exercise
more demanding than simpler tests, CPET testing. Breathe. 2009;5(3):229–234.
provides measurement of the peak V_ O2 (and 4. Palange P, Ward SA, Carlsen K-H, et al. Recom-
relationships involving the peak V_ O2), which mendations on the use of exercise testing in
remains the gold standard for assessing aerobic clinical practice–ERS Task Force. Eur Respir J.
exercise capacity. 2007;29(1):185–209.
5. Weisman IM, Beck K, Casaburi R, et al. American
Acknowledgment Thoracic Society/American College of Chest
Physicians Joint Statement on Cardiopulmonary
The author is indebted to Mr. R. Clemens for Exercise Testing. Am J Respir Crit Care Med. 2003;
his expert assistance in the preparation and 167(2):211–277.
review of the figures and the manuscript. 6. Colice G, Shafazan S, Griffin J, Keenan R, Bolliger
C. Physiologic evaluation of the patient with lung
Relationships Disclosed cancer being considered for resectional surgery:
ACCP evidence-based clinical practice guidelines
The author has disclosed the following (2nd edition). Chest. 2007;132(3 suppl):161S–177S.
relationships: University grant monies: Dalhou- 7. Sue DY. Excess ventilation during exercise and
sie University, McGill University. Grant monies prognosis in chronic heart failure. Am J Respir Crit
Care Med. 2011;183(10):1302–1310.
(from sources other than industry): Canadian
8. Guazzi M, Myers J, Arena R. Cardiopulmonary
Agency for Drugs and Technologies in Health,
exercise testing in the clinical and prognostic
Canadian Institutes of Health Research, Lung
evaluation of diastolic heart failure. JACC. 2005;
Association of Saskatchewan, Public Health
46(10):1883–1890.
Agency of Canada, Royal University Hospital
9. Crapo RO, Casaburi R, Coates AL, et al. ATS
Foundation, Saskatoon Health Region, Saskatch-
statement: guidelines for methacholine and exer-
ewan Ministry of Health. Grant monies (from
cise challenge testing–1999. Am J Respir Crit Care
industry related sources): AstraZeneca, Boeh-
Med. 2000;161(1):309–329.
ringer-Ingelheim, GlaxoSmithKline, Forest Re-
10. Trooster T, Sciurba F, Battaglia S, et al. Physical
search, Novartis, Nycomed, Pfizer, Shering-
inactivity in patients with COPD: a controlled
Plough. Employee: University of Saskatchewan.
multi-center pilot-study. Respir Med. 2010;104(7):
Fiduciary position (of any organization, associa- 1005–1011.
tion, society, etc, other than ACCP): Lung 11. ATS Committee on Proficiency Standards for
Association of Saskatchewan. Consultant fee, Clinical Pulmonary Function Laboratories. ATS
speaker bureau, advisory committee, etc: Cana- statement: guidelines for the six-minute walk test.
dian Lung Association, Health Canada, Health Am J Respir Crit Care Med. 2002;166(1):111–117.
Quality Council (Saskatchewan), Public Health 12. Marciniuk DD, Butcher SJ, Reid JK, et al. The
Agency of Canada, Saskatchewan Medical Asso- effects of helium-hyperoxia on 6-min walking
ciation, Saskatoon Health Region. Nothing to distance in COPD: a randomized, controlled trial.
disclose: Product/research disclosure informa- Chest. 2007;131(6):1659–1665.
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reviewed these relationships and resolved any index, airflow obstruction, dyspnea and exercise
potential conflict of interest. capacity index in chronic obstructive pulmonary
disease. N Engl J Med. 2004;350(10):1005–1012.
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walking versus shuttle walking: responsiveness to
1. Jones NL. Clinical Exercise Testing. 4th ed. Phila- bronchodilation in chronic obstructive pulmonary
delphia, PA: Saunders; 1997. disease. Thorax. 2007;62(4):291–298.

15. Brouillard D, Pepin V, Milot J, Lacasse Y, Maltais inflation and exercise endurance in COPD. Chest.
F. Endurance shuttle waling test: responsiveness 2006;130(3):647–656.
to salmeterol in COPD. Eur Respir J. 2008;31(3): 23. Gift AG. Visual analogue scales: measurement of
579–584. subjective phenomena. Nurs Res. 1989;38(5):
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MD. Exercise oscillatory breathing and increased 24. Borg GA. Psychophysical bases of perceived
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heart failure: an unfavorable combination with 25. Wasserman K, Hansen JE, Sue DY, et al. Principles
high prognostic value. Am Heart J. 2007;153(5): of Exercise Testing and Interpretation: Including
859–867. Pathophysiology and Clinical Applications. 5th ed.
17. Sun XG, Hansen JE, Beshai JF, Wasserman K. Philadelphia, PA: Lippincott Williams & Wilkins;
Oscillatory breathing and exercise gas exchange 2011.
26. Younes M. Interpretation of clinical exercise
abnormalities prognosticate early mortality and
testing in respiratory disease. Clin Chest Med.
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27. Marciniuk DD, Gallagher CG. Clinical exercise
18. Murphy RM, Shah RV, Malhotra R, et al. Exercise
testing in interstitial lung disease. Clin Chest Med.
oscillatory ventilation in systolic heart failure: an
1994;15(2):287–303.
indicator of impaired hemodynamic response to
28. Marciniuk DD, Gallagher CG. Clinical exercise
exercise. Circulation. 2011;124(13):1442–1451.
testing in chronic airflow limitation. Med Clin N
19. Johnson BD, Weisman IM, Zeballos RJ, et al.
Am. 1996;80(3):565–587.
Emerging concepts in the evaluation of ventilato-
29. Ora J, Laveneziana P, Ofir D, Deesomchok A,
ry limitation during exercise: the exercise tidal
Webb KA, O’Donnell DE. Combined effects of
flow-volume loop. Chest. 1999;116(2):488–503. obesity and chronic obstructive pulmonary dis-
20. Babb TG. Mechanical ventilatory constraints in ease on dyspnea and exercise tolerance. Am J
aging, lung disease, and obesity: perspectives and Respir Crit Care Med. 2009;180(10):964–971.
brief review. Med Sci Sports Exerc. 1999;31(1 30. Guazzi M, Myers J, Vicenzi M, et al. Cardiopul-
suppl):S12–S22. monary exercise testing characteristics in heart
21. Maltais F, Marciniuk DD, Hernandez P, et al. failure patients with and without concomitant
Improvements in symptom-limited exercise per- chronic obstructive pulmonary disease. Am Heart
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Notes

Chapter 6. Pulmonary Function Testing
Objectives: consistent, optimal effort. It is recommended that

Review the clinical indications, conduct, and interpreta- testing not be performed within 1 month of acute
tion of pulmonary function testing. coronary syndrome or myocardial infarction.1
Outline limitation(s) of various testing methods and
highlight the value of both laboratory and testing Similarly, patients with acute chest, abdominal,
standardization and quality assurance. or facial pain, as well as in those with confusion
Explore characteristic pulmonary function test results or significant dementia, are likely to generate
and diagnostic criteria associated with common respira-
tory clinical disorders.
suboptimal test results.
Accurate measurements of patient weight (in
Key words: interpretation; pulmonary function laboratory; street clothes and without shoes) and height
pulmonary function testing; quality assurance; spirometry (without shoes) should be recorded. In patients
with kyphoscoliosis or lower limb amputations,
Synopsis: arm span from fingertip to fingertip may be used
Pulmonary function testing (PFT) is one of the most as an estimate of height (regression equations are
important and most frequently utilized investigations in
our field. The conduct and interpretation of PFTs is a
available2). Alternatively, knee height can also be
defining competency of our specialty, and the PFT laboratory used for handicapped individuals when arm
is a fundamental and indispensable resource for the span is difficult to assess.3
pulmonologist. A thorough understanding of the indica-
tions, conduct, interpretation, and limitations of testing is
Dentures are often best left in place during
essential. In addition, as colleagues and our patients are testing unless they are loose or poorly fitting. It
dependent on and trust in results derived from laboratories would be prudent for patients to refrain from
we supervise, pulmonologists must also be expert in issues
related to quality assurance, standardization, and testing
smoking or undergoing vigorous exercise for 1 h,
procedures in the PFT laboratory. Although these roles are eating a large meal for 2 h, or consuming alcohol
closely related, the independent importance of each compe- for 4 h prior to testing.1
tency must be emphasized. In this regard, increasing
attention is being focused on mastery of the technical aspects
of testing and the laboratory, and these will be reviewed The Laboratory and Equipment
below. A comprehensive review of this area is beyond the
intent of this syllabus. Those wanting more complete
Efforts to avoid unintended factors unknow-
information are directed to the referenced source materials
at the end of this chapter. ingly contaminating results are important, as
these factors may subsequently lead to misinter-
pretation regarding the patient, disease, or
therapy. These influences are the most over-
Clinical Indications for PFT looked considerations in clinical PFT laboratories
today, and a thorough understanding of these
The indications for PFT are varied and
issues is especially necessary for PFT laboratory
depend on the clinical setting and question(s) to
directors. Although specific important issues will
be addressed. Generally accepted clinical indica-
be discussed in sections below and a number of
tions are listed in Table 1.
overall principles deserve highlighting, the topic
is also reviewed in detail elsewhere.4
Important Considerations for Testing
Temperature and barometric pressure mea-
The Patient surements must actually be recorded, and it is
important to ensure accuracy of the instrument
PFT results will be less meaningful in patients making those measurements. The time of day
who are not physically capable of providing should be noted and serial testing should ideally

Table 1—Clinical Indications for Pulmonary Function Table 2—Suggested Order for Conducting Lung Function
Testing Tests
Evaluate symptoms, signs, or abnormal investigations Spirometry and flow-volume curves

Assess and monitor the effect of disease/intervention/ Lung volumes
exposure on respiratory symptoms and/or pulmonary Bronchodilator administration
function Diffusing capacity
Early detect of individuals at risk of pulmonary Repeat spirometry and flow-volume curves
impairment or disease early
Assess and minimize preoperative risk Adapted from Miller et al.1
Objectively assess impairment
Understand severity and prognosis
5. In patients with known or suspected trans-
missible infectious diseases, additional pre-
cautions should be undertaken. These include:
be made at similar times of the day to minimize a) Utilizing equipment solely reserved for use
variation. in this clinical setting.
The order of testing is not necessarily rigid, b) Testing patients at the end of the day to
but the order in a specific laboratory should allow for complete spirometry disassembly
ideally be kept constant. Consideration should and disinfection.
also be given to the effects of bronchodilator c) Testing patients in their own rooms, or in
administration on lung volume determination or rooms with enhanced capabilities (ie, nega-
factors influencing the diffusing capacity (dis- tive pressure ventilation).
cussed below). A suggested order for performing
lung function tests is noted in Table 2. Inline disposable filters are currently almost
Patient and staff safety in the clinical labora- universally utilized. Although some significant
tory is paramount. Issues relating to building and differences between measurements with and
general facilities, accident, fire and evacuation without filters have been demonstrated, the
procedures, compressed gas storage and use, effects are not considered to be clinically signif-
electrical safety, and procedures and practices for icant and do not lead to misinterpretation.5,6
tending to patient urgencies and emergencies However, as the benefits of filters have not been
must be addressed. Appropriate procedures clearly identified, their use is not mandatory,
must be established, understood, practiced, and particular if all other precautions are strictly
regularly monitored. followed. Overall, most laboratories use inline
Infection control measures are also necessary filters, perhaps to reassure patients and staff that
for the protection of patients and staff. Although their safety and protection is a high priority. It
the risk of infection is small, the potential is real deserves emphasis that the use of inline filters
and the consequences are serious. To minimize should not be viewed as a shortcut for appropri-
these risks: ate infection control and does not eliminate the
need for regular cleaning and decontamination of
1. Hands must be washed properly and barrier lung function equipment.
devices such as gloves should be used.
2. Reusable mouthpieces, valves, mouthpieces, Laboratory Personnel
and manifolds must be appropriately disin-
fected or sterilized. Laboratory staff must be appropriately
3. Disposable equipment, sensors, and devices trained in order to understand the fundamentals
should be discarded, and never reused even if of testing, to be familiar with signs and
disinfected or sterilized. symptoms of common respiratory disease, and
4. Sterilizing and disinfecting techniques should to properly execute all aspects of testing.
be strictly adhered to and established in Training requirements vary across regions and
consultation with the manufacturer’s recom- many available opportunities for training cours-
mendations and local or hospital infection- es are available. A period of mentorship in the
control divisions. laboratory under the experience of seasoned
122 Chapter 6. Pulmonary Function Testing (Marciniuk)

technicians is crucial for new staff. Opportuni- Table 3—Evaluation and Feedback for Pulmonary Function
Laboratory Technicians
ties for ongoing professional development
should be made available to staff, ensuring that Information regarding acceptable maneuvers and
training and skills remain current and upgraded nonreproducible tests
Specific corrective actions the technicians can undertake
when appropriate. This is particularly important
to improve the quality and number of acceptable
with alterations to equipment or changes in PFT maneuvers
standards. Although manufacturers frequently Positive feedback for excellence and good performance
provide training for new equipment or signifi- Feedback regarding system setup and reporting results
Asking the technician to comment on current laboratory
cant upgrades, laboratories should not solely
procedures and testing, specifically inquiring about
rely on these methods as a guarantee that opportunities for improvement
technician skills are current.
Continuous in-house feedback and evalua- Adapted from Miller et al.1
tion of laboratory technicians has been validat-

ed.7 This practice promotes the collection of high- 4. Vital capacity (VC) decreases, whereas resid-
quality data and works to ensure staff remains ual volume (RV) increases with age, leaving
well motivated and enthusiastic. Appropriate total lung capacity (TLC) the same. The
content for regular and formalized feedback to diffusing capacity declines with age.
technicians is noted in Table 3. 5. Taller individuals have larger lung volumes
PFT laboratory medical directors must have and higher maximal flow rates.
all of the above attributes and skills, but are also 6. African Americans have spirometric values
responsible for all aspects of quality assurance, that are lower than those of Caucasians of the
selection of reference values, and practical same age, height, and gender. If predicted
operational issues relating to the day-to-day values for a healthy population of the same
conduct of the laboratory. ethnic background are not available, Cauca-
sian predicted values should be corrected by
Reference Values 0.88 for African Americans, Asians, and East
Indians. The FEV1/FVC ratio should not be
PFT interpretation is based on comparisons of race corrected.
data measured in an individual patient with
Various reference values have been both
reference values derived from a representative
developed and recommended, and this has led
population of healthy subjects. Unlike many
to uneasiness and frequently inappropriate ref-
physiologic variables, normal values of pulmo-
erence value selection. However, a new coordi-
nary function vary with age, height, gender, and
nated recommendation has recently been put
race. Moreover, because the range of normal is
forth for the third National Health and Nutrition
considerable (eg, 80%–120% of the predicted
Examination Survey reference equations to be
value), significant changes in pulmonary func-
used for spirometry in the United States.9
tion can occur while values still remain within
Recommendations for lung volume and diffusing
the normal range. These factors serve to compli-
capacity reference values are less specific (Table
cate the choice of the most appropriate reference
4). Selected reference equations should reflect a
value regression equations to use in the clinical
similar age range, gender, and ethnic background
laboratory.
to those of patients in the laboratory, and all
A number of observations regarding lung
spirometric data should use the same source for
function measurements in the population are
reference values.
known, and include:
Although reference values are fundamental
1. Males have larger lung function than females. for the correct interpretation of pulmonary
2. Lung function values plateau between the function test results, if serial testing is undertak-
ages of 20 and 35 years of age.8 en, comparison with the patient’s previous
3. FEV1 decreases approximately 30 mL/y. values is also appropriate and meaningful.

Table 4—Reference Values in the PFT Laboratory Spirometry
General principles
Predicted values should be obtained from normal Spirometry measures the exhaled volume of
subjects with the same anthropometric and ethnic air vs time, and is the most commonly performed
characteristics of the patient being tested. PFT. Volume or flow may be directly measured,
Height and weight should be measured for each
patient at each testing.
and in many instances both inhaled and exhaled
All parameters should be taken from the same maneuvers are undertaken. The primary vari-
reference source when possible. ables of interest are the FVC and the FEV1, both
Extrapolation beyond the size and age of the reference
expressed at body temperature, ambient pressure
population should be avoided when possible.
Values below the 5th percentile of the frequency saturated with water vapor (BTPS).
distribution of values from the reference population
should be considered as below the lower limit of Equipment
normal.
Spirometry
In the United States, ethnically appropriate NHANES A spirometer capable of measuring volume
III reference equations published in 1999 for those for at least 15 s and at least 8 L, with an accuracy
ages 8–80 y are recommended.10 of –3% or –0.05 L, whichever is greater, with
Lung volumes
No specific set of reference equations is
flows between 0 and 14.0 L/s is required.11 Total
recommended; however, a list of potentially suitable resistance to airflow, at up to 14 L/s, should be
reference equations is available.9 less than 1.5 cm H2O/L/s, including all tubing,
Diffusing capacity filters, and valves. Real-time display of flow vs
No specific set of reference equations is
recommended; however, a list of potentially suitable volume is useful for assessing the magnitude of
reference equations is available.9 effort during the initial portion of the maneuver,
and a volume vs time display provides informa-
NHANES ¼ National Health and Nutrition Examination
Survey. Adapted from Pelligrino et al.9
tion during the remainder of the maneuver for
determining a satisfactory end of test. The
spirometer must be appropriately calibrated at
least daily, which establishes the relationship
Specific values for normalcy are controver-
between sensor-determined values for flow or
sial, but in general there is a move to also report
volume and the actual flow or volume. Calibra-
the normal range in terms of a lower limit of
tion syringes must have an accuracy of –0.5% of
normal (LLN) (spirometry, lung volumes, diffus-
the full scale (ie, –15 mL for a 3-L syringe). It is
ing capacity) and an ‘‘upper limit of normal’’
important to ensure that the calibration syringe
(lung volumes and diffusing capacity). Utilizing
functions appropriately and that monthly leak
values such as 80% of predicted as the lower tests are done. The syringes themselves should
range of normal is useful, but in some instances be serviced, recalibrated, and verified on a
may result in false positives and false negatives regular basis. Finally, regular daily checks for
(see below, ‘‘Interpreting Pulmonary Function system leaks must be undertaken and are easily
Tests’’). It is therefore recommended that the performed. Detailed instructions regarding cali-
LLN be determined from the 5th percentile (ie, bration are discussed elsewhere.4,11
mean: 1.96 SD, two-tailed t test, P , 0.05). In
addition, categorizing results as borderline ab- Testing Procedure
normal if they encroach upon the upper limit of
normal or the LLN is an acceptable clinical Detailed information on testing procedures is
concept. Although software is available to beyond the scope of this syllabus; however,
readily supply these values, clinical comfort additional guidance and information is available
and acceptance with these recommended chang- elsewhere.4,11 A number of important fundamen-
es in reporting and interpretation is still evolv- tals will be highlighted below.
ing. There is significant unfamiliarity with assess-
Guiding principles for the use of reference ing the acceptability and repeatability of spirom-
values in the PFT laboratory are listed in Table 4. etry. Inherent in optimal quality control is the

Table 5—Within-Maneuver Acceptability Criteria for Spi- Table 6—Between-Maneuver Reproducibility Criteria for
rometry Spirometry
Individual spirograms are acceptable if they are free After 3 acceptable spirograms have been achieved,
from artifacts (cough during first second of exhalation, testing can be concluded if the 2 largest values for both
glottis closures, early termination, submaximal effort, the FEV1 and the FVC are within 0.15 L of each other.
leak, obstructed mouthpiece). After 3 acceptable spirograms have been achieved,
Efforts have good starts (extrapolated volume ,5% of testing is still continued if the 2 largest values for both
FVC or 0.15 L, whichever is greater). the FEV1 and the FVC are not within 0.15 L of each
Efforts show satisfactory exhalation (duration of .6 s, or other, until both criteria are met with analysis of
a plateau in the volume-time curve, or subject cannot/ additional acceptable spirograms; or until a total of 8
should not continue). tests have been performed; or until the patient cannot/
should not continue.
Adapted from Miller et al.11 All satisfactory maneuvers should be saved.
acceptability of each individual spirogram, as Adapted from Miller et al.11

well as the repeatability of a number of accept-
airflow obstruction, and in detecting central
able spirograms, recognizing that an adequate
airway obstruction. Both inspiratory and expira-
test requires at least three acceptable maneuvers.
tory loops are best obtained. The subject, while
Acceptability criteria are met if efforts are free
tidal breathing at rest, is typically asked to
from artifacts (cough, glottis closure, early
termination, submaximal effort, leak, or obstruct- inspire to TLC and then expire with maximal
ed mouthpiece), they have good starts (extrapo- force until empty, down to RV, followed by a
lated volume is ,5% of the FVC or 0.15 L, maximum inspiration back up to TLC. Evalua-
whichever is greater), and they show satisfactory tion of the efforts is the same as noted above,
exhalation duration of .6 s (or a plateau in the although the inspiratory portion of the curve is
curve is noted). Within-maneuver acceptability often assessed only qualitatively. A volume-vs-
criteria are listed in Table 5. time plot and a flow-vs-volume plot for the same
Repeatability criteria are applied only after maneuver are shown in Figure 2.
the acceptability of individual spirograms has Other measurements are possible as well
been met, as outlined above. The two largest (volume-vs-time plot shown in Figure 3, where
values (from three acceptable individual spiro- measured volumes are shown in clear bars and
grams) for both the FEV1 and FVC must be summed capacities are shown in shaded bars).
within 0.15 L of each other in order to achieve VC is the volume of gas that can be expelled
repeatability criteria. If FEV1 and FVC repeat- from full inspiration to complete expiration,
ability criteria are not achieved, testing may be whereas FVC is the same measurement when
terminated after a total of eight acceptable the patient exhales with maximal speed and
individual maneuvers have been performed, or effort. VC is occasionally higher than FVC, the
if the patient cannot or should not continue. difference being related to the degree of obstruc-
Between-maneuver criteria are listed in Table 6. tion. The inspiratory capacity (IC) is the volume
The largest FVC and the largest FEV1 should from a position of passive resting end-tidal
be reported after examining all acceptable curves, expiration (end-expiratory lung volume [EELV])
even if they do not come from the same curve. to full inspiration. IC has been demonstrated to
The best-test curve should be from the trial with correlate with lung hyperinflation at rest and is
the largest sum of the FEV1 and FVC; other flow responsive to changes in EELV with activity and
parameters should be derived from this best-test pharmacologic interventions. These measure-
curve. These procedures are summarized in ments are not forced, but at the same time
Figure 1. exhalation or inspiration should not be unduly
slow. In order to provide absolute placement of
Maximal Flow-Volume Curve these volumes and capacities (and to estimate
RV), actual measurement of functional residual
Assessing the maximal flow-volume curve is capacity (FRC) must be undertaken (see ‘‘Lung
helpful in quality assurance, in detecting mild Volumes’’ for further discussion). A tight seal

Figure 1. Required steps for performing spirometry.
between the lips and mouthpiece and a comfort-

Figure 2. Volume vs time and flow vs volume plots.
able, constant seated position with appropriate
height adjustment of the mouthpiece is necessary
to ensure validity and repeatability. and 200 mL is considered a positive bronchodi-
The IC should be reported as the average of lator response.9 The utility of a bronchodilator
at least three maneuvers (not the best). The mean response is dependent on the clinical setting, and
coefficient of variation (CV) for the IC in COPD is overreliance on the result often leads to inappro-
estimated to be 5% – 3%. priate clinical decision making. A lack of a
bronchodilator response does not necessarily
Reversibility Testing predict lack of a therapeutic response. In this
regard, it is important to know when the patient
Reversibility testing after administration of a last received any medication that might affect the
bronchodilator is frequently undertaken in the response. It is recommended patients withhold
PFT laboratory. Baseline testing is followed by
administration of a short-acting bronchodilator,
after which repeat testing is done. Either a short-
acting b2-agonist (eg, 400 lg salbutamol with
repeat testing at least 10 min afterwards) or an
anticholinergic (eg, 160 lg ipratropium with
repeat testing at least 30 min afterwards) can be
used. 11 Current recommendations are for
increased doses of the bronchodilator (four puffs
vs two puffs), as noted above, unless there is
concern for the patient’s heart rate or tremor. An
increase in either the FEV1 or the FVC of 12% Figure 3. Lung volumes and capacities.

taking short-acting bronchodilators for at least 4 h
prior to testing, and any long-acting or sustained-
release bronchodilators for at least 12 h prior to
testing.
Peak Expiratory Flow
Peak expiratory flow (PEF) is the highest flow

achieved from a maximal forced expiratory
maneuver from TLC. When obtained from a
spirometer, PEF is normally expressed at BTPS in
liters per second, whereas most portable moni-
toring instruments display results in liters per
minute. The measurement (and derived/related
variables) is highly dependent on lung volume
and effort. After achieving full inflation, the
patient should deliver the blow without hesita-
tion. A delay of as little as 2 s can alter tracheal
viscoelastic properties enough to cause a reduc-
tion in the PEF by as much as 10%.12
PEF measurements are embedded in asthma
management strategies, but some difficulties
with the measurement have been experienced.
There are many other variables related to and
derived from the PEF (Fig 4), but they have not
been proven to be equal or superior to spirom-
etry in the individual clinical setting.11
Maximum Voluntary Ventilation
Maximum voluntary ventilation is the full

volume of air a subject can breathe over a period
of time (typically 12–15 s), and is expressed in
liters per minute at BTPS. Its clinical contribution
has largely been superseded by the FEV1 and Figure 4. Peak expiratory flow and derived variables in flow
vs volume (A) and volume vs time (B) plots.
FVC, and it is now infrequently measured. It may
be useful in some clinical settings where venti-
latory capacity may be impaired by mechanisms
different than those directly affecting the FEV1, remains the gold standard for establishing a
for example neuromuscular disorders and central restrictive abnormality. There are a variety of
airway obstruction. Although it has been used as available techniques in the pulmonary function
an estimate of maximal ventilation during laboratory that may be used to measure absolute
exercise, there are significant limitations with lung volumes, including body plethysmography,
this approach (discussed in further detail in the nitrogen (N2) washout, and inhaled inert gas
‘‘Cardiopulmonary Exercise Testing’’ chapter). dilution. The lung volumes of interest are noted
in Figure 3. In addition to the VC and IC
Lung Volumes (discussed and defined above), the:
Although lung volume measurement is more FRC is the volume of gas present in the lung at
challenging and less available than spirometry, it end expiration during tidal breathing, and is

the absolute volume measured in the PFT
laboratory.
Expiratory reserve volume (ERV) is the volume
of gas maximally exhaled from EELV during
tidal breathing.
Inspiratory reserve volume is the volume of gas
that can be maximally inhaled from the end-
inspiratory lung volume during tidal breath-
ing.
Tidal volume is the volume of gas inhaled or
exhaled at rest with each breath.
TLC is the volume of gas in the lungs after
maximal inspiration (the sum of all volumes).
FRC determination is the key component in
the measurement of lung volumes. Regardless of Figure 5. Recommended method for measuring lung
volumes.
the technique used to measure FRC, TLC and RV
will be estimated from the FRC and the mea-
by plethysmography is typically higher than that
surements of IC and ERV. Although opinion
measured by gas dilution techniques.
varies on the best technique, the preferred
Plethysmographic testing is performed by
method is to measure ERV immediately after
having the patient sit in a sealed box and pant
the FRC measurement, followed by a slow
against a closed shutter. During the inspiratory
inspiratory VC (IVC) maneuver, all performed
with the patient remaining on the mouthpiece phase of the pant, thoracic volume increases
until the completion of the maneuver (Fig 5). slightly, decompressing the volume of air in the
Assuming technically satisfactory measure- lungs while slightly compressing the volume of
ments, the reported value for FRC is the mean of air in the box. Conversely, during the expiratory
FRC measurements associated with the ERV and phase of the pant, thoracic volume decreases
IVC maneuvers used to calculate the RV and slightly, compressing the volume of air in the
TLC. The reported value for the RV is the lungs while slightly decompressing the volume
reported FRC minus the ERV linked to the of air in the box. Using the Boyle Law, where at a
acceptable FRC. The reported value for the TLC given temperature, the product of gas volume
is the reported RV plus the largest of the IVCs.13 and pressure is constant:
An alternative recommended method in- V1 3 P1 ¼ V2 3 P2 ð1Þ
volves determination of IC immediately follow-
ing measurement of FRC to estimate TLC. The where the initial pressure and volume at FRC are
VC measurement can then either be linked to this P1 and V1. Pressure and volume at the end of the
maneuver or performed separately following an inspiratory phase of the pant are P2 (P1 þ DP)
ERV maneuver as described above. and V2 (V1 þ DV). Thus:
V1 3 P1 ¼ ðV1 þ DVÞ 3ðP1 þ DPÞ ð2Þ
Body Plethysmography Technique
P1 and DP are measured at the mouth, assuming
Thoracic gas volume refers to the plethysmo- that mouth and alveolar pressures are equal and
graphic measurement of intrathoracic gas vol- DV is measured using the change in box pressure,
ume at the time of airflow occlusion, the thus allowing for V1 to be solved.
compressible gas within the thorax. In normal Lung volumes measured by body plethys-
individuals, measurement of FRC by plethysmo- mography are considered the gold standard, but
graph and gas dilution techniques yields similar strict attention to testing methods, equipment
results; however, in patients with obstructive upkeep and quality control, and panting tech-
lung disease and gas trapping, FRC determined nique and frequency are essential.

Gas Dilution Techniques As a test of gas transfer, CO uptake by the
lung can be measured by a number of techniques
Gas dilution techniques measure the gas (steady-state, intrabreath, rebreathing, and single-
volume in the lungs that communicates via the breath), but the most commonly used methodol-
airways, using a mass balance approach. A mass ogy is the single-breath technique. Testing begins
balance equation uses the initial volume and with the patient exhaling down to RV, at which
tracer gas concentration and the final tracer time a valve opens and the patient rapidly
concentration to calculate the volume in the inhales the test gas to TLC. The patient holds
patient’s lungs at the moment the tracer gas his or her breath for 10 s, and then breathes out
breathing began. The assumption that the tracer rapidly while the exhaled gas is collected.
gas is largely insoluble, inert, and well mixed in The gas inspirate usually consists of a
the lung is fundamental. For example, incom- mixture of N2, 0.3% CO, an inert tracer gas such
plete gas mixing would cause lung volumes to be as He, and 19% to 21% O2. An alveolar sample of
underestimated, whereas use of a soluble gas the exhaled gas is considered after anatomic and
would cause lung volumes to be overestimated. mechanical dead space gas is discarded from the
Either helium (He) rebreathing or N2 washout collected gas (~0.75–1.0 L, but as little as 0.5 L if
techniques may be used, although both tend to the patient’s VC is ,2.0 L). A submaximal
underestimate lung volume when airway ob- inspired volume (VI) can affect CO uptake, so it
struction is present. For N2 washout, the washout is important that the VI be as close to the known
VC as possible. Because a reduction in VI of
is satisfactory when the N2 concentration is
.15% may significantly reduce the measured
,1.5% for at least three successive breaths.13
DLCO, a VI target of 85% of the largest VC is
For He rebreathing, a typical 10% He concentra-
suggested.14 In order to minimize variability in
tion with 25% to 30% oxygen (O2) gas mixture
the measurement, inspiration should be rapid
inspirate is breathed until equilibration, when
(,4 s), breath hold should be 10 – 2 s, and
the change in He concentration is ,0.02% for at
expiration should ideally also be ,4 s in
least 30 s.13 If only room air is added to the 10%
duration. At least 4 min should transpire
He gas mixture, it is important to ensure
between repeat testings to allow for adequate
adequate O2 replacement during the test. Both
elimination of the test gas from the lungs. This
measurements must be corrected to BTPS, and
time period should be extended (~10 min) in
the volume of the equipment dead space should
patients with significant obstruction.
be subtracted.
The DLCO may be affected by a number of
conditions (Table 7). Other factors known to
Diffusing Capacity affect the DLCO are diurnal variation (increased in
the morning, and reported to decrease 1% to
Carbon monoxide diffusing capacity of the 2%/h throughout the day15), menstrual cycle (up
lung (DLCO) assesses gas exchange by measuring to 13% change, increased premenses), alcohol
the rate of carbon monoxide (CO) transfer from consumption (increased after ingestion), and
the lungs to the blood, with values reported in bronchodilator administration (increased up to
mL/min/mm Hg. A number of both structural 6% after use).
and functional properties influence the capacity
of the lung to exchange gas across the alveolar- Adjusting the DLCO Measurement
capillary border. These include the volume and
distribution of ventilation, mixing and diffusion, DLCO measurement is dependent upon a
the composition of the gas, characteristics of the number of physiologic conditions, including
alveolar membrane and lung parenchyma, the changes with Hgb, lung volume, carboxyhemo-
volume of alveolar capillary plasma, the concen- globin (COHgb), FIO2, exercise, and body posi-
tration and binding properties of hemoglobin tion, in addition to age, sex, height, and possibly
(Hgb), and the gas tensions in blood entering the race.14 Specific adjustments should be made for
alveolar capillaries. Hgb, COHgb, and FIO2 prior to interpretation.

Table 7—Factors Affecting DLCO Hg, is:
Conditions that may reduce DLCO DLCO ðadjustedÞ ¼ DLCO ðpredictedÞ=

Submaximal inspiration or respiratory muscle
ð1:0 þ 0:0035½PAO2 100Þ ð5Þ
weakness
Anemia
The recommended equation for adjusting the
Valsalva maneuver
COHgb predicted DLCO for altitude, assuming a PIO2 at
Increased FIO2 sea level of 150 mm Hg, is:
Lung resection
COPD DLCO ðadjustedÞ ¼ DLCO ðpredictedÞ=
Interstitial lung diseases
ð1:0 þ 0:00311½PIO2 150Þ ð6Þ
Pulmonary vascular disease, ie, emboli, pulmonary
hypertension, vasculitis
Conditions that may increase DLCO
Polycythemia
Adjusting for COHgb Concentration and CO
Left to right shunt Back Pressure
Asthma
Pulmonary hemorrhage
COHgb may acutely reduce DLCO16 by occu-
Muller maneuver
Exercise pying Hgb binding sites and by reducing driving
Supine position pressure for CO transport from alveolar gas to
Obesity
capillary blood. Typical exposure to environmen-
Decreased FIO2
tal CO and endogenous production results in
Adapted from MacIntyre et al.14 measured COHgb of 1% to 2%, which is already
incorporated into reference values based on
Adjusting for Hgb healthy nonsmoking subjects. Cigarette smoke
and other environmental sources of CO can lead
Because COHgb binding is fundamental to to further appreciable increases in measured CO
the measurement of DLCO, Hgb concentration can back pressure and COHgb that should be
substantially affect its measurement. Expressing considered. Increases in COHgb also occur with
Hgb in g/dL, the recommended equation for repeated measurements, as CO is inspired in the
adjusting the predicted DLCO in adolescents and DLCO test. For example, five tests will increase
adult males is14: COHgb by ~3.5%, which will decrease the
measured DLCO by 3.0% to 3.5%. It is therefore
DLCO ðadjustedÞ ¼ DLCO ðpredictedÞ
recommended that no more than five repeated
3ð1:7 Hgb= 10:22 þ Hgb Þ
measurements be undertaken at any sitting.
ð3Þ Accounting for both the back pressure and
The recommended equation for adjusting the COHgb effects, a 1% increase in COHgb reduces
predicted DLCO in females is14: the measured DLCO by 0.8% to 1% from both
DLCO ðadjustedÞ ¼ DLCO ðpredictedÞ known effects. This is represented by the
following equation14:
3ð1:7 Hgb= 9:38 þ Hgb Þ ð4Þ
DLCO ðadjustedÞ ¼ DLCO ðpredictedÞ
3ð102% COHgb%Þ ð7Þ
Adjusting for PAO2
PAO2 also affects the measurement of DLCO, Adjusting for Lung Volume
either because of supplemental O2 or because of
testing at altitude. The DLCO will change by Adjusting DLCO for lung volume is both
~0.35% per mm Hg increase change in PAO2, or complex and confusing. It is complex because
by ~0.31% per mm Hg decrease change. The the reason(s) for a reduced lung volume vary, as
recommended equation for adjusting the pre- do the effects of the specific underlying reason on
dicted DLCO in a subject on supplemental O2, the resultant measured DLCO. Adjusting the DLCO
assuming a room air PAO2 at sea level of 100 mm for lung volume is confusing because in some

instances the relationship is proportional, whereas MIP measurement is performed with the
in other settings it is unpredictable and varied. In patient maintaining a tight seal between the lips
view of these realities, drawing definitive clinical and the mouthpiece, exhaling down to RV, and
conclusions based on a volume-corrected DLCO then breathing in as hard and fast as he or she
should be done only with caution. As recom- can. The patient should keep up the MIP for ~2 s,
mended in international guidelines,14 further with the largest negative pressure sustained for 1
study and understanding is required before more s being recorded. A longer continuous inspirato-
specific volume-adjustment recommendations for ry effort is neither required nor recommended.
the DLCO can be made and uniformly adopted. After the patient rests for ~1 min, the procedure
The average of at least two acceptable tests is repeated for a total of at least three times, with
should be reported for interpretation of the DLCO. the intent of obtaining repeat measurements with
Reporting should include the unadjusted DLCO, a variability of less than 10 cm H2O. It must be
predicted and percentage predicted DLCO, pre- emphasized that testing is very dependent on
dicted and percentage predicted DLCO/alveolar patient effort and cooperation, which may be
volume, and a list of any adjustments made to enhanced by the technician initially demonstrat-
the value because of corrections (ie, Hgb, ing the maneuver to the patient, and by the use of
COHgb, PAO2, lung volume). As always, techni- a practice test. Other potential sources of error in
cian comments regarding the quality of the the measurements include pressure gauge accu-
measurements should be noted. racy, the patient-device interface, and leaks.
MEP measurement is similarly performed
Respiratory Muscle Pressures except that the patient is instructed to inhale to
TLC, and then to blow out as hard and fast as he
Respiratory muscle strength can be assessed or she can. In similar fashion to the MIP, the
by determining the maximal inspiratory pressure largest positive pressure sustained for 1 s is
(MIP) and the maximal expiratory pressure recorded. After the patient rests for ~1 min, the
(MEP). The MIP reflects the strength of the procedure is repeated for a total of at least three
diaphragm and other inspiratory muscles, times, with the intent of obtaining repeat
whereas the MEP reflects the strength of the measurements with a variability of less than 10
abdominal and other expiratory muscles. Clinical cm H2O.
indications for assessing respiratory muscle The maximum value obtained from the three
strength are varied, but relate to any clinical suitable maneuvers should be reported for both
setting in which respiratory muscle weakness or the MIP and MEP. Definitive reference ranges for
the MIP and MEP have not been agreed upon,
neuromuscular disorders affecting respiratory
although many are available.17,18 In general, a
status are suspected. Testing can be helpful in
number of key observations are appropriate:
the diagnosis of respiratory muscle weakness, in
assessing the severity of respiratory muscle 1. Values decrease with age and are approxi-
weakness, in predicting clinical outcomes, and mately one-third lower in female when com-
in the longitudinal follow-up of patients diag- pared with male subjects.
nosed with respiratory muscle weakness. 2. In adults 18 to 65 years of age, the MIP should
Equipment for measuring the MIP and MEP exceed 90 cm H2O in men and 70 cm H2O in
is simple and similar techniques are used in both women. In adults over age 65, the MIP should
measurements. A pressure gauge connected to a generally exceed 65 cm H2O in men and
mouthpiece can be readily assembled, or alter- 45 cm H2O for women.
natively, commercially available systems may be 3. In adults, the MEP should exceed 140 cm H2O
used. In either case, there must be a small hole of in men and 90 cm H2O in women.
approximately 1 mm in the system to allow for 4. An MIP below one-third of normal predicts
an air leak, which minimizes the likelihood of the hypercarbic respiratory failure.19
patient generating pressure with the use of their 5. An MEP , 60 cm H2O predicts a weak cough
cheek muscles. and difficulty clearing secretions.20

A normal MIP reliably excludes inspiratory Methacholine responsiveness is usually re-
muscle weakness (ie, good negative predictive ported as the provocation concentration (PC) (or
value), but a low MIP does not reliably confirm dose) causing a 20% drop in the FEV1 (PC20). The
inspiratory muscle weakness. The poor positive PC20 is log-normally distributed in the popula-
predictive value reflects the high frequency of tion, can be measured into the normal range and
falsely low MIP measurements due to unrecog- is a relatively imprecise measurement with
nized poor effort or technique.21 In normal repeatability of –1 doubling concentration. The
healthy individuals, 95% of the test-to-test results are typically interpreted as follows26:
variation has a magnitude of less than 25 cm
H2O.22 Moreover, it has been demonstrated that Normal .16 mg/mL
Borderline 4–16 mg/mL
improvements in the MIP of 13 cm H2O and
Mild AHR 1–4 mg/mL
MEP of 24 cm H2O do not necessarily correlate Moderate AHR 0.25–1 mg/mL
with symptomatic improvement.23 Marked AHR ,0.25 mg/mL
VC and FVC are often used as alternatives or
complementary measurements to the MIP and
MEP in clinical practice. Comparisons of the MIP An example of results consistent with mod-
and the VC demonstrate similar sensitivity and erate AHR is demonstrated in Figure 6.
specificity for detecting hypercarbic respiratory From a diagnostic point of view, the test has a
failure. In the upright position, a reduced FVC strong negative predictive value and therefore
seems to be less specific for detecting respiratory functions best when normal to rule out current
muscle abnormalities than the MIP. However, a asthma. However several caveats should be
fall in the FVC from upright to the supine remembered. First, methacholine challenges
position appears to detect inspiratory muscle should not be done with TLC inhalations to
weakness more reliably than the MIP.24 maintain diagnostic sensitivity. Second, it is
critical that symptoms be current (ie, within the
Airway Challenges past few days). It follows that a normal (negative)
methacholine challenge test in a currently
Assessing airway responsiveness is most asymptomatic patient cannot rule out asthma.
commonly undertaken to either confirm or ex- Most patients with exercise-associated bron-
clude a suspected diagnosis of asthma, recogniz- choconstriction (which when clinically occurring
ing that airway hyperresponsiveness (AHR) to in isolation is frequently a manifestation of mild
exogenous stimuli is a characteristic feature of the asthma) will have a positive direct inhalational
disease. Testing can be performed using a number challenge. However, it is now recognized that
of various techniques, using either selective some patients, in particular high-performance
(typically specific allergens, but uncommonly used athletes, may have positive exercise challenges
outside of the research laboratory) or nonselective but a negative direct (ie, methacholine) challenge.
agents. Nonselective stimuli can be either direct The implication is that a negative methacholine
(eg, methacholine and histamine) or indirect (eg,
exercise, eucapnic voluntary hyperventilation,
cold air, and mannitol).
Methacholine is the most commonly per-
formed direct challenge. It is typically undertaken
with two different techniques: the tidal breathing
method and the dosimeter method. Recent studies
have questioned the sensitivity of the dosimeter
method utilizing TLC inhalations in patients with
mild AHR; thus the use of the tidal breathing
method or a modified dosimeter method are now
recommended.25 A more detailed description of
the testing methods is available elsewhere.26,27 Figure 6. Methacholine challenge test study results.

Table 8—Common Medications That Decrease Bronchial Table 9—Diagnosing Common Respiratory Disorders
Responsiveness
Obstruction
Suggested Time FEV1/VC ,5th percentile of predicted.
Interval to Withhold Reduced flows at low lung volumes are not specific
Administration for small airways disease in individual patients.
A combined reduction in both FEV1 and VC is
Short-acting b2-agonists 8h commonly related to suboptimal effort. This pattern
Short-acting anticholinergics 24 h may occasionally indicate airflow obstruction, but
Long-acting b2-agonists 48 h confirmation requires absolute lung volume
Long-acting anticholinergics Up to 7 d measurement.
Short-acting theophyllines 24 h Measurement of absolute lung volume measurement
Sustained-release theophyllines 48 h may assist in diagnosing and assessing COPD and
asthma.
Adapted from Crapo et al.26 Restriction
TLC ,5th percentile of predicted.
Spirometry cannot definitively diagnose restriction.
challenge will not completely rule out exercise- A reduced TLC from a single-breath technique should
associated bronchoconstriction in this popula- not be used to diagnosis restriction.
tion. Exercise challenge testing will be discussed Mixed obstruction/restriction
FEV1/VC and TLC ,5th percentile of predicted.
in further detail in the chapter ‘‘Cardiopulmo-
nary Exercise Testing.’’ Adapted from Pelligrino et al.9
Recent exposure to bronchodilating agents,
including both b2-agonists and anticholinergics, is repeatability, interpretation, and integration with
a frequent cause of a false-negative methacholine the patient’s clinical presentation. Interpretation
challenge. Suggested time periods these agents of PFT results should be meaningful; a rendition
should be withheld prior to testing are listed in of only which results are normal or abnormal can
Table 8. The specificity of direct (ie, methacholine readily be provided by a machine. Requisition
and histamine) challenge testing is affected by forms for PFTs should be designed to encourage
underlying airflow obstruction, which reflects the requesting physician to provide as much
resting airway geometry and not asthma.28 Air- clinical information as is reasonable to enable the
flow obstruction is a clinical feature that reduces interpretation to be valuable.
the specificity of the methacholine challenge, but The key principles for diagnosing common
it does not directly influence the sensitivity. abnormal disease patterns are noted in Table 9.
In summary, the clinical utility of the metha- Characteristic examples of flow-volume curves
choline challenge test is primarily to exclude are shown in Figure 7.
current asthma in a symptomatic patient when Early evidence of airflow obstruction may be
the tidal breathing methacholine PC20 exceeds 16 qualitatively demonstrated by a concave shape of
mg/mL. A positive methacholine challenge test the expiratory flow-volume curve. Quantitative
is not synonymous with a diagnosis of asthma, evidence is often inferred by a reduction in
particularly in the presence of significant airflow expiratory flows at mid-lung volumes (ie, forced
obstruction (ie, FEV1 ,70% predicted). It has expiratory flow 25%–75%, and others). However,
been suggested that 5% to 15% of normal a reduction in the midvolume expiratory flows is
individuals and 20% to 40% of patients with not specific and not necessarily diagnostic for
rhinitis may also have a false-positive methacho- small airways disease in an individual patient.
line challenge test.27 As airways disease becomes more pronounced,
a disproportionate reduction in the FEV1 com-
Interpreting Pulmonary Function pared to the FVC becomes evident, and as noted,
Tests this is more certain for a diagnosis of airway
obstruction.
Assessing pulmonary function requires ap- The specific method(s) for diagnosing air-
propriate equipment, calibration, testing proce- flow obstruction has been the recent topic of
dures, consideration of acceptability and spirited debate. The American Thoracic Society

Figure 7. Flow-volume curves in common respiratory disorders.
(ATS)/European Respiratory Society (ERS) 9). Central to this debate is one belief that
COPD guidelines, Global Initiative for Chronic rigorous statistical distributions of normal pop-
Obstructive Lung Disease, the Canadian Thoracic ulation lung function should be used to define
Society COPD guidelines, and the National abnormal lung function, whereas an alternative
Institute for Health and Clinical Excellence belief is that values associated with adverse
COPD guidelines 29–32 propose diagnosing clinical outcomes better delineate abnormalities
obstruction based on a fixed FEV1/FVC ratio of in this setting. Relevant to this discussion is the
,0.7 (suggested in some instances to be com- intended application of the definition. If the goal
bined with an FEV1 ,80% predicted). Converse- of testing is to identify, with specificity, the most
ly, the ATS/ERS spirometry guidelines advocate significantly impaired patients, then a very strict
for diagnosing obstruction using the LLN (Table standard would be appropriate. Alternatively, if

Table 10—Classifying Severity of Airflow Obstruction
ATS/ERS Standardization ATS/ERS COPD Guidelines,31

of Lung Function Testing9 Canadian Thoracic Society,32
Degree of Severity (FEV1 % Predicted) GOLD,33 NICE34 (FEV1 % Predicted)
Mild .70 80

Moderate 60–69 50–79
Moderately severe 50–59 —
Severe 35–49 30–49
Very severe ,35 ,30
GOLD ¼ Global Initiative for Chronic Obstructive Lung Disease; NICE ¼ National Institute for Health and Clinical Excellence.
the goal is for the early identification of patients Pneumothoraces and bullae are clinical situ-
at an early stage of disease, with sensitivity, then ations often characterized by a normal FEV1/
a more inclusive definition would be fitting. FVC and TLC measured in a body plethysmo-
It appears using the fixed-ratio definition graph, but reduced FEV1 and FVC values. In this
may underidentify younger patients, and over- instance, TLC assessed by gas dilution tech-
identify older patients with obstruction.33 How-
ever, perhaps more importantly in the clinical
setting, using the LLN seems to report as normal
lung function associated with adverse outcomes
such as increased hospitalization and mortality.
Patients interpreted as normal utilizing the LLN,
but classified as obstructed using the fixed ratio
of ,0.7 FEV1/FVC and FEV1 ,80% predicted,
appear to have a significantly elevated risk of
mortality (hazard ratio: 1.46; 95% CI: 1.21–1.76).34
Further study is clearly required to bring more
certainty to the best answer for this question.
Utilizing severity classification systems is
currently fraught with difficulty and frustration
for the practicing clinician. First, none have been
specifically validated (as stated by others, ‘‘the
number of categories and exact cut-off points are
arbitrary’’9). Second, as mentioned, conflicting
classifications schema exist (Table 10). It is
therefore recommended that clinicians choosing
to use a specific classification system should
recognize these limitations and make note of the
specific schema utilized in their interpretation
(and report).
Similarly, a severity classification scheme has
been proposed for the DLCO (mild .60% and
,LLN; moderate 40%–60%; severe ,40% pre-
dicted). As mentioned above, the relationship
between DLCO and lung volume is not linear, so
the DLCO/alveolar volume is not an appropriate
method to normalize DLCO for lung volume.9
Other methods to adjust the DLCO for lung
volume have not been validated. Figure 8. Relationship between BMI and FRC and ERV.37

niques will be low. This difference between TLC on the FRC and ERV (Figs 8, 9). FRC and ERV
measured in a body plethysmograph vs by gas decrease approximately 3% and 5% respectively
dilution is also seen in patients with significant for each unit increase in BMI from 20 to 30 kg/m2.
airflow obstruction often accompanied by a Above a BMI of 30 kg/m2, both FRC and ERV
significantly increased RV. decrease approximately 1% for each unit increase
Although the FVC is frequently utilized in in BMI. Effects on other lung volumes also are
place of the VC, it is suggested to use the largest significant, with an approximate 0.5% decrease in
measured VC, whether it is the IVC, the slow VC, TLC, and RV with each unit increase in BMI.
expiratory VC, or the FVC. The forced expiratory
However, as demonstrated in Figure 8, although
volume in 6 s may be substituted for the FVC if
the effects on VC, TLC, and RV (and DLCO) are
appropriate reference equations are used.
statistically significant, they infrequently lead to
The presence of obesity presents special
values outside the expected normal range.
challenges in the interpretation of PFTs.35 Ac-
knowledging the high incidence of obesity in the Careful attention should always be directed
North American population and the frequent towards possible technical issues as well as to
occurrence of respiratory symptoms in the obese, comments from the performing technicians. In
PFT is regularly requested in these patients. An addition to common obstructive, restrictive, and
elevated BMI has significant effects on all lung mixed disorders, suspicion of possible neuro-
volumes, although the changes of largest magni- muscular disorders and central airway obstruc-
tude and the most clinically meaningful effects are tion should always be present. Although
Figure 9. Relationship between BMI and DLCO, VC, TLC, and RV.37

Less than 5% of patients with a nonspecific
pulmonary function pattern demonstrate normal
PFT results on repeat testing (Fig 10). Interestingly,
it appears this nonspecific pattern is commonly
associated with airway hyperresponsiveness (52%)
and obesity (38%).37
Typical flow-volume plots observed with
differing types of physiologic central airway
obstruction are shown in Figure 11. Poor or
submaximal efforts should always be considered
and excluded in this setting. It is important that
repeated flow-volume maneuvers are maximal
and reproducible, and the technician should
Figure 10. Outcomes of repeat testing following initial confirm this in the report. In this setting a
nonspecific PFT results38 (n ¼ 1,284 patients). printout of each individual maneuver can be
very helpful.
Serial testing is routinely undertaken in clinical
infrequently found, these conditions should be
practice to monitor results over time and to
actively excluded.
evaluate change following intervention(s). An
Recently, a nonspecific pulmonary function
understanding of test variability is required before
pattern has been used to describe test results
one can conclude that any observed change relates
characterized by a normal TLC and FEV1/FVC, a to the underlying process or to an intervention.
reduced FEV1, a reduced FVC, or a reduced FEV1 The reproducibility of variables can be presented
and FVC.36 The use of the term nonspecific may be in many different ways and there is ongoing
misunderstood in this setting as the results appear debate about which method is best. For example,
to be a distinct entity, with ~64% of patients the ATS/ERS recommends that in normal indi-
demonstrating similar findings on repeat testing.36 viduals, the year-to-year change in the FEV1
Of the remaining patients, ~15% develop a should exceed 15% before confidence can be given
restrictive defect and ~15% an obstructive that a meaningful clinical change has occurred.9
abnormality, and a few develop a combined The CV is also commonly used for this purpose
obstructive-restrictive defect with serial testing. and is calculated as:
Figure 11. Flow-volume curves in physiologic central airway obstructions. A: variable intrathoracic obstruction; B: variable
extrathoracic obstruction; C: physiologically fixed central airway obstruction.

CV ð%Þ ¼ SD divided by the mean 3 100 References
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Chapter 7. Ethics in Pulmonary and Critical Care Medicine
Objectives: (SUPPORT) that attempted to improve end-of-life

Discuss the basic principles of bioethics as they apply to decision making, and to reduce the frequency of
the practice of medicine. prolonged and potentially unwanted and painful
Summarize the principles of ethical decision making in
care at the end of life.2 Despite interventions that
the clinical setting.
Apply principles of informed consent in decision included providing to physicians prediction mod-
making. els and decision-making tools, together with
Review the process of withholding and withdrawing life timely reports by trained nurses of patient and
support and its impact on families.
List the criteria and limitations for determining brain
surrogate preferences, there was no improvement
death. in physician communication, knowledge of pa-
tients’ preferences not to be resuscitated, control
of pain, or duration of ICU stay and mechanical
Key words: autonomy; brain death; end-of-life care; ethics;
futility; withholding and withdrawing life support ventilation. Some criticize the term medical ethics
as having a physician focus and prefer to use the
Synopsis: term health-care ethics to make it more comprehen-
sive. This section will review the general princi-
Medical decision making is often influenced by competing
interests of patients, families, the care setting, the payor, ples of bioethics, as they apply to patient care, and
society, and the law; these issues are of special relevance to will focus on the issues most pertinent to
pulmonary and critical care medicine physicians who deal pulmonary and critical care physicians.
every day with patients at the end of life. Discussions of
medical ethics can be framed in terms of the principles of
autonomy, beneficence, nonmaleficence, and justice. Auton- Basic Principles
omy is limited in that decisions must be legal and that the
patient must have capacity to make decisions; it depends on
informed consent, where the risks, benefits, and alternatives Discussions of medical ethics can be framed
are explained honestly. Critically ill patients usually lack
capacity, and psychiatry consultation is usually not neces-
in terms of four principles, often referred to as
sary except in cases in which the clinician believes that the the Georgetown mantra. The wide application of
patient is making an irrational decision, when there is these principles is criticized as sometimes sim-
associated mental illness, or in other situations that pose plistic and sometimes irrelevant; despite this,
uncertainty.
they are useful for frontline clinicians who lack
formal training. The four principles are as
Decisions about medical care often require judg- follows:
ment of appropriateness of action that is not based
on randomized clinical trials, or even science. The Autonomy: The patient has the right to accept
complex and at times competing interests of or refuse every treatment.
patients, families, the care setting, the payor, Beneficence: The clinician should act in the best
society, the law, and physicians often complicate interest of the patient.
patient care, and these issues are difficult to Nonmaleficence: ‘‘First, do no harm.’’
resolve with scientific methods.1 Pulmonary and Justice: The distribution of limited resources
critical care physicians are on the front lines of must be fair.
these dilemmas, but most lack formal training in
In addition, two other core values are also
bioethics, communication, conflict resolution, and
commonly applied to the analysis of ethical
related disciplines. Reluctance to confront difficult
issues, as follows:
problems and choices was demonstrated by the
landmark Study to Understand Prognosis and Dignity: Both the patient and the caregiver
Preferences for Outcomes and Risks of Treatments have a right to dignity.

Truthfulness and honesty: Clinicians should Justice
tell the truth.
Although justice is one of the four basic tenets of
Many (or most) bedside ethical dilemmas the Georgetown mantra, this should enter bedside
arise when two or more of these values are in decision making rarely, if ever, at least in the United
conflict. Some of these conflicts may be rooted in States. All physicians are obligated to use resources
lack of communication among patients, families, in an appropriate and efficient manner, but the
and the health-care team. With open communi- primary role of the physician is as a patient
cation (which may require the presence of a advocate. Therefore, we are not charged with
mediator when communications break down), rationing health-care resources at the bedside.
the ‘‘ethical issues’’ often disappear. Rather, this is a policy issue, and physicians should
advocate vigorously for rational health policies that
Autonomy would provide proper care to those who need it,
while educating the public about the limits of what
such care can provide. The perennial exercise of
The patient’s right to make an informed and ‘‘who gets the last bed in the medical ICU,’’
uncoerced decision regarding treatment general- followed by a list of candidates, is often amusing
ly overrides the other values, but autonomy has but usually meaningless, as there are probably
its limits. First, a decision must be legal; a request other ICU beds in the institution that could receive a
for euthanasia must be denied, even if it comes critically ill patient temporarily. Unless there is a
from an informed patient, as it is against the law shortage of beds, physicians must allocate ICU
everywhere. Second, the patient must have beds, dialysis slots, bags of packed RBCs, and any
capacity to make informed decisions. If patients other unit of resource fairly to all who would
with severe illness do not have that capacity, then qualify to receive it.
we depend on surrogate decision makers. Au-
tonomy depends on the proper process of Ethical Decision Making
informed consent, where the risks, benefits, and
alternatives are explained honestly. Ideally, medical decisions should be based on
empiric information such as the results of
Beneficence and Nonmaleficence randomized trials. However, ethical dilemmas
usually involve subjective considerations includ-
ing the preferences of patients, their surrogates
A physician is not obligated to provide care and clinicians, which in turn are often influenced
that would not benefit the patient. However, by their experiences. These defy a conventional
conflicts arise when the patient or surrogate ‘‘evidence-based’’ approach to decision making,
perceives of a benefit that is different from the although recent evidence-based clinical practice
clinicians’ view of their duty to beneficence and guidelines consider patient preferences when
nonmaleficence. The obvious example is the providing recommendations. There is also an
common conflict between a family who wants emerging and contentious literature on ‘‘evi-
‘‘everything’’ despite all evidence that ‘‘every- dence-based ethics’’ that attempts to apply
thing’’ will not be effective, and the clinician’s principles of evidence-based medicine to ethical
view that such care will not lead to a benefit, may dilemmas in clinical medicine.
cause harm, and wastes resources. In most cases, Regardless of the outcome of this controversy,
patient autonomy dictates that the benefit must basic principles apply. A simple but potentially
be judged by the patient’s and surrogate’s useful method includes first framing the ethical
preferences, not by those of the team. Frustrating dilemma in the dimensions of autonomy, benef-
as this often is, it also provides a check against icence, nonmaleficence, and justice. The next step
other pressures that may influence care (eg, need would be to evaluate potential decisions in terms
for an ICU bed or a perceived waste of money). of patient preferences, the medical benefits and
142 Chapter 7. Ethics in Pulmonary and Critical Care Medicine (Rosen)

harms, and how they impact on access to care Problems may arise in patients who lack the
and societal costs. capacity to make decisions and also lack a
surrogate. In most situations, physicians use the
Specific Issues principle of ‘‘substituted judgment’’ and proceed
with a course that most patients with capacity
Informed Consent would choose.4 Often, hospitals have policies that
require consultation and approval by an indepen-
Physicians are required to obtain informed dent practitioner or an ethics committee. With-
consent from patients before initiating treatment, drawing life support in a patient without capacity
and informed consent is valid only when a and with no surrogate presents a special problem.
patient has capacity to make voluntary choices In one study surveying seven medical centers,
among treatment options.3 This requires that the 5.5% of all deaths occurred among patients in this
patient is capable of understanding the relevant category; in most cases, physicians made deci-
information and the consequences of treatment sions with no institutional or judicial review,
options, can rationally process this information, contrary to their institution’s policies.
and can communicate a choice. Informed consent for research also presents
Patients with capacity may refuse any treat- unique issues, especially when it involves subjects
ment, even if that decision is contrary to the who are critically ill and incapable of providing
physician’s recommendation. Studies of compe- consent because of their illness or medications
tency in patients with unstable angina, diabetes that impair cognition.5 US federal regulations
mellitus, and HIV infection failed to show an permit consent by the subjects’ ‘‘legally autho-
increased likelihood of incapacity to make rized representative,’’ defined as ‘‘an individual or
medical decisions. However, impairment in the judicial or other body authorized under applicable
law to consent on behalf of a prospective subject
capacity for making medical decisions was found
to the subject’s participation in the procedure(s)
in outpatients with cancer, the elderly, and
involved in the research.’’ This requirement may
patients with dementia. Even patients with
be waived if an institutional review board
psychiatric illnesses may have capacity to make
determines that the research poses ‘‘minimal risk.’’
treatment decisions and they should be assessed
However, state laws vary widely in permitting
with the same criteria as used for other patients.
surrogates to consent for participation in clinical
As patients in an ICU are usually deemed to
research, and critical care research is generally not
lack the capacity to make decisions, the determi-
conducted in some states unless there is a court-
nation of capacity is an important part of ICU
appointed guardian. Others permit ‘‘emergency
management. Obviously, critically ill patients who
research’’ in situations such as after cardiopulmo-
are deeply sedated or obviously delirious do not nary resuscitation.
have decisional capacity, and their treating clini-
cians can determine incapacity. Other patients Withdrawal of Life Support
may lack capacity because they have cognitive
impairments due to preexisting disease, acute It is widely accepted in modern societies that
illness, or the effects of sedatives and analgesics. patients and their surrogates have the authority
Standardized assessment tools for these condi- to decline or withdraw any medical intervention,
tions may be helpful in assessing delirium, which as long as the decision maker has the intellectual
is usually underestimated in hospitalized patients. and psychological capacity to make such a
Psychiatric consultation is usually not necessary decision.6 Withdrawing ventilatory support is
to determine whether a patient lacks capacity; generally deemed the moral and ethical equiva-
rather, consultations should be reserved for cases lent of withholding it, but many families and
in which the clinician believes that the patient is physicians cannot help but feel and act other-
making an irrational decision, when there is wise. Although it is ethically and legally prohib-
associated mental illness, or in other situations ited to withdraw care with the specific intent of
that pose uncertainty. hastening death, the principle of ‘‘double effect’’

supports the use of medications intended to Neuromuscular blocking agents have no
prevent or relieve suffering even if it incidentally sedative or analgesic properties, would mask
hastens death. signs of discomfort after the withdrawal of
The withdrawal of mechanical ventilatory ventilatory support, and must be discontinued
support may be undertaken in most locations if before withdrawing ventilatory support. In ad-
there is an oral advance directive by the patient, dition, some patients survive to be discharged
or with the agreement of the clinical team and from the hospital despite predictions that the
family; the requirement for a written advance withdrawal of support will lead to death; this
directive is unusual. The process should begin would be impossible in the presence of neuro-
only after there is a consensus of both the muscular blockade. Rare situations in which
medical team and the patient and family that continuing therapy with these agents are war-
this treatment is both unwanted and not likely to ranted during the withdrawal of mechanical
lead to a desired patient outcome. When the ventilator support would include patients who
decision to limit or withdraw treatment is are certain not to survive more than a short
reached, the clinician is still responsible for interval after the withdrawal of support even
treating the patient throughout the dying pro- without this treatment, or if the benefits of
cess, while being attentive to the needs of the waiting for the return of neuromuscular function
patient, family, and the clinical team. The ICU do not outweigh the burdens.
team needs to attend the family almost as much Regardless of the process of extubation, there
as the patient, as they are often under great is no evidence that increasing the dose of
emotional stress. This process should be planned benzodiazepines and opiates before extubation
and communicated to the team and the family, with the goal of maintaining patient comfort is
preferably with an organized protocol including associated with a shorter time to death following
the administration of analgesics and sedatives extubation. Indeed, one study showed no rela-
titrated to maintain the comfort of the patient. tionship between narcotic dose and the time to
Whether to simply extubate the patient after death, and a direct relationship between the dose
administering and maintaining sedatives (called of benzodiazepines and the time to death after
terminal extubation) or to gradually reduce extubation. Therefore, a judicious use of sedation
support (ie, respiratory rate and fraction of and analgesics does not appear to hasten death in
inspired oxygen) with the endotracheal tube in these patients and should be part of any standard
place (called terminal wean) is a topic of ongoing protocol.
controversy. Prompt extubation has the advantages
of not prolonging the dying process, and the goals Brain Death
of care are clear and morally transparent. Gradual
withdrawal of support with the endotracheal tube It is now almost universally accepted that a
in place reduces the likelihood that visible distress person is considered to be dead when the whole
will develop in patients from stridor and oral brain (including the brainstem) is dead; therefore,
secretions, often promoting their own comfort and establishing a precise diagnosis of brain death is
that of their family by reducing anxiety. However, often crucial in decisions about terminating life
this approach may prolong the dying process, and support and organ donation.7 Although the
some family members may misinterpret this criteria for diagnosing brain death have evolved,
process as an attempt to extubate the patient the current guidelines and the laws in most
successfully. No randomized trials have com- countries require a detailed clinical assessment
pared these two approaches from a patient- that includes the presence of coma, and the
centered or family-centered perspective, and there absence of brainstem reflexes and apnea during
is no consensus among clinicians and ethicists on two successive examinations. These criteria must
which method is preferable. Rather, decisions on also be fulfilled in the absence of a complicating
how to extubate patients who are expected to die condition that may render clinical examination
depend on the preferences of the ICU team in unreliable, including severe hypothermia, hypo-
consultation with the family. tension, severe metabolic disturbances, drug

intoxication, and the use of neuromuscular insufficient evidence to determine the relative
blocking agents. A disorder that would preclude safety of different methods to determine apnea,
performing an apnea test (eg, high cervical cord and to recommend newer diagnostic tests to
injury, in which a patient may be incapable of determine whole brain function.
breathing spontaneously) would also make clin-
ical assessment impossible. In these cases, con- Relationships Disclosed
firmatory tests of the cessation of brain function
are needed. The author has disclosed the following
Although EEG is frequently used because it relationships: Product/procedure/technique that
can be performed at the bedside, the interpreta- is considered research and is NOT yet approved
tion of the findings is subject to interobserver for any purpose: B glucan in PCP. The ACCP
variability, as well as the possibility of false- Education Committee has reviewed these rela-
positive findings (eg, as a result of the use of tionships and resolved any potential conflict of
barbiturates or anesthetics, or undetectable sub- interest..
cortical neuronal activity) and false-negative
results (eg, as a result of electrical artifacts in an References
ICU environment or agonal electrical activity).
Tests of brain flow are more reliable for confirm- 1. Snyder L; for the American College of Physicians.
ing the diagnosis. Cerebral angiography with Ethics Manual, Sixth Edition. Ann Intern Med. 2012;
findings that show a cessation of blood flow to 156(1):73–104.
the brain is considered to be the gold standard, 2. Connors AF, Dawson NV, Desbiens NA, et al. A
and technetium nuclear imaging is also reliable. controlled trial to improve care for seriously ill
CT scanning and magnetic resonance angiogra- hospitalized patients: the Study to Understand
phy are probably as accurate, but are less well Prognosis and Preferences for Outcomes and Risks
validated. Transcranial Doppler examinations of
of Treatments (SUPPORT). JAMA. 1995;274(20):
cerebral blood flow are safe and noninvasive, and
1591–1598.
can be performed at the bedside, but performing
3. Applebaum PS. Assessment of patients’ compe-
them requires a high level of skill. The determi-
tence to consent to treatment. N Engl J Med. 2007;
nation of a complete absence of flow using this
357(18):1834–1840.
examination is unreliable in the diagnosis of
4. White DB, Curtis JR, Wolf LE, et al. Life support for
brain death, as false-positive results may occur in
patients without a surrogate decision maker: who
10% to 15% of cases owing to technical factors,
decides? Ann Intern Med. 2007;147(1):34–40.
which are often related to poor image acquisition.
5. Luce JM. Informed consent for clinical research
A 2010 update to the 1995 American Acad-
involving patients with chest disease in the United
emy of Neurology practice guidelines for deter-
mination of brain death offered guidance on five States. Chest. 2009;135(4):1061–1068.
issues found to vary among centers.8 First, 6. Truog RD, Campbell ML, Curtis JR, et al. Recom-
‘‘mimics’’ of brain death may include severe mendations for end-of-life care in the intensive care
fulminant Guillain-Barré syndrome or delayed unit: a consensus statement by the American
clearance of neuromuscular blockade, but the College of Critical Care Medicine. Crit Care Med.
authors found no case in the peer-reviewed 2008;36(3):953–963.
literature of a patient who recovered neurologic Reviews the ethical and practical aspects of withdrawing
function after a determination of brain death life-sustaining treatments
according to the 1995 practice guideline. The 7. Wijdicks EFM. Current concepts: the diagnosis of
minimum length of observation before initiating brain death. N Engl J Med. 2001;344(16):1215–1221.
a brain death protocol remains unknown, and no 8. Wijdicks EFM, Varelas PN, Gronseth GS, Greer
recommendations can be made. Spontaneous and DM. Evidence-based guideline update: determin-
reflex movements may occur in brain-dead ing brain death in adults: report of the Quality
patients, and autocycling of mechanical ventila- Standards Subcommittee of the American Acade-
tion may be misinterpreted. Finally, there was my of Neurology. Neurology. 2010;74(23):1911–1918.

Notes

Chapter 8. Other Lung Diseases
Objectives: icans and Hispanics from the Caribbean, Central

Describe the pathogenesis, clinical features, and treat- America, and South America.
ment of pulmonary disorders that occur in patients with
sickle cell anemia. Pathogenesis
Discuss the pathogenesis, clinical features, and treatment
of lung disease in patients with liver disease.
Describe the types of pulmonary disorders that occur in Vasoocclusion is central in the pathogenesis of
association with HIV infection, and how the spectrum of tissue injury in sickle cell disease. Deoxygenated
diseases is modified with the use of antiretroviral hemoglobin SS forms polymers, and red blood
therapy.
cells assume a rigid configuration and occlude the
microvasculature, leading to ischemia or infarc-
Key words: acute chest syndrome; hepatic hydrothorax;
tion of tissues. Compared with hemoglobin AA,
hepatopulmonary syndrome; HIV infection; Kaposi sarco-
ma; lung cancer; pneumocystis pneumonia; portopulmo- hemoglobin SS has reduced affinity for oxygen,
nary hypertension; pulmonary arterial hypertension; sickle accelerating polymerization. SS red cells also
cell anemia interact with vascular endothelium, and increased
adherence of these cells to endothelial surfaces is
Synopsis:
an important feature of vasoocclusive crises. In
Sickle cell anemia is accompanied by several pulmonary addition, release of arginase and free hemoglobin
complications. Acute chest syndrome includes chest pain,
fever, and pulmonary opacities, usually in the setting of an
from lysed RBCs leads to nitric oxide (NO)
acute painful crisis. Mechanisms for acute chest syndrome dysregulation and vasoconstriction, endothelial
include vasoocclusion, fat embolism, and vasoconstriction, dysfunction, and pulmonary hypertension. Sickle
the latter related at least in part to scavenging of nitric oxide cell disease is also associated with a hypercoag-
by free hemoglobin. Patients with severe liver diseases may
develop hepatopulmonary syndrome, characterized by
ulable state due to thrombocytosis and the
hypoxemia caused by dilation of the pulmonary capillary procoagulant effects of RBC membrane lipids.
bed and arteriovenous shunts; portopulmonary hyperten- Three overlapping pulmonary syndromes are
sion similar to idiopathic pulmonary hypertension; and described in patients with sickle cell hemoglobin-
hepatic hydrothorax. Lung cancer occurs with increased
frequency in HIV-positive persons and appears to present in opathies: acute chest syndrome, fat embolism
more advanced stages and with a more aggressive course syndrome, and chronic restrictive lung disease
than in HIV-negative persons. The incidence of pulmonary with pulmonary hypertension.1
arterial hypertension is also increased with HIV infection; it
may occur in any CD4þ stratum and is in all respects similar
to idiopathic arterial hypertension in HIV-negative persons. Acute Chest Syndrome
Immune reconstitution inflammatory syndrome (IRIS) oc-
curs when antiretroviral treatment inhibits viral replication Patients with sickle cell disease often present
and CD4þ lymphocyte counts and activity increase. with a syndrome of chest pain, fever, and cough,
usually during a painful crisis. In adults, the
radiograph typically shows multilobe or lower
Pulmonary Disorders in Persons With lobe pulmonary opacities; pleural effusion is
Sickle Cell Anemia present in around 15% of cases. Acute chest
syndrome is the leading cause of death in patients
The sickle cell hemoglobinopathies are charac- with sickle cell disease, most commonly due to
terized by a predominance of hemoglobin S. The respiratory failure or vasoocclusive neurologic
most common is sickle cell anemia (hemoglobin complications. The pathogenesis of acute chest
SS), which affects about 1 in 650 persons of syndrome is often multifactorial and attributable
African descent. In the United States, sickle cell to infection, fat embolism from infarcted bone
disease occurs predominantly in African Amer- marrow, pulmonary microvascular occlusion, and

in situ thrombosis. The most common pathogens hypoxemia, pulmonary fibrosis, and a restrictive
identified in acute chest syndrome are Chlamydia ventilatory impairment.
pneumoniae, Mycoplasma pneumoniae, and respira- Pulmonary arterial hypertension is common
tory viruses.2 Other bacteria are less common in sickle cell disease. Of the 25% of adults with
causes of acute chest syndrome but include SC disease who have contrast echocardiography
Streptococcus pneumoniae, Hemophilus influenzae, that suggests pulmonary hypertension (tricuspid
and Staphylococcus aureus. Thoracic bone infarction regurgitant jet velocity of at least 2.5 m/s), only
occurs commonly during an acute painful crisis one-fourth have mean pulmonary arterial pres-
and may lead to atelectasis and pneumonia by sure of at least 25 mm Hg on right heart
causing splinting from pain. catheterization.3 Patients with pulmonary hyper-
Since the pathogenesis of acute chest syn- tension are more likely to be older, have poorer
drome is multifactorial, an empiric combination of functional status, and have higher levels of N-
treatments is usually appropriate. These include terminal pro-brain natriuretic peptide than other
analgesics, hydration to prevent hemoconcentra- patients.
tion, and oxygen supplementation to reduce Hemolysis and NO downregulation may
sickling. Most patients receive antibiotics empir- play central roles in the development of pulmo-
ically since it is usually impossible to determine nary hypertension. NO is generated by conver-
whether or not they have pneumonia; the choice sion of L-arginine to citrulline; hemolysis releases
of drugs is similar to that in other patients with arginase from red blood cells, reducing plasma
pneumonia. In severe cases, transfusion of red arginine for NO synthesis; free hemoglobin itself
blood cells may improve acute chest syndrome is also an NO scavenger.4 Reduced NO activity in
rapidly. Inhaled NO appeared to be a promising turn leads to vasoconstriction both directly and
treatment, but a clinical trial showed no important through expression of endothelin-1, along with
benefits, compared with placebo. increased endothelial expression of adhesion
molecules and increased platelet activation.
Fat Embolization Syndrome Clinical trials of agents commonly used in
pulmonary arterial hypertension have generated
Besides being a common cause of acute chest
negative or conflicting results in patients with
syndrome, fat embolization may cause a systemic
sickle cell disease.
disorder with neurologic dysfunction (superim-
posed on central nervous system vasoocclusion),
Liver-Lung Syndromes
renal failure, petechiae, and multilobe lung
opacities or ARDS. The syndrome usually occurs Impaired hepatic synthetic and metabolic
during a painful crisis; circulation of free fatty function may lead to deranged production and
acids from necrotic bone marrow is implicated in metabolism of vasoactive substances and other
the pathogenesis of diffuse vascular injury that mediators that affect the lung. The major pulmo-
may lead to ARDS and multiorgan failure. Fat nary complications of liver disease are the so-
globules may be detected in sputum and urine, called hepatopulmonary syndrome (HPS), porto-
and bone scan test results are usually positive. pulmonary hypertension, and hepatic hydrotho-
Treatment is supportive. rax.
Chronic Lung Disease and Pulmonary HPS

Hypertension
An estimated 15% to 20% of patients with
Patients with sickle cell disease, and espe- cirrhosis have hepatopulmonary syndrome.5
cially those with recurrent acute chest syndrome This term refers to a syndrome of liver disease,
may develop progressive, irreversible, and pro- hypoxemia, and pulmonary vascular abnormal-
found lung disease. Recurrent lung injury caused ities referred to as intrapulmonary vascular dilata-
by fat embolization, infarction, and infection all tions. Abnormal vasoactive tone imposed by
contribute. Patients may develop progressive mediator imbalance in liver disease leads to
148 Chapter 8. Other Lung Diseases (Rosen)

dilatation of pulmonary precapillary and capil- pleural space, causing accumulation of pleural
lary vessels. This, in turn results in ‘‘diffusion- fluid with the same characteristics as the ascites.
perfusion’’ impairment, where oxygen may not This condition is referred to as hepatic hydro-
diffuse into the center of dilated pulmonary thorax.7 Pleural fluid is typically a transudate
capillaries. These vascular abnormalities, along and on the right side. Spontaneous bacterial
with pulmonary arteriovenous malformations empyema may occur with or without spontane-
analogous to cutaneous spider angiomas, are ous bacterial peritonitis. The initial treatment is
most prominent at the lung bases. Increased directed at reducing the volume of ascites with
perfusion of the lung bases in the upright salt restriction and diuretics. Thoracentesis may
position explains the symptoms of orthodeoxia be helpful to relieve dyspnea and hypoxemia
and platypnea, or worsening hypoxemia and acutely, but the fluid usually re-accumulates.
shortness of breath when upright. Hypoxemia Chest tube drainage is usually hazardous, as
may correct only partially, or not at all, with ascitic fluid translocates rapidly into the pleural
supplemental oxygen. space, leading to volume depletion and electro-
HPS is diagnosed by using the following lyte abnormalities. Pleurodesis is generally un-
criteria: portal hypertension (with or without successful because the fluid usually re-
cirrhosis), arterial hypoxemia (A-a oxygen dif- accumulates too rapidly for the pleural surfaces
ference . 15 mm Hg), and pulmonary vascular to come together and adhere. Surgical repair of
dilatation demonstrated by the echocardiograph- diaphragmatic defects by videothoracoscopy can
ic appearance of microbubbles in left atrium be attempted, but few centers are experienced in
within three to six cycles following injection of the procedure. Peritoneovenous shunts are usu-
hand-agitated circulation into a peripheral vein, ally not successful in patients with hepatic
indicating passage of blood through a dilated hydrothorax because the pleural space has a
vascular bed. Alternatively, abnormal brain lower pressure than the venous system, and fluid
uptake on radionuclide lung scanning may be moves preferentially to the pleural space. Trans-
diagnostic, but this test is less sensitive and more jugular intrahepatic portosystemic shunt is an
cumbersome than echocardiography. option for symptomatic relief in patients who
There is no medical therapy for HPS. The have recurrent hydrothorax despite diuretic
most effective treatment is liver transplant, which therapy and repeated thoracentesis; hepatic
may lead to resolution after several months. encephalopathy occurs in approximately a third
of cases. Therefore, this option is best used as a
Portopulmonary Hypertension
bridge to liver transplant, the most effective
treatment of refractory hepatic hydrothorax.
In contrast with the vasodilation characteris-
tic of hepatopulmonary syndrome, 1% to 2% of
Pulmonary Complications of HIV
patients with cirrhosis develop pulmonary vaso-
constriction and pathologic changes indistin-
Infection
guishable from idiopathic pulmonary arterial
Advances in antiretroviral therapy have
hypertension.6 The response of portopulmonary
dramatically increased survival in persons with
hypertension to liver transplant is unpredictable,
HIV infection, and noninfectious complications
and many centers consider portopulmonary are becoming more common.8 Their typical
hypertension a contraindication for transplant. radiographic patterns are summarized in Table
1. The severity of immune compromise as
Hepatic Hydrothorax measured by the CD4þ lymphocyte count is the
most reliable surrogate marker for immune
Some people have fenestrations in the tendi- function, the risk of opportunistic infection, and
nous portion of the diaphragm. If ascites devel- the risk of progression of HIV disease. Common
ops in patients with these defects, the positive respiratory problems, such as sinusitis and
infradiaphragmatic pressure moves fluid bronchitis, may occur at any CD4þ count, and
through these defects into the negative-pressure bacterial pneumonia and TB often occur before

AIDS-defining opportunistic infections and neo- Table 1—HIV Infection: Chest Radiographic Patterns and
plasms.9 The place of residence strongly influ- Common Etiologies
ences the risk of the development of specific
Focal opacities
infections. In the United States, the incidence of
Bacteria
HIV-associated TB is highest in the Northeast. M tuberculosis
The geographic distribution of endemic fungi is a P jiroveci
strong determinant of the risk of those infections Fungi
developing; disseminated histoplasmosis and Kaposi sarcoma
coccidioidomycosis are common in patients with Cancer
Cryptogenic organizing pneumonia
AIDS who live in endemic areas. Diffuse opacities
P jiroveci
Bacterial Pneumonia M tuberculosis
Kaposi sarcoma
Bacteria
HIV infection impairs humoral immunity Fungi
through quantitative and functional defects in Cytomegalovirus
CD4þ lymphocytes, increasing the risk of devel- Immune reconstitution
Diffuse nodules/cavities
oping bacterial infection, including sinusitis and Kaposi sarcoma (large nodules)
pneumonia. S pneumoniae and H influenzae are the M tuberculosis (military nodules)
most frequent bacterial pathogens. Rhodococcus Fungi (small nodules)
P jiroveci (small nodules, cavities)
equi, an aerobic gram-positive acid-fast bacillus,
R equi (cavities)
may cause focal consolidation, endobronchial Mediastinal lymphadenopathy
disease, and cavitation, usually in patients with M tuberculosis
advanced HIV disease. Pneumonia due to P Atypical mycobacteria
Kaposi sarcoma
aeruginosa may develop in patients with very low Lymphoma
CD4þ lymphocyte counts (typically ,50 cells/ Fungi
lL), even in the absence of risk factors such as Immune reconstitution
Pleural effusion
neutropenia, corticosteroid use, and hospital- Bacteria
acquired infection. N asteroides may cause nod- M tuberculosis
ules, consolidation, cavitation, pleural effusions, Kaposi sarcoma
Lymphoma (including primary effusion lymphoma)
empyema, and intrathoracic lymphadenopathy
Cardiomyopathy
in HIV-infected persons. The diagnosis and Hypoproteinemia
treatment of bacterial pneumonia in persons
with HIV infection is similar to that for HIV-
uninfected patients.
in patients with known or suspected HIV
Pneumocystis jiroveci Pneumonia infection are usually caused by PCP. PCP is
unlikely in a patient with a CD4þ cell count of
Pneumonia caused by P jiroveci (formerly .200 cells/lL in the preceding 2 months in the
classified as P carinii) was the first opportunistic absence of other HIV-associated symptoms.
infection described in AIDS patients, and has P jiroveci cannot be cultured in vitro; therefore,
always been a major cause of illness and death. the diagnosis can be confirmed only by demon-
The organism cannot be cultured reliably outside strating organisms in a lung-derived specimen,
the lung, and its source is still not identified, but either in sputum induced by the inhalation of
person-to-person transmission may occur. The hypertonic saline solution or by bronchoscopy.
chest radiograph usually shows diffuse granular Although establishing a diagnosis is not difficult,
opacities, which strongly suggest the diagnosis. many clinicians treat patients with suspected PCP
Some patients with pneumocystis pneumonia empirically, reserving bronchoscopy for patients
(PCP) have nodular densities, lobar consolida- who do not respond to treatment.
tion, or normal radiographic findings. Cystic Trimethoprim-sulfamethoxazole is the pre-
abnormalities and spontaneous pneumothorax ferred treatment for PCP in patients who have

not had an adverse reaction to this drug, causes a diverse range of symptoms and radio-
regardless of the severity of disease. Administra- graphic findings. Most patients with pulmonary
tion of corticosteroids at the start of antipneu- KS diagnosed during life have cough, dyspnea,
mocystis treatment reduces the likelihood of and fever. KS lesions in the airways are usually
respiratory failure, the deterioration of oxygena- asymptomatic but sometimes cause obstruction
tion, and death in patients with moderate to or hemoptysis; the finding of typical lesions on
severe pneumonia.10 Patients who are likely to inspection of the airways is usually considered to
benefit from therapy have a PaO2 of ,70 mm Hg be diagnostic. Parenchymal involvement with KS
or an arterial-alveolar oxygen pressure difference is suggested by bronchial wall thickening, nod-
of .35 mm Hg. No benefits have been shown ules, Kerley B lines, and coexisting pleural
with less severe gas exchange abnormalities at effusions, especially in patients with cutaneous
the start of therapy or in patients to whom disease. Therefore, the diagnosis of pulmonary
corticosteroids were administered .72 h after parenchymal KS is usually inferred in patients
antipneumocystis treatment was started. with cutaneous disease, chest radiograph find-
ings, or CT scan findings that suggest this
TB disorder; visual confirmation of airway lesions;
and no evidence of opportunistic infection in
Coinfection with HIV and M tuberculosis is BAL fluid or bronchoscopic lung biopsy speci-
discussed in detail in another section. Modest mens. Patients with parenchymal opacities who
reductions in cell-mediated immunity increase have typical lesions in the airways, and no
the risk of the reactivation of latent TB, and the identified pulmonary infection, are assumed to
risk increases as the CD4þ cell counts decline. In have parenchymal KS.
HIV-infected persons, TB often occurs before the Non-Hodgkin B-cell lymphoma is associated
development of opportunistic infections, proba- with HIV infection, and, unlike most other HIV-
bly because M tuberculosis is more virulent. In related disorders, it continues to occur despite
patients with mild immune deficiency, the the use of antiretrovirals. Although pulmonary
clinical presentation is similar to TB in HIV- involvement is usually clinically innocuous, the
negative patients. Atypical pulmonary presenta- lung is a common site of extranodal disease.
tions, including the presence of diffuse infiltrates, Primary effusion lymphoma or ‘‘body cavity
miliary patterns, intrathoracic lymphadenopathy, lymphoma’’ is a disorder characterized by
or normal chest radiograph findings, occur more pleural, pericardial, or peritoneal growth of
frequently in patients with advanced immuno- malignant lymphoma cells, usually in the ab-
suppression (Table 1). These patients also have a sence of solid tumors. In almost all cases, tumor
high incidence of extrapulmonary infection, DNA shows HHV-8, which is also the etiologic
including infections in the pleura, lymph nodes, agent of KS and multicentric Castleman disease,
GI tract, bone marrow, and blood. a dysplastic lymphoid disorder that may pro-
gress to plasmablastic lymphoma. The virus has
Intrathoracic Neoplastic Diseases a strong tropism for B cells, and in some patients
HHV-8-infected clones proliferate and transform
Kaposi sarcoma (KS) is the most common into a large cell ‘‘liquid lymphoma’’ within
malignancy in persons with HIV infection, and serous cavities.
the skin is the major site of involvement. Visceral The incidence of lung cancer is increased in
involvement with KS occurs in patients with persons with HIV infection. Although persons in
advanced disease and may involve the airways, most populations with HIV infection are current
lungs tissue, mediastinal lymph nodes, and or former smokers, their risk of the development
pleura. Patients with thoracic KS usually have of lung cancer appears to be increased even when
obvious mucocutaneous lesions, but the lung incidence ratios are adjusted for smoking. Ade-
may be the only site of disease in up to 15% of nocarcinoma is the most common histologic type,
cases. The involvement of the airways, paren- and the prognosis appears to be worse than for
chyma, pleura, and intrathoracic lymph nodes HIV-uninfected people.

Obstructive Lung Disease Fever with worsening or the emergence of
cervical intrathoracic lymphadenopathy, pulmo-
There is a propensity for the development of nary infiltrates, pleural effusions, or other tuber-
chronic bronchitis and bronchiectasis in patients culous lesions in these patients, shortly after the
with advanced HIV infection, even if they do not start of ART, is associated with the restoration of
smoke. The CD4þ count is usually low (,100 cutaneous reactivity to skin test antigens. Respi-
cells/lL). HIV infection also appears to acceler- ratory failure caused by IRIS may occur after the
ate the onset of smoking-related emphysema, introduction of ART after successful treatment of
possibly through cytotoxic lymphocyte activity, PCP and other infections.
lung capillary endothelial injury, and increased IRIS is a diagnosis of exclusion suggested by
oxidative stress. a compatible clinical syndrome in a patient who
is recovering from an infection and has begun
Pulmonary Arterial Hypertension receiving ART in the prior several months. The
plasma HIV load and CD4þ lymphocyte counts
Pulmonary hypertension occurs more com- are usually improved when compared with prior
monly in HIV-infected patients than in the measurements, but the circulating CD4þ count
general population. It may eventually lead to may be unchanged because these cells are
cor pulmonale and death. HIV-associated pul- compartmentalized to sites of active inflamma-
monary hypertension appears to occur at all tion. If bronchoscopy is performed, the mean
stages of HIV infection, and the approach to CD4 to CD8 ratio is significantly higher (0.54)
diagnosis and treatment is the same as that for than in HIV-infected patients who are undergo-
idiopathic pulmonary arterial hypertension in ing bronchoscopy for other respiratory com-
HIV-uninfected persons. The effects of starting plaints (0.07).
ART during a course of treatment for pulmonary
hypertension are not known. Relationship Disclosed
Immune Restoration Syndromes The author has disclosed the following

relationship: Product/procedure/technique that
The immune reconstitution inflammatory is considered research and is NOT yet approved
syndrome (IRIS) is a paradoxical deterioration for any purpose: B glucan in PCP. The ACCP
in clinical status that is attributable to the Education Committee has reviewed these rela-
recovery of the immune system during ART tionships and resolved any potential conflict of
when the number and activity of blood CD4þ interest.
lymphocytes increases, as does their activity.
Increased immune function then leads to inflam- References
mation that may have been otherwise clinically
silent, leading to overt clinical illness. The 1. Gladwin MT, Vichinsky E. Pulmonary complica-
diagnostic criteria for IRIS include the diagnosis tions of sickle cell disease. N Engl J Med. 2008;
of AIDS, treatment with anti-HIV medications 359(21):2254–2265.
that lead to a reduction in HIV viremia (followed 2. Vichinsky EP, Neumayr LD, Earles AN, et al.
by an increase in the CD4þ lymphocyte count), Causes and outcomes of the acute chest syndrome
symptoms consistent with an infectious or in sickle cell disease. N Engl J Med. 2000;342(25):
inflammatory condition that appeared while 1855–1865.
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that cannot be explained by a newly acquired study of pulmonary hypertension in sickle cell
infection, by the expected clinical course of the disease. N Engl J Med. 2011;365(1):44–53.
disease, or by the side effects of therapy. 4. Morris CR, Kato GJ, Poljakovic M, et al. Dysreg-
‘‘Paradoxical worsening of TB’’ was described ulated arginine metabolism, hemolysis- associated
in patients in whom transient worsening of TB- pulmonary hypertension and mortality in sickle
related symptoms developed following ART. cell disease. JAMA. 2005;294(1):81–90.

5. Rodrı́guez-Roisin R, Krowka MJ. Hepatopulmo- Report–emerging issues and current controversies
nary syndrome-a liver-induced lung vascular in HIV-associated pulmonary diseases. Proc Am
disorder. N Engl J Med. 2008;358(22):2378–2387. Thorac Soc. 2011;8(1):17–26.
6. Krowka MJ. Hepatopulmonary syndrome and 9. Hanson DL, Chu SY, Farizo KM, Ward JW. Adult
portopulmonary hypertension: implications for and Adolescent Spectrum of HIV Disease Project
liver transplantation. Clin Chest Med. 2005;26:587–
Group: distribution of CD4þ T lymphocytes at
597.
diagnosis of acquired immunodeficiency syn-
7. Roussos A, Philippou N, Mantzaris GJ, Gourgou-
drome-defining and other human immunodefi-
liannis KI. Hepatic hydrothorax: pathophysiology
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8. Morris A, Crothers K, Beck JM, Huang L. 10. Huang L, Quartin A, Jones D, Havlir DV.
American Thoracic Society Committee on HIV Intensive care of patients with HIV infection. N
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Notes

Chapter 9. Thoracic Imaging
Rakesh D. Shah, MD, FCCP
Objectives: Tracheal Stenosis

Review the basic plain radiograph and cross-sectional
anatomy and pathology of the tracheobronchial tree, Most tracheal stenoses are complications of
lobar atelectasis, and mediastinum. tracheal intubations. Narrowing occurs at the
Evaluate the role of CT pulmonary angiography in the
diagnosis of acute and chronic pulmonary thromboem- thoracic inlet where the cuff has been inflated for
bolic disease. tracheostomy or intubation. As the cuff pressure
Review the current methods for evaluating a solitary exceeds the capillary pressure, blood supply to
pulmonary nodule. the tracheal mucosa is compromised. This leads
Learn to interpret high-resolution CT scan images in
patients with diffuse lung disease.
to inflammation, followed by ulceration and
necrosis. Eventually, scarring occurs and leads
to stenosis. On CT scan, 1- to 2-cm long
Key words: chest imaging; CT pulmonary angiography;
high-resolution CT scan; positron emission tomography circumferential narrowing of the trachea is noted
at the thoracic inlet.
Synopsis:
This chapter is divided into six broad sections: (1)
Tracheobronchomalacia
evaluation of the nonneoplastic diseases of the tracheo-
bronchial tree, (2) lobar atelectasis, (3) evaluation of Tracheobronchomalacia is a condition de-
mediastinal structures and pathology, (4) CT pulmonary fined by excessive expiratory collapse of the
angiography in the diagnosis of acute and chronic
trachea and bronchi. It is a result of weakness of
thromboembolic disease, (5) current concepts in the
evaluation of solitary pulmonary nodule, and (6) high- the airway walls or supporting cartilage. Some
resolution CT (HRCT) scan findings in patients with cases are congenital in nature; however, a large
diffuse lung disease. majority of the cases are acquired and are caused
by prior intubation, trauma, infection, or chronic
inflammation. On CT, diagnosis is suggested
when greater than a 50% decrease in the cross-
Tracheobronchial Tree
sectional area of the airway lumen is noted on
dynamic expiratory images.
Focal or diffuse lesions of the tracheobronchial
tree are produced by a variety of diseases.
Saber-Sheath Trachea
The etiologies include infection, malignancy,
trauma, collagen vascular disease, and such Saber-sheath trachea is characterized by
idiopathic entities as amyloidosis and tracheo- marked decrease in the transverse diameter of
bronchopathia osteochondroplastica. These the intrathoracic trachea associated with an
conditions may produce symptoms of cough, increase in its sagittal diameter. Changes in
dyspnea, wheezing, or stridor. Despite signifi- tracheal configuration are a result of abnormal
cant symptoms, airway abnormalities are fre- intrathoracic transmural pressures. It is typically
quently not apparent or are often overlooked seen in men who smoke and have chronic
on chest radiographs, resulting in delay of the obstructive pulmonary disease.
diagnosis. CT scan of the chest is the imaging
modality of choice if there is a clinical Tracheobronchopathia Osteochondroplastica
suspicion of tracheobronchial abnormality. The
following is a brief description of the important Tracheobronchopathia osteochondroplastica
nonneoplastic diseases that are associated with is a rare, benign disease characterized by
tracheal narrowing. development of osseous or cartilaginous nodules

within the anterolateral walls of the trachea. The Mounier-Kuhn Syndrome
posterior membrane of the trachea is spared (Tracheobronchomegaly)
because of the absence of cartilage in this area. It
typically occurs in men older than 50 and is Tracheobronchomegaly, also referred to as
usually detected incidentally. On CT scan, calci- Mounier-Kuhn syndrome, is a rare condition
fied nodules protruding into the tracheal lumen characterized by diffuse dilatation of the trachea
are noted. Resultant tracheal narrowing may be and the main bronchi. It is thought to result from
present. atrophy of the muscular and elastic tissue found
in both trachea and main bronchi. On CT scan,
Relapsing Polychondritis thin wall trachea with scalloped or corrugated
appearance, increased tracheal diameter of great-
Relapsing polychondritis is a rare inflamma- er than 3 cm, and diverticulosis are present.
tory disease that affects the cartilages of the ear,
nose, respiratory tract, and joints. It is character- Summary
ized by repeated episodes of cartilaginous
inflammation leading to loss of structure and In summary, diagnosis of the nonneoplastic
fibrosis. The respiratory tract is affected in diseases of the tracheobronchial tree requires
approximately half of all the patients. On CT knowledge of the anatomy and observation of the
answers to the following questions on CT scans:
scan, thickening of the anterolateral tracheal wall
with sparing of the posterior membrane is noted. 1. Is the trachea dilated or narrowed?
Resultant luminal narrowing and airway collapse 2. If there is thickening of the airway wall? If so,
are best demonstrated on dynamic expiratory CT is it focal or diffuse? Is the thickening at the
scans. thoracic inlet or not?
3. Is there stenosis? If so is it focal or diffuse?
Amyloidosis 4. Is calcification present or not?
5. Is ulceration present or not?
Amyloidosis is a rare condition characterized 6. Is the posterior membrane involved or
by deposition of insoluble protein in the extra- spared?
cellular tissues. It may involve any portion of the 7. Is there collapse of the tracheal wall on
respiratory tract. Within the lung parenchyma, dynamic expiratory images?
abnormal amyloid deposition can appear as The differential diagnosis can be significantly
single or multiple nodules or diffuse interstitial narrowed once the above questions have been
opacities. Deposits within the tracheobronchial answered.
tree lead to concentric or nodular thickening of
the tracheal submucosa with resultant narrowing Atelectasis
of the lumen. Calcification and/or ossification of
the lesions may occur. Atelectasis is defined as a decrease in the
volume of the lung or a portion of the lung.
Granulomatosis With Polyangiitis (Wegener) Resorption, passive, cicatrization, and adhesive
are the four types of atelectasis that can be
Granulomatosis with polyangiitis is a necro- explained by the mechanism in which the loss of
tizing granulomatous vasculitis that involves the lung volume occurs. Resorptive atelectasis is the
upper and lower respiratory tract. Involvement most common type and results from absorption
of the lung parenchyma shows multiple nodules of gas from the alveoli when the communication
with or without cavitation. Involvement of the between the alveoli and the trachea is obstructed
tracheobronchial tree is rare and usually presents by an endobronchial lesion or mucous plug.
late in the disease. On CT scan, circumferential Passive atelectasis is caused by extrinsic pressure
thickening, ulceration, and luminal narrowing of on the lung from a large pleural effusion,
the trachea are noted. pneumothorax, or mass resulting in collapse.
156 Chapter 9. Thoracic Imaging (Shah)

Cicatrization atelectasis occurs in patients with between the apex of the atelectatic upper lobe
scarring or pulmonary fibrosis. The exact mech- and the aortic knob, creating a sharp lucent
anism of adhesive atelectasis is poorly under- interface called the Luftsichel sign. On the lateral
stood but is thought to be caused by widespread radiograph, there is forward displacement of the
collapse of alveoli. It is usually seen in patients major fissure, which is almost parallel to the
with respiratory distress syndrome and those anterior chest wall.
who are in the postsurgery period.
Lobar atelectasis may be complete or partial. Lower Lobe Atelectasis
The most common cause of lobar atelectasis is
obstruction by a central endobronchial lesion. The pattern of lower lobe collapse is similar
However, in the hospitalized patients, particu- in both lungs because of the equivalent anatomy
larly those who are intubated, mucous plug is the bilaterally. Both lower lobes collapse poster-
most common cause of partial or lobar atelecta- omedially and inferiorly. On the frontal radio-
sis. Primary and secondary signs on chest graph, a triangular opacity is visualized in the
radiograph help identify the atelectasis and the paraspinal location of the lower hemithorax,
site of the endobronchial obstruction. The major whereas on the lateral projection, increased
sign of lobar atelectasis is opacification of the opacity overlying the lower thoracic vertebral
affected lobe due to airlessness and displacement bodies and loss of visualization of the posterior
of the interlobar fissure. Secondary signs of left hemidiaphragm are noted.
atelectasis include displacement of the mediasti-
nal structures, elevation of the hemidiaphragm, Right Middle Lobe Atelectasis
decrease in the distance of the intercostals spaces,
displacement of the hila, and compensatory On the frontal chest radiograph, the right
overinflation of the remaining lung. Discussion middle lobe collapse shows a vague opacity in
of the major and minor radiographic features of the lower right hemithorax with obliteration of
the main lobar atelectasis follows. the border of the right side of the heart. On the
lateral projection, the collapse is seen as a linear
Right Upper Lobe (RUL) Atelectasis band or triangular opacity overlying the cardiac
silhouette as a result of displacement of the
On the frontal chest radiograph, the RUL minor fissure inferiorly and major fissure supe-
collapses superiorly and medially, creating a riorly.
wedge-shaped opacity in the upper right hemi-
thorax. The major fissure is displaced anteriorly, Rounded Atelectasis
and the minor fissure is displaced upward. RUL
collapse secondary to a central carcinoma may Rounded atelectasis is an unusual form of
produce a characteristic appearance on the passive atelectasis that is thought to occur from
frontal chest radiograph termed the ‘‘reverse S pleural fibrosis as a result of chronic pleural
sign of Golden.’’ On the lateral projection, the effusion and/or asbestos-related disease. The
collapsed lobe may appear as a triangular opacity pleural fibrosis causes folding of the adjacent
with its apex at the hilum and its base at the apex lung parenchyma, which appears as a focal
of the hemithorax. rounded opacity. On CT scan, a peripherally
situated rounded opacity is noted with associat-
Left Upper Lobe Atelectasis ed pleural thickening, a comet-tail sign, and
volume loss of the affected lobe.
When the left upper lobe collapses, the
frontal chest radiograph demonstrates a hazy Pulmonary Embolism (PE)
opacification in the left perihilar area with partial
obscuration of the border of the left side of the PE is an important cause of morbidity and
heart. Sometimes the resultant overinflation of mortality, particularly in postsurgical and hospi-
the superior segment of the left lower lobe inserts talized patients. Unfortunately, the diagnosis of

acute PE is often delayed or unrecognized Pitfalls in the diagnosis of PE can be divided
because of the nonspecific nature of its symp- into anatomic and technical etiologies. Common
toms, signs, and laboratory test findings. The anatomic pitfalls include lymph nodes, pulmo-
chest radiograph is often nonspecific or normal. nary veins, impacted bronchi, and volume
The ventilation-perfusion scans have high sensi- averaging of pulmonary arteries. On the com-
tivity but low specificity, whereas pulmonary puter workstation, if one scrolls in and out from
angiography is invasive, is underutilized, and the main pulmonary artery, following each of the
has considerable interobserver variability. lobar, segmental, and subsegmental arteries, it is
Regarding the pathophysiologic state of PE, impossible to mistake an artery for a vein,
PE refers to the transport of venous thrombus to lymph node, or mucoid impacted bronchi for
the pulmonary artery circulation. Most of the PE. Technical causes for suboptimal quality
thrombus arise from clots within the deep examinations are poor enhancement of pulmo-
venous system of the lower extremities. Emboli nary arteries, breathing motion artifact, and
are often multiple, and they have predilection for excessive noise in large patients. The bolus
the lower lobes of the lung. This is likely related tracking software built into most CT scanners
to increased blood flow in the lower lobes. today has significantly reduced nondiagnostic
scans from poor enhancement. In addition,
CT Scan Technique motion artifact is less of a problem with higher
detector scanners because of the shorter breath
In recent years, great advances have been holds.
made in the CT scan technology. Because of its
ability to directly visualize PE, noninvasively and Chronic Thromboembolism
with high accuracy, multi-row detector CT
scanners have become the imaging test of choice Chronic thromboembolism is thought to
for the diagnosis of PE. One of the other potential represent scarring of the pulmonary arteries after
advantages is the ability to diagnosis alternative lysis of thrombi from either single or repeated
diagnoses that may mimic PE clinically. bouts of PE. As a result, webs and occlusions are
On multi-row detector CT scanners, approx- formed within the branches of the pulmonary
imately 80 to 100 mL of iodinated IV contrast is arteries. The global effect of these is the overall
injected at 4 mL/s after a fixed scan delay or a increase of the pulmonary vascular resistance
timing bolus of 20 mL. The patient is scanned in a and subsequent pulmonary hypertension.
single breath-hold from the lung apices to the Characteristic CT scan findings can be divid-
level of the diaphragm. Approximately, 250 to ed into three categories: cardiac, pulmonary
400 images per scan are obtained because the arteries, and parenchymal. The cardiac findings
study is performed at 1.25 mm collimation. Thus, include right-sided chamber enlargement and
the CT scan interpretation is performed on the right ventricular hypertrophy. Pulmonary artery
computer workstation by actually scrolling findings include eccentric thrombus, abrupt
through the images and altering the window vessel cutoff, webs, beaded vessels, and enlarged
width and level to optimally evaluate the central arteries. Parenchymal findings include
pulmonary arteries. alternating hazy and lucent areas in lung, called
mosaic attenuation, and enlarged bronchial
CT Scan Findings arteries.
The CT scan findings of acute PE are direct Mediastinum

visualization of low-attenuation thrombus within
the contrast-opacified pulmonary artery. Throm- The mediastinum is an anatomic region
bus may be identified as partial or complete within the thoracic cavity that is bounded
filling defect in the vascular lumen. Secondary laterally by the lungs, anteriorly by the sternum,
signs of PE include oligemia of the affected and posteriorly by the vertebral bodies. A wide
segment and pulmonary infarcts. variety of focal and diffuse abnormalities occur

within the mediastinum. To facilitate the differ- Retrotracheal Clear Space
ential diagnosis, the mediastinum has been
divided into several compartments, primarily The retrotracheal clear space is posterior to
based on landmarks noted on the chest radio- the trachea, anterior to the thoracic spine, and
graphs and CT scan rather than true anatomic superior to the posterior portion of the aortic
fascial planes. These landmarks are (1) the arch. This region corresponds to the region of the
anterior mediastinum, which includes the retro- posterior junction line as noted on the frontal
sternal clear space and cardiophrenic angle; (2) chest radiograph. Normal structures that are
the middle mediastinum, which includes the present in this space are esophagus and lymph
retrosternal clear space, subcarinal region, and nodes. The differential diagnosis of lesions in this
retrocardiac clear space; and (3) the posterior region include abnormalities of the esophagus
mediastinum. (tumor, achalasia, Zenker’s diverticulum). How-
ever, a large percentage of lesions in this region
Retrosternal Clear Space are vascular (aberrant right subclavian artery) or
thyroid in origin. Most of the thyroid masses
The retrosternal clear space is the region that represent goiters, which almost always extend
is posterior to the sternum and anterior to the inferiorly from the thyroid gland into this space.
aorta and great vessels. It corresponds to the
region of the anterior junction line noted on the Subcarinal Region
frontal chest radiographs. Normal structures
The subcarinal region is inferior to the carina
that are present in this location include the
and superior to the left atrium. Fat, lymph nodes,
thymus gland, lymph nodes, and fat. The
and the esophagus are structures that normally
differential diagnoses of lesions in this space
live in this space. Differential diagnoses of lesions
include lesions of thymic origin (thymoma,
in this region include lymphadenopathy, bron-
thymic cyst), lymphoma, teratoma, aortic aneu-
chogenic cyst, esophageal diverticulums, and
rysm, lipomatosis, and sternal lesions. In adults,
esophageal tumors. Lymphadenopathy, the most
thymomas account for most of the lesions in this
common lesion in this space, may be neoplastic,
space. On CT scan they appear as round or
inflammatory, or infectious in nature. CT is very
lobulated lesions with a soft-tissue density. Most
helpful in detecting and characterizing the lymph
thymomas enhance homogeneously after intra-
nodes. On imaging, the nodes may demonstrate
venous contrast administration and may contain
homogeneous enhancement, hyperenhancement,
calcification. In addition, though most are
calcification, or low-density (fat or necrosis)
encapsulated and considered benign, roughly
center. When present, these lymph node charac-
30% demonstrate invasion through the fibrous
teristics help to significantly shorten very lengthy
capsule and are considered malignant. Imaging
differential diagnoses of subcarinal adenopathy.
features that support malignancy are (1) inva-
sion of mediastinal structures, including the
Retrocardiac Clear Space
superior vena cava and great vessels; (2) chest
wall invasion; and (3) contiguous spread along The retrocardiac clear space is posterior to the
pleural surfaces. heart and anterior to the thoracic spine. The
esophagus, aorta, azygos vein, fat, and lymph
Cardiophrenic Angle nodes are present in this region. Differential
diagnoses include esophageal lesions (duplica-
The cardiophrenic angle is situated anterior tion cyst, varices, hiatal hernia, tumor), aortic
and to the right of the heart. Typically, this region aneurysm, and lymphadenopathy.
contains fat and lymph nodes. Most of the lesions
occurring in this space are benign and include Posterior Mediastinum
prominent fat, lipoma, pericardial cyst, and
Morgagni hernia. Occasionally, it may contain The posterior mediastinum is defined as the
lymph nodes from lymphoma or metastasis. area posterior to the anterior margin of the

vertebral bodies. Normal structures that are Nodules that are less than 8 mm and are
present in this location are the vertebral column, present at the lung bases and in the peripheral
fat, and nerves. Most of the lesions in this space aspect of the lung may be classified as intrapul-
are neurogenic (congenital, malignant, infection) monary lymph nodes if they fulfill the following
in nature. Magnetic resonance imaging is the criteria: (1) have a triangular shape and are
preferred imaging modality of choice for evalu- situated on the fissure and/or peripheral sub-
ating posterior mediastinal lesions because of its pleural location, or (2) are well-defined, smooth,
ability to demonstrate intraspinal extension of round, or elliptical in contour, are situated on a
tumor and to detect spinal cord abnormalities. interlobular septa, and are adjacent to a draining
pulmonary vein. Nodules that fulfill these criteria
Solitary Pulmonary Nodule (SPN) are benign and do not require further workup.
Nodules that are ,1 cm and are not
An SPN is defined as a well-circumscribed characterized as benign should be monitored
round lesion that is surrounded by lung paren- according to the Fleischner Society guidelines.
chyma measuring less than 3 cm. A larger lesion For nodules that are .1 cm and are indetermi-
with the same characteristics is called a mass. An nate, further evaluation should be performed
SPN can be solid, ground-glass, or part-solid with (1) nodule enhancement; (2) transthoracic
(containing both ground-glass and solid compo- percutaneous needle (TTPN) biopsy, bronchos-
nents). The list of differential diagnoses is long copy, or surgery; (3) positron emission tomogra-
and includes benign and malignant neoplasms, phy (PET) scan; or (4) periodic follow-up as
granuloma, infection, vascular abnormalities, described in the sections that follow.
and intrapulmonary lymph nodes.
Once a nodule is detected on plain chest
Nodule Enhancement
radiographs, comparison with prior films, if
After obtaining noncontrast images, sections
available, is recommended. If none are available,
through the nodule are obtained after intrave-
then HRCT scans at 1- to 2-mm thick sections
nous contrast administration for up to 4 min at 1-
through the nodule should be obtained. This is
min intervals. Attenuation of the nodule is
helpful in detecting calcification and fat and
measured before and at the peak of contrast
defining the morphology of the nodule.
enhancement. Nodules that enhance less than 15
Morphologic characteristics of SPN are often
Hounsfield units (HU) are strongly predictive of
nonspecific. For example, malignant lesions can
benign lesions. Lesions that enhance greater than
be round and well-defined, whereas benign
15 HU are indeterminate as carcinomas, active
lesions can be irregular and speculated. Howev-
granulomas, inflammatory lesions, and hamarto-
er, some lesions have morphologic characteristics
mas can all demonstrate enhancement.
typical enough to allow a diagnosis to be made
on CT scan. These include arteriovenous fistula, TTPN Biopsy
pulmonary artery pseudoaneurysms, myceto-
mas, and mucous plugs. TTPN biopsy can be performed on most CT
Demonstration of specific types of calcifica- scan-visible lesions. It has a high sensitivity for
tion or fat is the only reliable sign that an SPN is the diagnosis of malignant cells (79%) but is less
benign. Benign types of calcification include accurate for benign processes.
those with a central nidus, popcorn, and lami-
nated. Eccentric calcification can be identified in PET Imaging
a small percentage of lung carcinomas that may
incorporate adjacent calcified granulomas or may PET is a physiologic imaging technique that
themselves calcify. In these instances, the calcifi- uses 2-[fluorine-18]fluoro-2-deoxy-D-glucose
cation is often stippled or punctuate. Presence of (FDG), a D-glucose analog, that is labeled with a
fat within a nodule suggests that the lesion is positron emitter (18F). Increased glucose metabo-
either a hamartoma or a lipoid pneumonia. lism in lesions results in increased uptake and

accumulation of FDG. Thus, metabolically active visceral pleura into the interlobular septa of the
lesions will demonstrate increased FDG uptake. secondary pulmonary nodule. It then flows to the
The degree of FDG accumulation is measured intralobular interstitium and into the peribron-
using a standardized uptake ratio. Typically, lung chovascular interstitium before reaching the
cancers demonstrate a standardized uptake ratio mediastinal lymph nodes.
of greater than 2.5. For nodules greater than 1 cm,
FDG-PET has sensitivity of about 95%. However, HRCT Patterns
its role in evaluation of SPN should be ap-
proached with caution because infectious and The following basic patterns of diffuse lung
inflammatory SPN can demonstrate increased disease are characterized on HRCT scans: (1)
FDG uptake and thus may give false-positive linear, (2) reticular, (3) nodular, (4) ground-glass
results. False-negative results may occur with opacity (GGO), (5) consolidation, and (6) cysts.
carcinoid and bronchioloalveolar carcinomas. Recognition of these basic patterns, along with
Nodules that are too small for the resolution their distribution (central or peripheral, upper or
of PET imaging, are not approachable by biopsy, lower) on HRCT scans, can help narrow the
and do not qualify as intrapulmonary lymph differential diagnosis in most cases.
The linear pattern is defined by the presence
nodes may require periodic follow-up CT scans
of Kerley lines and represents thickening of the
to ensure their stability or to assess for interval
interlobular septa. This pattern has a long list of
growth.
differential diagnoses but is commonly seen in
patients with pulmonary edema and lymphan-
Summary
gitic spread of carcinoma.
The reticular pattern consists of interlacing
In summary, SPN is a common radiologic
line shadows that appear as a mesh or are net-
finding that may require extensive workup to
like. Visualization of this pattern suggests that
establish a definitive diagnosis. There is no one
the patient has pulmonary fibrosis and honey-
correct management approach. The objective is to
combing. It is seen in patients with usual
use a logical approach incorporating clinical
interstitial pneumonia, asbestosis, collagen vas-
history and radiologic findings.
cular disease, and drug toxicity.
The nodular pattern refers to multiple round
HRCT Features of Diffuse Lung opacities that are ,1 cm in diameter. They are
Disease further classified based on their distribution
within the lung. They can be present in the
HRCT scans provide detailed visualization of perilymphatic space, may have a centrilobular
the lung parenchyma. Indications for HRCT location, or may be randomly distributed.
scans are (1) suspected diffuse lung disease, (2) Perilymphatic nodules occur at the pleural
the need for possible pre-biopsy workup, and (3) surfaces, on the interlobular septa, and in the
assessment of disease activity. peribronchovascular interstitium. Perilymphatic
Knowledge of the secondary pulmonary nodules are caused by such diseases as sarcoid-
lobule and the flow of lymphatics within the osis and lymphangitic spread of carcinoma.
pulmonary interstitium are absolutely necessary Random nodules are evenly distributed
for interpreting HRCT scans. The secondary throughout both lungs and suggest hematoge-
lobule is the smallest unit of the lung visible on nous spread of disease. Entities include metas-
HRCT. It is polyhedral in shape and measures tasis and infections such as military TB.
about 1–2.5 cm. The core structures of the lobule Centrilobular nodules occur in the center of
are the central pulmonary artery and terminal the secondary pulmonary lobule. They are seen
bronchiole. The septal structures include venules, in patients with hypersensitivity pneumonitis
lymphatics, and fibrous septa. The pulmonary and infection. Tree-in-bud opacities are a form
lymphatic channels flow from the subpleural of centrilobular nodules and represent dilated
interstitium, which is loculated beneath the and impacted distal terminal bronchioles. Their

presence is almost always indicative of endo- Tuddenham WJ. Glossary of terms for thoracic
bronchial spread of infection. radiology: recommendation of the Nomenclature
GGO represents hazy increased attenuation Committee of the Fleischner Society. Am J Radiol.
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and consolidation represents complete filling of
Suggested Reading
the air spaces by transudative fluid, infectious
material, blood, or malignancy. Both have a very
long list of differential diagnosis. The presence of Tracheobronchial Tree
GGO with superimposed interlobular septal
Gamsu G, Webb WR. Computed tomography of the
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trachea and mainstem bronchi. Semin Roentgenol. 1983;
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18:51–60.
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Nothing to Disclose
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The author has disclosed that no relation-
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Chapter 10. Bronchoscopy and Interventional
Pulmonology
David Feller-Kopman, MD, FCCP
Objectives: define endobronchial anatomy and endoluminal

Review the indications for flexible and rigid bronchoscopy. radiotherapy (brachytherapy). Chevalier Jackson,
Review the diagnostic yield from various bronchoscopic an otolaryngologist who practiced in Philadel-
procedures.

phia, is credited with advancing the field of
Review the procedures available to the interventional
pulmonologist. bronchoscopy and airway interventions in the
Stress the need for specific training in advanced United States. Over the next 150 years, broncho-
procedures. scopic techniques and instruments continued to
be refined. In 1966, Shigeto Ikeda presented the
Key words: airway obstruction; bronchoscopy; hemoptysis; first prototype flexible fiberoptic bronchoscope at
interventional pulmonology; laser; lung cancer; pleuro- the Ninth International Congress on Diseases of
scopy; stent; thoracoscopy
the Chest in Copenhagen. In 1968, Machita and
Synopsis:
Olympus both introduced commercially avail-
able fiberoptic bronchoscopes.4 In 1980, Dumon
The field of bronchoscopy and interventional pulmonology
has had significant advances in the last several years. The
presented his use of the Nd:YAG laser via the
development of convex-probe endobronchial ultrasound for fiberoptic bronchoscope, and since that time the
evaluating mediastinal and hilar adenopathy and the use of flexible bronchoscope has been widely utilized as
ultrasound to guide pleural access have likely had the most both a diagnostic and therapeutic tool for
significant impacts on daily practice. This chapter will
review the basics of bronchoscopy as well as some more diseases of both the parenchyma and the central
advanced techniques, the evolving role of minimally airways. With the miniaturization of electronic
invasive pleural intervention, and recent advances in the devices, the first video bronchoscope was intro-
training of those wishing to obtain additional training in
duced in 1987. This development allowed endo-
advanced procedures.
scopic pictures to be printed out and shared, and
even more importantly, physicians no longer
needed to look through an eyepiece, but instead
Introduction the endoscopic image could be projected onto
monitors, allowing everyone in the room to
Gustav Killian has been described as the ‘‘father visualize what was happening in the airway.
of bronchoscopy.’’1 Using a metallic tube, electric Little has changed in the appearance of
light, and topical cocaine anesthesia, Killian bronchoscopes since 1968. The external diameter
removed a pork bone from a farmer’s airway in of the flexible bronchoscope ranges from 2.8 to
1897.2 Prior to the development of rigid bron- 6.3 mm in diameter. The diameter of the working
choscopy, more than half of the patients who channel ranges from 1.2 to 3.2 mm. A working
aspirated foreign bodies died because of pneu- channel 2.8 mm is recommended for more
monia. Rigid bronchoscopy with foreign body therapeutic flexible bronchoscopy, as it allows for
removal quickly evolved into the treatment of better suction and the passage of larger instru-
choice in these patients, with a clinical success ments. It is important to note the relative
rate above 98%.3 Over the subsequent years, anatomy at the tip of the bronchoscope. By
Killian published extensively and lectured convention, as viewed from the operator ’s
throughout Europe and the United States. He perspective, the camera is at 9:00, suction at
went on to develop bronchoscopes, laryngo- 6:00, and the working channel at 3:00. These
scopes, and endoscopes and to describe tech- landmarks play a role when navigating the
niques such as using fluoroscopy and x-ray to airways, as the bronchoscope may need to be

rotated in order to visualize or biopsy the approximately 159,000 deaths in 2011, more than
intended target. colon, breast, and prostate cancers combined.17 It
There are several outstanding texts and is estimated that 220,000 new cases of lung cancer
review articles summarizing the current state of will be diagnosed in 2011, and the incidence and
the art for bronchoscopy and interventional number of lung cancer deaths continue to
pulmonology.5–9 This chapter will review some increase among women in the United States.18
of the key factors associated with these fields. Bronchoscopy provides a minimally invasive
approach for the diagnosis of tumors in the
Thoracic Anatomy central airways. Though the yield is somewhat
lower for solitary parenchymal lesions, advances
It is crucial that the bronchoscopist become an in navigation such as CT fluoroscopy and
expert in airway and thoracic anatomy. This electromagnetic and virtual bronchoscopic navi-
includes knowledge of the nasopharynx and gation (to be discussed later) have significantly
oropharynx in addition to the bronchial tree and improved the yield for peripheral tumors. Sev-
mediastinal structures, and there are several eral comprehensive reviews discussing the diag-
excellent chapters/texts to assist with this pro- nosis and staging of lung cancer as well as the
cess.10,11 The segmental anatomy of the lungs from role of bronchoscopy are available.19–23
both an external and internal perspective is The bronchoscopic evaluation of patients
required, and one should become familiar with with suspected malignancy is guided by clinical
the name system (eg, superior segment of the right symptoms as well as radiographic findings.
lower lobe), as well as the number system (eg, Depending upon the history and chest CT/PET-
RB6), as initially proposed by Jackson and Huber12 CT scan findings, bronchoscopy may be the
and Boyden.13 It is also important to appreciate diagnostic modality of choice, as it can both
mediastinal anatomy, including intrathoracic ves- make the diagnosis and stage the patient at the
sels and lymph nodes as well as their relationship same sitting. If appropriate staging is to be
to endobronchial landmarks. These will serve as performed, biopsy of the lesion that will place
reference points for transbronchial needle aspira- the patient in the highest clinical stage should
tion (TBNA) and endobronchial ultrasound occur prior to other biopsies. For example, if a
(EBUS), and will help avoid injury should the patient presents with a left lower lobe mass and
bronchoscopist use therapy such as the Nd:YAG an enlarged subcarinal (station 7) and right
laser or brachytherapy. The use of endoscopic paratracheal (station 4R) lymph node, the appro-
simulators has been associated with a more rapid priate procedure would be a bronchoscopy with
acquisition of bronchoscopic expertise.14 TBNA of the 4R node, as this would stage the
patient with N3 disease, making the patient
Diagnostic Bronchoscopy unresectable. If a diagnosis is not obtained from
4R, station 7 should be sampled next, as this
There are many indications for diagnostic would be considered an N2 node if involved
bronchoscopy. The most common indication is with cancer. Only if sampling of this node is
for the diagnosis of suspected lung cancer. Other nondiagnostic would one need to proceed with
indications include evaluation of diffuse lung addressing the left lower lobe mass. Initial biopsy
disease, infiltrates in the immunocompromised of the mass could contaminate the working
host, hemoptysis, and cough. Additionally, bron- channel and make the TBNA a false-positive,
choscopy with BAL and/or brushing may be precluding the patient from curative surgery.
useful for the diagnosis of ventilator-associated Recent data have suggested that the use of rapid
pneumonia.15,16 on-site evaluation by cytopathology can signifi-
cantly reduce the complication rate associated
Cancer Diagnosis and Staging with bronchoscopy (from 20% to 6%) by identi-
fying cancer in the lymph nodes and thus
Lung cancer is the leading cause of cancer reducing the need for sampling the primary
deaths in the United States, and will account for parenchymal lesions.24,25
166 Chapter 10. Bronchoscopy and Interventional Pulmonology (Feller-Kopman)

There are several available tools by which to years ago, it remains an underutilized technique,
obtain specimens during bronchoscopy, includ- with only 12% of pulmonologists reporting its
ing forceps biopsy, brushing, bronchial wash/ routine use for the evaluation of patients with
lavage, and TBNA. Electrocautery snare forceps suspected lung cancer.42,43 The technique, how-
is an excellent tool for the removal of a ever, is incredibly useful. A recent study of 365
pedunculated airway lesion, as it can open the patients with documented malignancy found
airway and also provide excellent tissue for the that standard TBNA (without EBUS) would
pathologist.26 The choice of the above modalities preclude further invasive surgery in 29% of
is primarily determined by the location of the patients and was able to establish exclusively a
pathology; however, data support the use of the diagnosis in 18% of cases.44,45 The yield with
combination of techniques to improve diagnostic TBNA has been associated with tumor cell type
yield, as opposed to using them in isola- (small cell . non-small cell . lymphoma), lymph
tion.19,20,27,28 Additionally, endobronchial needle node size, and lymph node location.46
aspiration should be used with all visible lesions, The use of CT fluoroscopy to guide TBNA
as its use in combination with conventional and TBBx has several advantages over standard
techniques has been associated with an improve- fluoroscopy. As opposed to standard fluoroscopy,
ment in yield from 65% to 96%.29 which is typically only used in two dimensions,
If the lesion is not visible endoscopically, CT scan provides the ability to visualize the
BAL can be performed.30–32 Briefly, the bron- target in three dimensions. With standard fluo-
choscope is wedged in the target segmental or
roscopy, either the patient or the C arm needs to
subsegmental bronchus leading to the lesion.
be rotated to confirm the biopsy tool is not
Aliquots of normal saline solution are instilled
anterior or posterior to the target. CT fluoroscopy
and then aspirated. Ideally, the return should be
provides real-time 3-D confirmation of the
between 40% and 60% of the instilled volume;
appropriate and inappropriate biopsy sites. The
however, this is dependent upon the segment
use of CT fluoroscopy has been associated with
lavaged, with better return coming from less
an accuracy of 88%, including patients who have
dependent locations.33 BAL is thought to sample
previously undergone a nondiagnostic bronchos-
approximately 1 million alveoli, and the cellular
copy with standard TBNA.47 The one frustration
and noncellular contents of the lavage fluid have
that can occur with CT-scan-guided bronchosco-
been shown to closely correlate with the
py is that one may be able to see the lesion, but
inflammatory nature of the entire lower respi-
ratory tract.32,34–36 not steer the bronchoscope/catheter into the
Transbronchial biopsy (TBBx), brushing, and correct airway.
TBNA can also be performed for peripheral EBUS is another important modality used to
lesions. The diagnostic yield of BAL for periph- help improve the accuracy of sampling periph-
eral cancer ranges from 4% to 68%.37–39 Without eral nodules, as well as in guiding TBNA. The
advanced guidance (discussed below), the yield earliest EBUS system used a radial probe with a
for TBBx ranges from 49% to 77% and for 20-MHz transducer that could be inserted via a
brushing 26% to 57%; however, again, the 2.8-mm working channel. Despite not allowing
combination of all three increases the yield to for real-time guidance, the early studies with
68%.37 TBNA of peripheral nodules has been radial-probe EBUS found significant improve-
shown to have a higher diagnostic yield than ments in the yield of TBNA, sampling of
other sampling techniques, and should be used peripheral nodules, and distinguishing tumor
for the biopsy of peripheral lesions.40,41 Some invasion vs compression in the central air-
authors recommend washing the tools used to ways.48–50 The sonographic characteristics of
obtain samples and sending the wash for peripheral nodules have also been shown to
cytology, with a combined diagnostic yield of correlate well with histologic findings.51,52
93%.39 More recently, a bronchoscope with a dedi-
As for peripheral nodules and masses, cated convex 7.5-MHz linear array transducer
despite TBNA being introduced more than 25 and a distinct working channel has been devel-

oped and has the major benefit of providing real- disorders that may involve the interstitial, alve-
time guidance for TBNA of mediastinal and hilar olar, bronchial, and vascular structures of the
lymph nodes, with excellent results, and has tracheobronchial tree. The most commonly used
even been found to perform as well as, if not sampling techniques for patients with diffuse
better than, mediastinoscopy.53–57 Additionally, disease include BAL, bronchial brushing, TBBx,
EBUS has been shown to provide excellent and occasionally endobronchial biopsy and
material for multi-gene mutation analysis, in- TBNA.
cluding epidermal growth factor receptor, Kirs- Though associated with a low morbidity and
ten-rat sarcoma virus oncogene, echinoderm mortality, TBBx should be used only when the
microtubule-associated protein-like 4 gene fusion potential results will affect treatment decisions.
to anaplastic lymphoma kinase, and p53 muta- Diseases in which TBBx can prove diagnostic, or
tions.58,59 Despite the high sensitivity and spec- has been shown to significantly increase the
ificity of EBUS-TBNA, it is crucial to understand diagnostic yield as compared with less invasive
that a nondiagnostic result is not equivalent to a means, include lymphangitic carcinomatosis,
negative result, and it is therefore mandatory to sarcoidosis, rejection after lung transplantation,
follow all nondiagnostic procedures with a hypersensitivity pneumonitis, and sometimes
confirmatory surgical biopsy or appropriate mycobacterial and invasive fungal infec-
clinical follow-up prior to concluding that the tion.31,63,64 The overall diagnostic yield for TBBx
test result was a true negative.60 Though there
clearly depends on the disease entity as well as
are not a lot of data regarding EBUS technique, a
severity. For example, the yield for sarcoidosis
recent study found no difference in specimen
can approach 90% in patients who have stage II
adequacy, diagnostic yield, or sample quality
and III disease.65
when performing EBUS with or without the
Aside from providing a specific diagnosis in
application of suction.61
cases of cancer or infection, the results of BAL
Autofluorescence (AF) bronchoscopy can be
can serve to limit the differential diagnosis
used for the early detection of cancer in the
considerably.63 For example, a BAL with lym-
central airways, primarily carcinoma in situ and
phocyte predominance suggests granulomatous
squamous cell carcinoma. When exposed to light
in the violet-blue spectrum (400–450 nm), the disease such as sarcoidosis, berylliosis, or a
normal airway fluoresces green. As submucosal lymphoproliferative disorder. Neutrophil pre-
disease progresses from normal to metaplasia, to dominance suggests bacterial infection or acute
dysplasia, to carcinoma in situ, there is a interstitial pneumonia, and may also be seen in
progressive loss of the green AF, causing a red- patients with asbestosis or usual interstitial
brown appearance of the airway wall. Several pneumonitis. Eosinophils are seen in patients
studies have shown that the use of AF increases with eosinophilic pneumonias, hypereosinophilic
the detection of early-stage lung cancer by up to syndromes, or Churg-Strauss syndrome. Patients
sixfold when compared with white-light bron- with pulmonary alveolar proteinosis have a
choscopy. The major limitation of AF lies in its unique appearance of the BAL fluid that is
low specificity, and a recent study suggests that it described as milky or opaque. The alveolar
detects only one case of carcinoma in situ per 100 macrophages are filled with periodic acid-
bronchoscopies.62 Other new technologies such Schiff-positive material, and lamellar bodies can
as narrow-band imaging, optical coherence to- be seen under electron microscopy.
mography, and confocal imaging may also help
in the diagnosis of early-stage lung cancer, Infectious Diseases
though definitive data are still pending.
Community-Acquired Pneumonia
Diffuse Parenchymal Lung Disease
The role of bronchoscopy in community-
Diffuse parenchymal lung disease describes a acquired pneumonia remains controversial.66
group of infectious, inflammatory, and fibrotic When used, BAL and protected brush are the

main diagnostic procedures, and the specimens was that they excluded patients with Pseudomo-
should ideally be sent for quantitative culture, nas and Staphylococcus pneumonia.
with a threshold of 104 colony-forming units in
the BAL and 103 colony-forming units in the The Immunocompromised Host
protected brush. A recent study by van der
Eerden and colleagues67 found bronchoscopy to The early diagnosis and initiation of the
be of additive diagnostic value in the 49% of appropriate antibiotic is the cornerstone of
patients who were unable to raise sputum for successful treatment of the immunocompro-
Gram stain and culture and in 52% of patients mised patient with pneumonia. Additionally, it
who had treatment failure. As expected, pre- is important to note that multiple diagnoses can
treatment with antibiotics may significantly often be present simultaneously in these pa-
reduce the yield,68 though Feinsilver’s group69 tients,71 and noninfectious conditions may have a
found an 86% yield in patients with nonresolving similar presentation of cough, dyspnea, fever and
pneumonia who had already received antibiotics. an infiltrate on imaging. Bronchoscopy is an
Another important indication for bronchoscopy excellent method of evaluating these patients, as
less-invasive techniques can miss the diagnosis
in patients with community-acquired pneumonia
in approximately 30% of patients,36 and earlier
is to rule out an obstructing endobronchial lesion.
diagnoses may improve mortality.72
Obviously, it is crucial to avoid contamination
Helmers and Pisani32 suggest three broad
with upper airway secretions when performing
categories of immunocompromised patients:
bronchoscopy in patients with pneumonia. Key
those who are pharmacologically immunosup-
procedural aspects include minimizing suction-
pressed, those with hematologic malignancy/
ing and minimizing the instillation of saline
malfunction, and those with immunodeficiency.
solution or lidocaine, as secretions in the working
The reason for these categories is that each type
channel will be flushed back into the airways,
of immunodeficiency predisposes to distinct
and high concentrations of lidocaine can be
infections. For example, infection with Strepto-
bacteriostatic. Baselski and Wunderink66 re-
coccus pneumoniae and Haemophilus influenzae is
viewed the indications, procedural details, mech- common in patients with hypogammaglobulin-
anisms for specimen transport/handling, and emia, whereas Aspergillus spp are more likely to
interpretation of results. cause disease in patients with neutropenia, and
Cryptococcus, Histoplasma, and viruses such as
Health-Care- and Ventilator-Associated cytomegalovirus are seen in patients with defects
Pneumonia in cell-mediated immunity.73
BAL is the most commonly used broncho-
The American Thoracic Society and Infec- scopic technique used to obtain a diagnosis in
tious Disease Society has recently reviewed these immunocompromised patients, with an overall
topics in great detail, and used the techniques of diagnostic yield of approximately 60% to 70%.73
evidence-based medicine to guide their recom- In comparative studies, the sensitivity of TBBx
mendations.70 Some major points included the has been shown to be roughly the same,74,75
collection of a lower respiratory tract culture though the combined use of both techniques may
prior to the initiation of antibiotics, the use of increase the yield.76 The results of BAL have been
semiquantitative or quantitative culture data, shown to change management in up to 84% of
and the use of negative culture data to discon- cases.77 Unfortunately, though bronchoscopy has
tinue antibiotics in patients who have not had changed management in patients who have had
changes in their antibiotic regimen within the last bone marrow transplantation, mortality remains
72 h.70 Additionally, the use of a bronchoscopic extremely high.71,78 Bronchoscopy with BAL
strategy was supported as a way to reduce 14- remains a safe procedure, even in the immuno-
day mortality.15,70 More recently, however, an compromised host. Brushing and TBBx have
invasive strategy was found to have no impact been associated with a higher incidence of
on mortality.16 A major criticism of this study bleeding complications in patients who are

thrombocytopenic.79 The gold standard, how- require, as well as improved quality and length
ever, remains open lung biopsy, which can yield of life.91–93
a specific diagnosis in 62% of patients and result
in a significant increase in survival.80 Hemoptysis
Hemoptysis The definition of massive hemoptysis has
ranged from 100 to 1,000 mL expectorated in a
There are many causes of hemoptysis, includ- 24-h period.94,95 As the majority of patients with
ing infectious, inflammatory, vascular, and neo- massive hemoptysis die of asphyxia and not
plastic processes.81 Though one would think that exsanguination, and the anatomic dead space is
bronchoscopy could often make the diagnosis of a approximately 150 mL, I consider any amount
radiographic occult neoplasm in a patient who over 100 mL in 24 h as massive. Using a
presents with hemoptysis, a bronchoscopic diag- definition of 500 mL/24 h, Hirshberg’s group81
nosis of malignancy is made in ,5%. The found that 14% of 208 patients presenting with
incidence of cancer is increased in patients who hemoptysis had ‘‘massive hemoptysis.’’
present with hemoptysis and normal chest In addition to identifying the source and
imaging if they are older than 40 years, are of cause of bleeding, bronchoscopy clearly plays an
male gender, and have a .40-pack-year smoking important therapeutic role in patients with
history.82–84 As such, bronchoscopy is recom- massive hemoptysis. If available, rigid bronchos-
mended in this patient population. Though the copy is generally considered the airway proce-
appropriate timing for bronchoscopy is contro-
dure of choice in these patients. If rigid
versial, there is a greater likelihood of identifying
bronchoscopy is not available, the options in-
the bleeding source when it is performed within
clude intubation with a single-lumen endotra-
the first 48 h of symptoms.85 The combined use of
cheal tube or a double-lumen tube or placement
bronchoscopy and CT scanning is also recom-
of a bronchial blocker. As double-lumen endo-
mended.81 If patients are clinically stable, I would
tracheal tubes, or specialized tubes that come
recommend obtaining the CT scan first, as it can
with an endobronchial blocker (ie, Univent;
serve as a ‘‘road map’’ to guide bronchoscopy.86
Vitaid), can be more difficult to place, especially
in the setting of massive hemoptysis, my practice
Therapeutic Bronchoscopy
is to place a larger single-lumen tube.
Though many advanced techniques can be The main role of flexible bronchoscopy in the
performed with flexible bronchoscopy, the rigid patient with massive hemoptysis lies in helping
bronchoscope is the preferred tool in many to obtaining lung isolation by guiding the
situations.87,88 The rigid bronchoscope provides endotracheal tube or bronchial blocker and
an airway in which to oxygenate/ventilate the providing some therapeutic aspiration to protect
patient as well as pass multiple devices, includ- the good lung. All bronchoscopists should
ing large-bore suction catheters, laser/argon become familiar with bronchial blockers (ie,
plasma coagulation (APC)/electrocautery fibers, Arndt Bronchial Blocker; Cook Critical Care),
the microdebrider blade, and larger biopsy which can be passed in parallel to the broncho-
instruments. The rigid bronchoscope itself can scope. These catheters are guided to the culprit
also be used to achieve relative lung isolation, segmental, lobar, or main-stem bronchus, and the
dilate stenosis, and ‘‘core out’’ tumor from the balloon is inflated to the recommended volume/
central airways. Unfortunately, only approxi- pressure. After a maximum of 24 h, the balloon
mately 4% of pulmonologists currently perform should be deflated under bronchoscopic visual-
rigid bronchoscopy,89 and its use is typically not ization.96–98
taught in pulmonary and critical care fellowship Other bronchoscopic techniques used to
programs.90 It should be noted that therapeutic control hemoptysis include the topical applica-
bronchoscopy has been associated with an tion of iced saline, epinephrine (1:20,000), and
immediate reduction in the level of care patients thrombin/thrombin-fibrinogen or cyanoacrylate

solutions, though the data supporting these 898C. Cryotherapy is especially useful for the
techniques are extremely limited.99–101 removal of organic foreign bodies with high
water content such as grapes and vegetable
Advanced Bronchoscopic Techniques matter, in addition to facilitating the removal of
tenacious mucus or blood clots when performing
Argon Plasma Coagulation flexible bronchoscopy. Compared with other
techniques for tumor destruction, cryotherapy
APC is a noncontact method using ionized has a delayed effect, and thus requires a repeat
argon gas (plasma) to achieve tissue coagulation bronchoscopy to remove the necrotic tissue. The
and hemostasis. As the plasma is directed to the distinct advantage of cryotherapy lies in the fact
closest grounded source, APC has the ability to that the normal airway tissue is relatively
treat lesions lateral to the probe. The depth of cryoresistant. Additionally, unlike ‘‘hot’’ thermal
penetration for APC is approximately 2 to 3 mm, techniques, cryotherapy is not associated with a
and hence the risk of airway perforation is less risk of airway fires.
when compared with lasers. Gas flow through
the APC fiber should be kept to the lowest setting Electrocautery
possible (ie, 0.5 L/min) in order to avoid the
potential of gas embolus formation.102 Electrocautery uses alternating current at
high frequency to generate heat, which cuts,
Laser Therapy vaporizes, or coagulates tissue, depending on the
power. Electrocautery is a contact mode of tissue
The Nd:YAG laser is the most widely used destruction, and a variety of cautery probes are
laser in the lower respiratory system, and has available, including blunt-tip probes, knives, and
been used for both benign and malignant snares. The snare is an ideal tool for peduncu-
disease.103 The primary advantage of laser photo- lated lesions, as the stalk can be cut and
resection is that it provides rapid destruction/ coagulated while preserving the majority of the
vaporization of tissue. Care must be taken, tissue for pathologic interpretation.107 The knife
however, as the depth of penetration can ap- is also an excellent tool for producing radial
proach 10 mm, and airway perforation with incisions prior to dilation of weblike tracheal
resultant pneumothorax, pneumomediastinum, stenosis. As with laser therapy, the risks of
and vascular injury have been reported. As such, electrocautery include airway perforation, air-
it should be used only by experienced interven- way fires, and damage to the bronchoscope.
tional bronchoscopists. Despite this, the safety
record of laser bronchoscopy is excellent, with an Photodynamic Therapy (PDT)
overall complication rate of ,1%.103 Lesions
most amenable to laser therapy are central, PDT involves the intravenous injection of a
intrinsic, and short (,4 cm), with a visible distal photosensitizing agent, then activation of the
endobronchial lumen.104 When lesions meet drug with a nonthermal laser to produce a
these criteria, patency can be reestablished in phototoxic reaction and cell death. Because the
more than 90% of cases. Of note, the tissue laser is not a heat source, airway fires are not an
destruction obtained with laser therapy is often issue. As tumor cells retain the drug longer than
more than is visually appreciated at the time of other tissues, waiting approximately 48 h after
the procedure. drug injection will lead to preferential tumor cell
death as compared with normal tissue injury.
Cryotherapy Similar to cryotherapy, maximal effects are
delayed, and a repeat, ‘‘clean-out’’ bronchoscopy
Cryotherapy is a safe and effective tool for a should be performed 24 to 48 h after drug
variety of airway problems.105,106 By releasing activation. The primary side effect from PDT is
nitrous oxide or carbon dioxide stored under systemic phototoxicity, which can last up to 6
pressure, the tip of the cryoprobe rapidly cools to weeks after injection. Newer drugs are being

developed with the hopes of increasing tumor in patients with tracheal stenosis.112 Dumon,113
selectivity and reducing the duration of skin however, introduced the first completely endo-
phototoxicity. PDT has been shown to be curative luminal airway stent in 1990. Airway stents are
for early-stage lung cancer of the airways and is the only technology that can alleviate extrinsic
an especially attractive option for patients with airway compression. They are commonly used in
endobronchial carcinoma in situ who are not conjunction with the other modalities for patients
surgical candidates because of other comorbidi- with intrinsic or mixed disease.
ties.108,109 Over the last 15 years, there has been an
explosion in both stent design and the number of
Brachytherapy endoscopists who place airway stents. As with
any procedure, it is crucial to understand the
Brachytherapy refers to endobronchial radia- indications and contraindications of the proce-
tion, primarily used for the treatment of endo- dure as well as be able to anticipate, prevent, and
bronchial malignant airway obstruction.110,111 manage the associated complications. Unfortu-
The most commonly used source of radiation is nately, the ideal stent has not yet been developed.
iridium-192 (192Ir), which is delivered through a This stent would be easy to insert and remove,
catheter inserted bronchoscopically. Brachyther- yet not migrate; of sufficient strength to support
apy may be delivered by either low-dose-rate, the airway, yet flexible enough to mimic normal
intermediate-dose-rate, or high-dose-rate (HDR) airway physiology and promote secretion clear-
methods, with most authors currently recom- ance; biologically inert to minimize the formation
mending the afterloading HDR technique. This of granulation tissue; and available in a variety of
allows the bronchoscopist to place the catheter in sizes.
the desired location and the radiation oncologist There are currently two main types of stents:
to deliver the radiation in a protected environ- metal, generally made of nitinol, and silicone.
ment. The main advantage of HDR is patient Though metal stents are easily placed, they can
convenience, as each session lasts ,30 min; be extremely difficult to extract. They are
however, multiple bronchoscopies are required available in covered (typically with silicone or
to achieve the total 1,500-cGy dose that is polyurethane) and uncovered varieties. For ma-
currently recommended. The low-dose-rate tech- lignant airway obstruction, the only appropriate
nique may be appropriate for patients who live metal stents are covered models, which minimize
far from the hospital or who are otherwise tumor ingrowth. Some authors feel that there is
hospitalized, as it requires only one bronchosco- no indication for an uncovered metal stent. The
py; however, the catheter has to stay in place for overuse of metallic stents in patients with
20 to 60 h, which is often poorly tolerated by the nonmalignant airway obstruction has lead to
patient. The main advantage of brachytherapy as the US Food and Drug Administration’s creating
compared with external-beam radiation is the a black-box warning recommending their use as
fact that less normal tissue is exposed to the toxic a modality of last resort in these patients.114 The
effects of radiation. The most common side main advantage of metal stents is their larger
effects include intolerance of the catheter, radia- internal:external diameter ratio as compared
tion bronchitis, airway perforation, and, occa- with silicone stents. Though silicone stents
sionally, massive hemorrhage. Treatment of require rigid bronchoscopy for placement, they
tumors in the right and left upper lobes has the are more easily removed and are significantly
highest incidence of hemorrhage, as these are less expensive.
located near the great vessels. In addition to malignant airway obstruction,
airway stents can be helpful in patients with
Airway Stents tracheobronchomalacia and tracheoesophageal
fistula. In patient with tracheoesophageal fistula,
Montgomery is credited as initiating the double stenting of the esophagus and airway has
widespread use of airway stents after his been recommend to maximally prevent aspira-
development of a silicone T-tube in 1965 for use tion, though it should be appreciated that it is

unlikely for the fistula to heal, and, in fact, the group.124 In the largest trial to date, in patients
fistula may enlarge because of the underlying with severe asthma, thermoplasty resulted in
malignancy, treatment with radiation, and the significant improvements in asthma-related qual-
pressure exerted by the stents.115 ity of life, emergency room visits, hospitaliza-
tions, and days lost from work/school. 125
Future Directions in Bronchoscopy Widespread clinical application of this technique
requires validation by other ongoing multicenter
Bronchoscopic Lung-Volume Reduction studies as well as determination of how the
required three procedures will be paid for, as this
In the patient with upper lobe-predominant can cost up to $12,000.
disease and low exercise capacity, lung volume
reduction surgery has been shown to improve Enhanced Navigation
both quality and quantity of life.116 The major
drawback to surgical lung-volume reduction is The use of electromagnetic navigation, espe-
its invasiveness and cost. As such, several cially in conjunction with radial-probe EBUS, is a
techniques to achieve lung-volume reduction novel technology that has been shown to allow
bronchoscopically are currently under investiga- accurate sampling of peripheral solitary pulmo-
tion, with the hopes of achieving similar efficacy nary nodules ,2 cm in diameter.126,127 Briefly, a
to surgical lung-volume reduction with less virtual bronchoscopy is generated from the
morbidity. Unfortunately, the investigation of patient’s CT scan. Anatomic landmarks that are
two techniques, one-way endobronchial valves easily identified, such as the carina, are marked,
for heterogeneous disease and the implantation
as is the target. At the time of bronchoscopy, the
of drug-eluding stents for patients with homog-
patient lies in an electromagnetic field and a
enous disease, resulted in negative clinical
steerable, locatable guide is placed through an
trials.117,118 Other techniques, which are available
extended working channel of the bronchoscope.
in Europe and though not currently available in
The location of the guide in the electromagnetic
the United States will start clinical trials within
field is accurate to ,5 mm in the X, Y, and Z axes
the next year in the United States, include
as well as yaw, pitch, and roll. The points
polymer sealants, steam, coils, and intrabronchial
previously identified in the virtual bronchoscopy
valves.119–122
are then marked with the locatable guide, which
Bronchial Thermoplasty in essence fuses the CT scan with the patient’s
anatomy. Navigation is then performed by
Bronchoscopic thermoplasty is a technique in looking at the CT scan in the axial, sagittal, and
which controlled thermal energy (radiofrequency coronal planes, and the guide is steered toward
energy at 658C) is applied directly to visible the target. Once found, the guide is removed, and
airways through the bronchoscope. The goal is to standard bronchoscopic tools such as TBNA
achieve ablation of the airway smooth muscle needles, forceps, and brushes are placed through
without causing scarring and stenosis. In prelim- the extended working channel. This technology
inary studies, the use of this technique in the can be used for both diagnostic bronchoscopy
treatment of patients with mild to moderate and therapeutic modalities. For example, if a
asthma led to reduction in airway hyperrespon- patient with a 2.5-cm, stage Ia, non-small cell
siveness, which was associated with improve- cancer is not an operative candidate, this
ments in daily symptoms and peak expiratory technology may allow for bronchoscopic treat-
flow for a period of 2 years.123 In a study of 112 ment by either radiofrequency ablation or the
subjects in whom asthma control was impaired, implantation of fiducials to allow stereotactic
bronchial thermoplasty reduced the rate of mild radiosurgery.128 Other techniques of virtual
exacerbations, and at 12 months, there were bronchoscopic navigation are also being devel-
significantly greater improvements in the bron- oped that do not require the presence of an
chial-thermoplasty group than in the control electromagnetic field and rely on high-definition

virtual bronchoscopic road maps with ultrathin Additional Airway Procedures
bronchoscopes.129–131
Many interventional pulmonologists routine-
Other Interventional Pulmonary ly perform percutaneous dilational tracheostomy.
Procedures As compared with open tracheostomy, percuta-
neous tracheostomy is at least as safe, and may
Pleural Interventions be associated with reduced infectious and bleed-
ing complications. It is also less expensive and
Ultrasound has revolutionized the evaluation does not require transport of a critically ill
and management of patients with pleural dis- patient to the operating room.140
ease.132 Though randomized trials have not been
performed, the use of ultrasound seems to be Complications
associated with an increased success as well as a
reduction in the pneumothorax rate for patients Bronchoscopy is generally considered a rela-
undergoing thoracentesis.133 Ultrasound allows tively safe procedure.5 That being said, it is
for the precise placement of small-bore chest common that patients in whom bronchoscopy is
tubes in loculated effusions, has been shown to performed can have multiple comorbidities, and
be extremely accurate in ruling out pneumotho- the bronchoscopist needs to be aware of the
rax, and is currently recommended by the British patient’s medical history, including medications
Thoracic Society for all pleural interven- and allergies. Additionally, the bronchoscopist
tions.134,135 needs to have a thorough understanding of the
Medical thoracoscopy describes the insertion effects and side effects of the medications to be
of a semirigid or rigid thoracoscope with the used to achieve adequate topical anesthesia and
intent of draining pleural fluid, obtaining biop- moderate sedation, and to be skilled in airway
sies of the parietal pleura, and/or instilling an management should the patient experience hyp-
agent to achieve pleurodesis.73,136,137 Whereas oxemia/hypercapnia. Transient fever is the most
video-assisted thoracic surgery is typically per- common adverse event following BAL, and can
formed in the operating room with general be seen in up to one-third of patients. Major
anesthesia and lung isolation, with two or three adverse events including hypoxemia, pneumo-
ports, medical thoracoscopy is commonly per- thorax, bleeding, and death may also occur, and
formed in an endoscopy suite with moderate both patient- and procedure-related factors are
sedation on a spontaneously breathing patient important determinants. The British Thoracic
with one access port. Common indications for Society has published its recommendations con-
medical thoracoscopy include a recurrent exuda- cerning the performance of diagnostic flexible
tive effusion with no clear diagnosis or a known bronchoscopy, including steps that should be
malignant effusion requiring pleurodesis. taken to minimize complications.5 Though still
Indwelling, tunneled pleural catheters are an relatively safe, complications associated with the
excellent treatment option for patients with more advanced procedures, including rigid
dyspnea due to a recurrent malignant pleural bronchoscopy, pleuroscopy/thoracoscopy, in-
effusion. Though the treatment of choice for dwelling pleural catheters, and percutaneous
patients with lung entrapment, they may also be tracheostomy, are slightly higher because of the
used for patients with expandable lung. Pleural increased acuity of the patient population as well
palliation can be achieved in close to 90% of as the invasiveness of the interventions.8,9
patients, and side effects are relatively few.138 A
recent study found that the combination of a Training
tunneled pleural catheter and talc pleurodesis, in
selected patients, can achieve the ‘‘best of both Flexible bronchoscopy is one of the proce-
worlds’’; that is, rapid and effective pleurodesis dures most commonly performed by the pulmo-
with a minimal hospital stay and a catheter nologist. Though 96% of fellowship programs
duration of approximately 1 week.139 offer the recommended number of diagnostic

flexible bronchoscopies, the percentage achieving 7. Wahidi MM, Herth FJF, Ernst A. State of the art:
the recommend number is only 69% for TBNA, interventional pulmonology. Chest. 2007;131(1):
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recommendations suggesting that a year of ATS statement on interventional pulmonology.
advanced training should be required for the European Respiratory Society/American Tho-
majority of procedures considered essential to racic Society. Eur Respir J. 2002;19(2):356–373.
interventional pulmonologists.141 Clearly, it is not 9. Ernst A, Silvestri GA, Johnstone D. Intervention-
necessary to obtain a formal additional year of al pulmonary procedures: guidelines from the
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Chapter 11. Pulmonary Complications of Cardiothoracic
Surgery and Trauma
Bruce P. Krieger, MD, FCCP
Objectives: Pulmonary Complications After Lung

Apply physiologic parameters preoperatively to predict Resection Surgery
postoperative pulmonary complications after thoracic
resection or cardiac surgery.
Explain the pathophysiology of hypoxemia in patients
Lung resection surgery is performed in the
after cardiac surgery and chest trauma. United States at least 30,000 times annually,
Describe the initial assessment of the patient who has usually in an attempt to cure bronchogenic
suffered blunt chest trauma. carcinoma. The pulmonologist is often consulted
Recognize and treat the most common causes of
respiratory failure after cardiac surgery.
preoperatively to evaluate the advisability of
lung resection. There are two general aspects to
this evaluation: (1) whether the cancer can be
Key words: diaphragm dysfunction; exercise testing; ster-
fully resected and cured (resectability), and (2)
notomy; thoracic surgery; thoracic trauma; thoracoscopy
whether the patient will survive the operation
and be able to function in a ‘‘reasonable manner’’
Synopsis: afterward (operability). Many patients undergo-
The pulmonologist’s role in the ICU has dramatically ing thoracic surgery have underlying lung
expanded during the past decade. Therefore, familiarity diseases, which are associated with an increase
with traditional surgical fields, such as trauma, cardiac in the morbidity and mortality from surgery,
surgery, and thoracic surgery, is essential for the care of our
patients. This chapter will discuss some physiologic
especially in the elderly. Therefore, preoperative
parameters that may predict postoperative pulmonary evaluation is critical before deciding on the
complications; pulmonary difficulties after cardiac surgery; advisability of thoracic surgery.
and the pulmonologist’s involvement with the complica- The decreases in lung function that occur
tions of blunt chest trauma.
after thoracic surgery are more complicated than
the changes that occur after upper abdominal or
cardiac surgery because a functioning lung is
Many recently trained chest surgeons have more removed. After laparotomy, there is an approx-
experience in cardiac surgery than in thoracic imately 50% decrease in FVC for the first few
surgery. For the pulmonologist, a surgeon with postoperative days. There are similar predict-
expertise in thoracic surgery is essential for able decreases in lung function after cardiac
patients undergoing complicated pulmonary surgery, as described later in this chapter. The
procedures. Thoracocardiac surgery encompass- effect of thoracic surgery on postoperative
es procedures involving the lungs, chest wall, pulmonary function is not only permanent but
mediastinum, thoracic aorta, and heart (Table 1). also more difficult to predict as it depends on
This chapter will concentrate on those problems the amount of viable lung parenchyma that
most frequently encountered by a practicing remains after surgery. If the patient has limited
pulmonologist, including evaluation before lung pulmonary reserve preoperatively, further wors-
resection surgery, pulmonary complications after ening after lung resection can result in postop-
thoracic and cardiac surgery, diagnostic thora- erative atelectasis, pneumonia, prolonged
coscopy, and pulmocardiac complications after mechanical ventilator support (MVS), or even
chest trauma. Lung transplantation and lung death. During the past 5 decades, various
volume reduction surgery (LVRS) are discussed pulmonary function tests have been used to
elsewhere. predict pulmonary function after resection and

Table 1—Thoracic Surgical Procedures
Indication Approach Procedures
Resectional Thoracotomy Pneumonectomy, lobectomy, segmentectomy, wedge resection, rib and chest wall
resection
Thoracoscopy Wedge resection, lobectomy
Diagnostic Thoracotomy Biopsy of lung, pleura, pericardium, mediastinal structures, adenopathy
Thoracoscopy Biopsy of lung, pleura, pericardium, mediastinal structures, nodes; diagnose
diaphragmatic injury
Therapeutic Thoracotomy Control hemorrhage/pneumothorax/pleural effusion/empyemas/granulomatous
lung infections; lung transplants; LVRS; othersa
Thoracoscopy Control pneumothorax; pleural effusion/empyema, granulomatous lung infection;
LVRS; othersa
LRVS ¼ lung volume reduction surgery.

a
Others ¼ pericardial window, ligation of thoracic duct, esophageal surgery, vagotomy.
thus screen for patients who are at increased risk difficult to perform (26% technical failure), and
for postoperative complications. pulmonary artery catheters are no longer
equipped with large balloons. Given the im-
Bronchospirometry provement in other less invasive testing tech-
niques for predicting postoperative pulmonary
Sixty years ago, thoracic surgery was most function, the temporary unilateral pulmonary
commonly performed to control tuberculosis. At artery occlusion is rarely used at present.
that time, bronchospirometry was introduced as
a means of predicting postoperative pulmonary Standard Pulmonary Function Testing
function. Bronchospirometry measures minute
ventilation (V̇E) and oxygen uptake (V̇O2) from The history of using pulmonary function
each individual lung. This is accomplished by testing (PFT) as a predictor of postoperative
placing a double-lumen endotracheal tube (un- morbidity and mortality dates back to 1955, when
der conscious sedation) that essentially isolates the combination of a preoperative maximal
the right from the left lung, therefore allowing breathing capacity (maximal voluntary ventilation
measurements to be made unilaterally. Predicted [MVV]) ,50% of predicted combined with a FVC
postpneumonectomy function is calculated by ,50% of normal predicted a 40% mortality rate in
multiplying the total preoperative pulmonary patients undergoing resection surgery or thoraco-
function by the percentage of lung that will plasty for tuberculosis. During the next 50 years,
remain postoperatively. other parameters were proposed to be more
accurate prognostic indicators of postoperative
Unilateral Pulmonary Artery Occlusion pulmonary failure. These included FEV1 ,2 L for
pneumonectomy or ,1 L for lobectomy, and
Unilateral pulmonary artery occlusion was FEV1:FVC ratio ,50%. In the 1980s, diffusing
used 50 years ago as a means of assessing capacity of the lung for carbon monoxide (DLCO)
whether a patient could withstand a pneumo- was proposed to be a reliable predictor of
nectomy. A catheter was placed into the pulmo- mortality when ,50% of predicted. In the early
nary artery of the lung that was going to be 1980s, the accepted criteria for pneumonectomy
resected, and a large (50 mL) balloon was then included an FEV1 of .2 L along with a MVV
inflated, thus directing all blood flow to the .55%, and for a lobectomy a MVV .40% of
contralateral lung. If the mean pulmonary artery predicted with an FEV1 of .1 L. However, most
pressure increased to .35 mm Hg or the PaO2 of these parameters were derived from studies
decreased to ,45 mm Hg, the candidate was that included mainly men in their sixth to eighth
deemed inoperable because of the risk of decades. As such, an FEV1 of 2 L would be
postoperative death. However, this technique is distinctly abnormal for a man but not necessarily
182 Chapter 11. Pulmonary Complications of Cardiothoracic Surgery and Trauma (Krieger)
for a small, female octogenarian. In addition, dates back to simple walking and stair climbing
these parameters lacked sufficient specificity for protocols. Refinement that used incremental
the individual patient, and therefore attention was exercise testing has shown that a preoperative
directed to more accurate predictors of postoper- maximum V̇O2 (V̇O2max) ,10 mL/kg/min or
ative pulmonary function based on the amount of 40% of predicted was associated with a high
predicted lung parenchyma that would remain percentage of fatal postoperative pulmonary
after resection. Radionuclide quantitative lung complications, whereas few postoperative pneu-
scanning coupled with preoperative PFT was monectomy complications occurred when the
introduced as a way of refining postoperative V̇O2max was .20 mL/kg/min or 75% of predict-
lung function by coupling anatomic and physio- ed. Lobectomy is considered to be relatively safe
logic relationships. The postoperative pneumo- when the V̇O2max is .15 mL/kg/min. Some
nectomy or postoperative lobectomy FEV1 and algorithms for assessing the operability of a lung
FVC are predicted by multiplying the percentage resection patient suggest using formal exercise
of total radioactivity that would remain after lung testing before undergoing quantitative lung
resection surgery by the preoperative FEV1 and scanning when either the preoperative FEV1 or
FVC. Initially, an absolute lower limit of accept- DLCO are ,80% of predicted. Recent studies have
able postoperative lung function was established correlated symptom-limited stair climbing with
to be ,0.8 L based on an accepted dictum that V̇O2 in patients with COPD. The inability to climb
hypercarbia frequently occurred in patients with two flights of stairs preoperatively had an 82%
COPD when the FEV1 was ,0.8 L. However, positive predictive value for the development of
Marshall and Olsen suggested that further accu- a postoperative cardiopulmonary complication.
racy could be obtained by this technique if the However, the simple shuttle (6-min) walk test
predicted postoperative FEV1 was corrected for was not useful in distinguishing lung cancer
the patient’s age, height, and sex (ie, based on surgical outcome.
percentage of predicted rather than an absolute
number). Cardiac Risk Factors
Markos and coworkers prospectively stud-
ied 55 consecutive patients using quantitative Cardiac complications are the second most
lung scanning, PFT based on percentage of common difficulty encountered after thoracoto-
predicted, and incremental load cycle ergometry. my. Therefore, exercise testing is theoretically
Three deaths occurred, all in patients with desirable as it stresses the combined cardiopul-
postoperative predicted FEV1 and DLCO ,35%. monary systems. Recently, a ‘‘risk index’’ that
Based on these data and other studies, ‘‘accept- combines cardiac and pulmonary signs and tests
able’’ criteria in the 1990s included either a has been advocated as a guide to reliably predict
postoperative predicted FEV1 of .40% or a postoperative risks.
combination of an FEV1 postoperative predicted From these studies, it is apparent that no
.30% along with a postoperative predicted single parameter can be used to exclude surgery
DLCO 40%. This combined approach is appli- in the individual patient. Rather, a combination
cable to pneumonectomy or lobectomy. Com- of parameters can be helpful in predicting a
bining LVRS with small resections has extended statistically high risk of postoperative morbidity
the limits of thoracic surgery, as postoperative and mortality, therefore patients, with the coun-
pulmonary function may actually improve after seling of their physicians, can make an informed
LVRS by successfully removing small broncho- decision as to whether to proceed with poten-
genic carcinomas. tially curative lung resection surgery. For many
patients, the relatively high likelihood of a poor
Exercise Testing as a Predictor of Postoperative quality of life postoperatively may be a more
Morbidity and Mortality important concern than a limited chance of
surviving for 5 years after resection of a
The history of establishing a global assess- pulmonary carcinoma. For other patients, an
ment of pulmonary reserve using exercise testing ‘‘acceptable’’ postoperative mortality is worth

Table 2—Causes of Pulmonary Complications After
Cardiac Surgery
Category Causes
Parenchymal lung Pulmonary edema (cardiogenic and

injury noncardiogenic)
Atelectasis
Pneumonia
Hemorrhage
Airways disease COPD, asthma
Bronchorrhea (bronchitis, infectious,
recurrent aspiration)
Chest bellows Diaphragm weakness, paresis,
disease paralysis or flutter
Figure 1. Stepwise approach for evaluating whether a Sternal instability
patient has the pulmonary reserve to undergo thoracic Morbid obesity
resectional surgery. Prolonged effect of muscle relaxants
Pain and chest tubes
Depressed Drugs
the risk if the alternative is close to 100% respiratory drive Neurologic complications
mortality. A guide to help the prediction of Pleural disease Pleural effusions and hemothorax
postoperative pulmonary function and thus Pneumothorax
Pulmonary vascular Pulmonary emboli
quality of life is shown in Figure 1. disease Pulmonary hypertension (valvular
surgery)
Pulmonary Complications After Cardiac Surgery Nonpulmonary SIRS (increased metabolic demands)
disease Cardiac dysfunction
Neurogenic hyperventilation
Pulmonologists are frequently asked to par- Psychosis
ticipate in the postoperative management of Postlaparotomy
patients after median sternotomy for cardiac
SIRS ¼ systemic inflammatory response syndrome, which
surgery. Respiratory failure is one of the most includes sepsis, septic syndrome, bacteremia, and septic
feared complications after this surgery. Rady and shock.
Ryan reported that patients who required ICU
care for .14 days after cardiac surgery had a pulmonary hypertension, severe left ventricular
43.5% in-hospital mortality, especially if the dysfunction, or cardiac shock; requirement for
requirement for mechanical ventilation was due hospitalization preoperatively; surgical parame-
to a nonpulmonary cause. As noted in Table 2, ters (multiple transfusions, prolonged cardiopul-
there are some causes of postoperative sternot- monary bypass time, redo operations, and
omy pulmonary complications that are unique to procedures involving thoracic aorta); and various
this surgical approach. These include diaphrag-
matic dysfunction, chest wall (sternal instability),
Table 3—Postoperative Cardiac Surgery Pulmonary
and various forms of noncardiogenic pulmonary Function
edema. In addition, there is a predictable decline
in pulmonary function after cardiac surgery that POD 2 POD 4 POD 50
in some respects is more severe than the changes
VC (% preop)
that occur after upper abdominal laparotomy IMA 36 56 74
(Table 3). Despite this, preoperative PFT has not SVG 45 63 84
been as accurate in predicting postoperative FRC (% preop)
IMA 59 69
complications as it has in thoracic procedures,
SVG 66 72 88
probably because lung volumes are decreased by
pulmonary edema. Rady and Ryan analyzed the POD ¼ postoperative day; VC (% preop) ¼ vital capacity
expressed as a percentage of the preoperative value; FRC (%
hospital outcome of 11,330 patients and reported
preop) ¼ functional residual capacity expressed as a
the following predictors of extubation failure: percentage of the preoperative value; IMA ¼ internal
age 65 years; the presence of COPD, mammary artery graft; SVG ¼ saphenous vein graft.
laboratory values (hematocrit 34%, elevated Pulmonary Edema After Cardiac Surgery
BUN, lower albumin concentrations, and sys-
temic oxygen delivery 320 mL/min/m2). Al- The most common cause of postoperative
though abnormal PFT results did not predict pulmonary edema is poor left ventricular func-
extubation failure in this study, they quantitated tion that sometimes is exaggerated by the
the patient’s physiologic pulmonary reserve and negative inotropic effects of anesthesia. In addi-
thus helped to determine the patient’s ability to tion, diastolic dysfunction may occur, which can
mount an appropriate response to postoperative be difficult to recognize. It is underappreciated
processes that increase carbon dioxide produc- that the pulmonary artery occlusion pressure
tion and V̇E requirements. In an analysis of 1112 may not necessarily reflect the propensity for
patients, reduced FEV1 was a statistically signif- cardiogenic edema to develop unless other
icant risk factor for prolonged intubation after factors, such as hypoalbuminemia, left ventricu-
coronary artery bypass grafting (CABG). Another lar compliance, and elevated intrathoracic pres-
retrospective multivariate survival analysis of sure from positive pressure ventilation, are
4863 consecutive patients who underwent CABG considered. In addition, alveolar-capillary mem-
also identified preoperative respiratory or cardiac brane permeability is often altered by cardiopul-
instability as a risk factor for MVS. Preoperative monary bypass, and therefore capillaries may
renal failure or mechanical ventilation for .24 h ‘‘leak’’ without an exceptionally high wedge
after CABG identified patients at risk for read- pressure reading. Postoperative sternotomy non-
mission to the ICU. cardiogenic pulmonary edema has been recog-
Yende and coworkers prospectively studied nized since the 1960s, when it was called ‘‘pump
lung.’’ Most of the theories that have been
400 patients and identified tumor necrosis factor
proposed to explain this form of ARDS revolve
(TNF) gene polymorphisms and angiotensin-
around the effect of extracorporeal membrane
converting enzyme gene polymorphisms preop-
oxygenation (ECMO) on neutrophils and alveo-
eratively and showed that the presence of
lar epithelial cells. The occurrence of ARDS after
specific haplotypes was associated with pro-
cardiac surgery carries a 15% mortality risk and
longed mechanical ventilation after CABG.
has been linearly correlated with the length of
Another recent study involving 325 consecutive
cardiopulmonary bypass. Studies in animals and
patients noted that an elevated lactate level (.3
humans have shown activation of polymorpho-
mmol/L) was associated with a significantly
nuclear leukocytes (PMNs), which results in an
elevated risk for morbidity and mortality after
increase in markers of toxic oxygen radical
cardiac surgery. production and adherence of PMNs to pulmo-
As noted in Table 3, postoperative declines in nary endothelium. The sequestration of PMNs
lung volume are more marked when the internal activates the complement and coagulation sys-
mammary artery is used rather than saphenous tems, as well as other proteolytic enzymes,
veins for grafts. Adverse effects may be even resulting in injury to pulmonary endothelial
more severe when patients have pulmonary cells. Proinflammatory cytokines (TNF, IL-6 and
diseases such as COPD or pulmonary fibrosis. IL-8) and intracellular and vascular cell adhesion
Oxygenation decreases by approximately 12 mm molecules measured in the plasma or on platelets
Hg postoperatively because of a combination of and PMNs have been demonstrated to be
shunting and low ventilation/perfusion units. increased in pulmonary venous blood compared
These effects have been shown to be secondary to with right atrial and preoperative blood. In
bibasilar atelectasis, which can be imaged on CT addition, it has been hypothesized that surfactant
scanning postoperatively. Hypoxemia is exagger- production may be depressed during bypass
ated when pulmonary edema (cardiogenic or because of inadequate blood supply to the
noncardiogenic) or pneumonia is present. In alveolar epithelium, which results in atelectasis
addition, thoracoabdominal discoordination has and ARDS. Despite these effects, ARDS has been
been shown to contribute to the physiologic reported in ,2% of patients undergoing cardio-
changes that occur after sternotomy. pulmonary bypass. Previous cardiac surgery,

shock, and the need for blood products were diaphragmatic flutter from a similar pattern that
associated with the development of ARDS. occurs when patients have increased V̇E require-
ments (such as during sepsis or neurogenic
Atelectasis and Diaphragmatic Dysfunction hyperventilation). Because flutter is an involun-
tary diaphragmatic contraction, it will be associ-
Partial atelectasis of the left lung has been ated with discoordination of the thoracic cage
reported in up to 88% of all patients who have and therefore thoracoabdominal asynchrony that
undergone CABG. In addition, partial atelectasis can be detected on physical examination or with
of the right lung has also been reported in 61% of respiratory inductive plethysmography or mag-
patients after CABG. In the 1980s, the term netometry.
frostbite injury to the left phrenic nerve was The adverse effect of median sternotomy on
introduced to describe the phrenic nerve palsy the chest bellows is often underappreciated. A
that was associated with the use of cold study by Locke and colleagues using magnetom-
(specifically, ice slush) cardioplegic solutions eters correlated the uncoordinated rib cage
intraoperatively However, phrenic nerve conduc- expansion that occurred after sternotomy with
tion studies subsequently showed that only 20% the restrictive ventilatory changes seen on PFT.
of patients with left lower lobe atelectasis after Although air flow and abdominal wall motion
sternotomy had evidence for phrenic neuropathy. remained coordinated, there was a delay in rib
Yet most surgeons use a protective insulation cage expansion. If increased ventilatory demands
blanket before the insertion of cold cardioplegic are required, this delay would act as a significant
solutions to minimize any physical effects on the preload to inspiration with a resulting increase in
phrenic nerve. If the phrenic nerve is severely work of breathing. Postoperative bone scans have
demyelinated, axonal repair requires up to 9 detected occult rib fractures or costochondral
months before diaphragm function is restored. dislocations in two-thirds of patients undergoing
Mild demyelination repair may occur within 6 to sternotomy. The worst postoperative lung func-
28 days. Other possible explanations for the tion is noted in patients undergoing internal
frequent occurrence of left lower lobe atelectasis mammary artery grafting, which is believed to be
include intraoperative compression of lung tis- due to loss of blood flow to the sternum.
sue, pulmonary endothelial damage with resul- However, detailed studies show that a significant
tant loss of surfactant, ischemia during ECMO, decrease in blood supply occurs in only approx-
and possibly decreased ventilation of the left imately 5% of patients.
lower lobe due to a combination of cardiomegaly The combination of diaphragmatic dysfunc-
and the supine operating position. Atelectasis of tion and chest bellows disease results in global
the left lung has been associated with the number respiratory muscle strength deterioration after
of coronary grafts, the length of surgery, the use median sternotomy. This amounts to an approx-
of the left anterior mammary artery for a graft, imately 17% decrease in the maximal inspiratory
and low body temperatures. However, the pressure measured at the mouth and a decrease
presence of atelectasis does not appear to of the maximal expiratory pressure of 47%,
increase the length of hospital stay. which reverses when measured 6 weeks postop-
Diaphragmatic flutter has been described in a eratively.
few patients after sternotomy. This is defined as
an involuntary contraction of the diaphragm at Other Pulmonary Complications After Cardiac
rates .40 times per minute, which is not Surgery
associated with contraction of other respiratory
muscles. Diaphragmatic flutter is not suppress- Left-sided pleural effusions occur in 50% to 80%
ible voluntarily or by mechanical hyperventila- of patients undergoing left internal mammary
tion. It appears to be associated with sternal artery grafting and in .35% receiving only saphe-
complications, and it can be an unrecognized nous vein grafting. These effusions are bilateral
cause for prolonged MVS. It is important to in approximately 10% of all patients under-
distinguish the rapid shallow breathing of going CABG. The effusions are characterized by
having a marked lymphocytosis (.82%) and a in deleterious effects reflected in decreased lung
potential to have a trapped lung due to fibrosis. volumes and respiratory muscle endurance.
The effusions occur less frequently when valvu-
lar surgery alone is performed. Usually, pleural Respiratory Management After Cardiac Surgery
effusions are small-to-moderate in volume but
contribute to a more marked reduction in FVC in The most important aspect of treating pa-
patients after CABG than when effusions are not tients with respiratory failure after cardiac
present (38% decrease compared with 26%). surgery is to determine the etiology or etiologies
Because pleurotomy is required when internal for their inability to support their required V̇E
mammary artery grafting is used, the occurrence postoperatively. Astute assessment of the patient
of pleural effusions .3 weeks after CABG is for diaphragmatic dysfunction, thoracic instabil-
more common in these patients. Delayed mas- ity, pulmonary edema (which may be radio-
sive effusions have also been reported. Etiolo- graphically masked by the use of high level
gies for these effusions include perioperative positive pressure ventilation), and nonpulmo-
hemorrhage or contusion, pulmonary throm- nary sources of increased ventilatory require-
boemboli, and postcardiac injury syndrome. ments is important. Often, the most important
Postcardiac injury syndrome (Dressler syn- approach to ‘‘weaning’’ patients postoperatively
is to place them back on full MVS while
drome) usually occurs 1 to 12 weeks after
improving their mechanics, decreasing their V̇E
surgery and is associated with a combination
requirements, and controlling their pain. The
of pleuritis, pericarditis, and pneumonitis, along
need for reintubation after CABG is associated
with fever, leukocytosis, and elevation of the
with prolonged hospitalization, infectious com-
sedimentation rate. The diagnosis is one of
plications, and increased mortality. Risk factors
exclusion, but is important to establish, as this
for prolonged MVS include a reduced FEV1,
syndrome requires treatment with nonsteroidal
renal failure, a positive fluid balance 24 h
antiinflammatory drugs or systemic corticoste-
postoperatively, and the presence of specific
roids. The incidence of this syndrome appears to
polymorphisms in the promoter region of the
be declining.
TNF gene.
Deep venous thrombosis and pulmonary
emboli occur less commonly after cardiac surgery Thoracoscopy
than after other major surgical procedures. It is
believed that the use of anticoagulants during Technologic advances, such as thoracoscopy,
ECMO may protect the patient from the devel- have allowed access to body cavities without the
opment of a nidus for clot formation intraoper- need for traditional surgery. By using fiberoptic
atively The incidence of pulmonary emboli technology and miniaturized cameras, diagnostic
reported after CABG is approximately 1%, and therapeutic procedures are now commonly
although when pulmonary embolism occurs performed without requiring large incisions and
there is a significant (.30%) postoperative prolonged recovery time. This type of surgery
mortality. This may reflect the finding that when has been termed minimally invasive, and when
pulmonary thromboembolic disease occurs in performed by thoracic surgeons usually uses
patients after CABG, it usually is in the setting of video assistance (video-assisted thoracic surgery
other postoperative complications. [VATS]). Proponents of VATS consider this
Infections significantly affect pulmonary procedure to have potentially revolutionary
function after sternotomy and thus contribute to effects on the fields of pulmonology and cardio-
morbidity and mortality. Postoperative pneumo- thoracic surgery.
nia has been associated with preexisting pulmo- The history of thoracoscopy dates back to
nary dysfunction and older patients. However, 1910, when Jacobaeus diagnosed two cases of
wound infections occur more commonly than tuberculous pleuritis. Thoracoscopy was used
postoperative pneumonias. When sternal infec- during the first half of the 20th century exclu-
tions occur, significant thoracic instability results sively for the lysis of pleural adhesions by means

of cautery. ‘‘Medical’’ thoracoscopy, performed Table 4—Life-Threatening Chest Trauma
under conscious sedation using nondisposable
Acutely Potentially
rigid instruments, is still commonly used in
Europe as a means of diagnosing pleural disease. Airway obstruction Tracheobronchial tear
However, in North America, VATS is more Tension pneumothorax Lung contusion
common, not only for diagnosis, but also for Open pneumothorax Multiple rib fractures
Flail chest Cardiac tamponade
resection and therapeutic procedures. Massive hemothorax Aortic rupture
The advantage of VATS vs thoracotomy is the
ability to access the thoracic cavity without rib
spreading or rib resection, resulting in less production, PMN activation, and the release of
postoperative thoracotomy pain, neuralgia, and endotoxin from ischemic tissues. The pulmonol-
delayed recovery. The procedure still requires ogist is often involved after the initial resusci-
general anesthesia, unilateral lung ventilation, tation to deal with problems such as hypoxemia
and lack of significant pleural adhesions that (Fig 2) associated with fractures, flail chest, and
would prevent safe insertion of instruments pulmonary contusions. In addition, the pulmo-
through small (2 cm) intercostal incisions. With nologist/intensivist may be asked to evaluate
perfection of the technique, complications are the patient for myocardial injuries or tracheo-
rare. This has become the diagnostic procedure bronchial tears.
of choice for patients with diffuse interstitial
lung disease who require lung biopsy and the Tracheobronchial Tears
therapeutic treatment of choice for pleural
diseases such as persistent pneumothorax or Although uncommon, tracheobronchial tears
empyema. In addition, as discussed elsewhere, it may be life threatening and are frequently
has become one of the most common approaches overlooked. The diagnosis is suspected when
to LVRS. persistent barotrauma and air leaks persist after
blunt chest trauma. Hemoptysis is usually, but
Chest Trauma not always, present along with concomitant
fracture of the first and second ribs. The tear is
Trauma remains the major cause of acciden- usually within 2.5 cm of the carina and often
tal death in the United States. Thoracic injuries involves the membranous trachea.
account for approximately 37,000 deaths per Bronchoscopic findings include lacerations,
year and significantly contribute to another transections, and bared cartilage that may be
37,000 trauma-related deaths. Fatal hemorrhage hidden below ‘‘heaped-up’’ mucosa. Early surgi-
or an inability to secure an adequate airway is cal repair is usually required except for small
the major cause of death in one-third of these tears (less than one-third the circumference of the
injuries. Other life-threatening conditions asso- bronchus or trachea). Stabilization often requires
ciated with chest trauma are listed in Table 4. placement of a double-lumen tube or use of high-
The severity of the injury relates to the frequency jet ventilation before repair.
magnitude and duration of the applied force,
the velocity and contact area of that force, body
compression that occurs in blast injuries and
falls, and the hyperdynamic stress response that
follows trauma. This stress response is mani-
fested by an increase in cardiac output, V̇O2, and
carbon dioxide production, along with a de-
crease in systemic vascular resistance and
oxygen extraction relative to oxygen delivery.
It is believed that the posttraumatic ‘‘stress’’
results from cytokine release from macrophages, Figure 2. Factors that contribute to hypoxemia after chest
which stimulates increased toxic oxygen radical trauma.
Barotrauma more contiguous ribs need to be fractured in two
or more places, which results in an unstable
Pneumothorax and hemothorax are poten- segment of the chest wall that paradoxes inward
tially life-threatening complications of chest during inspiration because of negative intratho-
trauma. Pneumomediastinum is reported in 5% racic pressure. However, diagnosis of a flail chest
to 10% of blunt chest trauma victims. This form can be delayed if the patient is only examined
of barotrauma can result from tracheobronchial while receiving ventilation with positive pres-
tears, pneumothorax with or without associated sure. The hypoxemia that frequently accompa-
rib fractures, or the Macklin effect. The Macklin nied a flail chest was thought to be due to
effect involves alveolar rupture that results in ‘‘internal rebreathing’’ (pendelluft). However, in
dissection of air along the bronchovascular a canine model of flail chest that specifically
sheath (pulmonary interstitial emphysema) and avoided any underlying pulmonary contusion,
then into a mediastinum. The Macklin effect has no significant changes in rib cage distortion or
been identified by chest CT scanning as the oxygenation occurred in the experimental ani-
cause of the pneumomediastinum in approxi- mals in comparison to controls despite multiple
mately 40% of blunt trauma cases and was rib fractures. Therefore, it was concluded that the
associated with a significantly prolonged stay in hypoxemia that accompanies a flail chest is due
the ICU. to underlying pulmonary contusion and other
associated injuries and not to internal rebreathing
Flail Chest (Fig 2).
Rib or sternal fractures are caused by sudden Pulmonary Contusion From Blunt Chest Trauma
decompression forces. Children’s ribs are more
flexible and therefore are less frequently frac- External forces applied to the pulmonary
tured by the same degree of force compared to parenchyma during blunt chest trauma, such as
older victims’ ribs. When first or second ribs are acceleration/deceleration during motor vehicle
fractured, suspicion is raised for injury to great accidents, or blast injury from explosions, can
vessels or to the tracheobronchial tree. Before result in disruption of the lung parenchyma. This
1960, various methods were used to try to disruption is amplified if the glottis is closed at
stabilize these fractures. After 1960, ‘‘internal the time that airway pressure is suddenly
stabilization’’ using positive pressure mechanical increased. It causes disruption of alveolar-capil-
ventilation with an endotracheal tube was the lary membranes, intraparenchymal hemorrhage,
treatment of choice. At present, internal stabili- an increase in ventilation/perfusion mismatch,
zation by CPAP mask is the desired approach if shunt, and dead space, as well as increased
the patient’s ventilatory status does not require permeability and extravascular lung water. Pul-
MVS (Table 5). For a flail chest to occur, two or monary edema after terrorist incidents is often
complicated by other tertiary effects, such as
Table 5—Treatment of Rib Fractures
crush, shrapnel, or inhalational injuries. Nosoco-
CPAP Mask CPAP by ETT mial pneumonia and ARDS can occur early or
(n ¼ 36) (n ¼ 33) late. The treatment for pulmonary contusion is
similar to treating other forms of ARDS, except
Age (years) 46 58
CPAP (cm H2O) 5.4 6.6 that concomitant injuries, such as barotrauma
Barotrauma 3 3 and neurologic injuries, may require modifica-
Pneumonia 5 16a tion of ventilatory strategies (such as having to
Septicemia 0 3
Death 0 2 avoid permissive hypercarbia) that would other-
LOS (days) 8.8 14.6 wise be used. If the patient survives his or her
injuries, lung recovery is usually complete except
ETT ¼ endotracheal tube; LOS ¼ length of stay. Adapted
from Bolliger and van Eeden (1990). when there has been significant permanent chest
a
P , .05 compared with CPAP mask group. wall damage.

Nonpulmonary Effects of Blunt Chest Trauma Used combination of postoperative predicted FEV ,35%
and DLCO ,35% to predict an unacceptably high risk of
Disruption of the esophagus, diaphragm, or mortality after lung resection.
great vessels can also occur. However, myocar- Marshall MC, Olsen GN. The physiologic evaluation
dial injuries are more frequent. At present, the of the lung resection candidate. Clin Chest Med. 1993;
most accurate test for the diagnosis of myocardial 14(2):305–320.
injury is either surface or transesophageal echo- Review of the history and scientific data of how to
cardiography. Other modalities, such as cardiac determine postoperative thoracic surgery pulmonary
enzymes, are too nonspecific to be diagnostic. An complications by one of the pioneers in this field (Dr.
echocardiogram is able to image wall motion as Olsen).
well as diagnose potentially life-threatening Reilly JJ. Evidence-based preoperative evaluation of
pericardial effusion and valvular damage. candidates for thoracotomy. Chest. 1999;116(6 Suppl):
474S–476S.
Acknowledgment Summary of criteria that can be used to predict postoper-
ative morbidity and mortality, including combined car-
This chapter is reprinted with permission diac-pulmonary risk index.
from the ACCP Pulmonary Medicine Board Review. Weisman IM. Cardiopulmonary exercise testing in
25th ed. Northbrook, IL: American College of preoperative assessment for lung resection surgery.
Semin Thorac Cardiovasc Surg. 2001;13(2):116–125.
Concise review of how to use exercise testing to help
Nothing to Disclose determine the advisability of allowing borderline candidates
to undergo lung resection. V̇O2 max ,40% of predicted or
The author has disclosed that no relation- ,10 mL/kg/min precludes resection surgery.
Win T, Groves AM, Wells FC, et al. Relationship of
ships exist with any companies/organizations
shuttle walk test and lung cancer surgical outcome.
whose products or services may be discussed in
Eur J Cardiothorac Surg. 2004;26(6):1216–1219.
this chapter.
The shuttle (6-min) walk distance was not predictive of a
poor surgical outcome.
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Chest. 1999;116(16):1683–1688. for .48 h or reintubation. Multivariate regression analysis
Despite requiring mechanical ventilation because of severe identified three factors that were associated with prolonged
lung injury, victims of blast injuries frequently recovered to intubation: elevated creatinine level, lower FEV1, and a
normal lung function. positive fluid balance at 24 h postoperatively. Prolonged
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ment, diagnosis, and management. Clin Chest Med. tality rates.
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Review article. Thirteen of 63 surgery patients had delayed phrenic nerve
Pretre R, Chilcott M. Blunt trauma to the heart and conduction latency times postoperatively compared with
great vessels. N Engl J Med. 1997;336(9):626–632. preoperative testing. The only risk factor that was
Reviews myocardial and great vessel injuries. significantly associated with this complication by logistic
Shaker KG, Hollingworth HM, Irwin RS, et al. regression analysis was the use of cardioplegic ice slush.
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with prolonged mechanical ventilation following surgery was associated with increased mortality.

Massoudy P, Zahler S, Becker BF, et al. Evidence for Wynne R, Botti M. Postoperative pulmonary dysfunc-
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artery bypass grafting with cardiopulmonary bypass. monary bypass: clinical significance and implications
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Proinflammatory cytokines (IL-6 and IL-8) increased in A nursing review that is worth reading with 159 references.
pulmonary venous blood after bypass. In addition, adhesion Yende S, Quasney M, Tolley E, et al. Association of
molecule counts on platelets and PMNs became elevated. tumor necrosis factor gene polymorphisms and
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The incidence of ARDS in a retrospective analysis of 3278 of angiotensin-converting enzyme gene polymor-
patients was 0.4% but carried a 15% mortality rate. Risk phisms to predict risk of mechanical ventilation after
factors identified by multivariate analysis included previ- coronary artery bypass graft surgery. Crit Care Med.
ous cardiac surgery, shock, and number of blood products 2004;32(4):922–927.
received. The presence of a specific haplotype in the promoter region
Ng CSH, Wan S, Yim APC, et al. Pulmonary of the TNF gene site and angiotensin-converting enzyme
dysfunction after cardiac surgery. Chest. 2002;121(4): gene polymorphisms were associated with a significantly
1269–1277 higher rate of prolonged MVS after a CABG procedure.
This article reviews the associated physiologic, biochemical,
and histologic changes associated with the pulmonary Thoracoscopy
dysfunction after cardiac surgery with particular attention
to PMN activation, free radicals, and cytokines. Colt HG. Thoracoscopy: window to the pleural space.
Rady MY, Ryan T. Perioperative predictors of extuba- Chest. 1999;116(5):1409–1415.
tion failure and the effect on clinical outcome after Reviews the indications for VATS and quotes a procedur-
cardiac surgery. Crit Care Med. 1999;27(2):340–347. e-related mortality rate of 0.24% ‘‘in experienced hands.’’
Clinical predictors of extubation failure included age .65 Loddenkemper R. Thoracoscopy: state of the art. Eur
years; inpatient hospitalization; COPD; pulmonary hyper- Respir J. 1998;11(1):218–221.
tension; severe left ventricular dysfunction; redo operation; Comprehensive review of the diagnostic utility of ‘‘medical’’
thoracic aorta procedures; and bypass time .120 min. thoracoscopy as performed by pulmonologists in Europe.
Chapter 12. Sleep Science and Polysomnography
Objectives: sleep. First-generation histamine receptor blockers

Understand the physiologic changes that occur during (diphenhydramine, low-dose doxepin) cause se-
sleep. dation. Catecholamine agonists (isoproterenol)
Identify the different sleep stages.

increase arousal and wakefulness. Stimulants act
Learn how to interpret a polysomnogram.
by increasing dopamine and norepinephrine (am-
Key words: Circadian rhythm; nonrapid eye movement phetamines, cocaine, methylphenidate) or hypo-
sleep; polysomnography; rapid eye movement sleep; sleep
cretin and dopamine (modafinil, armodafinil).
Synopsis: Systems generating nonrapid eye movement
Sleep is a complex reversible state characterized by (NREM) sleep are the (1) hypothalamus (gamma
behavioral quiescence and diminished responsiveness to aminobutyric acid [GABA]) and (2) basal fore-
external stimuli. Different neural systems (and neurotrans- brain (GABA and adenosine). The pons and basal
mitters) generate wakefulness, nonrapid eye movement,
and rapid eye movement sleep. Two basic intrinsic
forebrain (acetylcholine) generate and maintain
components interact to regulate the timing and consolida- rapid eye movement (REM) sleep. GABA-A
tion of sleep and wake, namely sleep homeostasis and receptor agonists (benzodiazepines) cause sleep-
circadian rhythms. Vulnerability to sleep deprivation varies iness. Adenosine receptor blockers (caffeine)
within individuals across time and between individuals.
Consequences of total sleep deprivation appear to differ increase wakefulness and decrease electroenceph-
from those of chronic partial sleep restriction. Polysomnog- alographic (EEG) slow-wave activity. Cholinergic
raphy involves the continuous and simultaneous recording agonists (physostigmine) increase REM sleep,
of several physiologic variables during sleep. In addition to and antagonists (tricyclic antidepressants) de-
polysomnography, other tests, including the Epworth
sleepiness scale, multiple sleep latency test, and mainte- crease REM sleep. Alcohol facilitates GABA and
nance of wakefulness test, are commonly used in the inhibits glutamate and is sedating at high doses.
evaluation of persons with sleep-related complaints. Glutamate is the main CNS excitatory neuro-
transmitter. GABA is the main CNS inhibitory
neurotransmitter. Glycine is the main inhibitory
Sleep is a complex reversible state characterized neurotransmitter in the spinal cord and is
by behavioral quiescence and diminished re- responsible for sleep-related muscle atonia-
sponsiveness to external stimuli. Sleep is gener- hypotonia that develops during REM sleep.
ated and maintained by CNS networks that are Acetylcholine is the main REM sleep neurotrans-
localized in specific areas of the brain using mitter. Adenosine is responsible for homeostatic
specific neurotransmitters. Sleep has significant sleep drive. Finally, hypocretin dysfunction is
effects on a number of physiologic processes. responsible for narcolepsy.
Changes in aminergic and cholinergic tone
Neuroscience of Sleep occur during sleep. Activity of aminergic neurons
(norepinephrine, serotonin, histamine) is in-
Systems generating wakefulness and their
creased during waking and decreases during
respective neurotransmitters are the following: (1)
both NREM and REM sleep. In contrast, activity
ascending reticular formation (glutamate); (2) basal
of cholinergic neurons (acetylcholine) increases
forebrain (acetylcholine); (3) perifornical area of the
during both waking and REM sleep and decreases
hypothalamus (hypocretin); (4) locus caeruleus
during NREM sleep.
(norepinephrine); (5) tuberomammillary nucleus
(histamine); (6) substantia nigra (dopamine); and
Sleep-Wake Regulation
(7) raphe nuclei (serotonin).1 Dopamine agonists
(amphetamines) increase wakefulness, whereas Two basic intrinsic components interact to
dopamine antagonists (haloperidol) promote regulate the timing and consolidation of sleep

and wake, namely sleep homeostasis, which is exposure. It causes a phase delay when given
dependent on the sleep-wake cycle, and circa- in the morning and advances the circadian phase
dian rhythm, which is independent of it. These when given in the evening. Melatonin is less
two processes influence sleep latency, duration effective than light exposure in phase shifting
and quality, and alertness. Specifically, constant circadian rhythms. Melatonin also possesses mild
alertness is maintained throughout the waking hypnotic properties.
period by a rising circadian alertness opposing
the increase in sleep-promoting homeostatic Suprachiasmatic Nuclei
pressure, and constant sleep throughout the
sleep period is possible because of a falling The suprachiasmatic nucleus (SCN) in the
circadian alerting tendency opposing the de- anterior hypothalamus is the master circadian
creasing homeostatic sleep drive. A third process, rhythm generator in mammals. The activity of
sleep inertia, is responsible for the transient the SCN is greater during the daytime than at
period of relative confusion and disorientation night. The main afferent SCN connection starts
during the transition between sleep and waking. with photosensitive (most sensitive to blue to
Finally, the timing of sleep and waking is also blue green wavelength light) retina ganglion cells
determined by behavioral influences. containing the photopigment, melanopsin, to the
Sleep homeostasis is the sleep pressure that SCN via the retinohypothalamic tract.
increases relative to the duration of prior The SCN promotes wakefulness during the
wakefulness (ie, the longer a person is awake, day and consolidates sleep during the night.
the sleepier the person becomes). This sleep There are two circadian peaks in alertness (late
pressure declines after a sufficient duration of morning and early evening) and two circadian
sleep. troughs in alertness (early morning and early
afternoon to midafternoon). Ablation of the SCN
Circadian System causes random distribution of sleep throughout
the day and night and, in some, a reduction in
Biological rhythms are ubiquitous and genet- duration of the waking period.
ically determined. A circadian rhythm is a
biological rhythm that consists of one oscillation Physiologic Processes During Sleep
approximately every 24 h.2 Endogenous human
circadian rhythms free run at slightly over 24 h Sleep has significant effects on a number of
(approximately 24.2 h [referred to as ‘‘tau’’]). physiologic processes.3
Entrainment is the process wherein environmen-
tal cues called zeitgebers, which can be photic Autonomic Nervous System
(light) or nonphotic, synchronize the circadian
rhythm to the external 24-h period. Entrainment There is a relative reduction in sympathetic
can produce either phase advances (shifts the activity and an increase in parasympathetic
circadian period to an earlier time) or phase activity during NREM sleep compared with
delays (shifts of the circadian period to a later wakefulness; these changes are even more
time) based on the nature and timing of zeitge- pronounced during tonic REM sleep compared
bers. Light is an important zeitgeber. Light with NREM sleep. Sympathetic activity tran-
exposure after minimum core body temperature siently increases during phasic REM sleep.
(CTmin; usually 2 h before habitual wake time)
can phase advance sleep-wake circadian rhythms, Respiratory System
whereas light exposure before CTmin will cause a
phase delay of sleep-wake circadian rhythms. Whereas both metabolic and behavioral
Melatonin, which is synthesized and released controls of respiration are present during wake-
by the pineal gland, also influences the circadian fulness, only metabolic control persists during
sleep-wake rhythms. Melatonin secretion is sleep. Hypoxic and hypercapnic ventilatory
greatest at night and is inhibited by light responses, upper airway dilator muscle tone,
194 Chapter 12. Sleep Science and Polysomnography (Lee-Chiong)

and activity of the accessory muscles of respira- cortisol secretion is linked primarily to circadian
tion are reduced during NREM sleep compared rhythms, TSH secretion is linked to both sleep
with wakefulness and decrease further during and circadian rhythms, and GH secretion is
REM sleep. (Note: Activity of the diaphragm linked primarily to sleep (during N3 sleep).
remains intact during REM sleep.) Thus, com- Acromegaly is associated with a higher preva-
pared with wakefulness, sleep is associated with lence of OSA and central sleep apnea (CSA);
falls in PaO2 and SaO2 by 2 to 12 mm Hg and by therapy of acromegaly with surgery or octreotide
2%, respectively, and by an increase in PaCO2 by 2 can improve sleep-disordered breathing (SDB).
to 8 mm Hg. Respiratory patterns also change Persons with OSA can have low levels of GH and
during sleep. Periodic breathing with episodes of testosterone, and both increase with PAP therapy.
hypopneas and hyperpneas may develop during Polycystic ovarian syndrome is associated with
stage 1 of NREM sleep (N1). Respiration is stable both increased testosterone levels and greater
and regular during stage 3 of NREM sleep (N3) risk of OSA. Obstructive sleep apnea increases
but becomes relatively irregular again, with risk of insulin resistance and type 2 diabetes
variable respiratory rates and tidal volumes mellitus, independent of BMI. Insulin sensitivity
during REM sleep. Central apneas or periodic improves with PAP therapy. Finally, increases in
breathing may be seen during phasic REM sleep. both leptin (leptin resistance?) and ghrelin levels
occur in OSA; levels of both decrease with
Cardiovascular System optimal PAP therapy.
Heart rate (HR), cardiac output (CO), and Musculoskeletal System

blood pressure (BP) decrease during NREM sleep
compared with wakefulness and fall further Sleep is associated with skeletal muscle
during tonic REM sleep. Heart rate, CO, and BP relaxation (hypotonia or atonia) and inhibition
increase during phasic REM sleep compared of deep tendon reflexes.
with NREM and tonic REM, as well as during
arousals and awakenings. Nighttime systolic BP Immunity
is commonly about 10% less than daytime
systolic BP levels, a phenomenon called ‘‘dip- Proinflammatory cytokines (interleukin-1b
ping.’’ [IL-1b] and tumor necrosis factor-alpha [TNF-
a]) enhance sleep, and antiinflammatory cyto-
Renal System kines (IL-4 and IL-10) suppress sleep.5 Changes
in sleep are seen during viral and bacterial
Sleep is accompanied by a decrease in urine infections (increase in NREM and decrease in
output as a result of an increase in water REM sleep). Changes in the immune system are
reabsorption, decreased glomerular filtration, also present in OSA (increased C-reactive pro-
and increase in renin (NREM sleep) and antidi- tein, IL-6, and TNF-a); these changes improve
uretic hormone. Obstructive sleep apnea (OSA) is with PAP therapy.
associated with an increased risk of nocturia; the
latter improves with optimal positive airway Thermoregulation
pressure (PAP) therapy.
Core body temperature peaks in the late
Endocrine System afternoon and early evening (6:00–8:00 PM) and
falls at the onset of sleep, with a nadir (CTmin) at
Certain hormones increase during sleep 2 h prior to usual wake time (4:00–5:00 AM).
(growth hormone [GH], prolactin, parathyroid Changes in thermoregulation that occur during
hormone, and testosterone), and others decrease sleep include (1) fall in core body temperature;
during sleep (cortisol, insulin, and thyroid- (2) decline in thermal set point; (3) reduced
stimulating hormone [TSH]).4 Hormone secretion response to thermal challenges; and (4) loss of
can be linked to circadian rhythms or sleep: heat production from shivering during REM

sleep. Sleep occurs during the falling phase of the processes decrease during SD, including vigi-
temperature rhythm (after maximum core body lance, cognition, attention, seizure threshold,
temperature), and waking occurs during the resistance to infection, growth hormone, and
rising phase of the temperature rhythm (after leptin activity.6
CTmin). Initiating sleep during the falling phase
of the temperature rhythm is associated with a Polysomnography
shortened sleep onset latency (SOL), greater total
sleep time (TST), and increased N3. Conversely, Polysomnography (PSG) involves the contin-
initiating sleep during the rising phase of the uous and simultaneous recording of several
temperature rhythm leads to a longer SOL, less physiologic variables during sleep. These vari-
TST and decreased N3. ables include EEG, electrooculography (EOG),
chin electromyography (EMG), electrocardiogra-
Summary phy (ECG), airflow, respiratory effort, oxygena-
tion, snoring, and leg (anterior tibialis) EMG.7
In summary, the physiologic parameters that PSG is indicated for the diagnosis of SDB;
‘‘go down’’ during sleep are (1) sympathetic PAP titration for SDB; follow-up after upper
activity; (2) PaO2 and SaO2; (3) tidal volume and airway surgery or dental devices for OSA; and
minute ventilation; (4) hypoxic and hypercapnic evaluation of narcolepsy, periodic limb move-
ventilatory responses; (5) upper airway dilator ment disorder (PLMD), atypical or injurious
muscle tone; (6) activity of the accessory muscles parasomnias, and sleep-related seizures.
of respiration; (7) HR, CO, and BP (during NREM PSG is performed with a polygraph, which is
and tonic REM sleep); (8) frequency of premature a series of alternating current (AC) and direct
ventricular complexes; (9) swallowing rate and current (DC) amplifiers and filters. AC amplifiers
salivary production; (10) esophageal and intesti- are used for high-frequency (fast) physiologic
nal motility; (11) glomerular filtration; (12) variables (EEG, EOG, EMG), and DC amplifiers
cortisol (levels decrease during N3 sleep); (13) are used for low-frequency (slow) physiologic
insulin secretion; (14) muscle tone; (15) core body variables (SaO2). Airflow and respiratory effort
temperature and thermoregulatory responses to are recorded using either AC or DC amplifiers. A
thermal challenges; and (16) metabolic rate derivation is the difference in voltage between
(during NREM sleep). In contrast, the physio- two electrodes and can be (1) bipolar if two
logic parameters that ‘‘go up’’ during sleep are standard electrodes are matched to each other or
parasympathetic activity, PaCO2, renal water (2) referential if a standard electrode is matched
reabsorption, and certain hormones (GH [during to a reference electrode.
N3 sleep], prolactin [during N3 sleep], parathy-
roid hormone, renin [during NREM sleep], EEG
antidiuretic hormone, and testosterone).
Electrode placement is based on the Interna-
Sleep Deprivation tional 10–20 system in which each electrode is
provided with a letter (region of the scalp) and a
Vulnerability to sleep deprivation (SD) varies numerical subscript, namely F ¼ frontal;
within individuals across time and among C ¼ central; O ¼ occipital; M ¼ mastoid; odd
different individuals. Consequences of total SD numbers ¼ left-sided electrodes; even num-
appear to differ from those of chronic partial bers ¼ right-sided electrodes; and ‘‘z’’ ¼ midline
sleep restriction. Persons often underestimate the electrodes. The recommended EEG electrode
negative effect of SD on their cognition and placements are F4M1, C4M1, and O2M1. Addi-
performance. Numerous physiologic variables tional EEG electrodes can be applied for evalu-
increase during SD, such as sleepiness, sympa- ating nocturnal seizures.
thetic activity, medical errors and motor vehicle EEG waves are classified based on frequency
accidents, certain hormones (cortisol and ghre- into delta (,4 Hz), theta (4-7 Hz), alpha (8-13
lin), and insulin resistance. Other physiologic Hz), and beta (.13 Hz). Beta waves dominate

during alert wakefulness. Alpha waves are seen transducers, inspiratory flow signals are flattened
during wakefulness with eyes closed. Theta (plateau) with obstructive events and reduced but
waves are present during N1, stage 2 of NREM rounded with central events.
sleep (N2) and R sleep, and delta waves are most
prominent during N3 sleep. There are two Measuring Respiratory Effort
additional EEG waveforms that are important
in the staging of sleep, namely K complexes Recommended sensors for measuring respi-
(high-amplitude, biphasic waves with duration ratory effort are esophageal manometry or
of 0.5 s) and sleep spindles (oscillations with a inductance plethysmography. These sensors are
frequency of 12-14 Hz lasting 0.5-1.5 s). important in distinguishing obstructive, central,
and mixed apneas.
EOG
EMG (Anterior Tibialis)
Recommended EOG electrode placements are
E1M2 and E2M2 (E1 ¼ below the left outer This is used to detect periodic limb move-
canthus; E2 ¼ above the right outer canthus; and ments during sleep. Additional electrodes in the
M2 ¼ right mastoid process). These electrodes upper extremities may help identify REM sleep
record the difference in potentials (dipole) behavior disorder (RBD).
between a positively charged cornea and a
Scoring Sleep Stages
negatively charged retina. Dipole changes with
eye movements—an eye moving toward an
Polysomnographic data are divided into 30-s
electrode creates a positive voltage (downward
time periods (epochs). Each epoch is assigned a
deflection), whereas an eye moving away from
sleep stage that comprises the greatest percent-
an electrode results in a negative voltage (up-
age of the epoch. A healthy adult typically
ward deflection).
spends the following percentages of the night in
There are two basic patterns of eye move-
different sleep stages: N1 (5%), N2 (45%), N3
ments, slow and rapid eye movements. Slow
(25%), and REM (25%).7
rolling eye movements consist of slow undulat-
ing deflections that are present during wakeful- Stage W (Wake)
ness with closed eyes, N1 sleep, or brief
awakenings and that disappear during N2 sleep. Wakefulness is defined by .50% of an epoch
Rapid eye movements, conversely, are sharper having alpha EEG waves when the eyes are
deflections that can occur during wakefulness closed. If alpha waves are absent, the presence of
with open eyes (eye blinks) or REM sleep. vertical eye blinks, reading eye movements, or
voluntary rapid open eye movements is useful in
Chin EMG identifying stage W. Chin EMG tone is high.
Three chin electrodes are used for PSG: (1) Stage N1 Sleep
midline, above the mandible; (2) right of midline
below the mandible; and (3) left of midline below In this sleep stage, alpha waves are replaced
the mandible. Chin EMG derivation consists of by low-amplitude, mixed-frequency (4-7 Hz)
any one electrode below and the midline elec- waves that occupy .50% of the epoch. There
trode above the mandible. are no K complexes or sleep spindles. Slow eye
movements may be present. Tonic chin EMG
Measuring Airflow levels are lower than in stage W.
The oronasal thermal sensor is the recom- Stage N2 Sleep

mended technique for identifying apneas, and
nasal air pressure transducers are recommended Low-amplitude, mixed-frequency waves, as
for identifying hypopneas. With nasal air pressure in N1, are present. In addition, K complexes (not

associated with arousals) or sleep spindles are EEG (as in NREM arousals) and EMG (increase
seen during the first half of the epoch or during in chin EMG 1 s).
the last half of the previous epoch. Importantly,
criteria for stage N3 (see below) are absent. General Patterns of Sleep Architecture
Stage N3 Sleep There are three general patterns of sleep
architecture: high sleep input pattern, low sleep
Sleep is scored as N3 if 20% of the epoch is input pattern, and circadian rhythm sleep disor-
occupied by slow-wave (0.5-2 Hz and .75 lV) der patterns. High sleep input pattern (short SOL,
EEG activity. increase in sleep efficiency [SE; total sleep time ‚
time in bed], greater TST and low wake time after
Stage REM (R) Sleep sleep onset [WASO]) is seen in SD and disorders
presenting with excessive daytime sleepiness
REM sleep is characterized by low-ampli- (EDS) or use of sedating medications. Low sleep
tude, mixed-frequency EEG activity, rapid eye input pattern (prolonged SOL, decreased SE and
movements, and low chin EMG tone. TST, and increase in WASO), conversely, is
characteristic of disorders presenting with insom-
Scoring Respiratory Events nia or use of stimulant medications. Circadian
rhythm sleep disorder patterns will be described
An apnea is defined as a decrease in peak in Chapter 14 on ‘‘Other Sleep Disorders.’’
thermal sensor amplitude by 90% of baseline There are exceptions to these general rules of
for 10 s. Events can be obstructive (inspiratory sleep architecture. Persons with narcolepsy, a
effort is present throughout the entire event), disorder associated with hypersomnia, may
central (inspiratory effort is absent throughout occasionally have decreased SE and TST and
the entire event), or mixed (central event is increase in WASO. Idiopathic hypersomnia with-
followed by an obstructive event). A hypopnea out long sleep time, by definition, is associated
is scored is there is a decrease in nasal pressure with normal TST. Polysomnographic parameters
by 30% of baseline for a duration of 10 s may be normal in (1) psychophysiologic insom-
accompanied by 4% oxygen desaturation. Sleep nia (reverse first-night effect or sleeping better in
hypoventilation is present if there is an increase a new sleep environment); (2) paradoxical in-
in PaCO2 by 10 mm Hg during sleep compared somnia, in which patients complain of significant
with supine wake values. subjective sleep disturbance despite normal SOL
and TST; and (3) environmental sleep disorder
Scoring Periodic Limb Movements of when PSG is performed in the sleep laboratory
Sleep and away from the usual home bedroom
environment.
Leg EMG activity is scored as periodic limb Other factors affecting general sleep architec-
movements if (1) there are 4 consecutive leg ture include aging (decrease in N3), recovery
movements, (2) each leg movement is 0.5 to 10 s from SD (increase in N3 and R sleep), and first-
in duration, (3) 5 to 90 s between leg movements, night effect or sleeping poorly in a new sleep
and (4) leg movements in different legs are environment (decrease in N3 and R sleep).
counted as one movement if separated by ,5 s.
Other Tests
Scoring Arousals
In addition to PSG, other tests, including the
Scoring arousals from NREM sleep requires Epworth sleepiness scale (ESS), multiple sleep
changes in EEG only (abrupt EEG frequency shift latency test (MSLT), and maintenance of wake-
[alpha, theta, or .16 Hz, but not spindles] 3 s fulness test (MWT), are commonly used in the
and preceded by 10 seconds of stable sleep). evaluation of persons with sleep-related com-
Scoring REM arousals requires changes in both plaints.

ESS suppressants, and alcohol withdrawal; they may
also be present in 1% to 3% of healthy individuals.
This is an eight-item questionnaire that
measures propensity to fall asleep in recent MWT
times, namely (1) sitting and reading; (2) watch-
ing television; (3) sitting and inactive in a public This test is a measure of a person’s ability to
place; (4) as a passenger in a car for an hour remain awake in quiet situations. Unlike MSLT,
without a break; (5) lying down to rest in the PSG is not required prior to testing. The MWT
afternoon; (6) sitting and talking to someone; (7) consists of four 40-min nap opportunities con-
sitting quietly after lunch without drinking ducted at 2-h intervals. During testing, the
alcohol; and (8) stopped in a car for a few patient is instructed to sit in bed in a semi-
minutes in traffic. Chances of dozing during reclined position in a dark, quiet room and to try
these situations are graded as 0 (never), 1 (slight to stay awake. Standard MWT leads consist of
chance), 2 (moderate chance), and 3 (high EEG, EOG, and chin EMG. Each MWT nap trial is
chance). An aggregate score between 0 and 9 is terminated if there is/are (1) three consecutive
normal, and 10 suggests that sleepiness is epochs of N1 sleep; (2) one epoch of any other
present and that sleep specialist advice is sleep stage; or (3) no sleep after 40 min. The
recommended. Unfortunately, correlation be- MWT is less sensitive than the MSLT in measur-
tween severity of sleepiness measured with ing sleepiness. Mean SOL correlates with the
ESS, MSLT, and MWT is poor. The ESS score is ability to stay awake (,8 min ¼ abnormal; .8
increased in patients with OSA, and scores and ,40 min ¼ indeterminate; and 40 min ¼
improve with effective treatment of OSA. normal).
MSLT Aging
The MSLT is a measure of a person’s With aging, specific sleep parameters may
tendency to fall asleep in quiet situations. PSG remain unchanged (sleep requirements), increase
is required prior to testing. This test consists of (nocturnal sleep disturbance; EDS; frequency of
four to five nap opportunities performed at 2-h napping; tolerance for SD; and prevalence of
intervals. During each 20-min nap trial, the insomnia, OSA, CSA, restless legs syndrome
patient is asked to lie down in a comfortable [RLS], PLMD, RBD, and advanced sleep phase
position in a dark, quiet room, to close his or her syndrome), or decrease (N3 sleep, melatonin
eyes, and to try to fall asleep. EEG, EOG, chin secretion, amplitude of circadian sleep-wake
EMG, and ECG are monitored continuously. rhythms, homeostatic sleep drive, arousal thresh-
Each nap trial is terminated if there is no sleep old, GH secretion during sleep, and tolerance for
noted after 20 min or 15 min after the onset of shift work and jet lag).9
any sleep stage.8 Sleep disturbance in older adults can result
MSLT is indicated to evaluate unexplained from aging physiology itself (rarely the sole
hypersomnia and suspected narcolepsy and to cause), menopause, medical disorders (nocturia),
distinguish between narcolepsy and idiopathic neurologic disorders (dementia and Parkinson
hypersomnia. A short mean SOL (,8 min) disease), psychiatric disorders (depression), ad-
suggests the presence of EDS. Causes of short verse effects of medications, or primary sleep
SOL include narcolepsy, idiopathic hypersomnia, disorders.
SD, OSA, PLMD, and acute withdrawal of OSA is more common in men; this difference
stimulant agents. An estimated 15% to 30% of in prevalence persists with aging. Risk of OSA
healthy individuals will have a short SOL during increases with menopause. Hormone replace-
testing. ment therapy decreases the prevalence of OSA in
Sleep-onset REM periods (the occurrence of postmenopausal women, but data do not support
REM sleep during MSLT) are seen in persons with the use of hormone replacement therapy as
narcolepsy, SD, OSA, withdrawal from REM therapy for OSA in this population.

Gender ed. Westchester, IL: Sleep Research Society, 2009;
63–68.
Certain sleep disorders are more common in 2. Reppert SM, Weaver DR. Circadian regulation of
men (sleep-related breathing disorders and sleep in mammals: role of the suprachiasmatic
RBD), whereas others are more prevalent in nucleus. Brain Res Rev. 2005;49(3):429–454.
women (insomnia and RLS). 3. Fuller PM, Lu J. Neurobiology of sleep. In:
Amlaner CJ, Fuller PM, eds. Basics of Sleep Guide.
Summary: Bottom Line 2nd ed. Westchester, IL: Sleep Research Society,
2009; 53–62.
Sleep and waking are controlled by specific 4. Leproult R, Spiegel K, Van Cauter E. Sleep and
neurotransmitters located in specific areas of the endocrinology. In: Amlaner CJ, Fuller PM, eds.
brain. Changes in physiologic processes occur- Basics of Sleep Guide. 2nd ed. Westchester, IL: Sleep
ring during sleep are responsible for differences Research Society, 2009; 157–167.
in the clinical presentation of various medical 5. Opp MR. Cytokines and sleep. Sleep Med Rev.
disorders. Characteristic changes in EEG, EOG, 2005;9(9):355–364.
and EMG are used to define specific sleep stages. 6. Mullington JM, Haack M, Toth M, Serrador JM,
Meier-Ewert HK. Cardiovascular, inflammatory,
Relationship Disclosed
and metabolic consequences of sleep deprivation.
Prog Cardiovasc Dis. 2009;51(4):294–302.
The author has disclosed the following
7. Iber C, Ancoli-Israel S, Chesson A, Quan SF
relationships: Grant Monies (from sources other
for the American Academy of Sleep Medicine.
than industry): NIH. Grant Monies (from indus-
try-related sources): Embla, Respironics. Employ- The AASM Manual for the Scoring of Sleep and
ee: Philips Respironics (Medical Liaison Officer). Associated Events: Rules, Terminology and Technical
Consultant fee, speaker bureau, advisory com- Specifications. 1st ed. Westchester, IL: American
mittee, etc: Consultant for Sleep Medicine Clinics Academy of Sleep Medicine, 2007.
(Elsevier), Consultant for CareCore National. The 8. Standards of Practice Committee of the American
ACCP Education Committee has reviewed these Academy of Sleep Medicine. Practice parameters
relationships and resolved any potential conflict for clinical use of the multiple sleep latency test
of interest. and the maintenance of wakefulness test. Sleep.
2005;28(1):113–121.
References 9. Ancoli-Israel S, Ayalon L, Salzman C. Sleep in the
elderly: normal variations and common sleep
1. Zeitzer JM. Neurochemistry of sleep. In: Amlaner disorders. Harv Rev Psychiatry. 2008;16(5):279–
CJ, Fuller PM, eds. Basics of Sleep Guide. 2nd 286.

Chapter 13. Sleep-Related Breathing Disorders
Objectives: OSA affects an estimated 24% of adult men

Recognize the clinical features and consequences of and 9% of adult women (if OSA is defined by an
sleep-disordered breathing. apnea-hypopnea index [AHI, number of apneas
Determine effective treatment options for sleep apnea.

and hypopneas per hour of sleep] of 5) or 4% of
Understand the mechanisms responsible for central sleep
apnea. adult men and 2% of adult women (if OSA is
defined by AHI 5 plus complaints of excessive
Key words: Central sleep apnea; hypoventilation; obstruc- daytime sleepiness [EDS]). Adult men are affect-
tive sleep apnea; positive airway pressure therapy ed more frequently than women; prevalence
among women increases with menopause.
Synopsis: The human UA can be conceptualized as a
Obstructive sleep apnea (OSA) is characterized by repetitive collapsible cylinder. Airflow through the UA is
cessation (apnea) or reduction (hypopnea) of airflow during determined by the difference in upstream (nasal)
sleep that develops despite the presence of respiratory
and downstream pressure, as well as by airway
efforts and that is caused by complete (apnea) or partial
(hypopnea) upper airway occlusion during sleep. OSA is a resistance. Thus, airflow is greater with greater
systemic disorder with wide-ranging consequences on the upstream pressure, lesser downstream pressure,
cardiovascular, respiratory, renal, gastrointestinal, endo- or reduced airway resistance. Patency of the UA
crine, neurocognitive, and immune functions if left untreat-
is dependent on the balance of factors that (1)
ed. Polysomnography is required for the diagnosis of OSA.
Positive airway pressure therapy is the treatment of choice maintain airway opening (activation of dilator
for most persons with OSA; other therapies include oral muscles) and (2) promote airway closure (de-
devices and upper airway surgery. Central sleep apnea is crease in intraluminal pressure and Bernoulli
defined as repetitive cessation of airflow during sleep
caused by loss of ventilatory effort. Central sleep apnea
forces). Airway size is also influenced by lung
can be classified into hypercapnic and nonhypercapnic volume, both of which decrease during sleep.
forms. Nocturnal hypoventilation syndromes are character- The critical closing pressure (PCRIT ) is the
ized by sleep-related oxygen desaturation and elevated
intraluminal pressure at which the UA collapses
PaCO2 during sleep.
and is progressively less negative from non-
snorers and snorers to persons with OSA.
Activation of UA dilator muscles lowers PCRIT.
Obstructive Sleep Apnea The UAs of persons with OSA are generally
narrower and are more vulnerable to collapse
Obstructive sleep apnea (OSA) is characterized by than those in persons without OSA. The most
repetitive cessation (apnea) or reduction (hypo- common sites of UA obstruction are retropalatal
pnea) of airflow during sleep that develops despite (behind the palate) and retrolingual (behind the
the presence of respiratory efforts and that is tongue). Repetitive UA obstruction is associated
caused by complete (apnea) or partial (hypopnea) with (1) decrease in oxygen saturation (SaO2), (2)
upper airway (UA) occlusion during sleep. An snoring alternating with periods of silence; (3)
apnea can be defined polysomnographically as a arrhythmias (heart rate [HR] decreases during
decrease in peak thermal sensor amplitude by UA obstruction and increases during apnea
90% of baseline for 10 s and can be central, termination); (4) arousal at apnea termination;
obstructive, or mixed in nature. A hypopnea, and (5) transient increase in blood pressure (BP)
conversely, is a decrease in nasal pressure by in the immediate postapneic period.
30% of baseline for a duration of 10 s Severity of OSA can be classified based on
accompanied by 4% oxygen desaturation.1,2 AHI as mild (5-15 per h), moderate (16–30), or

severe (.30). In addition to AHI, other factors OSA: A Systemic Disorder
that influence the clinical severity of OSA are
degree of EDS, nadir of SaO2, severity of sleep OSA is a systemic disorder with wide-
fragmentation, presence of nocturnal arrhythmi- ranging consequences for the cardiovascular,
as, and presence of comorbid cardiovascular or respiratory, renal, gastrointestinal, endocrine,
neurologic disorders. neurocognitive, and immune functions if left
Risk factors for OSA include family history untreated.
of OSA, male sex (for adults), menopausal state Heart failure (HF) is associated with an
in women, aging, race (African Americans, increased prevalence of OSA (20%–30%), central
Mexican Americans, Asians, and Pacific Island- sleep apnea (CSA), and Cheyne-Stokes respira-
ers), and excess body weight (major risk factor). tion (CSR) (30%–40%). Left ventricular (LV)
A majority of OSA patients are overweight or systolic dysfunction is an independent risk factor
obese, and the prevalence of OSA increases with for OSA; conversely, OSA itself may contribute to
greater obesity. There are several mechanisms worsening LV dysfunction. Mortality from HF is
whereby obesity can predispose to OSA; these higher in persons with untreated OSA compared
include UA fat deposition leading to decrease in with those with mild or no disease.3 Positive
its size and muscle tone, as well as reductions in airway pressure (PAP) therapy has been shown
lung volume. Central obesity (waist-hip ratio to improve LV ejection fraction in persons with
[WHR]) is more important than general obesity acute HF and OSA.4
(body weight or BMI). Other risk factors for Cardiac arrhythmias are more common in
OSA are increased neck circumference (.17 persons with OSA. In the Sleep Heart Health
Study (SHHS), there was a higher prevalence of
inches in men; .16 inches in women), nasal
atrial fibrillation (AF), nonsustained ventricular
narrowing or congestion, macroglossia, low-
tachycardia (VT), and complex ventricular ectopy
lying soft palate, enlarged tonsils and adenoids,
in subjects with OSA.5 PAP therapy can decrease
midface hypoplasia, retrognathia, micrognathia
the frequency of premature ventricular complexes
or mandibular hypoplasia, smoking and alcohol
(PVCs) during sleep, as well as reduce the
use, muscle relaxants and primary medical
recurrence rate of AF after cardioversion.7 Lastly,
disorders (acromegaly, androgen therapy, neu-
there is a cyclic variation of HR in OSA, with the
romuscular disorders, and stroke).
former decreasing during apneas and increasing
Patients with OSA may present with com-
during arousals.
plaints of EDS (most common complaint; how- The risk of ischemic heart disease (IHD) is
ever, severity of EDS does not correlate closely increased among middle-aged adults with OSA.
with AHI), repeated awakenings with gasping or This greater risk is independent of age, BMI, BP,
choking, snoring, witnessed apneas, attention and smoking and is reduced by reversal of OSA.
deficit and/or hyperactivity (in children), chang- Possible mechanisms for greater risk of IHD in
es in mood (treatment-resistant depression), dry OSA are (1) endothelial dysfunction, (2) hyper-
mouth/throat sensation upon awakening, fa- coagulable state, (3) increased plasma fibrinogen
tigue, gastric reflux, impaired memory and levels, (4) increased platelet activity, (5) de-
concentration, insomnia, morning headaches, creased fibrinolytic capacity, (6) insulin resis-
nighttime diaphoresis, and nocturia. At exami- tance, (7) increase in proinflammatory cytokines
nation, patients with OSA may have excess body and adhesion molecules (tumor necrosis factor
weight (BMI .25 kg/m2), a large neck circum- alpha [TNF-a], interleukin 6 [IL-6], and interleu-
ference, nasal septal deviation or turbinate kin 8 [IL-8]), (8) greater stress, (9) heightened
hypertrophy, crowded posterior pharyngeal sympathetic activity during arousals from sleep,
space, enlarged tonsils and adenoids, narrow and (10) marked sleep-related hypotension (par-
hard palate, large uvula, low-lying soft palate, ticularly during stage [N3] of nonrapid eye
macroglossia, and retrognathia or micrognathia. movement [NREM] sleep). In one study, at a
Alternatively, physical examination results may mean follow-up period of 10.1 years, untreated
be entirely normal. severe OSA (AHI .30) significantly increased the
202 Chapter 13. Sleep-Related Breathing Disorders (Lee-Chiong)

risk of fatal and nonfatal cardiovascular events mild. One study’s results showed that CPAP
compared with findings in healthy control therapy for 12 weeks was effective in lowering
subjects. In treated OSA patients, the incidences pulmonary artery (PA) systolic pressure (mea-
of both fatal and nonfatal events were 50% lower sured by means of echocardiography) in patients
than in patients with untreated severe OSA and with severe OSA.12
approached levels of simple snorers.8 Metabolic syndrome is characterized by
Patients with OSA have an altered circadian obesity, insulin resistance, and dyslipidemia.
rhythm of cardiac ischemic events and sudden OSA may predispose a person to worsening
cardiac deaths. OSA affects the timing of sudden obesity via changes in leptin and ghrelin levels,
cardiac deaths, but it remains uncertain whether insulin resistance and diabetes, sleep depriva-
it increases its risk. In the general population, the tion, and physical inactivity due to EDS. Serum
incidence of sudden cardiac death peaks from 6 leptin levels are increased in OSA, suggesting
AM to noon and has its nadir from midnight to 6 leptin resistance; this increase is correlated with
AM. In contrast, sudden cardiac death peaks from WHR, AHI, and hypoxemia.13 Leptin levels
midnight to 6 AM in patients with OSA. decrease during CPAP therapy. Plasma ghrelin
OSA is a risk factor for hypertension (HTN) levels are also higher in OSA; these too, decrease
independent of known confounding factors. with effective CPAP therapy.14 Finally, a signifi-
Untreated OSA is associated with an increase in cant percentage of patients with type 2 diabetes
both systolic and diastolic BP and loss of mellitus have OSA. Insulin sensitivity improves
nocturnal fall in BP (‘‘dipping’’ phenomenon). It with CPAP therapy.
appears that risk of cardiovascular disease may Several important changes in the immune
be greater among ‘‘BP nondippers’’ compared system occur in OSA, including an increase in C-
with ‘‘BP dippers.’’ In the Wisconsin Sleep reactive protein, IL-6, and TNF-levels. These
Cohort Study, 709 participants were followed changes reverse with PAP therapy. Both erectile
for 4 years, and relative to a reference category of dysfunction and nocturia are consequences of
an AHI of 0, the odds ratio for the presence of OSA; both improve with PAP therapy. OSA can
HTN at 4-year follow-up ranged from 1.42 (AHI give rise to low levels of growth hormone and
of 0.1–4.9 at baseline) to 2.03 (AHI of 5-14.9) to testosterone; these hormones increase with PAP
2.89 (AHI of 15.0 or more).9 Not all study results, therapy. An increased likelihood of gastrointesti-
however, demonstrate this association. In the nal reflux has been described in persons with
SHHS, AHI was not a significant predictor of OSA. Finally, OSA can result in impairments in
future HTN among middle-aged and older neurocognition (cognition, alertness, executive
persons after adjustment for BMI at 5-year function, learning, and memory). Patients with
follow-up. Subjects in the SHHS were, on OSA may also have a greater risk of developing
average, older and less obese compared with depression and anxiety.
the Wisconsin sleep cohort.10 Improvement in BP
control has been shown during PAP therapy in Evaluation of OSA
persons with OSA and HTN. Several factors
predict a more favorable BP response during Patients suspected of having OSA should
CPAP use in patients with OSA—namely the undergo a thorough clinical history and physical
presence of severe OSA, EDS, difficult-to-control examination. Laboratory testing might be helpful
HTN, need for antihypertensive therapy, and to explain other causes of EDS or fatigue or to
good CPAP compliance.11 evaluate for polycythemia, but routine screening
An estimated 20% of patients with OSA but for hypothyroidism is not indicated.
without cardiopulmonary disease may develop Polysomnography (PSG) is required for the
pulmonary HTN. It is postulated that recurrent diagnosis of OSA. The current standard of
episodes of nocturnal hypoxia caused by OSA practice is an attended laboratory study, either
give rise to pulmonary vasoconstriction and, full night with separate diagnostic and PAP
eventually, to sustained pulmonary HTN. Sever- titration studies, or a split-night, consisting of
ity of pulmonary HTN related to OSA is mostly an initial diagnostic portion and a subsequent

PAP titration on the same night. There is (Cflex) that delivers a single pressure throughout
increasing use of home sleep studies to diagnose the respiratory cycle but allows a transient
OSA. During PSG, respiratory events are more reduction in pressure during expiration that
frequent, last longer, and are associated with subsequently returns to baseline before the next
more profound O2 desaturation during rapid eye inspiratory cycle.
movement (REM) sleep compared with NREM Bilevel PAP (BPAP) consists of two pressure
sleep. Paradoxical breathing may be observed. levels provided during the respiratory cycle,
Multiple sleep latency testing is indicated if EDS namely a higher level during inspiration (inspi-
persists despite optimal PAP therapy.15 ratory PAP [IPAP]) and a lower pressure during
expiration (expiratory PAP [EPAP]). BPAP may
Therapy of OSA be considered for patients who (1) require
excessively high pressures; (2) complain of
Treatment options for OSA consist of general difficulty breathing out against high pressures;
measures, PAP therapy, oral devices (ODs), or (3) have gastric distension due to aerophagia; (4)
UA surgery. have comorbid lung disease (obstructive or
General measures include the avoidance of restrictive); (5) have hypoventilation syndrome;
alcohol, smoking, and muscle relaxants; proper or (6) have persistent O2 desaturation despite
sleep hygiene; safety counseling; and optimal CPAP therapy.17
weight management. Positional therapy (avoid- Autotitrating PAP (APAP) generates and
ance of a supine sleep position) may be consid- delivers variable pressures by using device-
ered if respiratory events occur exclusively or specific diagnostic and therapeutic algorithms,
predominantly during supine sleep, and if PSG and, therefore, is able to automatically and
demonstrates a normal AHI in the lateral or continuously adjust delivered PAP to maintain
prone sleep position. O2 therapy is not indicated UA patency. This modality can be used for either
as sole therapy for OSA but may be considered in titration to identify a single fixed pressure for
patients with significant hypoxemia uncontrolled subsequent treatment with a conventional CPAP
with PAP therapy alone. Topical nasal corticoste- device (however, it is not recommended for split-
roids are useful adjuncts for concurrent rhinitis. night PAP titration) or treatment when used in a
Finally, modafinil/armodafinil is US Food and self-adjusting mode for nightly therapy for
Drug Administration-approved for the treatment OSA.18 Contraindications to APAP include HF,
of residual EDS during effective PAP therapy and significant respiratory disease (eg, COPD), day-
if no other treatable cause for EDS can be time hypoxemia and respiratory failure, and
identified. nocturnal O2 desaturation unrelated to OSA,
such as that seen in obesity hypoventilation
PAP Therapy syndrome. Compared with CPAP, APAP has no
significant differences in effectiveness (reduc-
PAP therapy is the treatment of choice for tions in AHI and arousal), changes in sleep
most persons with OSA. It essentially functions architecture, SaO2 levels, or subsequent CPAP
as a pneumatic splint that maintains UA patency acceptance. However, APAP use often results in
by increasing pressure above PCRIT. Higher lower mean airway pressures compared with
pressures may be required for REM sleep and CPAP. In addition, use of APAP may result in
supine sleep. PAP therapy is indicated in persons higher peak airway pressures (because of air
with AHI of 15 events per hour; or AHI of 5 to leaks); thus, proper mask fitting is crucial prior to
14 events per hour plus complaints of EDS, unattended APAP use.
impaired cognition, mood disorder, or insomnia, Adaptive servo-ventilation (ASV) provides
or documented HTN or IHD, or history of stroke. variable pressure support (EPAP minus IPAP)
There are several PAP modalities. CPAP that increases during hypoventilation and de-
provides a single constant pressure throughout creases during hyperventilation, in addition to
the entire respiratory cycle.16 Another device is end-expiratory pressures. Finally, nocturnal non-
CPAP with expiratory pressure-relief technology invasive positive pressure ventilation consists of

two pressure levels provided at a set rate to assist securing it in a soft bulb located anterior to the
ventilation; this modality is used for patients teeth; these devices are preferred for edentulous
with persistent sleep-related hypoventilation and persons or those with compromised dentition.
CO2 retention. Overall effectiveness of ODs is about 40% to
PAP therapy has several significant beneficial 80%, and long-term compliance is 50% to 80%.
effects, such as (1) reduction in mortality; (2) Follow-up PSG is essential for optimal fit.
decrease in both subjective and objective sleep- Periodic assessments by a dentist and sleep
iness; (3) reduction or elimination of snoring; (4) physician are recommended.
decrease in AHI; (5) improvement in SaO2; (6) Contraindications to the use of ODs for sleep-
enhanced BP control; (7) improved LV ejection disordered breathing include (1) inability to
fraction in persons with HF; and (8) decrease in breathe nasally, (2) sleep apnea that is primarily
health-care use19 PAP therapy is also associated central in nature, (3) use in growing children, (4)
with several important consequences; these inadequate or compromised dentition (for man-
include nasal congestion, dryness, epistaxis, or dibular repositioners), and (5) significant tempo-
rhinorrhea; sinus discomfort or pain; facial skin romandibular joint dysfunction (for mandibular
irritation, rash, or abrasion; eye irritation; gastric repositioners).
distension caused by aerophagia; and chest
discomfort and tightness. These adverse conse- UA Surgery for OSA
quences are responsible, in part, for the subop-
timal adherence to this therapy. Objective UA surgery is indicated primarily for pa-
compliance (use for .4 h/night for 70% of tients with definitive craniofacial or UA abnor-
nights) is estimated at 50% to 80%, and average malities. PSG following UA surgery is
nightly use is about 5 h. Thus, PAP use should be recommended to determine efficacy. Long-term
monitored objectively. Adherence to PAP therapy follow-up is required.
can be improved by patient education, selective There are several types of UA surgery,
use of heated humidification, and administration including (1) tonsillectomy and adenoidectomy;
of eszopiclone during the PAP titration study.20 (2) nasal septoplasty, polyp removal, and turbi-
Heated humidification is especially useful for nectomy (to increase the dimensions of the nasal
patients older than 60 years, using drying airway); (3) UPPP (to increase the dimensions of
medications, with chronic mucosal disease, or the retropalatal air space); (4) genioglossus
with prior uvulopalatopharyngoplasty (UPPP). advancement, hyoid myotomy and suspension,
Although the following have inconsistent bene- or mandibular advancement (to increase the
fits on improving PAP adherence—(1) BPAP, (2) dimensions of the retrolingual airway); (5)
Cflex; (3) ramping mechanism; and (4) changing uvulopalatopharyngoglossoplasty or maxillo-
a poorly fitting nasal mask after therapy has mandibular advancement (to increase the dimen-
started—they may be considered in select pa- sions of the retrolingual, retropalatal, and
tients. transpalatal airways); and (6) tracheotomy (to
bypass the UA).23 The most effective surgical
ODs for OSA techniques are tracheotomy, which is the only
surgical procedure that is consistently effective as
ODs are indicated for snoring, mild to a sole procedure for OSA; bariatric surgery for
moderate OSA, and for some patients with weight management; and maxillomandibular
severe OSA.21,22 There are two main types of advancement.
ODs currently being used, namely, mandibular
repositioners and tongue retainers. Mandibular CSA
repositioners are designed to displace the
mandible and tongue anteriorly and are the CSA is defined as repetitive cessation of
most commonly used ODs. Tongue-retaining airflow during sleep caused by loss of ventilatory
devices hold the tongue in a forward position by effort. Patients with CSA present with insomnia

or sleepiness but may be asymptomatic. PSG is elevation, (3) faster speed of ascent, and (4) male
necessary for diagnosis of CSA.24 sex.
CSA can be classified into hypercapnic and
nonhypercapnic forms. Hypercapnic CSA is CSA Caused by Medications
characterized by high sleep PaCO2 caused by
decreased ventilatory responsiveness to hyper- Depression of hypercapnic respiratory drive
capnia. Patients often have high waking PaCO2 as can result from use of long-acting opioids (eg,
well. Causes include neuromuscular disorders methadone).
and chronic use of long-acting opioids. Persons
with nonhypercapnic CSA have normal or low CSA at Sleep Onset
waking PaCO2 and increased ventilatory response
CSAs may occur if PaCO2 (higher during sleep
to hypercapnia. Causes of nonhypercapnic CSA
and lower during wakefulness) fluctuates above
are idiopathic CSA, sleep-onset CSA, CSA caused
or below the apnea threshold. This type of CSA is
by HF, high-altitude periodic breathing, and
generally transient and resolves as sleep pro-
complex sleep apnea.
gresses.
Idiopathic CSA
Complex Sleep Apnea
The cause of this rare condition is unknown.
CSA can develop during acute application of
Men appear to be more commonly affected than
CPAP in patients with predominantly OSA at
women. Prevalence is greatest in middle-aged
baseline. Complex sleep apnea occurs acutely in
and older adults.
approximately15% of persons with OSA titrated
with CPAP; many of these cases may improve or
CSR
resolve over time.
CSR is periodic breathing with recurring CSA Caused by HF

periods of waxing-waning ventilation separated
by CSAs or hypopneas. CSR generally develops The prevalence and severity of CSA and CSR
during NREM sleep and improves or resolves are correlated with LV function. Mortality is
during REM sleep. Risk factors for CSR are HF, higher in HF patients with CSR than in those
male sex, age . 60 years, AF, hypocapnia, and without CSR. Mortality is increased in persons
stroke. There are important differences between with systolic HF with (1) worse AHI (CSR or
CSA and CSR. In CSA, both the nadir of O2 CSA), (2) increased left atrial size, (3) severe right
desaturation and arousals occur following the ventricular systolic dysfunction, and (4) low
termination of apnea, cycle time is shorter (,45 diastolic BP.25
s), and period of hyperpnea is shorter compared Therapy for CSA: It is important to treat any
with those with CSR. In CSR, the nadir of O2 underlying cause of CSA, such as HF, as well as
desaturation is more delayed, arousals occur at to avoid respiratory depressants in hypercapnic
the peak of hyperpnea, cycle time is longer (.45 CSA. O2 therapy and acetazolamide may be tried
s), and period of hyperpnea is longer. for high-altitude periodic breathing. Patients
with symptomatic sleep-onset CSAs may benefit
High-Altitude Periodic Breathing from hypnotic agents to help consolidate sleep.
PAP therapy is indicated for CSA or CSR
Cycles of CSA and hyperpnea may develop caused by HF. Although PAP therapy might
on ascent to high altitudes (usually .4,000–7,600 improve cardiac function, it may have no benefit
m). High-altitude periodic breathing occurs on mortality. It is important to monitor the
primarily during NREM sleep and improves effectiveness of therapy closely. ASV is useful
during REM sleep. Risk factors include (1) for complex sleep apnea, and nocturnal noninva-
greater hypoxic ventilatory drive, (2) higher sive ventilation is effective for hypercapnic CSA.

Nocturnal Hypoventilation Syndromes nostic and Coding Manual. 2nd ed. Westchester, IL:
American Academy of Sleep Medicine; 2005.
Nocturnal hypoventilation has two important 2. Olson EJ, Park JG, Morgenthaler TI. Obstructive
features, namely, sleep-related O2 desaturation sleep apnea-hypopnea syndrome. Prim Care. 2005;
and elevated PaCO2 during sleep (PaCO2 . 45 mm 32(2):329–359.
Hg, or PaCO2 , 45 mm Hg but abnormally 3. Wang H, Parker JD, Newton GE, et al. Influence of
increased relative to waking levels). Waking obstructive sleep apnea on mortality in patients
arterial blood gases may be normal or abnormal. with heart failure. J Am Coll Cardiol. 2007;49(15):
Underlying pathophysiology may be a decrease 1625–1631.
in minute ventilation and/or tidal volume, 4. Khayat RN, Abraham WT, Patt B, Pu M, Jarjoura
abnormal ventilation-perfusion relationships, D. In-hospital treatment of obstructive sleep
and changes in ventilatory chemosensitivity and apnea during decompensation of heart failure.
respiratory load responsiveness. Therapy con- Chest. 2009;136(4):991–997.
sists of treatment of underlying disorders and, in 5. Mehra R, Benjamin EJ, Shahar E, et al. Association
some, ventilatory assistance during sleep.26 of nocturnal arrhythmias with sleep-disordered
breathing: the Sleep Heart Health Study. Am J
Congenital Central Hypoventilation Syndrome Respir Crit Care Med. 2006;173(8):910–916.
6. Ryan CM, Usui K, Floras JS, Bradley TD. Effect of
There is failure of automatic control of continuous positive airway pressure on ventricu-
breathing in this syndrome, with hypoxemia lar ectopy in heart failure patients with obstruc-
and hypercapnia, as well as diminished respon- tive sleep apnoea. Thorax. 2005;60(9):781–785.
siveness to O2 and CO2. Onset is during infancy. 7. Kanagala R, Murali NS, Friedman PA, et al.
Hypoventilation is more severe during N3 than Obstructive sleep apnea and the recurrence of
REM sleep. Associated features consist of auto- atrial fibrillation. Circulation. 2003;107(20):2589–
nomic dysfunction, Hirschsprung disease, and 2594.
neural crest tumors. Many cases involve de novo 8. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-
mutations in the PHOX2B gene.27,28 term cardiovascular outcomes in men with ob-
structive sleep apnoea-hypopnoea with or with-
Conclusions out treatment with continuous positive airway
pressure: an observational study. Lancet. 2005;
OSA is a systemic disease. CSA is not a single 365(9464):1046–1053.
disorder. 9. Peppard PE, Young T, Palta M, Skatrud J.
Prospective study of the association between
Relationships Disclosed
sleep-disordered breathing and hypertension. N
Engl J Med. 2000;342(19):1378–1384.
The author has disclosed the following
10. O’Connor GT, Caffo B, Newman AB, et al.
relationships: Grant Monies (from sources other
Prospective study of sleep-disordered breathing
and hypertension: the Sleep Heart Health Study.
try-related sources): Embla, Respironics. Employ-
Am J Respir Crit Care Med. 2009;179(12):1159–1164.
ee: Philips Respironics (Medical Liaison Officer).
11. Bazzano LA, Khan Z, Reynolds K, He J. Effect of
Consultant fee, speaker bureau, advisory com-
nocturnal nasal continuous positive airway pres-
mittee, etc: Consultant for Sleep Medicine Clinics
sure on blood pressure in obstructive sleep apnea.
(Elsevier), Consultant for CareCore National. The
Hypertension. 2007;50(2):417–423.
ACCP Education Committee has reviewed these
12. Arias MA, Garcı́a-Rı́o F, Alonso-Fernández A,
relationships and resolved any potential conflict
Martı́nez I, Villamor J. Pulmonary hypertension in
of interest.
obstructive sleep apnoea: effects of continuous
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noninvasive positive pressure ventilation (NPPV)
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19. Marshall NS, Barnes M, Travier N, et al. Contin- committee. An official ATS clinical policy
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Chapter 14. Other Sleep Disorders
Objectives: Insomnia is the most common sleep disorder.

Learn how to evaluate and treat patients presenting with Transient or occasional insomnia has been de-
insomnia or excessive sleepiness. scribed by 30% to 50% of adults, and chronic
Recognize the causes of abnormal sleep-related behav-
insomnia affects about 10% to 30% of adults. Risk
iors.
Identify the different circadian rhythm sleep disorders. factors for insomnia include (1) female sex; (2)
aging; (3) lower socioeconomic status or unem-
Key words: circadian rhythm sleep disorders; hypersomnia; ployment; (4) divorced or widowed marital
insomnia; parasomnia; restless legs syndrome status; (5) poor health status and physical
disability; and (6) the presence of medical,
Synopsis: neurologic, and psychiatric diseases (eg, respira-
Insomnia can be defined as repeated difficulty with either tory disorders).
falling or staying asleep, or earlier than desired morning Chronic insomnia is associated with signifi-
awakenings. Excessive daytime sleepiness is characterized
by the inability to consistently achieve and sustain wake- cant adverse consequences, such as increased
fulness and alertness to accomplish the tasks of daily living. risk of developing a psychiatric illness (depres-
Narcolepsy is a neurologic disorder characterized by the sion); cognitive impairment; impaired academic
clinical tetrad of excessive daytime sleepiness, cataplexy,
and occupational performance; and greater
sleep paralysis, and sleep hallucinations. Parasomnias are
physical or experiential phenomena that develop during health-care use.1
sleep. Restless legs syndrome is characterized by an urge to
move, or unpleasant sensations, in the legs (less commonly Specific Causes of Insomnia
the arms) that begin or worsen during periods of rest or
inactivity; is relieved transiently by movement; and is
worse, or occur only, at night. Circadian rhythm sleep Adjustment Insomnia: Sleep disturbance is
disorders are caused by a recurrent or persistent misalign- caused by an acute stressor, such as a momentous
ment between the desired sleep schedule and the circadian life event, sudden change in sleeping environ-
sleep-wake rhythm.
ment, or an acute illness. Sleep improves after
resolution of the acute stressor or with adapta-
tion to it.
Insomnia Idiopathic Insomnia: In this disorder, chronic
life long sleep disturbance starts during infancy
Insomnia can be defined either clinically or or early childhood. There is no identifiable cause
polysomnographically. Clinically, it is character- for the sleep disturbance.
ized by repeated difficulty with either falling Inadequate Sleep Hygiene: Insomnia is caused
(sleep-onset insomnia) or staying asleep (sleep- by activities or behavior that increases arousal or
maintenance insomnia), or earlier than desired decreases sleep propensity and that are under a
morning awakenings (terminal insomnia). This person’s control. Activities include drinking
sleep disturbance is associated with impairment coffee close to bedtime or watching television in
of daytime function. Polysomnographic (PSG) bed.
features of insomnia include a sleep-onset laten- Paradoxical Insomnia: Also known as sleep-
cy (SOL) 30 min; wake time after sleep onset state misperception, paradoxical insomnia in-
(WASO) 30 min; sleep efficiency (SE) ,85%; volves very minimal or no sleep during most
and total sleep time (TST) ,6 to 6.5 h. Insomnia is nights but PSG demonstrates normal sleep
commonly classified as either transient (lasting quality and architecture. In addition, there is
only a few days) or chronic (persisting for more commonly no daytime napping or impairment of
than 1–3 mo). daytime functioning.

Psychophysiological Insomnia: Sleep distur- irrational expectations, excessive worry, and
bance is caused by heightened cognitive and unrealistic concerns, and provides a more appro-
somatic arousal at bedtime and manifests as priate understanding of insomnia and its conse-
rumination, increased agitation and muscle tone, quences.
learned maladaptive sleep-preventing behaviors, Paradoxical Intention: To decrease perfor-
and excessive anxiety about inability to sleep. mance anxiety related with efforts to fall asleep,
Medications and Substances: Many common patients are instructed to go to bed and try to stay
agents can give rise to insomnia. These include awake as long as they can.
antidepressants (fluoxetine or protriptyline), b- Relaxation Techniques: These are designed to
blockers, bronchodilators, decongestants, ste- reduce somatic and cognitive hyperarousal via
roids, and stimulants. progressive muscle relaxation, biofeedback, or
guided imagery.
Evaluation of Insomnia Sleep Restriction: Reducing time spent awake
in bed can enhance homeostatic sleep drive.
Patients presenting with complaints of recur- Bedtime is advanced or delayed based on
ring or chronic insomnia should undergo a calculated sleep efficiency (TST/time in bed). If
comprehensive medical history. Sleep logs and SE .90%, bedtime is advanced (earlier), and if SE
sleep diaries may assist with both diagnosis and
,80%, bedtime is delayed (later). Bedtime is
assessment of response to therapy. PSG, actig-
unchanged if SE is 80% to 90%. Thus, time in bed
raphy, and laboratory tests are not routinely
is increased once SE improves. Patients are asked
indicated. Nevertheless, PSG may be considered
to wake up at the same time every morning and
to exclude obstructive sleep apnea (OSA), peri-
to avoid naps.
odic limb movement disorder (PLMD), or para-
Stimulus Control: To strengthen the associa-
doxical insomnia as causes of the sleep
tion of the bedroom and bedtime to a condi-
disturbance.2
tioned response for sleep, patients are instructed
Treatment of Insomnia to use the bed only for sleep or sex; to lie down to
sleep only when sleepy; and to get out of bed and
Treatment of insomnia consists of either go to another room if unable to fall asleep,
behavioral (cognitive behavioral therapy for engage in a restful activity, and return to bed
insomnia [CBT-I]) or pharmacologic therapy. only when sleepy.
Behavioral Therapy Pharmacotherapy
Short-term benefits of CBT-I are comparable Pharmacotherapy for insomnia may enhance
with those of pharmacologic therapy, but, unlike sleep but often does not improve daytime
the latter, its beneficial effects are sustained performance. In addition, there are minimal
across time; that is, CBT-I is more effective than long-term beneficial effects on sleep after drug
pharmacotherapy at long-term follow-up. Com- discontinuation. There is insufficient evidence
pared with pharmacotherapy, CBT-I is more regarding the efficacy of sedating antipsychotic
effective in shortening SOL but may be less agents, antihistamines (including over-the-coun-
effective in increasing TST.3,4 ter agents), and botanical compounds for chronic
Several techniques can be used for CBT-I, insomnia.
namely, cognitive therapy, paradoxical intention, Hypnotic therapy is indicated for patients
relaxation techniques, sleep restriction, and stim- with transient sleep disruption (jet lag or
ulus control. Sleep restriction and stimulus adjustment sleep disorder), chronic primary
control are the most effective of the nonpharma- insomnia that fails to respond to CBT-I, and
cologic treatments for insomnia. chronic comorbid insomnia that does not im-
Cognitive Therapy: This technique addresses prove with treatment of the underlying condition
dysfunctional beliefs related to insomnia, such as and CBT-I.
210 Chapter 14. Other Sleep Disorders (Lee-Chiong)

Hypnotic agents vary in terms of their half- risk of accidents, impaired work and academic
lives, from ,1 h (ramelteon and zaleplon), 2 to performance, and development of mood disor-
5 h (eszopiclone, triazolam, and zolpidem), 5 to ders.
24 h (low-dose doxepin, estazolam, and temaz-
epam), and .40 h (flurazepam and quazepam). Causes of Hypersomnia
Short-acting agents are used for patients with
sleep-onset insomnia; intermediate-acting agents 1. Insufficient sleep syndrome. This is the most
for those with both sleep-onset and sleep- common cause of EDS. Sleepiness is caused by
maintenance insomnia; and long-acting agents chronic voluntary, but unintentional, sleep
for individuals complaining of early morning deprivation. Diagnosis is based on clinical
awakenings and daytime anxiety.5 history and sleep diaries. PSG is not routinely
Benzodiazepines are among the most com- indicated. Therapy involves sleep extension.
monly prescribed hypnotic agents. Adverse 2. Narcolepsy.
effects of benzodiazepines include (1) rebound 3. Idiopathic hypersomnia (IH).
daytime anxiety (with short-acting agents), (2) 4. Recurrent hypersomnia.
daytime sleepiness (with long-acting agents), (3)
cognitive and psychomotor impairment, (4) Narcolepsy
development of tolerance, (5) withdrawal symp-
toms (anxiety, irritability, and restlessness), (6) This neurologic disorder is characterized by
rebound insomnia, (7) respiratory depression the clinical tetrad of EDS, cataplexy, sleep
and worsening of OSA, (8) increase in falls in paralysis, and sleep hallucinations. However,
some older adults, and (9) dependency and only 10% to 15% of patients demonstrate this
abuse liability (low risk). full tetrad. Narcolepsy has a prevalence of 0.05%
The newer nonbenzodiazepine benzodiaze- in the United States, with perhaps a slightly
pine receptor agonists consist of eszopiclone,
higher prevalence among men.1
zaleplon, and zolpidem. Compared with conven-
Excessive Sleepiness: The first, primary, and
tional benzodiazepines, they have comparable
most disabling symptom of narcolepsy. Patients
hypnotic effects. However, they possess no
may take frequent brief naps (10-20 min) that
muscle relaxant, anticonvulsant, or anxiolytic
occur repeatedly throughout the day; EDS
properties; are less likely to cause rebound
typically improves transiently after these naps.
insomnia, withdrawal symptoms, or tolerance;
Sleep attacks can occur.
and are less likely to alter sleep architecture.
Cataplexy: Consists of transient episodes of
The melatonin receptor agonist ramelteon has
a short half-life and is indicated for sleep-onset muscle atonia-hypotonia precipitated by intense
insomnia. Contraindications include the use of emotion, such as laughter, anger, or excitement.
fluvoxamine and hepatic impairment. Melatonin Respiratory and oculomotor muscles are spared.
also has a short half-life (20-30 min) and is used Memory and consciousness are unaffected. Epi-
primarily for insomnia associated with circadian sodes generally last ,2 min, and recovery is
rhythm sleep disorders (CRSDs). immediate and complete. Cataplexy is the only
pathognomonic symptom of narcolepsy.
Hypersomnia Sleep Hallucinations: May be visual, auditory,
tactile, or kinetic and may be accompanied by
Excessive daytime sleepiness (EDS) is char- sleep paralysis. They can occur at the onset of
acterized by an inability to consistently achieve sleep (hypnagogic) or upon awakening (hypno-
and sustain wakefulness and alertness to accom- pompic).
plish the tasks of daily living. Hypersomnia can Sleep Paralysis: affects voluntary muscles,
manifest as frequent napping, acute sleep attacks, with sparing of respiratory, oculomotor, and
repetitive microsleep episodes, paradoxical hy- sphincter muscles, and lasts a few seconds or
peractivity (in children), and automatic behavior. minutes. Sensorium is unaffected. It can either be
Consequences of hypersomnia include greater hypnagogic or hypnopompic.

Sleep Disturbance: is common, consists of Idiopathic Hypersomnia
repetitive arousals and awakenings, and can
result in sleep-maintenance insomnia. Other Patients complain of constant sleepiness
features of narcolepsy include memory impair- despite sufficient, or even increased, amounts of
ment, automatic behavior, and hyperactivity and nighttime sleep and daytime napping. There is
learning disability (in children). no identifiable cause of EDS. There are several
Loss of hypothalamic hypocretin neurons is important differences between narcolepsy and
the primary mechanism responsible for narco- idiopathic hypersomnia (IH): (1) cataplexy may
lepsy-cataplexy. Defective cholinergic systems be present in narcolepsy but is absent in IH; (2)
regulating rapid eye movement (REM) sleep daytime napping is transiently refreshing in
and impairment of norepinephrine and dopa- narcolepsy but unrefreshing in IH; (3) sleep
mine systems are contributory. disturbance is common in narcolepsy, but sleep
Narcolepsy can present without cataplexy. In patterns may be normal or prolonged in duration
these patients, cataplexy-like symptoms may be in IH; (4) CSF hypocretin levels are low in
present (eg, prolonged episodes of tiredness or narcolepsy with cataplexy, normal in some cases
muscle weakness associated with atypical trig- of narcolepsy without cataplexy, and normal in
gers). It accounts for 10% to 50% of cases of IH; and (5) there is a more predictable improve-
narcolepsy. Most patients with narcolepsy with- ment in EDS in response to stimulant therapy in
out cataplexy have normal cerebrospinal fluid narcolepsy than in IH.
(CSF) hypocretin-1 levels.
Diagnosis of narcolepsy starts with a thor- Recurrent Hypersomnia
ough clinical history. Narcolepsy with cataplexy
Episodes of hypersomnia occur weeks or
can be diagnosed by history alone. PSG followed
months apart, with normal sleep and alertness
by a multiple sleep latency test (MSLT) is
between episodes. Kleine-Levin syndrome is
necessary when cataplexy is absent, atypical, or
characterized by bouts of EDS (severity of
equivocal.
hypersomnia may decrease over time), hyper-
PSG features of narcolepsy consist of a
sexuality, hyperphagia, and abnormal behavior,
shortened SOL (,10 min), sleep-onset REM
occurring most commonly in young men. Dien-
periods (SOREMPs; REM latency ,20 min), and
cephalic hypoperfusion may be present on
increase in WASO (repetitive awakenings). The
single-photon emission CT. Affected individuals
MSLT demonstrates a mean SOL ,8 min and two
may respond favorably to lithium therapy.
or more SOREMPs. The combination of a short
SOL and multiple SOREMPs is present in 60% to Other Causes of Hypersomnia
85% of cases. A maintenance of wakefulness test
(MWT) may be used to monitor treatment Hypersomnia can also develop as a result of
response to stimulant medications used for EDS. an underlying medical disorder (eg, hepatic
Narcolepsy with cataplexy is commonly encephalopathy, hypothyroidism, Prader-Willi
associated with low CSF hypocretin-1 levels syndrome, or renal failure) or neurologic and
(,110 pg/mL, or ,1/3 of mean normal control psychiatric disorders (eg, CNS infections or tumor,
values). Human leukocyte antigen typing is head trauma, Parkinson disease, stroke, atypical
generally not clinically useful. depression, bipolar type II mood disorder, or
Therapy for narcolepsy with cataplexy con- seasonal affective disorder). Finally, EDS can arise
sists of treatments for EDS (modafinil, armoda- from either use or abuse of sedative-hypnotic
finil, dextroamphetamine, or methylphenidate), agents or withdrawal from stimulant agents.
sleep disturbance (hypnotic agents or c-hydroxy-
butyrate [sodium oxybate]), and cataplexy (REM Evaluation of Hypersomnia
sleep suppressant agents, such as selective
serotonin reuptake inhibitors, or c-hydroxybuty- Sleep history, medical history, and sleep diary
rate). should be obtained from all patients complaining

of hypersomnia. Actigraphy may provide clues or partial amnesia. Risk factors for sleep-
to duration and timing of sleep and waking. related eating disorder include OSA, sleep-
Subjective (Epworth Sleepiness Scale) and objec- walking, and medications (eg, zolpidem).
tive (MSLT and MWT) tests of sleepiness are
useful for diagnosis, as well as assessment of Therapy for Parasomnias
treatment efficacy. PSG may be performed to
exclude OSA and PLMD. A mean MSLT SOL ,8 Avoidance of sleep deprivation, including a
min or mean MWT SOL ,40 min commonly trial of sleep extension, may be tried. Low-dose
defines hypersomnia. clonazepam or melatonin at bedtime is effective
for many patients with RBD. Environmental
Therapy for Hypersomnia
precautions are important to prevent injury to
both sleeper and bed partner.10
Sleep extension is often the only intervention
needed for patients with insufficient sleep syn-
Restless Legs Syndrome (RLS) and
drome. Countermeasures for EDS include
planned napping, caffeine, and stimulant agents
Periodic Limb Movement Disorder
(amphetamines, methylphenidate, or modafinil/
(PLMD)
armodafinil).6,7
RLS
Parasomnias
There is an urge to move, or unpleasant
sensations, in the legs (less commonly the arms)
These are physical or experiential phenomena
that begins or worsens during periods of rest or
that develop during sleep. Certain parasomnias
inactivity; is relieved transiently by movement;
occur during nonrapid eye movement (NREM)
and is worse, or occurs only, at night.11
sleep, such as confusional arousals, sleep terrors,
RLS affects about 3% to 15% of the general
and sleepwalking, whereas others are REM-sleep
population. Prevalence increases with anemia,
specific, including nightmares and REM sleep
uremia, pregnancy, and aging. Women are affect-
behavior disorder (RBD).1,8,9
ed more commonly than men. It is most
1. Nightmares. These REM parasomnias tend to frequently diagnosed in middle-aged and older
develop during the latter half of the night. adults. The course tends to be chronic. About 70%
Affected persons are typically awake and alert to 90% of persons have concurrent periodic limb
during these episodes and have full recall of movements during sleep (PLMS). Conversely,
the event. Subsequent return to sleep is one-third of persons with PLMS have RLS.
delayed. Consequences of RLS include sleep-onset and
2. Sleep terrors. Unlike nightmares, sleep terrors sleep-maintenance insomnia, as well as EDS
occur during N3 sleep, are more likely to caused by sleep fragmentation.
develop during the first half of the night, and Diagnosis is by means of clinical history.
are characterized by confusion and disorien- Laboratory evaluation to exclude iron deficiency
tation, partial or complete amnesia of the should be considered. PSG is not routinely
event, and rapid return to sleep. indicated. Therapy for RLS consists of (1)
3. RBD. Episodes often develop during the latter treatment of underlying causes or precipitating
half of the night. Seemingly purposeful and factors; (2) iron supplementation if serum ferritin
frequently violent behavior occurs during value ,50 lg/L; and (3) use of dopaminergic
REM sleep. There is variable memory of the agents, such as levodopa, pramipexole, and
episode. ropinirole. Important adverse effects of dopami-
4. Sleep-related eating disorder. In this syndrome, nergic agents include augmentation (particularly
repetitive bouts of eating or drinking occur with levodopa); nausea, sleepiness, orthostasis,
during arousals from sleep. There is lack of and development of dysregulation syndrome
awareness of the abnormal behavior and total (pramipexole and ropinirole); and development

of pleuropulmonary and cardiac valve fibrosis of excessive sleepiness in the late afternoon or
(pergolide). Other medications that might be early evening, as well as morning awakenings
helpful for patients with RLS are benzodiaze- that are earlier than desired (sleep-maintenance
pines (clonazepam) for symptomatic relief; opi- or terminal insomnia). Onset is commonly
oid agents for severe symptoms refractory to during middle or older age. Depression, since it
other therapy; and neurontin for RLS, especially can also present with early morning awakenings,
if accompanied by pain.12,13 should be excluded. Therapy consists of early
evening bright light therapy.
PLMD
DSPS
Recurrent leg movements (partial flexion of
the ankle, knee, and hip with extension of the big These ‘‘night owls’’ have a stable late bedtime
toe) are accompanied by complaints of sleep (1:00 AM–6:00 AM) and delayed wake time (10:00
disturbance or EDS. Involvement of the upper AM–2:00 PM). Both sleep-onset insomnia and
extremity manifests as flexion at the elbow. morning sleepiness occur when sleep is attempt-
PLMD shares many of the risk factors of RLS. ed at more conventional (earlier) bedtimes. Onset
Unlike RLS, PSG is required for diagnosis of is often during adolescence, and the course is
PLMD. The periodic limb movement index is long-term, although severity may diminish with
abnormal if .5/h in children and .15/h in increasing age. Timed early morning light expo-
adults. Therapy for symptomatic PLMD (ie, sure (after minimum core body temperature),
associated with sleep disturbance or EDS) is avoidance of bright light in the evening, chrono-
similar to that of RLS. Specific therapy is not therapy (progressive phase delay or progressive
indicated for asymptomatic PLMS. phase advancement), and melatonin adminis-
tered in the early evening are helpful therapeu-
Circadian Rhythm Sleep Disorders tically.
This group of disorders is caused by recur- Free-Running Circadian Disorder

rent or persistent misalignment between the
desired sleep schedule and the circadian sleep- Because of a progressive daily delay in sleep-
wake rhythm, and patients can present with onset and wake times, the major sleep period
insomnia, EDS, or both. History and sleep diaries progressively ‘‘marches’’ throughout the day,
are useful for diagnosing all circadian rhythm afternoon, and evening. This gives rise to
sleep disorders (CRSDs). Actigraphy may be periodically recurring problems of insomnia or
useful both in diagnosis and in assessing EDS. Most of these patients are totally blind and
response to therapy. PSG is not routinely indi- lack photic entrainment; this disorder is relative-
cated. ly rare in the general population. The course is
There are six CRSDs, namely, advanced sleep chronic. Patients may respond to evening ad-
phase syndrome (ASPS), delayed sleep phase ministration of melatonin, as well as strict
syndrome (DSPS), free-running circadian disor- adherence to a regular sleep-wake and daytime
der (FRD), irregular sleep-wake rhythm (ISWR), activity schedule.
jet lag, and shift work disorder.1,14,15 The first
four CRSDs will be discussed in this section. Irregular Sleep-Wake Rhythm
ASPS There are no stable circadian sleep-wake

rhythms. Variable, inconsistent, and multiple sleep
Persons with ASPS are the typical ‘‘morning and wake periods occur throughout the day and
larks’’ who have an early bedtime (6:00 PM–9:00 from one day to another. Nonetheless, aggregate
PM) and early wake time (2:00 AM–5:00 AM). Sleep, sleep time during a 24-h period is normal. This
itself, is normal for age. Because of the advanced syndrome is most frequently seen in association
sleep schedule, patients present with complaints with dementia or mental retardation. Therapy

consists of evening administration of melatonin in persons with COPD. The prevalence of
and maintenance of sleep hygiene. insomnia is related to the number of symptoms
(cough or wheezing) present. The cause of sleep
PSG Patterns of CRSDs disturbance in COPD is often multifactorial and
may include nocturnal coughing, wheezing,
With ASPS and DSPS, sleep architecture is dyspnea, orthopnea, or increased work of breath-
generally normal when PSG is performed during ing. The frequency of arousals does not appear to
a person’s habitual sleep schedule. In ASPS, SOL be related to the degree of nighttime hypoxemia.
may be shortened or normal, and TST is Sleep-related oxygen desaturation can devel-
decreased with an early wake time when PSG op in moderate to severe disease. Nocturnal
is performed during the conventional sleep- hypoxemia is more frequent and of greater
laboratory sleep schedule. Conversely, SOL is duration and is more severe during REM sleep
prolonged and TST is reduced in persons with compared with NREM sleep, and it is more
DSPS when PSG is performed during a conven- common in persons with chronic bronchitis than
tional sleep schedule. in those with emphysema. Mechanisms for sleep-
In persons with ISWR, 24-h PSG performed related hypoxemia include hypoventilation (most
across several days shows a variable and important), ventilation-perfusion mismatching,
disorganized pattern of sleep and wake. Finally, and decrease in lung volumes. Oxygen level
in FRD, PSG recorded at a fixed time period daily during wakefulness is the major predictor of
across several days demonstrates progressively mean and lowest oxygen saturation during sleep.
longer SOL and decreased TST; SE is commonly Overlap syndrome is characterized by the
normal. presence of both COPD and OSA. Although the
prevalence of OSA in persons with COPD is
Medical Disorders similar to that in the general population, comor-
bid COPD-OSA is associated with lower PaO2,
The relationship between sleep and medical higher PaCO2, higher mean pulmonary arterial
disorders is bidirectional. Sleep quality is pressures, and increased risk of death and
affected by medical disorders (and by medica- hospitalization compared with isolated COPD.
tions used to treat them) and vice versa. Both home sleep testing and automated positive
airway pressure titration are contraindicated in
Nocturnal Asthma patients with COPD.
Patients with nocturnal asthma often complain Conclusions

of sleep disturbance, insomnia, EDS, and noctur-
nal hypoxemia. Asthma attacks are not specific to Many disorders present with disturbances in
any sleep stage, and nocturnal symptoms merely duration, timing, or quality of sleep. Evaluation
indicate suboptimally treated asthma. There are of sleep complaints relies chiefly on a compre-
several mechanisms for nocturnal asthma, includ- hensive sleep history. Regular follow-up is
ing (1) sleep-related changes in autonomic nervous recommended to determine response to therapy,
system activity, lung capacity, and inflammatory as well as development of new sleep complaints.
mediators; (2) circadian variability in airflow
(lowest levels in the early morning); and (3) Relationships Disclosed
presence of other disorders that occur either
during the night or sleep (nocturnal gastroesoph- The author has disclosed the following
ageal reflux or OSA). relationships: Grant Monies (from sources other
COPD try-related sources): Embla, Respironics. Employ-
ee: Philips Respironics (Medical Liaison Officer).
Sleep-related complaints, including insom- Consultant fee, speaker bureau, advisory com-
nia, nonrestorative sleep, and EDS, are common mittee, etc: Consultant for Sleep Medicine Clinics

(Elsevier), Consultant for CareCore National. The hypersomnias of central origin. Sleep. 2007;
ACCP Education Committee has reviewed these 30(12):1712–1727.
relationships and resolved any potential conflict 8. Mahowald MW, Schenck CH. Non-rapid eye
of interest. movement sleep parasomnias. Neurol Clin.
2005;23(4):1077–1106.
References 9. Schenck CH, Mahowald MW. Rapid eye move-
ment sleep parasomnias. Neurol Clin. 2005;
1. American Academy of Sleep Medicine. The 23(4):1107–1126.
International Classification of Sleep Disorders. Diag- 10. Aurora RN, Zak RS, Maganti RK, et al. Best
nostic and Coding Manual. 2nd ed. Westchester, IL: practice guide for the treatment of REM sleep
American Academy of Sleep Medicine; 2005. behavior disorder (RBD). J Clin Sleep Med.
2. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, 2010;6(1):85–95.
Sateia M. Clinical guideline for the evaluation and 11. Itin I, Comella CL. Restless legs syndrome. Prim
management of chronic insomnia in adults. J Clin Care. 2005;32(2):435–448.
Sleep Med. 2008;4(5):487–504. 12. Standards of Practice Committee of the American
3. Morin CM, Bootzin RR, Buysse DJ, et al. Psycho- Academy of Sleep Medicine. Practice parameters
logical and behavioral treatment of insomnia: for the dopaminergic treatment of restless legs
update of the recent evidence (1998–2004). Sleep. syndrome and periodic limb movement disorder.
2006;29(11):1398–1414. Sleep. 2004;27(3):557–559.
4. Morgenthaler T, Kramer M, Alessi C, et al. 13. A Review by the Restless Legs Syndrome Task
Practice parameters for the psychological and Force of the Standards of Practice Committee of
behavioral treatment of insomnia: an update: an the American Academy of Sleep Medicine. An
American Academy of Sleep Medicine report. update on the dopaminergic treatment of restless
Sleep. 2006;29(11):1415–1419. legs syndrome and periodic limb movement
5. Buscemi N, Vandermeer B, Friesen C, et al. The disorder. Sleep. 2004;27(3):560–583.
efficacy and safety of drug treatments for chronic 14. Morgenthaler TI, Lee-Chiong T, Alessi C, et al.
insomnia in adults: a meta-analysis of RCTs. J Gen Practice parameters for the clinical evaluation and
Intern Med. 2007;22(9):1335–1350. treatment of circadian rhythm sleep disorders.
6. Morgenthaler TI, Kapur VK, Brown TM, et al. Sleep. 2007;30(11):1445–1459.
Practice parameters for the treatment of narcolep- 15. Sack R, Auckley D, Auger RR, et al. Circadian
sy and other hypersomnias of central origin. Sleep. rhythm sleep disorders: part II, advanced sleep
2007;30(12):1705–1711. phase disorder, delayed sleep phase disorder,
7. Wise MS, Arand DL, Auger RR, Brooks SN, free-running disorder, and irregular sleep-wake
Watson NF. Treatment of narcolepsy and other rhythm. Sleep. 2007;30(11):1484–1501.

Chapter 15. Epidemiology and Statistics for the Boards
Objectives: these topics, one can better read the literature,

Appreciate principles of hypothesis testing. apply it, and enhance patient care.
Understand the different types of error.
Review the interpretation of screening tests.
Hypothesis Testing
Key words: epidemiology; error; hypothesis; probability;
Hypothesis testing describes the process
screening
through which an investigator assesses the truth
Synopsis: or falseness of a hypothesis. This is specifically
completed by computing a specific test statistic
Epidemiology and statistics remain crucial tools for the
clinician, especially in pulmonary and critical care medicine. based on a sample from a given population. For
Hypothesis testing describes the process through which one the board examinations it is not crucial to
develops a specific question, articulates it, and then understand in what circumstances which partic-
determines whether the available data support or refute it.
Hypothesis testing is more complex than selecting a specific
ular test statistics are used. However, one should
statistical test for evaluating data and assessing whether the always be certain that when reading an article the
pattern observed in the data is likely to have occurred by statistical approach has been clearly delineated
chance or not. By convention, one attempts to restate the and described.
research question as a null hypothesis—therefore, if one
predicts a difference, the null hypothesis is stated such that Hypothesis testing has three steps. First,
we believe there is no difference. Then, the investigator decide on the hypothesis. Second, sample the
attempts to reject the null hypothesis. In hypothesis testing population. Third, review the population and
there are two potential types of error: type I and type II.
Type I error indicates the error that occurs when the null
determine whether the sample actually agrees
hypothesis is rejected and it was in fact true, whereas type II with or refutes the hypothesis. The reason one
error reflects accepting the null hypothesis when it was in samples the population rather than evaluating
fact false. These are essentially two sides to the same coin. the entire population is that exploring the entire
Generally epidemiology reflects the study of the distribution
and burdens of disease in a population. Descriptive population is impractical.
measures in epidemiology distinguish between rates and By convention the approach to hypothesis
ratios such as incidence and prevalence. Epidemiology also testing requires one to disprove the null hypoth-
encompasses the analysis of systematic error that arises
related to study design. Bias confounds the interpretation of
esis (Ho). The null hypothesis, simply put, is that
data and clouds the assessment of the truthfulness or there is no difference when in fact there exists a
falseness of the hypothesis understudy. Finally, screening difference. Therefore, the results observed oc-
tests and their characteristics reflect a crucial component of curred purely by chance. Hence, if we reject the
clinical epidemiology.
null hypothesis (eg, reject that there is no
difference), then, as a result, a difference is
present. The alternative hypothesis, denoted by
Introduction H1 or Ha, reflects the hypothesis that the
observations from the sample population are, in
The topics of statistics and epidemiology often fact, affected by some nonrandom factor.
intimidate clinicians. However, a basic grasp of A more subtle approach is also possible. It is
these subjects and the principles that surround more than simply a bivariate option of either
them is crucial for success in medicine. Whether accepting or rejecting the null hypothesis. Rather,
when reading clinical studies or making deci- one either rejects the null hypothesis or fails to
sions at the bedside, the physician either implic- reject the null hypothesis. The distinction be-
itly or explicitly confronts issues of epidemiology tween ‘‘acceptance’’ and ‘‘failure to reject’’ re-
and statistics. With a more formal appreciation of flects the fact that ‘‘failure to reject’’ could

indicate that the data are insufficiently persua- medicine. One often cannot assume that the
sive in terms of opting for the alternative randomness will only move in one direction.
hypothesis over the null hypothesis. In summary, the general procedure for
When testing a hypothesis two types of error hypothesis testing begins with a clear formula-
may occur. Type I error reflects the error that tion of the hypothesis and, therefore, the null and
occurs when the researcher rejects a null hypoth- alternative hypotheses. The statement of these
esis that is actually true. Type I error is indicated competing hypotheses must be made in such a
by alpha (eg, alpha error). The likelihood of way that they are clearly mutually exclusive.
committing an alpha error is a function of the Then one formulates an analysis plan that
significance level chosen. This is the common P specifies the significance level and the sampling
value that readers come across when reviewing approach to the population. Next follows an
the literature and reflects the probability that a analysis of the actual data that entail a calculation
type I error has been committed. Type II error is of the test statistic and of P values. Finally, one
described by beta and is a function of a study’s interprets the results and reevaluates the null
power. Therefore, this is when one does not reject hypothesis.
a null hypothesis that is actually false. Readers should note that when it comes to
Historically the alpha value is set at 0.05 or a determining the test statistic and the calculation
5% chance that the findings are due to random of the P value, a key issue revolves around the
variability. Occasionally, alpha is set at 0.01. This distribution of the data. Generally data are
can be the case when multiple testing is done or considered either continuous (eg, blood pressure
in analyses of genetic associations where a 5% readings) or categorical (eg, gender). It is
probability of a chance finding is not considered inappropriate to use tests for comparing contin-
biologically appropriate. Practically when the P uous variables for evaluating categorical data
value is ,.05 (or whatever significance level was and vice versa. Similarly, many statistical tests
predetermined) we reject the null hypothesis. presume that data are normally distributed.
Beta error sometimes is ignored. This is a sign However, many phenomenon in medicine are
of sloppiness, especially in prospective analyses. not normally distributed. Rather there is a skew
Determining the beta error one is willing to in the data to one extreme (eg, the age of patients
accept determines the eventual sample size in the ICU). In such cases there are specific
needed for a study. Beta is inversely related to statistical tests for non-normally distributed data.
alpha. Again, the determination of power needed When reviewing an article, one should examine
to feel that the sample size is adequate for the statistics section of the article to determine
avoiding type II error is arbitrary. Traditionally, whether and how the authors addressed this
people set the beta at 80% or 90%. possibility. Skewness of data also becomes a
Tests can be one-tailed or two-tailed. This particular problem when the sample size is small.
refers to the region of rejection for the null
hypothesis. The region of rejection is a concept Epidemiology
akin to the P value in terms of significance
testing. Hence if a value of a test statistic falls into Epidemiology describes the specific study of
the region of rejection, one rejects the null the distribution and determinants of health in a
hypothesis. If the region of rejection falls only population. Epidemiology represents a compli-
to one side of a bell curve, for example, then it is cated field that encompasses a range of issues
considered a one-tailed test. If the region of varying from understanding the incidence and
rejection could be at either extreme of the prevalence of disease to the evaluation of various
distribution (eg, at the low or high extreme), the ways of organizing health-care delivery. Al-
test is considered two-tailed. Whether a test though most physicians have a brief formal
should be one-tailed or two-tailed reflects a exposure to epidemiology while in medical
determination about whether there exists vari- school, several specific epidemiological topics
ability in only one direction or potentially two. In warrant review in preparation for the board
general, two-tailed testing is most appropriate in examinations.
218 Chapter 15. Epidemiology and Statistics for the Boards (Shorr)
Epidemiology often relies on comparing language to describe how well tests accomplish
various rates and ratios. In addition, the appro- this goal of classification.
priate use of rates and ratios depends on the Potentially a disease can be either present or
situation in question and the study design. A key absent. Likewise, a screening test can be either
distinction is the difference between prevalence positive or negative. From this, four main
and incidence. Prevalence simply describes the concepts emerge. Sensitivity (Sens) describes
proportion of cases in a population. The numer- the proportion of persons correctly classified as
ator reflects the number of cases and the having disease. Specificity (Spec) reflects the
denominator comprises the population. Hence proportion of patients properly classified as
this is a simple proportion. Prevalence is a good non-cases (eg, healthy). Sensitivity and specificity
measure for describing the burden of disease (eg, are functions of the population and the test.
10% of the patients in the ICU have pneumonia). Predictive value, however, reflects the perfor-
Incidence, on the other hand, is a rate and mance of the test when applied to the popula-
includes some description of time. The numera- tion—a subtle but important change in
tor here is only NEW cases whereas the denom- perspective. Rather than the point of focus being
inator is the population at risk for the event cases and non-cases, predictive value begins the
during a defined period of time. Incidence best analysis as a function of the test results. Positive
describes risk (eg, the risk for ventilator-associ- predictive value (PPV), therefore, describes the
ated pneumonia is 1% per day of mechanical proportion of cases among all persons with a
ventilation). positive test. Negative predictive value (NPV) is
defined as persons for whom the test was
Epidemiology also addresses issues and
negative and who actually lack the disease.
sources of error, many of which are crucial to
Logically, when a screening test is performed,
consider in light of the earlier discussion of
there are four outcomes. The person has disease
hypothesis testing. The accuracy of an item, test,
and the test was positive (eg, true-positive/TP).
or study simply describes the absence of error. Of
The persons has disease and the test was
course, error can occur as a random event and
negative (eg, false-negative/FN). The person
the inverse of random error is defined as
lacks disease and the test was negative (eg,
precision. The more precise something is the less
true-negative/TN). The person lacks disease but
prone it is to random error. Beyond being
the test was positive (eg, false-negative/FN).
random, error can be systematic. Systematic error
Mathematically, Sens ¼ TP / (TP þ FN) and
is referred to as bias. There are multiple forms of Spec ¼ TN / (TN þ FP); PPV ¼ TP / (TP þ FP)
bias including recall bias, selection bias, infor- whereas NPV ¼ TN / (TN þ FN). The overall
mation bias, and lead-time bias. Bias often arises prevalence of a disease in a population reflects
because of issues in study design and in all the patients who actually have disease in the
sampling. A well-done study acknowledges population, for example, TP þ FN / (TP þ FN
potential sources of bias and attempts to describe þ TN þ FP).
their potential impact so that the conclusions Usually there is a tradeoff between Sen and
reflect the adverse effects of bias. Spec. One chooses to emphasize one characteris-
Clinicians confront daily issues of screening tic over the other based on the weight that is
for disease. A crucial aspect of our profession assigned to either missing disease (eg, trying to
requires sorting the healthy from the unhealthy. minimize the FN rate) as opposed to incorrectly
We try to determine whether a specific charac- classifying persons as diseased when they are
teristic (disease) is present or absent. We accom- healthy (eg, minimizing the FP rate). This is a
plish this by using tests and interventions that matter of public policy and not a pure medical or
have limitations and are never perfectly accurate. scientific issue. The Sens and Spec are functions
Some subjects who may lack disease may be of the screening test in question. One improves
incorrectly classified as being ill, whereas those the Sens and Spec by improving accuracy of the
who are in fact ill may be falsely categorized as test. PPV and NPV are impacted not only by the
healthy. Epidemiology has developed a specific attributes of the test but also by the prevalence of

the disease in the population. If the prevalence is fore, will expect a basic mastery of several
low, no matter how perfect the test is, the PPV straightforward topics.
will be limited. If the prevalence of disease
increases, the PPV will rise. Relationship Disclosed
The tradeoff between Sens and Spec can be
shown graphically on a receiver operating The author has disclosed the following
characteristic (ROC) curve. By plotting Sens on relationships: Consultant fee, speaker bureau,
the y-axis and 1-Spec on the x-axis the relation- advisory committee, etc: Relevant to stats: None.
ship between the two can be plotted. Different Relevant to fungus: Speaker and consultant for
tests can also be compared in this fashion. The Pfizer and Astellas. The ACCP Education Com-
mittee has reviewed these relationships and
more accurate the test is the greater the area
resolved any potential conflict of interest.
under the ROC. The nearer the curve approaches
the upper left corner, the more accurate the test.
Often ROC curves are shown with a straight line
Selected References
running from the lower left corner to the upper
Fletcher RH, Fletcher SW. Clinical Epidemiology: The
right corner. This plot indicates a test that would
Essentials. 4th ed. New York, NY: Lippincott Williams
perform no better than chance.
& Wilkins; 2005.
Conclusions Gordis L. Epidemiology. 4th ed. New York, NY:

Elsevier; 2008.
Basic concepts of hypothesis testing and Merril RM. Introduction to Epidemiology. 5th ed. New
epidemiology confront the clinician in his/her York, NY: Jones & Publishers; Bartlett 2009.
everyday practice. Although they have their own Schoenbach VJ, Rosamond WD. Understanding the
separate vocabulary, understanding the princi- Fundamentals of Epidemiology: An Evolving Text.
ples underlying these topics are crucial for 2000; http://www.epidemiolog.net/evolving/
improving patient outcomes. The boards, there- TableOfContents.htm. Accessed February 3, 2012.
220 Chapter 15. Epidemiology and Statistics for the Boards (Shorr)
Chapter 16. Fungal Infections in Pulmonary Medicine
Objectives: addition, clinicians must note that immunosup-

Review the epidemiology of and risk factors for mold pressed individuals face a heightened risk for
and yeast infections. disease due to either type of pathogen. Although
Illustrate the clinical syndromes associated with different
mold and yeast share many similarities, these
mold pathogens.
Describe newer diagnostic approaches for aspergillosis organisms result in distinct clinical syndromes.
and candidemia. The range of potential mold infections extends
Review new treatment options and guidelines for yeast beyond Aspergillus spp. Furthermore, mold in-
and mold infections.
fections predominantly affect the lungs but can
cause disease in other organs. Yeast, however,
Key words: Aspergillus; Candida; fungus; mold; yeast
rarely cause pneumonia and predominantly
Synopsis:
manifests as a BSI in the critically ill. For all
types of fungal infections the diagnosis remains
Fungal infections comprise processes including both mold
and yeast. Although Aspergillus accounts for the major
challenging. Newer approaches are currently in
concern with respect to mold, other organisms cause development but all present diagnostic para-
important human disease. Specifically, mucormycosis, his- digms and have limitations. Similarly, novel
toplasmosis, blastomycosis, and coccidioidomycosis repre-
agents have been approved for use in fungal
sent examples of mold that cause a range of potential
illnesses. The clinical manifestations of mold infection vary infections. Nonetheless, little evidence exists to
based on the species involved and the host’s immune status. guide the clinician when choosing between
Aspergillus and mucormycosis may be difficult to distin- agents. Readers should be familiar with recent
guish clinically but mucromycosis remains much less
common. Diagnostically, all mold are challenging and the
guidelines promulgated by professional societies
role for invasive techniques is controversial. Historically, guiding the approach to fungal infections.
amphotericin served as the primary therapeutic agent. Now
alternative options exist. However, the specific preferred Mold
treatment varies based on the particular mold in question. In
terms of yeast, these pathogens mainly result in blood-
stream infection (BSI) and sepsis. In the ICU, BSIs due to Aspergillus
yeast often complicate the use of central venous catheters.
Many other variables can predispose to candidal BSIs and
Aspergillus causes a range of illness including
include prior exposure to broad spectrum antibiotics,
corticosteroids, and/or total parentral nutrition. Candida both hypersensitivity reactions and invasive
albicans continue to be the most common specific yeast pulmonary and CNS disease. Although more
species encountered. Other species, however, are increasing than 200 species of Aspergillus have been de-
in frequency, and several of these are not presumptively
susceptible to fluconazole. For both yeast and mold, recent
scribed, disease generally arises due to one of
research has focused on novel diagnostic strategies using four potential organisms: A fumigatus, A flavus, A
serum assays. These, however, continue to have limitations. niger, and A terrus.1 Unlike mucormycosis,
Finally, there are new guidelines from professional societies Aspergillus branches at a 458 angle rather than a
addressing infections caused by yeast and mold.
908 angle. In general, colonization of the airway
precedes clinical infection. In the healthy host
with both intact local and systemic immune
Introduction system function, Aspergillus exposure often leads
to no sequelae. Clinically, Aspergillus results in
Pulmonologists routinely treat patients at risk for one of four distinct syndromes: allergic broncho-
infections due to both mold and yeast. Infection pulmonary aspergillosis (ABPA), invasive pul-
with either lead to severe disease, and crude monary aspergillosis (IPA), cavitary lung disease,
mortality rates for such processes exceed 30%. In and chronic necrotizing aspergillosis (CNA).1

This review will specifically focus on the first two prednisone.4 There is limited information regard-
entities. ing the utility of antileukotrine agents. The role for
ABPA is unique in that it reflects a hypersen- antifungal agents remains unclear. One random-
sitivity reaction to airway colonization with ized trial demonstrated that daily itraconazole
Aspergillus. The hypersensitivity features reflect improved outcomes and functioned well as a
both type I and type III responses.2 The patho- steroid-sparing agent.5
physiology of this disease is poorly understood, With respect to IPA, the true incidence of this
but it appears that enzymes released from disease is unclear but may be increasing. For
immune cells, along with toxin from the mold, example, Lehrnbecher and coworkers6 in exam-
prevent the clearance of Aspergillus from the ining autopsy data noted an increase in preva-
airways. A key first step in the disease’s lence of all invasive mycoses and Aspergillus as
progression is colonization in abnormal airways. the causative organism increased from 17% to
Populations at risk for ABPA therefore mainly 60% during the same time period. This evolution
comprise persons with asthma and cystic fibro- in epidemiology may reflect broader use of more
sis.2 ABPA should be included in the differential aggressive forms of immunosuppression. One
diagnosis of difficult-to-control asthma, and should note that not all forms of immunosup-
further manifests as recurrent exacerbations of pression confer a similar risk for IPA. Both the
asthmalike symptoms. In addition to causing extent and duration of neutropenia after chemo-
respiratory distress, ABPA results in repeated therapy continue to represent the most signifi-
airway damage that does not necessarily abate cant risk factors for IPA.7,8 Hematopoietic stem-
during quiescent periods. Epidemiologically, the cell transplant similarly increases the potential
true prevalence of ABPA is unknown. for IPA. Graft-versus-host disease has also been
The diagnosis of ABPA rests on a combina- linked to invasive mold infections.7,8 Cytomega-
tion of clinical, laboratory, and radiographic lovirus disease after either liquid or solid organ
criteria. Imaging studies may reveal alveolar transplant amplifies the potential for IPA.
infiltrates and classically these wax and wane.3 A recent systematic review illustrates the
Evidence of airway wall thickening and bronchi- overall burden of IPA in the setting of organ
ectasis is also often present. Beyond airway transplantation and underscores the risk for this
hyperreactivity and clinical asthma, patients tend disease relative to the extent of immunosuppres-
to have peripheral eosinophilia.2,3 The total IgE sion. IPA occurred most often in those patients
level is elevated and generally exceeds 1,000 ng/ undergoing lung transplantation and rarely after
mL. Clinical criteria for the diagnosis of ABPA kidney transplantation.9 Approximately 6% of
also require the presence of precipitating anti- hematopoietic stem-cell transplants were com-
bodies against Aspergillus, a positive skin test plicated by IPA.9 Persons receiving kidney
against Aspergillus, or a positive IgE RAST for transplants face a substantially lower risk for
Aspergillus.2,3 Total IgE levels correlate well with IPA (0.7%).9 Illustrating the mortality penalty of
disease activity and increases in IgE may herald a IPA, nearly 12% of all deaths after transplant
decline in disease stability. were attributed to IPA.
Corticosteroids remain the cornerstone of Clinically IPA can present in multiple fash-
therapy. Serial measurement of IgE along with ions, but the lungs represent the organ most
spirometry and chest imaging are crucial to affected. In select cases, IPA leads to CNS
titrating treatment.2,3 The key goals of treatment disease. Common presenting symptoms include
are to prevent exacerbations and to control them fever, cough, and dyspnea, which are non-
when they occur. In certain cases, inhaled corti- specific.7,8 Because Aspergillus can be angioinva-
costeroids may be used to minimize the exposure sive, occasionally patients present with
and side effects of oral corticosteroid therapy. syndromes that mimic acute pulmonary embo-
Generally the corticosteroid dose is tapered lism. Therefore, IPA can lead to hemopytsis and
slowly for 6 to 12 weeks. Current treatment pleuritic chest pain. In subjects with advanced
guidelines from the American Thoracic Society HIV disease or who have undergone lung
recommend an initial dose of 0.5 mg/kg/d of transplant, IPA can result in a tracheobronchitis.
222 Chapter 16. Fungal Infections in Pulmonary Medicine (Shorr)

In individuals with a recent lung transplant, this for IPA are coagulopathic and/or thrombocyto-
tracheobronchitis can lead to strictures at the site penic. One strategy to improve the value of
of graft anastomosis.10 bronchoscopy is to measure GM levels on BAL
The diagnosis of IPA remains exceedingly fluid.17 This is a current focus of study and not
difficult, particularly as 30% of patients may be widely applied in clinical practice.
initially asymptomatic. Similarly, IPA can lead to The past decade has witnessed a major
a range of findings on chest imaging. Cavitation change in treatment approaches for IPA. Current
occurs late and the absence of this does not options include: amphotericin B deoxycholate (D-
obviate a diagnosis of IPA.11,12 IPA can also result AMB) or its less toxic lipid formulations (L-
in nodular infiltrates. The air-crescent sign reflects AMB), azoles, and echinocandins. Rarely, surgical
the contraction of infarcted tissue surrounding a resection of disease is needed. Guidelines indi-
site of infection. An area of low attenuation near cate that voriconazole represents the primary
the primary lesion is described as the halo sign choice for probable or definite IPA.4,18 This agent
and, if seen, is generally noted early. Both the halo is a broad-spectrum triazole that comes with both
and air-crescent sign tend to be specific for IV and oral formulations. The largest trial of this
IPA.11,12 Because IPA is angioinvasive and can agent in IPA randomized patients in an unblind-
mimic pulmonary embolism, IPA can also man- ed fashion to either voriconazole or D-AMB.
ifest as peripheral, wedge-shaped opacities. Response rates were significantly higher in
To facilitate the diagnosis of IPA, several persons treated with voirconazole.19 Voriconazole
approaches exist. Because colonization with is associated with the possibility of important
Aspergillus precedes subsequent infection in side effects relative to visual disturbances and
between 16% and 80% of at-risk populations, hallucinations.19 It also is metabolized by the
presumptive treatment is often suggested. Alter- liver and has many drug-to-drug interactions.
natively, serologic testing may play a broader Intensivists must note that the IV form of the
role in the future. Galactomannan (GM) is a molecule should not be given to persons with
component of the mold cell wall and can be impaired renal function. The carrier of the drug is
directly measured as can 1,3 b-D-glucan. Initial diluted and can accumulate if the glomerular
reports indicated that these assays may be filtration rate is less than 35 mL/min. L-AMB
helpful in excluding the diagnosis of IPA. represents an alternative option and is preferred
Unfortunately, however, these tests are not to D-AMB because of its lower toxicity profile.
routinely available or are confounded by other Head-to-head studies suggest similar general
patient factors. A meta-analysis of GM testing outcomes between L-AMB and D-AMB, with
indicated that the assay performed moderately tolerability being the only main clinical distinc-
well (approximate sensitivity and specificity tion.4,18 Posaconazole is an additional extended
80%) but varied widely based on the cutoff used spectrum triazole available in the Europe for the
for defining a positive test.13 The utility of the treatment of refractory IPA.20 Finally, echinocan-
GM assays may be less in patients receiving dins can be given for IPA, but the data supporting
antifungal prophylaxis.14,15 their role are quite limited.4,18 Generally these
Bronchoscopy is routinely performed in cases agents are given as last-line, salvage alternatives.
of suspected IPA and early use of bronchoscopy Although combination therapy with multiple
improves outcomes in immunosuppressed pa- agents (eg, voriconazole and an echinocandins)
tients with pulmonary infiltrates.16 Despite its appears theoretically attractive, a recent prospec-
regular application, bronchoscopy has several tive trial suggested that this paradigm did not
limitations. Sampling error represents one con- improve cure rates.21
cern because Aspergillus can have only patchy
involvement in the lung. Thus, historically, BAL Other Mold Species
has a yield of only 50%, even in cases of known
or probable IPA. Transbronchial biopsy may A number of other mold species cause human
enhance the value of bronchoscopy but has disease. Mucormycosis represents a distinct
substantial risks given that many patients at risk group of infections caused by organisms in the

Zygomycetes class. It is a ubiquitous saprophytic that has failed to respond to multiple courses of
fungi naturally occurring in soil or decaying antibiotics. Infiltrates on chest imaging can be
matter. Generally, infection occurs after inhalation lobar or nodular. In select instances blastomyco-
of airborne spores. This mold can cause aggressive sis can present with fibrocavitary disease. Blas-
infections along the sinopulmonary tract, and at tomycosis routinely remains isolated to the
times is angioinvasive. Clinically mucormycosis respiratory system unless advanced HIV disease
causes syndromes very similar to those related to is present. Blastomycosis can also cause disease
IPA.22 Risk factors for mucormycosis are also in other mammals. As with histoplasmosis,
similar to those associated with IPA. On added itraconazole is the primary treatment.
concern, however, is the importance of poorly Coccidioidomycosis is yet another soil fungi
controlled diabetes as a risk for this disease. that causes human illness and has a distinct
Unlike Aspergillus, the septated hyphae of mucor- geographic distribution (southwestern United
mycosis branch at 908 rather than 458. Further- States). Most patients are asymptomatic after
more, this pathogen does not respond to treatment acute infection. In some persons an acute pneu-
with voriconazole. Thus amphotericin com- monia syndrome evolves.25 In many ways this
pounds remain the backbone of therapy. Often resembles the typical presentation for pneumonia.
surgery is required for local disease control in the Unlike traditional pneumonia, however, coccidi-
head and neck. There are emerging data regarding oidomycosis can cause hilar adenopathy and
a possible role for posaconazole.4 eosinophilia. Erythema nodosum can also arise.
Histoplasmosis is a soil fungus endemic to Thus, acute coccidioidomycosis may be confused
select parts of the United States. The clinical for sarcoidosis. Serologic tests are often necessary
manifestations of histoplasmosis infection de- to confirm a diagnosis of coccidioidomycosis.
pend on several variables: the extent of the Beyond acute pneumonic processes, this organism
exposure, the host’s underlying immune system, can also manifest as nodules and occasionally
and whether the underlying lung architecture is cavitary disease. In the severely immunosup-
normal or abnormal.4 Histoplasmosis can result pressed patient meningitis can result from coccid-
in a severe acute pneumonia and acute lung ioidomycosis. In immunocompetent subjects there
injury. Both broncholithiasis and fibrosis media- is usually no role for treatment.4 In other situations
stiniits can ensue from histoplasmosis. Histoplas- fluconazole and amphotericn are used. For men-
mosis most often causes pulmonary nodules. ingitis, treatment must continue indefinitely.4
These nodules can be singular or multiple and
are not always calcified. Occasionally they can Candidemia
appear as PET-positive and, thus, are biop-
sied.23,24 In nearly all cases, whatever the presen- Candida spp are rarely a cause of lung disease.
tation, patients are asymptomatic and do not However, this organism remains associated with
require specific therapy. For acute respiratory substantial morbidity and mortality in the ICU as
syndromes the need for and type of treatment is a BSI pathogen. In contrast to the scenario
often determined based on disease severity and surrounding mold, the epidemiology of BSIs
the patient’s immune status. For moderate dis- due to Candida is more clearly understood.,
ease, itraconazole is recommended.18 For more Candidal BSIs have a prevalence that is 10 to 15
severe disease, amphotericin serves as the first times greater relative to IPA. Candida therefore
choice agent. represents the most common invasive fungal
Blastomycosis has a more isolated geography organism. Recent surveillance data indicate that
than histoplasmosis and is generally confined to Candida now accounts for approximately 12% of
the central and southeastern United States. all hospital-acquired BSIs.26 More recently, rates
Microscopically this is a very broad-based mold. of BSI due to Candida have stabilized or declined.
Manifestations of blastomycosis comprise acute, Information arising from the National Nosoco-
subacute, and chronic syndromes.4 Most com- mial Surveillance System noted that the rate of
monly patients with blastomycosis seek medical BSIs specifically due to C albicans in critically ill
attention for a moderate pneumonitis syndrome adults with central venous catheters (CVCs) fell

from approximately 8.1 cases per 1,000 CVC days Common risk factors predisposing to candidemia
in 1989 to about 2.2 cases per 1,000 CVC days in include candidal colonization, prior exposure to
1989.27 Strikingly, rates of non-albicans candide- antibiotics, renal failure, presence of a CVC, and
mia in aggregate remained stable during this need for total parenteral nutrition.35–38 Multiple
period, although proportion of infections due to observational analyses using differing approach-
C glabrata BSI increased significantly.27 Candida is es have all confirmed repeatedly the significance
now increasingly reported as a cause of sepsis. In of these factors. The impact of total parenteral
an evaluation of the microbiology of sepsis nutrition is independent of the need for a CVC to
during a 20-year period, Martin and colleagues28 administer it. Corticosteroid exposure and recent
reported a tripling in the incidence of fungal abdominal surgery, along with immunosuppres-
sepsis. Similarly, a survey of hospital discharge sion further predispose to candidal BSI. Patho-
data between 2000 and 2005 reported a 50% physiologically, many process of care variables
increase in the incidence of hospitalizations result in colonization of the skin with Candida.
involving candidemia.29 After that, some factor leads to compromise in
Crude mortality rates from candidemia re- the host that allows the yeast to invade. This
main high. Nearly 35% of all persons with could be through colonization of a CVC or
candidal BSI die while hospitalized. The attrib- through injury to the bowel that permits yeast
utable mortality of this process is harder to parse (which reside in the gut) to transmigrate into the
as some subjects die with this infection rather blood or other traditionally sterile compartments.
than of it. The economic burdens of candidemia Many of the risk factors related to candide-
are clearer to understand. Nearly every analysis mia are prevalent in the ICU. However, relatively
of the costs of candidemia calculates that this few patients actually are diagnosed with BSIs
condition results in excess health-care costs of due to yeast. Clinical risk stratification schemes
between $15,000 and $40,000 per case.30,31 and risk scoring approaches have proven un-
Physicians must appreciate that the specific helpful.39 They often lack sensitivity and speci-
species of yeast implicated in candidemia are ficity. Blood culture techniques also are not
shifting. The percentage of infections due to C perfectly accurate. Because of this concern, newer
albicans has dropped. Although the most fre- diagnostic modalities have become a focus of
quently isolated pathogen, C albicans accounts for attention. Akin to the situation with GM for
only half of all BSIs due to yeast.32 In 1990, 80% of Aspergillus, b-D-glucan has emerged as a promis-
all fungal BSIs were due to C albicans.32 In a large ing target to facilitate rapid diagnosis.40 Al-
3.5-year multicenter prospective observational though this assay appears to have good
study of candidemia within the United States, sensitivity and specificity, few validation studies
Nguyen and colleagues33 demonstrated that have been completed in critically ill patients.
nearly 50% of all candidal isolates were non- Molecular testing for Candida DNA is in early
albicans, with C glabrata (6.3%) and C kruzei development.
(4.3%) representing more than 10% of all cul-
tures. The prevalence of these non-albicans Prophylaxis and Presumptive Therapy
organisms is not restricted to the ICU. Bassetti
and coworkers34 examined candidal BSIs at two Because of the efficacy of prophylaxis in
large US hospitals. They specifically focused on immunocompromised populations, interest ex-
the microbiology of these infections and ob- ists in the potential for a similar paradigm in
served no difference in the proportion of non- critically ill surgical patients. Several studies
albicans isolates recovered from ward patients have investigated this option and none demon-
and critically ill patients.34 strate that fluconazole prophylaxis lowers rates
of BSI with yeast.41 It is important to acknowl-
Risk Factors edge that indiscriminate use of fluconazole also
runs the risk of promoting the emergence of non-
Investigators have identified multiple risk albicans species. This fact further underscores
factors that can facilitate infection with yeast. why physicians must be cautious in treating

evident instances of candidal colonization (rather As noted earlier, voriconazole serves as a first
than true infection), such as Candida, recovered line agent for IPA. The utility of voriconazole in
either in urine or sputum cultures of immuno- candidemia is less clear. One randomized trial
competent hosts. revealed that voriconazole performed as well as
Presumptive therapy describes a paradigm AMB and provided an option for oral step-down in
where treatment is begun in an at-risk population patients with C krusei and C glabrata BSIs.47 For
pending cultures. The role for this in Candida BSI many patients in ICU, oral absorption of drugs is
rests on the observation that delay in initiation of unpredictable, therefore it is uncertain whether
treatment for fungemia independently increases having an oral step-down alternative represents an
the risk for mortality. Several retrospective cohort advantage. Also, IV voriconazole presents dosing
studies document that, as with bacterial patho- issues in subjects with impaired renal function.
gens, a delay in beginning appropriate antiinfec- Three echinocandins are commercially
tive treatment independently heightens the available: caspofungin, micafungin, and anidu-
potential for in-hospital mortality. Morrell and lafungin. These agents have many similar
colleagues,42 for example, assessed the effect of characteristics and target the cell wall. Because
treatment delay on mortality among 157 consec- this class of drugs provides coverage against
utive patients with Candida BSI. A delay of as albicans and non-albicans isolates they have
little as 12 h from when the eventually positive become part of routine use. In addition, these
blood cultures were drawn more than doubled molecules have few drug-to-drug interactions
the risk for death.42 and few side effects. Caspofungin became
available first and must be dose reduced when
Treatment given to patients with reduced liver function.48
Neither anidulafungin nor micafungin requires
Management of fungemia encompasses more dose reduction in persons with mild-to-moder-
than selection of an antiinfective. Removal of the ate liver disease.
CVC represents a crucial first step. The CVC not With respect to clinical trials, the echinocan-
only serves as a potential portal of entry but also dins have been compared variously against
as a nidus for ongoing seeding of the blood. The AMB, fluconazole, and, in one instance, head-
biofilm coating a CVC presents a rather protected to-head. Most of these trials were not designed
environment for the yeast adhering to it and few nor powered to necessarily show superiority. The
antifungal agents penetrate biofilm. Multiple only analysis revealing a difference in clinical
analyses indicated that failure to remove all cure compared anidulafungin to fluconazole. In
CVCs in persons with fungemia is an indepen- that trial by Reboli et al.49 statistically signifi-
dent predictor of mortality.43,44 cantly greater cure rates were noted with
In terms of available agents, clinicians now anidulafungin. This, however, did not lead to
have multiple options. Generally, one can select changes in overall mortality. It remains unclear
from three classes of antifungals—amphotericins, whether one can generalize the findings from this
azoles, and echinocandins. Historically, ampho- trial to other echinocandins. Furthermore, one
tericin served as the standard of care. However, a need not be familiar with the intricacies of the
randomized trial more than 15 years ago docu- comparative trials for the purposes of the board
mented that in non-neutropenic subjects, flucon- examination. However, a careful reading of all
azole performed as well as amphotericin.45 This the studies in this area shows that most trials
trial and others may not be generalizable to the enrolled less severely ill patients and that the
modern era in that the prevalence of Candida spp proportion of non-albicans pathogens in these
resistant (or presumptively resistant) to flucona- reports often failed to exceed 30%.46
zole was low. Despite being very well tolerated, Both the Infectious Diseases Society of Amer-
one difficulty with fluconazole remains selection ica and the American Thoracic Society have
of an appropriate dose. Newer guidelines sug- promulgated guidelines for the management of
gest that higher doses of this agent are required candidemia.45,46 The documents are strikingly
for effective therapy.45,46 similar. First, they recommend removal of all

CVCs. Second, they suggest that all patients have 2. Knutsen AP, Slavin RG. Allergic bronchopulmo-
an ophthalmologic evaluation for disseminated nary aspergillosis in asthma and cystic fibrosis.
disease. Third, whatever the therapy, it should be Clin Dev Immunol. 2011;2011:843763.
continued for at least 2 weeks after the last 3. Patterson K, Strek ME. Allergic bronchopulmonary
positive blood culture. Finally, any of the aspergillosis. Proc Am Thorac Soc. 2010;7(3):237–
approved agents discussed previously can func- 244.
tion as initial therapy for candidemia. However, 4. Limper AH, Knox KS, Sarosi GA, et al. An official
if the patient is critically ill or if the prevalence of American Thoracic Society statement: treatment
non-albicans species is .10%, then one should of fungal infections in adult pulmonary and
consider beginning treatment with an echinocan- critical care patients. Am J Respir Crit Care Med.
dins. If patients have been exposed to an azole 2011;183(1):96–128.
previously, this class of drugs ought be avoided. 5. Stevens DA, Schwartz HJ, Lee JY, et al. A
randomized trial of itraconazole in allergic bron-
chopulmonary aspergillosis. N Engl J Med.
Conclusions
2000;342(11):756–762.
6. Lehrnbecher T, Frank C, Engels K, Kriener S, Groll
Mold and yeast are rare but important
AH, Schwabe D. Trends in the postmortem
pathogens in pulmonary and critical care medi-
epidemiology of invasive fungal infections at a
cine. Predominantly, Aspergillus and Candida
university hospital. J Infect. 2010;61(3):259–265.
represent the main concern. However, mold
7. Chai LY, Hsu LY. Recent advances in invasive
and yeast can cause a range of illnesses that are
pulmonary aspergillosis. Curr Opin Pulm Med.
not always confined to the lung. Assuring good
2011;17(3):160–166.
patient outcomes requires maintaining a high
8. Glöckner A, Karthaus M. Current aspects of
index of suspicion for these organisms, particu-
invasive candidiasis and aspergillosis in adult
larly in immunocompromised subjects. All diag-
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there are newer treatment agents that are better 9. Paterson DL, Singh N. Invasive aspergillosis in
tolerated that older options. transplant recipients. Medicine (Baltimore).
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Acknowledgment 10. Nathan SD, Shorr AF, Schmidt ME, Burton NA.
Aspergillus and endobronchial abnormalities in
Parts of this article are adapted from Zilber- lung transplant recipients. Chest. 2000;118(2):403–
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Infect Dis Clin North Am. 2009;23(3):625-642. 11. Georgiadou SP, Sipsas NV, Marom EM, Kontoyian-
nis DP. The diagnostic value of halo and reversed
Relationship Disclosed halo signs for invasive mold infections in compro-
mised hosts. Clin Infect Dis. 2011;52(9):1144–1155.
The author has disclosed the following rela- 12. Greene R. The radiological spectrum of pulmo-
tionships: Consultant fee, speaker bureau, adviso- nary aspergillosis. Med Mycol. 2005;43(Suppl
ry committee, etc, relevant to stats: None. Relevant 1):S147–S154.
to fungus: Speaker and consultant for Pfizer and 13. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive
Astellas. The ACCP Education Committee has aspergillosis using a galactomannan assay: a meta-
reviewed these relationships and resolved any analysis. Clin Infect Dis. 2006;42(10):1417–1427.
potential conflict of interest. 14. Herbrecht R, Letscher-Bru V, Oprea C, et al.
Aspergillus galactomannan detection in the diag-
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Notes

Chapter 17. Drug-Induced Lung Diseases
Objectives: drugs that clearly caused pulmonary toxicity. A

Appreciate the diverse clinical syndromes of drug- decade later, Cooper and colleagues2 expanded
induced pulmonary diseases. the list to 37 drugs. Since then, .430 drugs have
Understand the general approach to the patient with
been implicated in causing a wide array of
suspected drug toxicity.
Review the common abnormalities associated with pulmonary manifestations that involve virtually
specific chemotherapeutic agents. all components of the respiratory system, includ-
Comprehend the typical manifestations of pulmonary ing the airways, parenchyma, pleura, pulmonary
toxicity due to nonchemotherapeutic agents.
circulation, mediastinum, vocal cords, and respi-
ratory muscles (Table 1).3–6 The number of drugs
Key words: acute lung injury; drugs; hypersensitivity
that cause lung disease will undoubtedly contin-
pneumonitis; pulmonary fibrosis
ue to grow as new agents and biological response
Synopsis: modifiers are developed.
Although the clinical syndromes associated
Drug-induced lung diseases have challenged clinicians
since the dawn of modern medicine, in part because there with certain drugs are well defined, the full scope
are so many drugs implicated (.430) and in part because it of the epidemiology of drug-induced lung dis-
is a diagnosis of exclusion. A patient with a drug-induced ease is not firmly established. This is partly due to
lung disease often presents with nonspecific respiratory
symptoms, such as cough and dyspnea, and abnormal chest the fact that the diagnosis is one of exclusion (eg,
imaging. A thorough drug history is crucial in identifying infection and tumor). Notably, there are no
the potential cause of pulmonary toxicity. With few pathognomonic clinical, laboratory, physiologic,
exceptions (eg, bleomycin, amiodarone), the molecular
radiographic, or histologic findings. Also, most
mechanisms underlying drug-induced lung diseases are
largely unknown but appear distinct depending on the drug reactions are idiosyncratic without any clear
and host genetics affecting susceptibility. In this chapter, we relationship to dose or time of exposure. Indeed,
focus on four broad areas: (1) appreciating the diverse some drugs can cause toxicity years after expo-
clinical syndromes of drug-induced pulmonary diseases; (2)
understanding the general approach to the patient with sure (eg, cyclophosphamide). With few excep-
suspected drug toxicity; (3) reviewing the common abnor- tions, the risk factors for drug-induced lung
malities associated with specific chemotherapeutic agents; diseases are poorly defined. Moreover, confound-
and (4) comprehending the typical manifestations of
ing variables, such as the use of other drugs,
pulmonary toxicity due to nonchemotherapeutic agents.
Understanding the clinical manifestations of drug-induced oxygen, or radiation therapy, each of which can
lung diseases should facilitate early diagnosis and effective cause pulmonary injury or have interactive effects
management of these patients as well as help ascertain the (eg, bleomycin and oxygen), often hamper the
origin of other more common pulmonary disorders, such as
idiopathic pulmonary fibrosis, noncardiogenic pulmonary
diagnosis. Rechallenge with the implicated drug
edema, and hypersensitivity pneumonitis. is rarely performed because effective alternative
agents are nearly always available. Thus, clini-
cians evaluating patients with possible drug-
induced pulmonary symptoms must obtain a
thorough drug exposure history, maintain a high
Drug-induced lung diseases have challenged index of suspicion, and utilize a systematic
clinicians since the dawn of modern medicine. diagnostic approach that is reviewed below.
In 1880, William Osler described a patient with The management of patients with drug-
pulmonary edema associated with opiate expo- induced pulmonary side effects is largely sup-
sure and suggested that there was a pathophys- portive. Typically, therapy with the implicated
iologic relationship. In 1972, Edward Rosenow1 drug is withdrawn, and a trial of corticosteroids
extensively reviewed this topic and identified 20 is considered, particularly in the setting of

Table 1—Major Clinical Syndromes of Drug-Induced Table 2—Some Drugs That Cause Chronic Pneumonitis/
Pulmonary Disease Fibrosis
1. Chronic pneumonitis/fibrosisa Chemotherapeutic Agents Nonchemotherapeutic Agents

2. Hypersensitivity-type lung diseasea
3. Acute noncardiogenic pulmonary edemaa Azathioprine Amiodaronea
4. Bronchiolitis obliterans with organizing pneumonia BCNU Anti-TNF-a-targeted
5. Alveolar hypoventilaton Bleomycina therapy
6. Bronchospasm Busulfan Cocaine
7. Cough Chlorambucil Gold
8. Concentric bronchiolitis obliterans Cyclophospamide Heroin
9. Pleural effusions Fludarabine Methysergide
10. Venous thromboembolism Gemcitabine Nitrofurantoin
11. Pulmonary vasculitis 6-Mercaptopurine Penicillamine
12. Pulmonary hypertension Methotrexate Phenytoin
13. Drug-induced SLE Mitomycin C Sirolimus
14. Alveolar hemorrhage Taxanes (paclitaxel/ Statins
15. Pulmonary renal syndrome docetaxel) Sulfasalazine
16. Alveolar proteinosis Tyrosine kinase Tocainide
17. Mediastinal abnormalities (eg, adenopathy, lipomatosis, inhibitors (imatinib)
or mediastinitis)
18. Panlobular emphysema Reprinted with permission from ACCP Pulmonary Medicine
19. Pulmonary calcinosis Board Review. 25th ed. Northbrook, IL: American College of
20. Pseudosepsis syndrome Chest Physicians; 2009.
a
Most commonly implicated.
a
Most commonly implicated. radiograph and high-resolution chest CT (HRCT)
scan generally reveal reticular infiltrates begin-
ning in the basilar subpleural regions and
significant symptoms and/or gas-exchange ab-
progressing to diffuse disease.8 Pulmonary func-
normalities. The scientific basis for using corti-
tion tests (PFTs) typically show reduced lung
costeroids is largely supported solely by
anecdotal reports rather than well-designed volumes (eg, restrictive physiology), a reduced
controlled studies. diffusing capacity of the lung for carbon mon-
oxide (DLCO), and arterial hypoxemia at rest or
Major Clinical Syndromes of Drug- with exercise.
Induced Pulmonary Disease
Chronic Pneumonitis/Fibrosis Table 3—Some Drugs That Cause Hypersensitivity-Type
Lung Disease
A wide array of drugs cause chronic intersti-
Chemotherapeutic Agents Nonchemotherapeutic Agents
tial pneumonitis and/or fibrosis, making it the
most common manifestation of drug-induced Azathioprine Antibiotics (b-lactam
lung disease. Some of the agents implicated are Bleomycin and sulfa containing)a
Busulfan Anti-TNF-a-targeted
listed in Table 2. There is a small increase in Imatinib therapy
antidepressant use, especially tricyclic-related Methotrexatea Isoniazide
agents and selective seratonin receptor inhibi- Nitrogen mustards Nitrofurantoin
Procarbazine NSAIDs
tors, in patients with idiopathic pulmonary
Taxanes Penicillamine
fibrosis (IPF; odds ratio [OR: 1.52; 95% confi- Phenytoin
dence interval: 1.24 to 1.86]).7 These patients Statins
commonly present with insidious onset of cough
and dyspnea. Weight loss and clubbing may also
be present, raising the possibility of an underly- Chest Physicians; 2009.
a
ing malignancy or IPF, respectively. The chest Most commonly implicated.
232 Chapter 17. Drug-Induced Lung Diseases (Kamp)

Hypersensitivity-Type Lung Disease ops over a period of hours. A physical examina-
tion of the chest reveals inspiratory crackles,
Virtually any drug can cause a generalized while arterial blood gas levels show hypoxemia
hypersensitivity-type reaction with respiratory with a reduced arterial pressure of oxygen (PaO2)
symptoms associated with pulmonary infiltrates to fractional inspired O2 (FIO2) ratio (PaO2/ FIO2)
and eosinophilia (PIE). The agents commonly of ,300 with acute lung injury and ,200 with
implicated are listed in Table 3. Patients can ARDS. The chest radiograph generally demon-
present with Loeffler syndrome, consisting of an strates diffuse acinar and/or ground-glass infil-
acute onset over several days of cough, dyspnea, trates. The histopathology can be similar to
fever, rash, myalgias, peripheral eosinophilia, ARDS. Several mechanisms have been implicated
and fleeting infiltrates. Alternatively, patients in causing drug-induced noncardiogenic pulmo-
may present with subacute-chronic onset, over nary edema. First, some drugs increase the
several weeks to months, of low-grade fever, filtration coefficient of the respiratory membrane,
night sweats, nonproductive cough, and weight making it more permeable (eg, overdose of
loss. The chest radiographic findings can be narcotics/sedatives). Second, certain agents de-
similar to that seen with chronic eosinophilic press the CNS, resulting in neurogenic pulmo-
pneumonia or hypersensitivity pneumonitis. nary edema. Finally, drugs most commonly cause
Establishing a diagnosis may be challenging an idiosyncratic reaction, resulting in noncardio-
because not all findings, especially peripheral genic pulmonary edema within hours of absorp-
eosinophilia, are present in each patient. The tion. The prognosis varies depending on the
diagnosis is often secured by bronchoscopy with offending agent. For example, pulmonary edema
BAL and biopsy and, in some instances, after a associated with an overdose of salicylates is
prompt response to therapy with corticosteroids. potentially reversible with appropriate manage-
The prognosis is generally favorable with a ment, while patients with carmustine-induced
mortality rate of ,1%.
pulmonary edema generally have a poor prog-
nosis.
Acute Noncardiogenic Pulmonary Edema
Cryptogenic Organizing Pneumonia
Noncardiogenic pulmonary edema can occur
after exposure to a variety of drugs (Table 4).
A variety of drugs cause bronchiolitis oblit-
These patients generally present with acute
erans with organizing pneumonia (BOOP) or
dyspnea and a nonproductive cough that devel-
cryptogenic organizing pneumonia (COP) when
no identifiable cause is detected (Table 5). Thus,
Table 4—Some Drugs That Cause Acute Noncardiogenic
Pulmonary Edema
Table 5—Some Drugs That Cause Bronchiolitis Obliterans
Chemotherapeutic Agents Nonchemotherapeutic Agents With Organizing Pneumonia
Azathioprine Amiodarone Chemotherapeutic Agents Nonchemotherapeutic Agents

Cytosine arabinoside Aspirin and NSAID
Gemcitabine overdose Bleomycin Amiodarone
G-CSF Cocaine Cyclophosphamide Amphotericin B
IL-2 Opiate overdose (eg, heroin) Methotrexate Carbamazepine
Methotrexate Sedative/hypnotic drug Mitomycin C Cocaine
Mitomycin C overdose Nitrofurantoin
Nitrogen mustards Sulfasalazine Penicillamine
Retinoic Acid Tocolytic therapy (eg, Phenytoin
TNF terbutaline, ritodrine) Sirolimus
Vinblastine IFN-clb Sulfasalazine
(with mitomycin) Ticlodipine
Reprinted with permission from ACCP Pulmonary Medicine Reprinted with permission from ACCP Pulmonary Medicine
Board Review. 25th ed. Northbrook, IL: American College of Board Review. 25th ed. Northbrook, IL: American College of
Chest Physicians; 2009. Chest Physicians; 2009.

any patient with newly diagnosed COP requires Table 7—Some Drugs That Cause Bronchospasm
a careful review of their drug exposure before
Chemotherapeutic Agents Nonchemotherapeutic Agents
concluding that COP is cryptogenic. These
patients typically present with cough, dyspnea, IL-2 Aspirin/NSAIDs
crackles on physical examination, and patchy Methotrexate b-blockers
Vinblastine Contrast media
airspace infiltrates seen on the chest radiograph.
Vinca alkaloids Corticosteroids
PFTs reveal a mixed obstructive and restrictive plus mitomycin Dipyridamole
defect. Gold and penicillamine, the two best- Gold
Nitrofurantoin (acute)
characterized etiologic agents, are often used in
Opiates (cocaine, heroin)
the management of rheumatoid arthritis (RA), a Penicillamine
disease that can also cause COP. Thus, it may be Protamine
difficult to distinguish drug-induced COP from
the patient’s underlying collagen vascular disor- Board Review. 25th ed. Northbrook, IL: American College of
der. Management requires a high clinical suspi- Chest Physicians; 2009.
cion, lung biopsy, prompt withdrawal of therapy
with the implicated drug, and therapy with described in patients who have been exposed to
corticosteroids. The outcome is generally favor- neomycin, streptomycin, tobramycin, gentami-
able, as it is with idiopathic COP. cin, amikacin, kanamycin, and netilmicin.9 The
risk of aminoglycoside-induced neuromuscular
Alveolar Hypoventilation blockade is increased in the presence of a disease
or drug that promotes neuromuscular blockade,
Alveolar hypoventilation is caused by drugs rising aminoglycoside drug levels, hypomagne-
that induce respiratory depression or block semia, and hypocalcemia. The management of
respiratory muscle function. Patients with un- these disorders requires a high clinical suspicion
derlying pulmonary or neuromuscular disorders to identify the offending drug and withdrawal of
are particularly prone to the development of therapy with the agent to avoid further respira-
acute hypercarbic respiratory failure. Some of the tory failure.
agents implicated in causing neuromuscular
blockade or motor neuropathies/myopathies Bronchospasm
are listed in Table 6. Aminoglycoside-induced
neuromuscular blockade is a rare but potentially Drug-induced bronchospasm is caused by
life-threatening adverse effect that has been various agents (Table 7). Patients generally
present with wheezing, cough, and/or dyspnea.
Table 6—Some Drugs That Cause Alveolar Hypoventilation Spirometry typically shows airway obstruction.
Neuromuscular blockade
The mechanism of drug-induced bronchospasm
Aminoglycosides varies with the particular agent. In patients with
Cocaine asthma, unlike healthy individuals, b-adrenergic
Gamma-hydroxybutyrate (GHB)
Opiates (eg, heroin)
blockers induce bronchospasm within minutes
Polymixins by mechanisms involving the inhibition of
Sedative/hypnotic drugs adrenergic bronchodilator tone. Virtually any
Motor neuropathies or myopathies route of administration (eg, oral, IV, or ophthal-
Amiodarone
Captopril mic) can induce bronchospasm. Aspirin-induced
Corticosteroids bronchospasm is mediated by an enhanced 5-
Diuretics
lipoxygenase pathway, resulting in the produc-
Isoniazid
Phenytoin tion of bronchoconstricting cysteinyl-leukotri-
Procainamide enes, and to a lesser extent, by a reduction in
bronchodilating prostaglandins (eg, prostaglan-
Board Review. 25th ed. Northbrook, IL: American College of din E2). Dipyridamole causes bronchospasm by
Chest Physicians; 2009. augmenting the levels of adenosine, a broncho-

constricting agent. Gold and penicillamine cause reaction that is described below. Anticoagulants
irreversible airways obstruction due to concentric can induce an acute bloody effusion. Chronic
bronchiolitis obliterans. pleural effusion may occur after long-term
exposure to drugs that induce a delayed hyper-
Isolated Cough sensitivity-type response (eg, methotrexate or
procarbazine) or in association with the devel-
Cough, which is one of the most common opment of interstitial pulmonary inflammation/
manifestations of drug-induced lung disease, is a fibrosis (eg, busulfan and methotrexate). A
vagus nerve-mediated reflex caused by various variety of chemotherapeutic agents, including
chemical and mechanical stimuli virtually any- some of the newer antineoplastic agents, are
where within the upper and lower respiratory associated with an increased risk of pleural fluid
tracts. Cough often occurs in patients with drug- formation.14
induced bronchospasm or drug-induced intersti-
tial lung disease (ILD). However, angiotensin- Pulmonary Vascular Disease
converting enzyme (ACE) inhibitors induce an
isolated nonproductive cough without associated Drugs that affect the pulmonary vascular
bronchospasm or parenchymal lung disease in circulation by causing VTE, pulmonary hyper-
5% to 35% of patients receiving any type of ACE tension, vasculitis, or pulmonary venoocclusive
inhibitor.10 Cough resolution typically requires disease are listed in Table 9. Oral contraceptives
up to 4 weeks from cessation of the ACE and other estrogen-containing agents can induce
inhibitor. Although there are case reports11,12 VTE. The VTE risks are relatively small in
suggesting that angiotensin receptor blockers patients using second-generation and third-gen-
(ARB) can induce a cough, the frequency of eration oral contraceptives compared to nonusers
ARB-induced cough is approximately the same (15, 30, and 5 per 100,000 patients treated,
order of magnitude as that seen with controls.10 respectively).15 There is an important synergistic
interaction between hypercoagulable conditions
Pleural Effusions (eg, factor V Leiden mutation) and the risks of
VTE from hormonal replacement therapy.16
Although a number of drugs can cause a Thus, the risk from hormonal replacement in
pleural effusion (Table 8), the number is much the absence of other VTE risk factors appears too
less than those that involve the lung parenchy- small to recommend against using these agents.
ma.13 Pleural effusions occur with acute onset as Drug-induced pulmonary hypertension can
part of a hypersensitivity reaction after exposure occur after exposure to a variety of drugs by
to amiodarone, methotrexate, and nitrofurantoin mechanisms that are unclear. A case-control
as well as a systemic lupus erythematosus-like study17 showed that appetite suppressants (eg,
amphetamines, fenfluramine, and dexfenflur-
Table 8—Some Drugs That Cause Pleural Effusions
amine) are associated with an increased risk of
Chemotherapeutic Agents Nonchemotherapeutic Agents primary pulmonary hypertension (OR: 6.3) but a
higher risk if the drugs were used for .3 months
Bleomycin Amiodarone (OR: 20), albeit still with a fairly rare incidence of
Busulfan Anticoagulants
0.005%. Although fenfluramine and dexfenflur-
Etoposide Bromocriptine
Gemcitabine Dantrolene amine have been withdrawn from the market
Methotrexate Esophageal sclerosing agents worldwide, clinicians should remain vigilant for
Mitomycin Methysergide drug-induced pulmonary hypertension because
Procarbazine Nitrofurantoin
Taxanes an estimated 5 million adults in the United States
Tyrosine kinase inhibitors continue to use appetite suppressants. Oral
contraceptives and other estrogen-containing
Board Review. 25th ed. Northbrook, IL: American College of agents also have been associated with an
Chest Physicians; 2009. increased risk of pulmonary hypertension.

Table 9—Some Drugs That Cause Pulmonary Vascular Disease
Complication Chemotherapeutic Agents Nonchemotherapeutic Agents
Thromboembolic disease Estrogens/hormonal treatment

Phenytoin
Steroids
Pulmonary hypertension Mitomycin Aminorex (recalled)
IL-2 Amphetamines
Dexfenfluramine (recalled)
Fenfluramine (recalled)
L-tryptophan (recalled)
Oral contraceptives
Vasculitis Busulfan Cocaine/heroin
Nitrofurantoin
Zafirlukast/montelukast
Veno-occlusive disease Bleomycin Oral contraceptives
Busulfan
BCNU
Mitomycin
Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest
Physicians; 2009.
An inflammatory vasculitis has been noted in vasculitis, and (3) use in steroid naive patients.20
conjunction with a generalized hypersensitivity Pulmonary venoocclusive disease is a very rare
reaction in patients exposed to busulfan, nitro- adverse effect reported after exposure to various
furantoin, or illicit drugs such as cocaine and agents (Table 9).
heroin. However, it is uncertain whether the
vascular response represents a primary or a Miscellaneous Drug-Induced Pulmonary
secondary effect of drug exposure. Leukotriene Reactions
receptor antagonists (LTRA) such as zafirlukast
and montelukast rarely (1 case per 15,000 to There are a variety of less common drug-
20,000 patient-years treated) induce an idiosyn- induced adverse pulmonary effects (Table 10).
cratic syndrome similar to Churg Strauss vascu- Systemic lupus erythematosus (SLE) is associated
litis with peripheral eosinophilia, eosinophilic with the use of a wide variety of drugs, although
vasculitis, peripheral neuropathy, and cardiac five agents are involved in .90% of the cases
failure.18 Since most of the patients were receiv- (Table 10). More recently, anti-tumor necrosis
ing either high-dose inhaled or systemic cortico- factor (TNF)-a-targeted therapy (eg, etanercept,
steroids, a preexisting vasculitis may have infliximab, and adalimumab) has also been
accounted for their symptoms. However, a recent associated with drug-induced SLE reactions; 5%
review of the literature through 2007 identified to 12% of all cases of SLE are due to drugs. It is
62 cases from 40 publications, seven of whom unclear whether these agents cause or unmask a
were entirely steroid naive (eg, not receiving any latent case of SLE. Hydralazine-induced and
form of inhaled or oral steroids when symptoms isoniazid-induced SLE occurs more frequently
developed), suggesting that there may be a in patients who are slow acetylators of these
causal relationship.19 An accompanying editorial drugs. Hydralazine-induced SLE occurs in up to
reviewing this study as well as another case- 20% of patients receiving doses of 400 mg/d
control study involving 78 patients concluded but can develop in patients receiving low-dose
that Churg Strauss vasculitis can occur in therapy. Hydralazine can induce an ANCA-
association with exposure to LTRA in three associated vasculitis concomitant with a SLE
settings: (1) use for worsening asthma, (2) use reaction.21 Procainamide-induced SLE is time
resulting in clinical improvement leading to a related rather than dose related in that positivity
reduction in steroids and an unmasking of the for antinuclear antibodies (ANAs) develops in

Table 10—Miscellaneous Drug-Induced Pulmonary Reactions
Condition Implicated Drugs
Drug-induced SLE Hydralazine Procainamide

Isoniazide Penicillamine
Anti-TNF-a-targeted therapy Quinidine
Alveolar hemorrhage Abciximab Cocaine
Bevacizumab Amphotericin B
Alemtuzumab Mitomycin C
Amiodarone Nitrofurantoin
Anticoagulants Penicillamine
Alveolar proteinosis Busulfan
Churg-Strauss vasculitis Zafirlukast Montelukast
Mediastinal abnormalities Methotrexate Phenytoin
Lipomatosis Corticosteroids
Mediastinitis Esophageal sclerosing agents
Panlobular emphysema Methylphenidate
Pulmonary calcification Antacids High-dose vitamin D
Calcium
Pseudosepsis syndrome Chronic salicylate intoxication
Physicians; 2009.
approximately 50% of patients after 3 months of control subjects) should be suspected in patients
therapy and in nearly all patients by 1 year. presenting with hemoptysis, hypoxemic respira-
Notably, patients with drug-induced SLE, unlike tory failure, diffuse alveolar infiltrates, and pro-
other patients with SLE, are usually negative for gressive decline in hemoglobin levels within
double-stranded DNA ANA. Typically, pleurisy hours to 2 days after the first dose of abciximab.
and dyspnea, in conjunction with systemic Bevacizumab, a monoclonal antibody against
complaints of fever and arthralgias, develop in vascular endothelial growth factor that is used to
an insidious manner after use of the drug for treat a variety of cancers including lung and colon
several months or even years. Chest radiograph cancer, can result in fatal pulmonary hemor-
abnormalities include pleural effusions, atelecta- rhage.23
sis, diffuse interstitial infiltrates, and alveolar Mediastinal abnormalities can be a manifes-
infiltrates. The withdrawal of therapy with the
tation of an adverse drug effect (Table 10).
offending agent generally results in the prompt
Phenytoin can induce a pseudolymphoma syn-
resolution of symptoms within days, but occa-
drome associated with peripheral adenopathy
sionally corticosteroids are required for symp-
and, rarely, mediastinal adenopathy. Methotrex-
tomatic relief.
ate may cause transient hilar adenopathy during
Alveolar hemorrhage and hemoptysis can
a hypersensitivity-type response. Typically, the
occur after exposure to certain drugs (Table 10).
Drug-induced hemoptysis is most commonly due adenopathy regresses 1 to 2 weeks after drug
to pulmonary embolism with infarction. Penicil- withdrawal. Mediastinal fullness due to lipoma-
lamine can cause a pulmonary-renal syndrome tosis is an unusual manifestation of an adverse
similar to Goodpasture syndrome. Therapy with effect of corticosteroids. Although mediastinal
oral anticoagulants can induce spontaneous pul- widening in patients receiving corticosteroids
monary hemorrhage days to years after the onset may raise the suspicion of adenopathy, the
of therapy. Abciximab, a chimeric monoclonal diagnosis of lipomatosis is suggested by the
antibody directed against platelet glycoprotein characteristic chest radiograph appearance of a
IIb/IIIa receptor that reduces restenosis after straight mediastinal border without the lumpy
angioplasty and stent placement, can cause severe features of adenopathy and the typical CT scan
alveolar hemorrhage.22 This relatively rare com- findings of lipid-containing tissue. Mediastinitis
plication (7 of 2,533 patients [0.3%] vs 0 of 5,412 associated with fever and chest pain is a

Table 11—Differential Diagnosis of Radiographic Abnor- may have minimal or absent symptoms and
malities findings but demonstrate abnormalities on the
Diffuse Disease Localized Disease
chest radiograph or PFT results. A high level of
clinical suspicion is required because drug-
Infection Infection induced disease may occur years after initial
Malignancy Malignancy exposure and the radiographic abnormalities
Lymphangitic metastasis Pulmonary emboli
Pulmonary edema Radiation pneumonitis
may be subtle.
Pulmonary fibrosis Drug toxicity
Radiation pneumonitis/fibrosis Diagnostic Approach
Leukoagglutinin reaction
ARDS
Hypersensitivity pneumonitis
Because drug-induced pulmonary toxicity
Pulmonary hemorrhage has a profound impact on patient management,
Drug toxicity it is important to establish a firm diagnosis as
soon as possible. This begins with an under-
Board Review. 25th ed. Northbrook, IL: American College of standing of the clinical syndromes caused by
Chest Physicians; 2009. various agents combined with the prudent use of
noninvasive studies and invasive procedures.
relatively rare adverse effect of esophageal Evaluation of the chest radiograph, PFT results,
variceal sclerotherapy. and, on occasion, chest CT scan help narrow the
differential diagnosis. Noninvasive studies that
Other rare pulmonary-adverse drug effects
may be useful include the following: (1) an
reported in the literature include busulfan-
echocardiogram to assess cardiac function, (2)
induced alveolar proteinosis, methylphenidate-
sputum studies to identify an infectious patho-
induced panlobular emphysema, and pulmonary
gen (eg, Gram stain, culture, direct fluorescent
parenchymal calcium deposition associated with
antibody for Pneumocystis carinii or Legionella,
hypercalcemic conditions or drugs such as
and acid-fast bacteria stain and culture), and (3)
antacids, calcium, and high-dose vitamin D.
immunologic studies to exclude collagen vascu-
Long-term salicylate ingestion can cause a
lar disorders and vasculitis.
pseudosepsis syndrome (reviewed in the section
If a firm diagnosis is not established, then the
‘‘Antiinflammatory Drugs’’).
judicious use of invasive diagnostic procedures is
warranted. Typically, fiber optic bronchoscopy
Approach to the Patient With with BAL and transbronchial lung biopsy is the
Suspected Drug-Induced Lung next step in the evaluation of patients with
Disease localized or diffuse pulmonary disease of unclear
etiology. Although this procedure has an excel-
Differential Diagnosis lent diagnostic yield for infections and malignant
lesions (approximately 70% to 90%), it has a
As mentioned earlier, the diagnosis of drug- lower diagnostic yield for interstitial inflamma-
induced lung disease is one of exclusion since tory lesions, including those due to drug-induced
there are no pathognomonic criteria. The differ- toxicity. In the proper clinical setting, a nondiag-
ential diagnosis is broad, especially in cancer nostic bronchoscopy may be sufficient to suggest
patients receiving therapy with multiple drugs, the diagnosis of drug-induced injury. A thoraco-
which often includes immunosuppressive scopic biopsy or, less commonly these days, an
agents. However, the differential diagnosis can open lung biopsy, is recommended in patients for
be narrowed on the basis of the presenting whom the diagnosis remains unclear and the
clinical syndrome reviewed above as well as by differential diagnosis includes other pulmonary
the presence of localized or diffuse infiltrates abnormalities, especially ILD. These procedures
(Table 11). Drug-induced lung diseases most have the highest diagnostic yield and a relatively
commonly present with diffuse radiographic low complication rate, even in critically ill
abnormalities. In some instances, the patient patients. The histopathologic changes associated

with drug toxicity are nonspecific, revealing BCNU
elements of diffuse alveolar damage, fibrinous
exudate, atypical or reactive alveolar type II cells, BCNU, or carmustine, is the best-known and
inflammatory cells, and fibrotic foci. One study24 most extensively studied member of the nitroso-
showed that up to 20% of patients with diffuse urea family of drugs that includes lomustine
infiltrates undergoing an open lung biopsy had (chloroethylnitrosourea), semustine (methyl-
histologic changes that could be attributed to a chloroethylnitrosourea), and chlorozotocin.
drug reaction. These cytotoxic agents, which are unique in their
ability to cross the blood-brain barrier, are active
PFTs against a variety of neoplasms, including CNS
malignancies. BCNU causes interstitial pulmo-
The role of PFTs for detecting adverse drug- nary fibrosis and granulomatous inflammation
induced pulmonary effects has been extensively that can progress after drug withdrawal. The
investigated. The majority of the studies have pathogenesis of BCNU-induced pulmonary tox-
focused on bleomycin, busulfan, and amioda- icity is unclear. BCNU promotes oxidant-induced
rone. The most common PFT result abnormalities lung injury by inhibiting glutathione reductase,
are diminished lung volumes and a reduced thereby reducing glutathione stores, which is an
DLCO. However, it is controversial whether these important antioxidant defense. BCNU causes
abnormalities accurately predict that clinically cytotoxic changes characterized by alveolar type
overt disease will develop.25,26 Overt drug- II cell hyperplasia and dysplasia, fibroblastic foci
induced disease can develop in patients in the of proliferation, and interstitial fibrosis.
absence of PFT result abnormalities, and con- Patients presenting with BCNU-induced pul-
versely, patients can have abnormal PFT results monary toxicity will typically note an insidious
onset of a nonproductive cough and dyspnea
in the absence of drug-induced lung disease.
associated with reticular nodular interstitial infil-
Patient effort and anemia are important con-
trates seen on the chest radiograph. However, the
founding variables that impact PFT results. For
onset of symptoms is highly variable, appearing
most drugs, well-designed clinical studies vali-
within days to as many as 17 years after beginning
dating the role of PFTs to detect adverse
therapy BCNU.27 Risk factors include the follow-
pulmonary effects are not available. Until defin-
ing: (1) total dose: the incidence of pulmonary
itive data are available, it is reasonable for
toxicity with high-dose BCNU (.1,500 mg/m2)
clinicians to continue utilizing PFTs in select
varies from 20% to 50%, while with low-dose
settings with the goal of identifying subclinical
BCNU the incidence is on the order of 1% to 5%,
disease as long as the physiologic interpretation primarily when administered concurrently with
is made in the context of the entire clinical other agents; (2) other agents: cyclophosphamide
situation. and radiation increase the risk of BCNU-induced
lung injury; however, a synergistic interaction has
Chemotherapy-Associated Pulmonary not been documented; and (3) preexisting lung
Toxicity disease: patients with preexisting symptomatic
pulmonary disorders, especially with a reduced
Azathioprine/Mercaptopurine vital capacity or DLCO, are typically excluded from
receiving BCNU. A reduced DLCO without chest
Azathioprine, a purine analog that inhibits radiographic abnormalities occurs in patients
DNA synthesis, is an immunosuppressive agent receiving BCNU. Although there are no prospec-
used in the treatment of nonmalignant disease (eg, tive studies to guide the timing of PFT monitor-
IPF and organ transplantation). Mercaptopurine, ing, PFTs are typically followed during BCNU
the active metabolite of azathioprine, is an therapy to monitor for subclinical disease as well
antineoplastic agent. Azathioprine rarely (,1%) as intermittently long term, given the extended
causes pulmonary fibrosis, hypersensitivity-type latency period between treatment and pulmonary
reactions/PIE, or diffuse alveolar damage. toxicity. This approach is supported in part by the

poor outcomes of patients in whom BCNU- phase of ARDS. Bleomycin binds to intracellular
induced pulmonary fibrosis develops. BCNU- iron in alveolar epithelial and vascular endothe-
induced lung injury is associated with a mortality lial cells and, in the presence of oxygen,
rate of nearly 90%. Corticosteroid therapy has generates highly reactive oxygen species (ROS)
little impact in preventing or treating BCNU- such as hydroxyl radicals. ROS alter important
induced lung injury. The primary treatment is to cellular components (eg, DNA, lipids, and
withdraw BCNU promptly and provide support- proteins), resulting in damage to the respiratory
ive care. Although there is less information about membrane. Intratracheal or IV bleomycin in-
the frequency of pulmonary injury caused by the creases cytokine levels within the lung in animal
other nitrosoureas, each has been reported to have models. The important cytokines implicated in
effects similar to those of BCNU. the pathogenesis of bleomycin-induced pulmo-
nary toxicity include transforming growth factor
Bleomycin (TGF)-b, TNF-a, interleukin (IL)-1, and others.
Pathogenic roles for ROS and certain cytokines
Bleomycin, which is a cytotoxic antibiotic that are supported by the protective effects of various
is isolated from Streptomyces verticillus, is very agents, including antioxidants; iron chelators;
useful in treating patients with head and neck IL-1 receptor antagonists; IL-12; keratinocyte
carcinomas, germ cell tumors, and Hodgkin’s
growth factor; CD36 peptides (binds TGF-b1); or
and non-Hodgkin’s lymphomas. Bleomycin ac-
antibodies against TGF-b, TNF-a, or CD3
cumulates in the skin and lung, resulting in skin
receptors.26,29 A crucial role for alveolar epithelial
ulcerations and pulmonary fibrosis. Bleomycin-
cell injury is supported by the finding that trans-
induced pulmonary damage, which is the major
genic mice deficient in the epithelial cell restricted
dose-limiting side effect, was first recognized in
integrin (avb6 do not develop bleomycin-induced
1972.28 The overall incidence of pulmonary
pulmonary inflammation or fibrosis because
toxicity is 10% (range, 3% to 40%) and is fatal
they are unable to activate latent TGF-b.30
in 1% to 2% of patients.
Bleomycin lung toxicity can also be prevented
The pathogenesis of bleomycin-induced lung
by blocking excessive alveolar epithelial cell
injury is not firmly established, but much is
apoptosis or DNA damage, by enhancing DNA
known about some of the important mecha-
nisms.26 Because bleomycin reproducibly causes repair, and by augmenting fibrinolysis. 31–34
interstitial pneumonitis and fibrosis in animal Notably, the expression of the bleomycin-resis-
models, it has become a paradigm for the study tant Streptoalloteichus hindustanus ble gene, which
of the pathogenic mechanisms underlying pul- encodes a protein that binds bleomycin and
monary fibrosis. Although there is no ideal blocks DNA damage, can prevent bleomycin-
animal model of IPF, a 2008 review29 of 240 induced fibrosis.33 Recently, increased expres-
bleomycin studies reporting a beneficial antifi- sion of epithelial cell-derived integrin avb6 was
brotic effect found that 222 of the studies used noted35 in the distal alveoli of patients with IPF
pharmacologic treatments prior to bleomycin and antibodies against avb6 blocked bleomycin-
exposure and as such, served primarily as a induced fibrosis in mice, even when adminis-
proof of principle regarding a putative mecha- tered after the development of fibrosis. A
nistic pathway but were of limited clinical utility. disease-specific gene expression profiling study
Of the 240 bleomycin studies, only 13 used using multiple murine models of lung disease
treatment protocols .7 days following the last identified 12 unique transcripts characteristic of
dose of bleomycin, and of these only one, the bleomycin-induced pulmonary fibrosis that
antioxidant N-acetylcysteine may have a role in were not evident in the other models.36 Al-
IPF management that is actively being investi- though the pathogenic mechanisms underlying
gated (PANTHER Trial, National Institutes of bleomycin toxicity are better understood and are
Health).29 Early bleomycin-induced pulmonary leading to potentially novel antifibrotic thera-
injury shows acute and organizing diffuse pies, it is unclear why certain patients are
alveolar damage similar to the fibroproliferative predisposed to pulmonary fibrosis.

There are three major clinical manifestations the fact that the kidneys primarily excrete bleo-
of bleomycin-induced lung toxicity, as follows: (1) mycin; and (6) concurrent use of other cytotoxic
chronic interstitial fibrosis; (2) hypersensitivity- agents: some drugs may increase the risk of
type disease; and (3) BOOP. Interstitial fibrosis is bleomycin-related injury, including cyclophospha-
by far the most common, occurring in approxi- mide, doxorubicin, granulocyte colony-stimulat-
mately 11% of those patients treated. Patients ing factor (G-CSF), methotrexate, and vincristine.
typically present with a subacute onset of a The management of patients with bleomycin-
nonproductive cough and dyspnea within a few induced pulmonary toxicity centers on with-
weeks to 6 months after treatment.26 Pleuritic drawing the drug and limiting exposure to
substernal chest pain occurs in approximately 3% exogenous oxygen, as noted above. Although
of patients. However, nearly 20% of patients with the overall mortality rate is approximately 1% to
bleomycin-induced lung injury will be asymp- 2%, the mortality rate varies from 10% to 83% in
tomatic. Physical examination findings may show patients with pulmonary disease. Corticosteroids
tachypnea, bibasilar crackles, and hyperpigment- (60 to 100 mg/day) are generally administered to
ed skin lesions. Chest radiographs typically all patients with clinically significant toxicity and
reveal basilar, predominant reticular, or fine then slowly tapered according to the patient’s
nodular infiltrates that often originate from the clinical response. Clinical improvement typically
costophrenic angles. Other, less common radio- occurs within weeks and may take 2 years to
graphic patterns include patchy alveolar infil- completely resolve. Select patients will be left
trates, lobar consolidation, and lung nodules. with residual radiographic and abnormalities on
PFT results generally show reduced lung vol- the PFT results.
umes and D LCO . Patients with bleomycin-
Busulfan
induced hypersensitivity-type disease may have
similar symptoms but often with an associated
Busulfan, an alkylating agent that is used in
fever, malaise, and chest radiographic changes
the management of chronic myeloproliferative
of chronic pneumonitis and ground glass-
disorders, was the first chemotherapeutic agent
appearing parenchyma with little fibrosis. The
implicated in causing chronic pneumonitis/
radiographic and pathologic distinctions between
pulmonary fibrosis. In general, alkylating agents
fibrosis and pneumonitis are not always clear.
(eg, busulfan, cyclophosphamide, chlorambucil,
Risk factors for the development of bleomycin- and melphalan) have a lower frequency of
induced pulmonary toxicity include the following: inducing lung injury than other cytotoxic agents.
(1) total dose: a dose relationship has been Like bleomycin, these agents can induce syner-
described with an incidence of 3% to 5% when gistic pulmonary damage when a patient is
the total dose is below 300 U but .20% when the exposed to oxygen, radiation, or other cytotoxic
total dose is .500 U26; however, pulmonary chemotherapeutic agents. The incidence of symp-
toxicity can occur after receiving only 20 U; (2) tomatic busulfan-induced pulmonary fibrosis is
oxygen: bleomycin, more than any other drug, has approximately 4% to 5%. However, histologically
a well-known synergistic toxic interaction with evident fibrosis and cytotoxic changes (hyper-
oxygen that can occur years after bleomycin plastic and dysplastic type II cells) occur in up to
exposure (although this reaction does not develop 46% of busulfan-treated patients, most of whom
in all patients, the inspired oxygen concentration are asymptomatic.37 A threshold dose has not
for patients who have ever received bleomycin been established.
should be kept below 25% if possible); (3) The clinical presentation is an insidious
radiation: radiation therapy, even years after onset, often .3 years after initiating therapy, of
bleomycin exposure, increases the risk; (4) age: cough, dyspnea, fever, malaise, and weight loss.
persons .70 years of age are at an increased risk of The PFT results show restrictive lung volumes, a
lung injury; (5) abnormal renal function: patients reduced DLCO, and hypoxemia. The chest radio-
with reduced renal function are more susceptible graph typically shows diffuse interstitial and
to bleomycin-induced pulmonary toxicity due to alveolar infiltrates with a basilar predominance.

Occasionally, pleural effusions, nodular densi- Methotrexate
ties, or normal chest radiograph findings are
noted. Management centers on drug withdrawal Methotrexate is a folic acid antagonist used in
and the administration of corticosteroids. The the management of malignant and nonmalignant
prognosis is poor, with the mortality rate ranging inflammatory diseases. The incidence of pulmo-
from 50% to 80%. Alveolar proteinosis has also nary toxicity is nearly 7% for high-dose metho-
been reported after exposure to busulfan. Unlike trexate, as used to treat malignancies, but 2% to
primary alveolar proteinosis, it does not respond 3% with low-dose methotrexate regimens used to
to therapeutic BAL. treat chronic inflammatory conditions such as RA.
Methotrexate-induced pulmonary toxicity does
Cyclophosphamide not have a clear dose relationship since it occurs
over a broad range of doses (40 to 6,500 mg).
Cyclophosphamide, which is an alkylating The clinical manifestations include the fol-
agent that causes pulmonary toxicity less fre- lowing: (1) hypersensitivity-type disease, the
quently than busulfan, is widely used to treat most common form; (2) chronic pneumonitis/
malignant diseases (eg, lymphomas, breast car- fibrosis; (3) BOOP; (4) acute chest pain; (5)
cinoma, and ovarian carcinoma) and nonmalig- noncardiogenic pulmonary edema; (6) acute
nant diseases (eg, collagen vascular disorders, pleurisy/pleural effusions; and (7) broncho-
IPF, and granulomatosis with polyangiitis [Weg- spasm.41,42 Methotrexate-induced hypersensi-
ener]). The incidence of adverse pulmonary tivity-type reactions typically occur within 10
effects is ,1%. The extensive clinical indications days to 4 months after initiating therapy but can
for cyclophosphamide and its frequent use in occur up to 1 month after stopping therapy with
conjunction with other cytotoxic drugs increase methotrexate.41,42 Patients may complain of
the likelihood that lung toxicity will be seen by fever, cough, dyspnea, arthralgias, and, less
pulmonologists. Although cyclophosphamide commonly, skin rash (approximately 17%).
alone induces pulmonary toxicity in humans Chest radiographs reveal diffuse interstitial
relatively infrequently,38 it clearly does so in infiltrates with ground-glass changes seen on
animals.39 The pathogenesis of pulmonary tox- HRCT scans. Other radiographic abnormalities
icity has not been established but likely involves that are occasionally seen include nodular
oxidant-mediated mechanisms. Cyclophospha- infiltrates, hilar/mediastinal adenopathy, and
mide is metabolized into two active agents, pleural effusions. Blood eosinophilia is present
phosphoramide mustard and acrolein, both of in nearly 40% of patients. BAL findings typically
which reduce hepatic glutathione stores. reveal a predominance of lymphocytes, espe-
Chronic pneumonitis and/or fibrosis are the cially T-suppressor cells, which are characteris-
most common clinical manifestations of pulmo- tic of a hypersensitivity reaction.43
nary toxicity. Symptoms develop as soon as 2 The diagnosis of methotrexate-induced pul-
weeks to as long as 13 years after the initiation of monary toxicity requires the following three major
therapy, without any clear dose relationship. The criteria: (1) hypersensitivity pneumonitis by his-
patients present with cough, dyspnea, fever, and topathologic findings; (2) radiographic evidence
bibasilar interstitial infiltrates seen on chest of interstitial and/or alveolar infiltrates; and (3)
radiographs. Synergistic toxicity has been de- blood cultures (if febrile) and sputum cultures (if
scribed in patients receiving radiation therapy or available) that are negative for microbes. Patients
other cytotoxic agents.40 Cyclophosphamide- must also have three of the following five minor
induced pulmonary fibrosis, unlike IPF, may criteria: (1) dyspnea of ,8 weeks duration; (2)
present with bilateral pleural thickening, typical- nonproductive cough; (3) room air oxygen satu-
ly without clubbing and ‘‘velcro’’ crackles.38 The ration of 90%, (4) DLCO of 70% predicted, and
prognosis is generally poor, with a mortality rate (5) leukocyte count of 15,000 cells/lL.44
approaching 50%. Most patients are treated with Risk factors for the development of metho-
corticosteroids based on anecdotal reports of trexate-induced pulmonary toxicity include the
benefit. following: (1) appearance of symptoms within

the first 32 weeks of therapy, (2) multidrug associated with this uncommon reaction is
regimens (synergy with cyclophosphamide has .90%.
been reported), (3) diabetes mellitus, (4) age 50 The combination of mitomycin with vinca
years, (5) rheumatoid pleuropulmonary disease, alkaloids (eg, vinblastine and vincristine) induces
and (6) hypoalbuminemia.45 Dose, frequency, an acute onset (,3 h after receiving the vinca
smoking status, previous lung disease, and route alkaloid) of bronchospasm associated with focal
of administration route (eg, oral, IV, intrathecal, or diffuse interstitial infiltrates seen on chest
and IM) do not consistently affect the frequency radiographs and hypoxemia.48 Vinca alkaloids
of methotrexate-induced adverse pulmonary alone do not cause this adverse side effect.
effects. Notably, PFT results have not been Chronic respiratory symptoms that respond to
helpful in identifying patients with RA who are corticosteroids develop in approximately two-
at risk for the development of pulmonary toxicity thirds of the patients.
while receiving chronic, low-dose methotrex-
ate.46 Chronic pneumonitis/fibrosis, which oc- Retinoic Acid
curs less commonly due to methotrexate than
other chemotherapeutic agents, typically pre- All-trans-retinoic acid (ATRA) is a highly
sents 4 months to .3 years after initiating effective biological response modifier that induc-
therapy. es clinical remission in patients with acute
Management centers on the withdrawal of promyelocytic leukemia by augmenting the
therapy with the drug and the administration of differentiation of malignant stem cells into
corticosteroids. Chronic fibrosis will develop in mature neutrophils. An ARDS-like picture,
approximately 7% of patients with methotrexate- termed retinoic acid syndrome, developed in nearly
induced hypersensitivity reactions, and 8% will 25% of patients who were initially treated with
die of progressive respiratory failure. ATRA. Prednisolone therapy (75 mg/day) reduc-
es the incidence of ATRA to approximately 8%.49
Mitomycin The syndrome is characterized by the sudden
onset of fever, dyspnea, effusions (pleural and
Mitomycin is an alkylating cytotoxic antibi- pericardial), diffuse alveolar infiltrates seen on
otic used in the treatment of breast, GI, gyneco- chest radiographs, and hypoxemic respiratory
logic, and lung carcinomas. The incidence of failure. Before the efficacy of steroid therapy was
pulmonary cytotoxicity is approximately 5% recognized, more than half the patients required
(range 3% to 39%).47 However, the full scope of mechanical ventilation, and the mortality rate
the problem is difficult to assess because mito- was 33%. The pathogenesis has not been estab-
mycin is typically administered concurrently lished but likely relates in part to the rapid
with other agents and is also a cotoxin with increase in mature leukocytes. Autopsy studies
oxygen and radiation. The presenting features as reveal diffuse alveolar damage with edema and
well as the radiographic and physiologic changes hemorrhage as well as leukemic cells in the
are similar to those seen with bleomycin-induced interstitium. Mechanisms implicated in ATRA-
interstitial pneumonitis/fibrosis. Of note, this induced capillary leak syndrome include the
reaction seems to occur most frequently after release of vasoactive cytokines, oxidants, and
the third cycle of treatment. Although serial lipid mediators from inflammatory cells as well
monitoring of the DLCO to detect clinically occult as enhanced expression of leukocyte adhesion
disease is unproven, it is generally recommended molecules that impair leukocyte transit through
and widely used for this purpose. Prednisone can the pulmonary microcirculation. Some patients
rapidly resolve the symptoms and interstitial in whom retinoic acid syndrome develop while
infiltrates. A unique reaction of mitomycin is the they are receiving prednisolone have responded
induction of microangiopathic hemolytic anemia to therapy with dexamethasone. Management is
concurrently with noncardiogenic pulmonary otherwise largely supportive, similar to patients
edema and renal failure. The mortality rate with ARDS.

Other Chemotherapeutic Agents/Newer bronchiolitis obliterans.14,52 Synergy between iri-
Antineoplastic Drugs notecan and paclitaxel or radiation increases the
frequency of pulmonary toxicity from 1.8% to 13%
Other chemotherapeutic drugs are less com- or 56%, respectively. Tyrosine kinase inhibitors
monly associated with adverse pulmonary ef- (eg, gefitinib and imatinib) uncommonly cause
fects, which are seen more often than with the pulmonary toxicity (approximately 2%), consist-
agents reviewed earlier. Chlorambucil, which is ing of NSIP, hypersensitivity pneumonitis, pul-
an alkylating agent similar to cyclophosphamide, monary fibrosis, COP, alveolar hemorrhage,
is used in the treatment of lymphoproliferative ARDS, and pleural effusions.14,52 Biological re-
disorders as well as nonmalignant diseases. sponse modifiers, such as IL-2 and TNF-a, are
Pulmonary toxicity is relatively rare, but chronic used in experimental protocols to treat various
pneumonitis/fibrosis has been reported. Cyto- malignancies. Each can induce noncardiogenic
sine arabinoside, which is an antimetabolite used pulmonary edema, which, in the case of IL-2, is
to treat acute leukemia, causes noncardiogenic also associated with massive fluid retention.
pulmonary edema in 13% to 20% of patients.50 Granulocyte-macrophage colony-stimulating fac-
The mortality rate varies from 2% to 50%. tor and G-CSF can cause a hypersensitivity-type
Corticosteroids may improve outcome, but this pneumonitis when administered in conjunction
remains uncertain. Fludarabine, which is an with other cytotoxic agents. Also, G-CSF, espe-
antimetabolite used in the management of cially in the presence of other cytotoxic agents, can
patients with chronic lymphoproliferative disor- induce ARDS.53 Thalidomide and its more potent
ders, can cause both chronic pneumonitis/fibro- derivatives (lenalidomide and pomalidomide),
which are immunomodulating agents effective in
sis as well as a hypersensitivity-type reaction in
the management of multiple myeloma, are associ-
nearly 9% of patients. It is often responsive to
ated with pulmonary toxicity, such as hypersensi-
therapy with corticosteroids.51
tivity pneumonitis, interstitial fibrosis, COP, and
Although older chemotherapeutic agents in-
eosinophillic pneumonia in ~6% of patients.54
duce a wide array of pulmonary toxicity in nearly
Although it is beyond the scope of this review,
10% of patients, there is less information concern-
immunosuppressive agents can promote the de-
ing the frequency as well as the clinical manifes-
velopment of opportunistic pulmonary infections.
tations resulting from exposure to the newer
agents.14,52 Gemcitabine, which is an agent that
Nonchemotherapy-Associated
is increasingly being used in the management of a
Pulmonary Toxicity
variety of solid tumors, can induce an ARDS-like
condition that is potentially fatal.52 The estimated
Antiinflammatory Drugs
frequency of gemcitabine-induced pulmonary
toxicity ranges from ,1% to 1.4% and, in addition Aspirin: Aspirin (acetylsalicylic acid), which is
to ARDS, includes nonspecific interstitial pneu- the most commonly prescribed drug worldwide,
monitis (NSIP), pulmonary fibrosis, and pleural causes the following two forms of pulmonary
effusions.14,52 Taxanes (eg, paclitaxel and docetax- toxicity: bronchospasm and noncardiogenic pul-
el) are used in the management of solid tumors monary edema. Aspirin-induced asthma (AIA)
(eg, breast, lung, gastric, and ovarian). Paclitaxel occurs in ,1% of healthy individuals and in up to
induces bronchospasm and a type 1 hypersensi- 20% of asthmatic individuals. However, aspirin
tivity reaction in up to 30% of patients.14,52 Other sensitivity occurs in a larger proportion of
much less common taxane-induced pulmonary asthmatic patients with nasal polyps, which is a
manifestations include NSIP, hypersensitivity clinical triad that was first identified by Samter
pneumonitis, pulmonary fibrosis, ARDS, and and Beers.55 Symptoms of AIA occur within
pleural effusion. Topoisomerase I inhibitors (eg, minutes to hours after ingestion and may be
irinotecan and topotecan), which are used in the associated with facial flushing, rhinorrhea, angio-
management of various solid tumors, causes edema, and conjunctivitis. The pathogenesis of
pulmonary toxicity that includes NSIP and AIA is mediated by the enhanced production of

cysteinyl leukotrienes via the 5-lipoxygenase salicylates. Management is based on drug with-
pathway and, to a lesser extent, by a reduction drawal and supportive care, often in the ICU
in bronchodilating prostaglandins secondary to with the patient receiving mechanical ventilation.
cyclooxygenase inhibition. Aspirin-sensitive asth- Alkaline diuresis should be performed as soon as
matic patients who are challenged with aspirin the diagnosis is suspected to enhance renal
have increased levels of urinary leukotriene E4, clearance and thereby reduce the serum salicy-
which is a general marker of serum leukotriene late level. Hemodialysis is reserved for patients
levels. This is due to the increased activity of with aspirin-associated seizures, refractory aci-
leukotriene C synthase, the rate-limiting step in dosis, coma, or very high salicylate levels (80 to
leukotriene synthesis.56 As expected, they exhibit 100 mg/dL). Outcome is generally favorable in
symptomatic and spirometric improvement in the young patients with an acute salicylate overdose.
presence of 5-lipoxygenase inhibition and cystein- However, there is a high mortality rate in older
yl leukotriene receptor antagonism.56 An inpatients who have multiple medical problems
creased risk of AIA is also associated with and a long-term history of the ingestion of
several single-nucleotide polymorphisms in the salicylates, and they have a more subtle presen-
promoters of prostaglandin E2 receptor subtype 2, tation.
cysteinyl leukotriene receptor 1, cysteinyl leuko- Gold: Gold has been widely used for decades
triene receptor 2, and T-cell T box.57 A similar in the management of chronic inflammatory
syndrome occurs with other nonsteroidal antiin- conditions, most notably, RA, but also pemphi-
flammatory drugs (NSAIDs). Agents that do not gus, psoriatic arthritis, bronchial asthma, and
block the cyclooxygenase pathway, such as ankylosing spondylitis. Both the oral (auranofin)
acetaminophen and salicylate, can be safely used and the IM (gold sodium thiomalate) prepara-
in patients with aspirin-induced or NSAID- tions can induce chronic pneumonitis/interstitial
induced bronchospasm.56 fibrosis and bronchiolitis obliterans in the pres-
Aspirin-induced noncardiogenic pulmonary ence or absence of organizing pneumonia.59 ILD
edema occurs in 10% to 15% of patients with a due to gold therapy can be distinguished from
severe salicylate overdose. This can occur inad- the patient’s underlying rheumatoid lung disease
vertently in long-term aspirin users, typically by the following: (1) an acute onset of dyspnea
elderly patients with multiple medical problems, and a nonproductive cough; (2) fever (ie,
or intentionally in individuals attempting sui- temperature .388C); (3) skin rash; (4) crackles
cide. These patients will often present with on chest examination; (5) absence of finger
dyspnea, tachypnea, altered mental status, and clubbing or subcutaneous nodules; (6) the pres-
a chest radiograph revealing diffuse alveolar ence of blood eosinophilia, proteinuria, or liver
infiltrates. Most patients will manifest with a dysfunction; (7) BAL fluid lymphocytosis with a
simple respiratory alkalosis or a mixed anion gap predominance of CD8 (suppressor) cells typical
metabolic acidosis plus a respiratory alkalosis. of a hypersensitivity-type reaction; (8) alveolar
The constellation of findings can mimic a opacities in a nonbasilar distribution; and (9) an
pseudosepsis syndrome.58 The diagnosis is made HRCT scan that shows bronchovascular infil-
by first considering aspirin ingestion in the trates rather than peripheral infiltrates.60 A
differential diagnosis of patients presenting with favorable clinical response typically occurs after
noncardiogenic pulmonary edema or a sepsis- drug withdrawal and a course of corticosteroids.
like picture and then determining the serum Recurrent disease has been documented follow-
salicylate level. Respiratory alkalosis is typically ing retreatment, which is not warranted.
seen with serum salicylate levels of 35 mg/dL NSAIDs: NSAIDs are among the most com-
(therapeutic range 10 to 20 mg/dL), while non- monly prescribed drugs because they are widely
cardiogenic pulmonary edema occurs at serum used in the management of an array of rheuma-
levels of 45 mg/dL. Although the pathogenesis tologic disorders as well as for minor musculo-
of aspirin-induced noncardiogenic pulmonary skeletal pain in healthy individuals. Similar to
edema is unclear, it likely results from increased salicylates, NSAIDs can precipitate asthma as
capillary permeability due to toxic levels of well as noncardiogenic pulmonary edema in

aspirin-sensitive individuals. Ophthalmic nearly 50% of patients die, while the remainder
NSAIDs also can trigger bronchospasm. Nearly have very poor quality of life because of a severe
every type of NSAID can induce a hypersensi- permanent residual obstructive impairment.
tivity-type reaction that may be associated with Penicillamine rarely induces Goodpasture
PIE. In general, prompt resolution occurs with syndrome, consisting of diffuse alveolar hemor-
drug withdrawal, and, rarely, a course of rhage and rapidly progressive glomerulonephri-
corticosteroids is required. tis due to autoantibodies directed against
Methotrexate: See the section ‘‘Chemotherapy- components of the alveolar and glomerular
Associated Pulmonary Toxicity.’’ basement membranes. There are case reports of
Penicillamine: Penicillamine is an antiinflam- this syndrome occurring after penicillamine was
matory, antifibrotic, and copper-chelating agent used to treat RA as well as Wilson disease,
used in the treatment of RA, scleroderma, demonstrating that it is not simply due to the
primary biliary cirrhosis, and Wilson disease. patient’s underlying collagen vascular disease.
The manifestations of penicillamine-induced Typically, the serum ANA level is elevated, but
pulmonary toxicity include the following: (1) the double-stranded DNA antibodies seen in
interstitial pneumonitis/fibrosis, (2) bronchiolitis classic SLE are not apparent. However, it is
obliterans in the presence or absence of organiz- important to consider SLE or an antineutrophil
ing pneumonia, (3) drug-induced SLE, and (4) cytoplasmic antibody-related vasculitis in the
alveolar hemorrhage due to a pulmonary-renal differential diagnosis because a number of these
syndrome. patients will not have serum and tissue anti-
Patients with penicillamine-induced intersti- glomerular basement membrane antibodies. De-
tial pneumonitis/fibrosis generally present with spite drug withdrawal and corticosteroids, the
the insidious onset of dyspnea and cough mortality rate is nearly 50%, and there is a high
associated with restricted lung volumes and a incidence of progression to chronic renal failure,
reduced DLCO. A subset of patients present with a necessitating long-term dialysis.
hypersensitivity-type reaction associated with TNF-a-Targeted Therapy: Anti-TNF-a antibod-
peripheral blood eosinophilia and elevated se- ies (eg, etanercept, infliximab, adalimumab, and
rum IgE levels. As with gold therapy, it can be golimumab) are increasingly being used to block
challenging to distinguish drug-induced pulmo- the effects of TNF-a in autoimmune diseases
nary toxicity from the patient’s underlying such as RA, inflammatory bowel disease, anky-
collagen vascular disorder. losing spondylitis, and psoriatic arthritis, as well
The incidence of penicillamine-induced bron- as an emerging role in over 40 other diseases (eg,
chiolitis obliterans is unknown but is estimated sarcoidosis, scleroderma, hepatitis C, and oth-
to occur in ,1% of patients with RA receiving ers).61 Because TNF-a has a critical role in host
this therapy. There are no clear risk factors. defense against infections, not surprisingly their
Patients present with a subacute onset of utility is complicated by pulmonary infections,
dyspnea, cough, and wheeze. The chest radio- most prominently the reactivation of tuberculosis
graph reveals hyperinflation in the absence of as well as fungal infections.62,63 Of the mycobac-
infiltrates, while PFT results confirm the presence terial infections that develop during TNF-a-
of increased lung volumes as well as airflow targeted therapy, nearly a third are Myobacterium
limitation without a bronchodilator effect. Lung tuberculosis (MTB), a third are mycobacterium
biopsy specimens from these patients reveal avium intracellulare, and the remaining are
bronchiolar constriction due to mononuclear mycobacterial infections other than MTB.62 Re-
inflammation and fibrosis. Management centers activation of latent MTB occurs three- to fourfold
on drug withdrawal, supportive therapy, and more commonly with infliximab and adalimu-
possibly using corticosteroids, azathioprine, or mab as compared to etanercept for unclear
cyclophosphamide. However, there are no data reasons.63 Of 10,712 patients on TNF-a-targeted
demonstrating the value of immunosuppressive therapy for 1 to 4 years, 40 patients developed
therapy. The prognosis for patients with penicil- MTB with a cumulative incidence rate over 4
lamine-induced bronchiolitis obliterans is poor; years of ~0.5% to 1%.63 It is recommended that

all patients receiving TNF-a-targeted therapy be minimal, nonspecific respiratory complaints.
screened and treated for latent tuberculosis Prompt resolution occurs with drug withdrawal,
before the drug is utilized. Further, these agents perhaps with a short course of corticosteroids
can also cause various noninfectious pulmonary and antihistamines.
manifestations, such as NSIP, pulmonary fibrosis, Nitrofurantoin: Nitrofurantoin has been used
hypersensitivity pneumonitis, sarcoid-like gran- for decades in the management of acute urinary
ulomatous inflammation, COP, pleural effusions tract infections and as long-term suppressive
(þANA), increased size of RA nodules, and SLE- therapy for patients with asymptomatic bacteru-
like reactions.64–66 In a prospective, observational ria. Nitrofurantoin has the following two main
study65 involving 367 patients with RA-ILD distinct adverse pulmonary manifestations: (1)
followed for 1 to 5 years, the all-cause mortality acute hypersensitivity-type reaction and (2)
trended higher in patients treated with TNF-a- chronic pneumonitis/fibrosis that mimics IPF.
targeted therapy as compared to other disease- Alveolar hemorrhage and noncardiogenic pul-
modifying agents (RR: 1.3 [0.7 to 2.3]). Risk of monary edema have also been described but are
death from pulmonary toxicity due to TNF-a- less common. The incidence of nitrofurantoin-
targeted therapy includes age 65 years old and induced adverse pulmonary effects is not firmly
late-onset ILD following TNF-a-targeted therapy established. One study68 has shown that the
(46 vs. 15 weeks).66 Management of pulmonary nitrofurantoin-induced acute hypersensitivity-
toxicity from TNF-a-targeted therapy in 52 type reaction that was severe enough to warrant
patients studied included stopping the drug hospitalization occurred in 1 in 5,000 new drug
and an empiric course of steroids with com- administrations, while the chronic form occurred
plete/partial remission in 65%, persistent disease in 1 in 50,000 new drug administrations.
in 35%, and death in 29%.66 Acute nitrofurantoin pulmonary toxicity is a
Rituximab: Rituximab is a chimeric human- very rare (,0.1%) side effect that occurs within 1
mouse antibody directed against CD20 surface month of the first dose in 86% of patients.
antigens on B lymphocytes that is effective in the Symptoms consist of dyspnea, cough, fever, chest
treatment of autoimmune diseases such as RA as pain, and a macularpapular skin rash. There is an
well as malignancies such as non-Hodgkin’s elevated erythrocyte sedimentation rate (ESR)
lymphoma and chronic lymphocytic leukemia.67 and peripheral blood eosinophilia in most
Rituximab-induced pulmonary toxicity (eg, patients. The chest radiograph shows a mixed
acute/subacute ILD most commonly but also alveolar/interstitial infiltrative pattern but is
pulmonary fibrosis, COP, ARDS, and diffuse normal in 18% of patients. One-third of patients
alveolar hemorrhage) occurs 15 days following have a small pleural effusion. PFT results
the last dose (range 1 to 28 days) and is typically reveal a restrictive pattern with a
associated with a prominent BAL lymphocytosis reduced DLCO. Although the diagnosis is gener-
(13% to 90% CD4þ T lymphocytes).67 ally made clinically, a lung biopsy specimen and
BAL fluid should be obtained in any patient in
Antimicrobial Drugs whom infection, metastatic tumor, and/or an
inflammatory condition are in the differential
Antibiotic-Induced Hypersensitivity-Type Dis- diagnosis. Histopathologic findings include in-
ease: The most common antibiotics causing a terstitial inflammation with lymphocytes and
hypersensitivity-type lung reaction in the pres- plasma cells, and, in the more severe cases,
ence of PIE include b-lactam and sulfa antibiot- alveolar edema, hyaline membranes, and hem-
ics. Less commonly, fluoroquinolones, tetra- orrhage. The prognosis is generally favorable
cycline, erythromycin, nitrofurantoin, isoniazid, with drug withdrawal and, occasionally, therapy
paraaminosalicylic acid, and ethambutol cause with corticosteroids. Although ARDS develops in
this type of a reaction. There are no known risk some patients, the overall mortality rate is
factors, and most reactions are idiosyncratic. ,1%.69
Typically, the patients present over a period of Chronic nitrofurantoin pulmonary toxicity
1 to 4 weeks (can be delayed up to 1 year) with occurs in elderly patients who have been treated

with long-term suppressive therapy for asymp- However, the utility of this drug is limited by
tomatic bacteruria. Although much less common adverse pulmonary effects that can occur in 5%
than the acute form, it is similar to the acute form to 10% of patients as well as toxicity to the eyes,
in that patients present with dyspnea and cough, thyroid gland, liver, GI tract, and nervous
but, in contrast, fever and rash are uncommon. system. The adverse effects of amiodarone are
Unlike the acute form, patients with the chronic typically associated with a high daily dose
form of the disease have systemic complaints of (.400 mg/day) and a prolonged duration of
fatigue and weight loss and infrequently have an therapy (.12 months). A meta-analysis70 of
elevated ESR and peripheral blood eosinophilia. randomized, placebo-controlled, low-dose ami-
Low-level elevations of the serum ANA and odarone efficacy trials involving 1,465 patients
rheumatoid factor can be seen that are similar to receiving ,400 mg/d amiodarone for a mini-
those in patients with IPF. The chest radiograph mum of 12 months demonstrated a trend toward
shows a bilateral interstitial infiltrative pattern increased pulmonary toxicity compared to those
typically without pleural effusions. PFT results patients receiving placebo (OR: 2.0; 95% confi-
generally reveal a restrictive pattern with a dence interval: 0.9 to 5.3; P ¼ 0.07), but this
reduced DLCO. As with the acute form, the difference did not reach statistical significance.
diagnosis is usually made on clinical grounds. In contrast, compared to placebo, low-dose
However, lung biopsy and BAL are indicated in amiodarone did increase pulmonary toxicity
any patient who might have an infection, a (1.2% vs. 3.8%, respectively) in the Canadian
metastatic tumor, and/or an inflammatory con- Myocardial Infarction Amiodarone Trial.71 An
dition. The characteristic histopathologic findings analysis of 237 patients with amiodarone-
include lymphocytic interstitial inflammation induced pulmonary toxicity demonstrated that
along with interstitial and alveolar fibrosis that patient age (.60 years; OR: 3 [1.3 to 7]) and
can be indistinguishable from the usual intersti- duration of therapy (.6 to 12 months; OR: 18 [6
tial pneumonitis form of IPF. Unlike the generally to 52]) significantly impacted the risk.72 A
reversible acute form of the disease, three- retrospective, cohort study73 of 6,460 patients
quarters of patients with chronic nitrofurantoin 65 years old receiving amiodarone for atrial
pulmonary toxicity fail to improve at all or are left fibrillation identified 250 (3.9%) patients that
with substantial residual disease despite drug developed pulmonary toxicity (primarily pul-
withdrawal and a trial of corticosteroids. The monary fibrosis) occurring following exposure
overall mortality rate is nearly 8%.69 to all doses (200 mg/day; hazard ratio [HR]:
Sulfasalazine/Mesalamine: Sulfasalazine, which 1.62 [1.35 to 1.96]; .200 mg/day, HR: 1.46 [1.22
is an antibiotic used in the management of to 1.75]). Risk factors for amiodarone pulmonary
inflammatory bowel disease, can cause COP, toxicity included increasing age, male gender,
PIE, pulmonary fibrosis, and bronchospasm. COPD, and chronic kidney disease.73
Sulfapyridine, which is the carrier component of The mechanisms underlying amiodarone-
sulfasalazine, is responsible for the majority of the induced pulmonary toxicity are not firmly
side effects. However, mesalamine, the clinically established. As reviewed elsewhere,74 several
active component, can also induce pulmonary theories that are not mutually exclusive have
adverse side effects. been implicated, including (1) direct cellular
Pentamidine: Pentamidine can cause broncho- damage in part due to alveolar epithelial cell
spasm when given by either the IV or nebulized apoptosis, (2) enhanced phospholipidosis, (3)
route. The adverse effect can be prevented by immunologic injury, (4) ROS-induced damage,
pretreatment with b-agonists or ipratropium. (5) alterations in membrane properties, (6)
increased intracellular calcium in vascular endo-
Cardiovascular Drugs thelial cells, (7) activation of G proteins, and (8)
inhibition of pulmonary epithelial cell sodium-
Amiodarone: Amiodarone is an effective agent potassium adenosine triphosphatase. More re-
for treating ventricular and supraventricular cent studies show that amiiodarone causes lung
arrhythmias that are refractory to other drugs. epithelial cell mitochondrial dysfunction, ROS

production, and mitochondria-regulated apopto- established, but some that have been implicated
sis that can be blocked with angiotensin system include the following: (1) maintenance dose of
antagonists.75,76 An important role for blocking .400 mg/day, (2) age .60 years, (3) duration .6
the angiotensin system was suggested in an 8- to 12 months, (4) angiography-acute lung injury,
year retrospective study77 of 883 patients receiv- and (5) cardiothoracic surgery-ARDS. The total
ing amiodarone in the presence or absence of an cumulative dose or serum levels of amiodarone
ACE inhibitor or an ARB and demonstrated are not useful. Further, a reduction in the DLCO
reduced pulmonary toxicity from ~3.9% (14 of and increased gallium uptake may support a
359) to ~1.0% (5 of 524 patients) while receiving clinical diagnosis but are not reliable predictors
either an ACE inhibitor or an ARB. Amiodarone of pulmonary toxicity in the absence of clinical
has a large volume of distribution with a very and radiographic abnormalities.
long half-life of 30 to 60 days. Thus, the The diagnosis of amiodarone-induced pul-
antiarrhythmic effects as well as the adverse monary toxicity is one of exclusion, especially
effects of amiodarone will persist for weeks to heart failure, pulmonary embolism, infection,
months after the drug is withdrawn from and other inflammatory interstitial diseases (eg,
therapy. Amiodarone is an iodine-containing BOOP and chronic eosinophilic pneumonia).
phospholipase inhibitor that causes lipid accu- Chest CT scans may reveal high attenuation
mulation in nearly all tissues, especially the areas due to the iodine present in amiodarone.
lungs, skin, and liver. This blockade results in However, this is a nonspecific finding that may
the accumulation of undigested surfactant phos- be present in healthy subjects. The typical PFT
pholipids in the lung, which is a feature that is abnormalities include a reduction in the DLCO
seen in virtually all patients receiving the drug. and reduced lung volumes. Although a de-
The histologic features of amiodarone- creased DLCO is a nonspecific finding seen in all
induced pulmonary toxicity include the follow- patients with amiodarone-induced disease, a
ing: (1) accumulation of foamy macrophages normal DLCO suggests that heart failure rather
with characteristic lamellated inclusions in the than amiodarone may account for the patient’s
interstitium and alveolar spaces, (2) hyperplasia respiratory symptoms. In patients being consid-
of alveolar type II cells, and (3) widening of the ered for amiodarone, guideline recommenda-
alveolar septa with infiltration of lymphocytes, tions recommend a yearly chest radiograph and
plasma cells, eosinophils, and neutrophils. Ede- baseline PFT that should be repeated if the
ma, intra-alveolar fibrin exudation, lamellar patient develops unexplained dyspnea.25 Bron-
inclusions in pulmonary endothelial cells, bronchoscopy may be necessary to exclude infection.
chiolar epithelial cells and type II cells, and KL-6, which is a high-molecular-weight glyco-
fibrosis can also occur. protein secreted by alveolar type II cells, is a
The clinical and laboratory manifestations of potentially useful serum marker that is elevated
amiodarone-induced pulmonary toxicity include (.500 U/mL) in patients with interstitial lung
the following: (1) interstitial pneumonitis/fibro- disease due to IPF, radiation, and amioda-
sis, (2) ARDS, (3) COP, (4) mass lesions that can rone.78,79 Serum KL-6 levels are typically ,500
cavitate, (5) eosinophilic pneumonia, (6) diffuse U/mL in patients with congestive heart failure
alveolar hemorrhage, and (7) pleural effusions. and pneumonia. Although further studies are
Uncommon reactions include hypersensitivity necessary to corroborate the findings of these
pneumonitis, alveolar hypoventilation, and bron- small observational studies, the sensitivity and
chospasm. The patients typically present with an specificity of an elevated serum KL-6 level in
insidious onset of a nonproductive cough and identifying interstitial disease approaches 94%
dyspnea with radiographic evidence of asym- and 96%, respectively.78,79
metric chronic pneumonitis/fibrosis and an The management of amiodarone-induced pul-
elevated ESR. Occasionally, ill-defined alveolar monary toxicity includes drug withdrawal and the
infiltrates, a lung mass, or pleural effusions may initiation of a new antiarrhythmic agent or
be seen. Risk factors for amiodarone-induced implantation of an automatic cardioverter/defi-
adverse pulmonary side effects are not firmly brillator if required. A trial of corticosteroids is

often used in symptomatic patients, but the Angioneurotic edema is a rare adverse effect
efficacy of steroids has not been established. of ACE inhibitors (0.1% to 0.2% of patients) that
Radiographic resolution generally occurs over 2 is potentially life threatening.82 It is manifested
months, and patients are treated for at least 6 by swelling of the tongue, lips, and mucous
months to reduce the likelihood of relapse. membranes within hours or at most 1 week after
Recurrent amiodarone pulmonary toxicity can initiating treatment and can rapidly evolve into
also occur. If amiodarone is the only effective acute respiratory distress, upper airway obstruc-
agent in a patient with life-threatening arrhythmi- tion, and death. Patients with a history of
as, the dose must be reduced to the minimum that idiopathic angioneurotic edema should avoid
is effective (ideally ,400 mg/day) and corticoste- using ACE inhibitors since they may be at
roids added to therapy. Dronedarone, a synthetic increased risk. The mechanism underlying this
analogue of amiodarone, is efficacious in prevent- serious adverse effect is unknown, but immune
ing recurrence of atrial fibrillation but without pathways, increased tissue levels of bradykinin
significant pulmonary toxicity evident to date.80 or histamine, and/or a deficiency of complement
However, the utility of dronedarone is limited by 1-esterase inactivator have all been implicated.
its uncertain efficacy in preventing ventricular The management of ACE inhibitor-induced
arrhythmias as well as concerns about mortality in angioedema includes drug withdrawal, attention
patients with congestive heart failure.80 to airway patency, and, if severe, the subcutane-
ACE Inhibitors: Cough occurs in 5% to 35% of ous injection of epinephrine (0.01 mL/kg body
weight of a 1:1000 solution) every 15 to 20 min
patients receiving any type of ACE inhibitor.10
along with IV saline solution to correct hypoten-
The cough generally appears from 1 to 2 months
sion. Diphenhydramine (1 to 2 mg/kg up to 50
up to 1 year after initiating therapy. Patients
mg IV or IM) and steroids are also useful.
without asthma in whom ACE inhibitor-induced
b-Blockers: b-Adrenergic receptor blockers
cough develops, compared to those patients
administered by any route (eg, oral, IV, or
without cough, are slightly more sensitive to
ophthalmic solutions) can precipitate broncho-
methacholine. However, ACE inhibitors do not
spasm, especially in patients with asthma or
consistently cause airways obstruction nor are
COPD. Propranolol, a nonselective b-blocker,
patients with asthma at an increased risk.81
causes dose-dependent reductions in airflows
Although the mechanism of ACE inhibitor-
and should be avoided in patients with asthma
induced cough has not been firmly established,
or COPD.83 Timolol, a nonselective b-blocker
it likely involves blocking the metabolism of used in ophthalmic solutions, has predictable
cough-inducing neuropeptides, such as sub- adverse effects on these patients similar to
stance P and bradykinin. Before extensive testing propranolol and should also be avoided. Severe
is performed to evaluate the source of a cough in bronchospasm and sporadic deaths have been
a patient receiving ACE inhibitors, therapy with reported with nonselective b-blocker ophthalmic
the drug should be discontinued. Patients with solutions. Physicians should specifically inquire
an ACE inhibitor-induced cough will generally about ophthalmic solutions in patients with
show resolution within 1 to 4 days. Management glaucoma presenting with respiratory complaints
is simple: avoid all ACE inhibitors. Patients can since most patients do not consider these to be
be switched to an angiotensin II receptor antag- drugs. Selective b1-blockers (eg, atenolol and
onist (eg, losartan), which rarely induces cough.11 betaxolol ophthalmic solution) are better tolerat-
However, losartan can induce angioedema in a ed in patients with airflow obstruction. A 2002
manner similar to that of ACE inhibitors.12 If meta-analysis84 showed that selective b1-blockers
ACE inhibitors are required for the management are well tolerated in patients with asthma and
of a patient’s cardiovascular disease and there COPD and result in minimal reductions in FEV1
are no alternative agents, there are reports that when used over the long term. A recent study
the cough can be partly controlled with either showed that cardioselective b-blockers reduce
theophylline, inhaled cromolyn, nifedipine, in- mortality in patients with COPD undergoing
domethacin, amlodipine, or ferrous sulfate.10 vascular surgery.85 Thus, in carefully selected

patients with COPD, the use of cardioselective b- Statins: Statins are the most widely prescribed
blockers can be safely used. However, caution is lipid-lowering drug, primarily because of their
warranted because b1 selectivity is relative since well-documented beneficial effect on cardiovas-
b1-selective inhibitors, especially in high doses, cular morbidity and mortality. Statins inhibit
can block b2-adrenergic receptors and trigger cholesterol formation by blocking 3-hydroxy-3-
bronchospasm. Esmolol is the drug of choice in methylglutamyl reductase. There have been
critically ill patients with asthma or COPD who several case reports88,89 of statin-induced hyper-
require a b-blocker (eg, unstable angina) because sensitivity pneumonitis and NSIP resulting from
it is an IV selective b1-blocker in doses of ,300 exposure to pravastatin, lovastatin, or simvasta-
lg/kg/min and has an extremely short half-life tin. The chest radiographic abnormalities include
(approximately 9 min). bilateral patchy ground-glass opacities and in-
Long-Acting b-Agonists: Long-acting b-ago- terstitial infiltrates. Although the mechanism of
nists (LABA), which were introduced in the lung injury is unknown, increased alveolar CD8þ
1990s, are efficacious as ‘‘add-on’’ medication to suppressor T lymphocytes, hyperplastic type II
inhaled corticosteroids (ICS) in patients with pneumocytes, peripheral blood eosinophilia, and
asthma and COPD as well as monotherapy in clinical deterioration accompanying statin rein-
patients with COPD without asthma. As re- troduction support hypersensitivity in the path-
viewed in detail elsewhere,86,87 the US Food ogenesis. Statin-induced pneumonitis may
and Drug Administration released a ‘‘black-box become more commonly observed when used
warning’’ in 2010 regarding safety concerns of at the higher doses advocated in some reports for
LABAs (salmeterol and formoterol) in patients the prevention of cardiovascular diseases.
with asthma largely due to increased asthma
deaths, intubations, and hospitalizations relative Illicit Drugs
to non-LABA treatment. Based on these studies,
the specific US Food and Drug Administration- The use of illicit drugs continues to be a
regulated label changes for asthma included (1) significant health-care problem of epidemic pro-
the use of LABAs without the use of an asthma portions worldwide. Respiratory symptoms in
controller medication such as an ICS is contrain- patients using illicit drugs may be due to a wide
dicated (absolutely advised against) in the array of pulmonary disorders, including (1)
treatment of asthma; (2) LABAs should be used alveolar hypoventilation (hypercarbic respiratory
only as additional therapy for patients with failure); (2) aspiration; (3) noncardiogenic pulmo-
asthma who are currently taking a long-term nary edema; (4) barotrauma (eg, pneumothorax,
asthma control medication such as an ICS but pneumomediastinum, and pneumoperitoneum);
whose symptoms are not adequately controlled; (5) endocarditis/septic emboli; (6) foreign-body
(3) LABAs should be used only for the shortest granulomatosis; (7) PIE; (8) BOOP; (9) alveolar
period of time required to achieve control of hemorrhage; (10) bronchospasm; (11) interstitial
asthma symptoms and then discontinued, if pneumonitis/fibrosis; and (12) HIV-associated
possible, once asthma control is achieved; and infections. Knowledge about the drugs used, the
(4) pediatric and adolescent patients who require route of administration, and the presenting
the addition of an LABA to an ICS should use a clinical syndrome helps to narrow the broad
combination product containing both an ICS and differential diagnosis in these patients.
a LABA to ensure adherence to both medi- Noncardiac Pulmonary Edema: Noncardiac pul-
cations.86 Although the combination of LABAs monary edema is an infrequent complication of
and ICS is clearly efficacious in improving heroin, cocaine, or methadone abuse, but heroin
asthma control in patients who have failed low abuse is by far the most common cause.90
to high doses of ICS monotherapy, further Naloxone, an opiate antagonist, also causes a
studies that are adequately powered to deter- similar syndrome. There are no known risk factors
mine whether LABA-ICS treatment is associated for opiate-induced pulmonary edema. Although
with adverse asthma outcomes, such as asthma- the pathogenesis is not established, several mech-
related deaths, are necessary.86,87 anisms have been proposed, including: (1) altered

alveolar/capillary permeability, (2) neurogenic black, soot-like material (approximately 10% to
pulmonary edema, (3) direct opiate cytotoxicity, 33% of patients), bronchospasm (approximately
(4) drug hypersensitivity, and (5) hypoxemic 50% of patients), and thermal burns to the upper
alveolar injury. However, none of these mecha- and lower airways. Other pulmonary complica-
nisms have been adequately tested in animal tions of crack cocaine use include PIE, COP,
models or human studies. Typically, patients pulmonary hypertension, alveolar hemorrhage/
present within minutes to hours (at most 24 h) hemoptysis, and barotrauma (eg, pneumothorax,
after use with dyspnea, reduced respirations and pneumomediastinum, and pneumoperitoneum).
mental status, miotic pupils, and a chest radio- Barotrauma is likely due to the Valsalva maneu-
graph demonstrating perihilar alveolar infiltrates ver performed to enhance alveolar-capillary
in a ‘‘batwing’’ distribution. Pathologic studies cocaine absorption. The DLCO is either normal or
from autopsies have revealed changes similar to mildly reduced within weeks to months after
ARDS, such as (1) alveolar edema and hemor- using crack cocaine.91–93 The reason for the
rhage, (2) diffuse alveolar damage, (3) hyaline reduction in DLCO is unclear but may reflect a
membranes, (4) interstitial inflammatory cell loss of alveolar-capillary surface area.91–93 Some
infiltrates, and (5) type II cell hyperplasia. evidence94 has demonstrated that crack users
Management centers on supportive care, includ- have increased lower respiratory tract iron and
ing mechanical ventilation, which is needed in ferritin levels that may contribute to lung injury
40% of cases.90 Unlike other causes of ARDS, the via oxidant-induced mechanisms.
prognosis in opiate-induced noncardiogenic pul- Foreign-Body Granulomatosis: Foreign-body
monary edema is good, with resolution of granulomatosis is due to the IV injection of
pulmonary edema over 48 to 72 h, and nearly all insoluble particulate contaminants used to ‘‘cut’’
patients survive. street heroin or from talc or cellulose in crushed
Cocaine: Cocaine, which is an alkaloid ex- tablets (eg, amphetamines, methadone, or hydro-
tracted from the leaves of Erythroxylon coca morphine). Initially, patients may be asymptom-
species is a sympathomimetic agent that causes atic despite abnormal chest radiograph findings
topical anesthesia and CNS stimulation. Cocaine showing reticular nodular interstitial infiltrates.
hydrochloride, the salt form that can be injected However, relentless progression of the infiltrates
IV or rapidly absorbed across the nasal mucosa, generally occurs, accompanied by increasing
causes pulmonary manifestations similar to those dyspnea. The nodules may coalesce in a manner
of IV opiates (eg, heroin). A unique feature of similar to that seen in silicosis, resulting in
cocaine is that it causes nasal mucosal vasocon- progressive massive pulmonary fibrosis with
striction that can result in ischemic necrosis and surrounding cysts and bullae. Notably, PFT
the perforation of the nasal septum. Free-base results reveal airways obstruction, rather than
cocaine, which is derived from the alkaline restriction, that progresses to severe disease with
crystallization of the salt, vaporizes when heated a reduced DLCO.95 The lungs demonstrate vascu-
and is rapidly absorbed across the respiratory lar and interstitial noncaseating giant cell gran-
membranes. The term crack refers to the popping ulomatous infiltrates containing birefringent talc
sound that occurs when cocaine crystals are crystals. As the disease progresses, parenchymal
heated. destruction and pulmonary hypertension occur,
Free-base crack cocaine smoking causes a leading to respiratory failure/cor pulmonale. The
distinct set of pulmonary abnormalities that are poor outcome noted in most patients is generally
termed crack lung.91 These patients typically not altered by therapy with corticosteroids.
present with cough, chest pain, dyspnea, hemop-
tysis, and wheezing. Chest pain from either a Miscellaneous Agents
pulmonary or cardiac origin occurs in approxi-
mately 20% to 40% of cocaine users. Cocaine can Contrast Media: Both the ionic and the
induce direct coronary artery vasoconstriction. nonionic forms of contrast media can induce
Unlike IV crack users, patients with crack lung bronchospasm and a reduction in air flow.
from inhalation may have a cough productive of Typically, this occurs within 5 min of infusion

and resolves within 30 min after infusion. pain, tachycardia, tachypnea, hypoxemic respi-
Contrast media rarely induces potentially fatal ratory failure, and diffuse alveolar infiltrates seen
leukostasis in the pulmonary arterioles and on a chest radiograph. The differential diagnosis
capillaries.96 This occurs within minutes to an includes gastric acid aspiration, cardiac pulmo-
hour after injection, resulting in dyspnea and nary edema, pulmonary embolism, amniotic
hypoxemic respiratory failure due to noncardio- fluid embolism, and peripartum cardiomyopa-
genic pulmonary edema. Although the mecha- thy. The transthoracic echocardiogram findings
nism is unclear, a complement-mediated are generally normal. Management involves
pathway has been implicated. Management supportive care and diuresis. The prognosis is
centers on supportive care and therapy with generally favorable, with intubation/mechanical
high-dose corticosteroids, IV diphenhydramine, ventilation required in ,10% of patients and a
and heparin. mortality rate of nearly 3%.99
Interferon-c1b: Although there are no proven Sirolimus (Rapamycin): Sirolimus is an immu-
treatments for IPF, some studies have suggested nosuppressive agent used in organ transplant
a possible role for interferon (IFN)-c1b based on patients in the presence or absence of cyclospor-
its antifibrotic actions (eg, decreases fibroblast ine. The frequency of pulmonary toxicity varies
proliferation and collagen synthesis, augments from rare to approximately 11%.100,101 Of 24
fibroblast apoptosis, and inhibits profibrotic patients with sirolimus associated pneumonitis,
cytokine production) and its protective effect in symptoms occurred within 5 months of initiating
animal models of pulmonary fibrosis. Acute therapy and consisted of cough (96%), fatigue
respiratory failure developed in four patients (83%), fever (67%), and dyspnea (33%).100,101 The
with severe IPF (total lung capacity: 38% to 59% HRCT scan/pathologic patterns include BOOP
predicted; DLCO: 20% to 37% predicted) after 2 to (79%), ground-glass attenuation (17%), and, less
35 doses of IFN-clb.97 In two patients who commonly, interstitial fibrosis, alveolar proteino-
underwent a lung biopsy, pathologic studies sis, necrotizing vasculitis, and pleural effu-
revealed diffuse alveolar damage. To date, there sions.100,101 BAL findings show a lymphocyte
is no clear beneficial role for IFN-clb in the predominance (CD4 . CD8) with occasional
management of IPF, yet serious adverse pulmo- eosinophils and rarely (8%) diffuse alveolar
nary toxicity can occur, especially in patients hemorrhage. Sirolimus withdrawal results in
with severe disease. complete recovery within weeks to 6 months.
Tocolytic Agents: Tocolytic agents, such as
albuterol, terbutaline, ritodrine, isoxuprine, and Acknowledgment
salbutamol, are b-adrenergic agents used to
inhibit uterine contractions during premature This work was supported in part by a
labor. Although acute pulmonary edema report- Veterans Affairs Merit Award and the NIEHS
edly occurs in 0.5% to 5% of patients, in one (RO1ES020357).
study98 of 8,700 patients there was an incidence
of only 0.32% The mechanism of pulmonary Relationships Disclosed
edema has not been established but is believed to
be due to b-adrenergic-induced peripheral vaso- The author has disclosed the following
dilation and increased intravascular volume. relationships: Grant monies (from sources other
After the tocolytic drug is discontinued, the than industry): VA Merit Review. Fiduciary
vascular tone normalizes, thereby promoting position (of any organization, association, society,
fluid movement into the extravascular spaces, etc, other than ACCP: Associate Editor—Trans-
including the alveoli. Left ventricular function lational Research. Consultant fee, speaker bu-
and pulmonary wedge pressure are usually reau, advisory committee, etc: Speaker bureau:
normal. Patients typically present during or Boehringer Ingelheim, GSK, Pfizer. The ACCP
within 12 h of delivery (rarely beyond 12 h Education Committee has reviewed these rela-
postpartum) with an acute onset of dyspnea, tionships and resolved any potential conflict of
cough productive of pink-tinged sputum, chest interest.

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Chapter 18. Pneumoconiosis
Objectives: with mineral dust exposure. The term has

Review the epidemiology, pathophysiology, and clinical evolved to imply the putative dust (eg, silico-
manifestations of silicosis and coal workers’ pneumoco- sis/silica, asbestosis/asbestos, berylliosis/beryl-
niosis.
Understand the pulmonary manifestations of asbestos-
lium, stannosis/tin) or workers who are at risk
induced diseases of the lung (asbestosis and rounded (coal workers’ pneumoconiosis [CWP], hard-
atelectasis) and of the pleura (effusions and plaques). metal lung disease). The International Labor
Discuss the malignancies associated with asbestos
Organization (ILO) defines pneumoconiosis as
exposure (bronchogenic carcinoma and mesothelioma).
Review a variety of other pneumoconioses (talcosis, the accumulation of mineral dusts inciting tissue
berylliosis, and hard-metal lung disease). reactions that range from minimal stromal
reactions that are reversible to interstitial fibrosis
Key words: asbestos; coal; lung cancer; mesothelioma; that results in permanent scarring.1 The term is
pulmonary fibrosis; silica often further restricted to nonneoplastic disease
excluding asthma, chronic bronchitis, and em-
Synopsis:
physema, all of which can occur with occupa-
Pneumoconiosis includes lung diseases associated with
tional dust exposure. The patient with
mineral dust exposure. The term is often restricted to
nonneoplastic disease excluding asthma, chronic bronchitis, pneumoconiosis typically presents with nonspe-
and emphysema, all of which can occur with occupational dust cific respiratory symptoms (eg, cough and
exposure. The patient with a pneumoconiosis often presents dyspnea) and an abnormal chest radiograph
with nonspecific respiratory symptoms (eg, cough and
dyspnea) and/or abnormal chest imaging findings. A thor- finding. A careful lifetime occupational history
ough lifetime occupational history is crucial in identifying the is absolutely essential in the evaluation of the
origin of a particular patient’s complaints. Mineral dusts cause cause of a particular patient’s complaints. This is
pulmonary interstitial lung diseases and malignancies by
molecular mechanisms that are not fully understood. The
especially important given the large number of
mode of action underlying each pneumoconiosis appears workers exposed to mineral dusts during their
distinct depending upon the mineral dust type and host lifetime and the significant morbidity and mor-
genetics affecting susceptibility. In this chapter we focus on tality associated with this exposure.
four broad areas including (1) reviewing the epidemiology,
pathophysiology, and clinical manifestations of silicosis and
coal workers’ pneumoconiosis; (2) understanding the pulmo- Silicosis
nary manifestations of asbestos-induced diseases of the lung
and of the pleura; (3) discussing the malignancies associated
with asbestos exposure; and (4) reviewing some of the other
Definition
relevant pneumoconioses, such as talcosis, berylliosis, and
hard-metal lung disease. A better understanding of the clinical Silicosis is a chronic lung disease that is
manifestations and the underlying molecular basis of mineral caused by the inhalation of crystalline silica
dust-induced lung diseases will hopefully augment early
diagnosis, as well as the development of novel therapeutic (usually quartz, and, less commonly, cristobalite,
targets for managing these diseases and other more common tridymite, coesite, and stishovite), which is
degenerative diseases (eg, pulmonary fibrosis), lung cancer, characterized by progressive parenchymal nod-
and aging for which effective management is lacking.
ules and pulmonary fibrosis. Silica or silicon
dioxide is the most abundant mineral in the crust
of the earth and is used in a wide range of
Introduction industrial products. Amorphous or noncrystal-
line silica particulates (eg, diatomite and vitreous
Pneumoconiosis is a 19th century Greek term silica) are relatively less fibrogenic, but when
(pneumo meaning ‘‘breath’’; konis meaning they are combined with metal complexes to form
‘‘dust’’) that describes lung diseases associated silicates, as occurs with asbestos, mica, or talc,

Table 1—Some High-Risk Industries and Occupations Associated With Silica Exposure
Industries (Examples) Occupations
Mining, Tunneling, and Excavating

Underground: gold, copper, iron, tin Miner, driller, tunneler
Surface: coal, iron, foundation excavation Drill operator
Quarrying: granite, slate, sandstone Digger, driller, hammerer
Stonework: granite sheds, monument masonry Cutter, dresser, polisher, grinder
Foundries: iron and noniron metals Molder, caster, knockout man
Abrasives: metal polish, paint fillers, sandblasting, oil rigs, tombstones Crusher, mixer, abrasive work
Denim jean sandblasting
Ceramics: pottery, stoneware, oven bricks Oven-brick maker
Others: glassmaking, boiler scaling, gemstone working, dental Dental technicians
Modified from Cowie et al.1
they induce unique forms of pulmonary toxicity, concentration of .100 lg/m3, which is greater
each of which will be reviewed separately. than the Occupational Safety and Health Admin-
Silica-associated lung disease is among the istration (OSHA) PEL for an 8-h work exposure.3
earliest lung diseases described and has been the
most intensively studied occupational lung dis- Industries/Occupations at Risk
ease. In 1556, Agricola described the pulmonary
effects of inhaled dusts from mining and the Some of the major industries in which
production of metals; van Diemerbroeck in 1672 workers are at high risk for silica exposure are
noted similar problems in stone cutters.2 listed in Table 1, along with some examples of
hazardous occupations. These include industries
Epidemiology that involve work in mines, in quarries, with
stonework, and in foundries; the use of abrasives;
Silicosis is the most prevalent chronic occu- and ceramic production. Another high-risk
pational disease worldwide. The risk for silicosis group includes persons working in road mainte-
is directly proportional to the particle concentra- nance that involves ‘‘cut and repair,’’ where
tion, the duration of exposure, and the silica potentially elevated levels of silica exposure
content of different rock types, which ranges occur during the cutting, breaking up, and
from nearly 100% (sandstone and flint) to ,10% removal of concrete. Since 2005, an epidemic of
(shale). In 2006, the National Institute for accelerated and acute silicosis has been reported
Occupational Safety and Health (NIOSH) esti- in Turkish laborers involved with sandblasting
mated that each year .1 million US workers are denim jeans to fade color.5 With an estimated
at risk for the development of silicosis.3 The silica exposure level approaching 100 mg/m3
annual number of silicosis deaths have declined (1,000-fold higher than the OSHA PEL), it is not
nearly 85% from a high of 1,135 (8.74 per million surprising that nearly 50% of the workers
per year) to a low of 125 (0.52 per million per (approximately 5,000 overall) develop silicosis.5
year) in 2006.3,4 The dust control measures and Although the Turkish Ministry of Health banned
workplace permissible exposure limits (PELs) denim jean sandblasting in 2009, this work has
that have been established by most industrial moved to China, India, Mexico, and other
countries have significantly decreased the num- countries.5 A careful occupational history for
ber of deaths due to silicosis. However, the silica exposure is essential for any patient
number of silicosis-associated deaths among presenting with pulmonary nodules, masses, or
persons aged 15 to 44 years has not decreased interstitial lung disease. This is particularly
significantly in the United States.3 Furthermore, important given the long latency between toxic
11% to 40% of the workplaces (especially iron exposure and appearance of the disease; the large
and steel foundries) inspected between 1993 and number of workers exposed in past years before
2003 had at least one air sample containing a stringent work safety measures were invoked in
260 Chapter 18. Pneumoconiosis (Kamp)

Figure 1. A, Silicotic nodule. B, Coal macule. Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed.
Northbrook, IL: American College of Chest Physicians; 2009.
the 1970s; and the fact that silicosis, like most concentrically layered collagen; and (3) a periph-
pneumoconioses, can progress in the absence of eral thick capsule consisting of dust-laden mac-
additional exposure. rophages and lymphocytes mixed with collagen.
Silicotic nodules, which can develop decades
Pathology after exposure, are typically scattered throughout
the upper lung zones, sparing most of the lung
There are three distinct forms of silicosis, as parenchyma, and thereby causing minimal
follows: chronic (the most common), acute, and symptoms (Fig 2).
accelerated. The chronic form is characterized by Simple silicosis, which is the earliest stage of
silicotic nodules that are typically located in the chronic silicosis, can become complex silicosis as
peribronchial regions with interstitial extension, the nodules expand, affecting the bronchioles
,1 cm in diameter, well formed, spherical, hard, and vasculature, and eventually coalescing into
and light gray (Fig 1, A). This is in contrast to the large masses (progressive pulmonary fibrosis
heavily pigmented, black stellate nodules that are [PMF]) that can undergo necrosis (Fig 3).
associated with coal exposure (Fig 1, B). The However, the presence of central cavitation
silicotic nodule has three components, as follows: should raise concern about TB. The adjacent
(1) a central area of dense, acellular, hyalinized lung may show signs of retraction and emphy-
collagen-containing silica particles that are visi- sema. If silica is mixed with other dusts (eg, coal,
ble with polarized light; (2) a midzone of mica, and kaolin), then the nodules become less

Figure 3. Progressive massive pulmonary fibrosis due to
silica exposure. Reprinted with permission from ACCP
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
relationship between specific silica subtypes and

the development of pulmonary fibrosis is unclear,
but quartz, cristobalite, and tridymite are more
fibrogenic than is amorphous silica. Silica parti-
Figure 2. Simple silicosis. Reprinted with permission from cles that are ,5 lm in size can make their way to
ACCP Pulmonary Medicine Board Review. 25th ed. North- the distal alveoli, where they are ingested by
brook, IL: American College of Chest Physicians; 2009.
alveolar macrophages (AMs), which are the first
line of alveolar defense. Silica-activated AMs
distinct and more stellate in appearance. Silicotic
subsequently release reactive oxygen species
nodules may also form in the hilar and medias-
(ROS), reactive nitrogen species, fibronectin, and
tinal lymph nodes, which can become calcified
various cytokines and growth factors. In partic-
(so-called eggshell calcification, as shown in Fig
ular, silica and other particulates activate the
4) and may impinge on the airways (broncho-
expression of transforming growth factor-b (TGF-
liths). Silicotic nodules can form outside the
b), resulting in excess extracellular matrix depo-
lungs (eg, liver, spleen, bone marrow, and sition. Silica can also directly injure alveolar type I
kidney). In the kidney, silicon nephropathy can cells, which leads to the formation of hyperplastic
have a variable presentation from mild renal type II cells. If extensive alveolar damage occurs,
insufficiency to rapidly progressive renal failure as seen with intense exposure to high levels of
associated with necrotizing vasculitis. silica, surfactant production and processing are
Acute silicosis is characterized by diffuse altered, resulting in acute silicosis. PMF, which
fluid-filled alveolar spaces that consist of eosin- can occur with both silica and coal exposure, may
ophilic, proteinaceous, and surfactant-containing ensue over time but may also occur in association
material. The interstitial space typically shows with a mycobacterial infection. Figure 5 depicts
extensive alveolar epithelial cell damage with some of the key pathogenic events leading to
hypertrophic alveolar type II cells, as well as silicosis and highlights the overlapping molecular
small focal nodules and fibrosis. pathways that are activated by other mineral
dusts such as coal and asbestos. Accumulating
Pathogenic Mechanisms evidence implicates an important role for regula-
tory T lymphocytes (Tregs) mediating silicosis in
The risk for silicosis depends on the level of a murine model via mechanisms involving TGFb
particle exposure (dose and duration), as well as and platelet-derived growth factor release.7 In the
the content and type of silica inhaled.6 The precise absence of Tregs, however, effector T cells

Figure 4. A, Chest radiograph from a patient with silicosis, showing left hilar adenopathy with eggshell calcification. B, Chest
CT scan demonstrating eggshell calcification. Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed.
promote silicosis by mechanisms involving the underlying the distinct clinical manifestations of
release of IL-4, IL-1b, and interferon c.7 The role of each mineral dust are unknown but likely relate
Tregs and effector T cells after coal and asbestos in part to the differences in the deposition
exposure is uncertain. The precise mechanisms patterns of the various dusts into the distal
Figure 5. A simplified, hypothetical model of mineral dust-induced pulmonary toxicity (see text for details). Reprinted with
permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.

airways, the chemical composition of each par- dyspnea, cough, and sputum production. Inspira-
ticulate, and the genetic background of the tory crackles and digital clubbing are unusual and
worker in whom the host response is regulated. suggest an alternative cause such as another
Control study results involving 183 patients with interstitial lung disease, bronchogenic carcinoma,
silicosis and 111 silica-exposed miners in China or infection. In a study10 of 243 patients with
identified several interesting genetic polymor- silicosis/mixed-dust pneumoconiosis and 62 pa-
phisms that will need to be verified by a larger tients with idiopathic pulmonary fibrosis (IPF), the
cohort.8 prevalence of chronic interstitial fibrosis, as defined
by chest CT scan, was 12% in the silicosis/mixed-
Clinical Features dust exposure group, for which 75% of the lesions
were IPF-like. Cor pulmonale and cyanosis can
Patients with silica-induced lung disease can occur in the advanced phase of silicosis.
present with chronic, accelerated, or acute onset Patients with accelerated and acute forms of
of disease, depending on the intensity and silicosis typically present within months to a few
duration of the silica exposure. Chronic silicosis, years after intense silica exposure rather than
the most common form, typically occurs after decades. Dyspnea occurs after 5 to 15 years of high
low-dose silica exposure for .20 years. The levels of occupational exposure to material with
prevalence estimates of silicosis in exposed moderate levels of quartz-containing silica. The
workers varies from 0.4% to 11% after 20 years condition of these patients often progresses to
of exposure to the OSHA PEL of 100 lg/m3 to respiratory failure and death. Patients with acute
1.2% to 53% after a cumulative exposure of 4 silicosis generally present within several months to
mg/m3 (Finkelstein9). Silica death rates during years after intense exposure to high levels of silica
the period between 1995 and 2004 were higher (eg, sandblasting, surface drilling, tunneling, silica
among black men than among white men.3 Most flour milling, and ceramic production), often with
patients with chronic simple silicosis are rela- little or no respiratory protection. The chest
tively asymptomatic, and the diagnosis is estab- radiograph is characterized by a diffuse alveolar
lished by the occupational exposure history and pattern similar to that seen in patients with alveolar
characteristic chest radiograph findings. A lung proteinosis. Dyspnea, cough, and weight loss,
biopsy is generally reserved for patients with which will rapidly progress to respiratory failure
atypical occupational exposure or chest radio- and death, develop in these patients.
graph findings. Silicotic nodules are generally Pulmonary function tests (PFTs) correlate
small (1 to 3 mm), symmetrical, upper lobe- poorly with the presence of nodules as assessed
predominant lesions that favor the posterior by means of a chest CT scan. Patients with early
aspects of the lungs but can involve other lung silicosis may show normal volumes, airflows,
zones. Calcification is evident in 10% to 20% of and diffusing capacity of the lung for carbon
the pulmonary nodules. monoxide (DLCO). AS the disease progresses or
Complicated silicosis consists of conglomerat- the level of silica exposure increases, a progres-
ed nodules that can eventually form masslike PMF sive restrictive pattern with a reduced DLCO
lesions. The PMF lesions, unlike those in broncho- typically develops.11,12 Occasionally, an obstruc-
genic carcinoma, are typically symmetrical in tive or mixed pattern may be evident. Among
location and may have an ‘‘angel’s wing’’ appear- 529 patients with silicosis, 30% of never-smokers
ance. Eggshell calcification (Fig 4) is infrequent; if and 28% of smokers had restriction; 17% and
present, it strongly suggests a silicosis diagnosis but 26.5%, respectively, had obstruction; and 22.4%
is not pathognomonic. Over time, the mass lesions and 25.7%, respectively, had a mixed restrictive/
tend to contract, especially in the upper lobes, obstructive defect.13 In patients with simple
resulting in a rim of emphysema surrounding the silicosis, the chest radiographic abnormalities
mass. Although central necrosis similar to TB may are typically more impressive than the PFT
develop in the mass, active TB should be suspected changes. When compared with patients with
whenever a lesion changes in size or cavitates. As simple silicosis, however, patients with conglom-
the disease progresses, patients may note exertional erate, accelerated, or acute silicosis invariably

demonstrate progressive restrictive physiology The risk for lung cancer in workers exposed
and reduced DLCO. to silica but who do not have silicosis is
controversial. In 1997, the International Agency
Complications for Research on Cancer concluded that there was
sufficient evidence implicating silica in the form
TB can occur at any stage of silicosis, but of quartz or cristobalite as a group 1 human
generally the rate increases as silicosis progresses. carcinogen.9,16 Results from more than 20 studies
Pulmonary TB must always be considered in have suggested that men with silicosis have a
patients with PMF, a group of patients with a twofold to fourfold increased risk of dying of
significantly increased risk of morbidity and lung cancer. However, the risk from confounding
mortality. There is a threefold greater risk for variables (eg, smoking and exposures to other
developing pulmonary TB in patients with chronic dust, such as asbestos) in some of these stud-
silicosis than in healthy individuals.14 Silica expo- ies12,17 is unclear. It is uncertain whether the lung
sure alone in the absence of silicosis is also a risk cancer risk is restricted to workers with silicosis,
factor for pulmonary TB, and the increased risk since pulmonary fibrosis per se is a well-known
persists after silica exposure has stopped.4 Among risk factor for lung cancer. Investigators in some
16,648 silicotic deaths in the United States between studies18,19 have noted a dose-response relation-
1968 and 2006, 2,278 (13.7%) had pulmonary TB ship between lung cancer mortality and cumula-
listed on the death certificate.4 Notably, in 2006 tive silica exposure among workers without
silicotic pulmonary TB deaths were zero for the first silicosis. A 2011 analysis20 of 38 studies involving
time since 1968.4 Current smokers have a dose- patients with silicosis reported a twofold increase
dependent increased risk for developing TB, in lung cancer risk (relative risk [RR], 2.1; 95%
compared with that for other silicotic patients, after confidence interval [CI], 2.0–2.3), whereas results
from eight studies involving patients without
correcting for confounders.15 Because silica impairs
silicosis without a smoking adjustment had
AM function, the risk for mycobacterial infections
marginally increased risk (RR, 1.2; CI, 1.0–1.4),
such as Mycobacterium tuberculosis, Mycobacterium
but 3 studies that adjusted for tobacco exposure
kansasii, and Mycobacterium avium-intracellulare is
showed a null response. Thus, the carcinogenic
increased. A clinical suspicion of pulmonary TB
role of silica alone in the absence of silicosis
should be considered with nonspecific complaints
remains unclear.
such as fever, weight loss, hemoptysis, malaise, or
Crystalline silica exposure has also been
increased dyspnea, all of which can be seen in
causally attributed to other diseases such as
patients with PMF or a variety of other infections.
collagen vascular diseases (eg, rheumatoid ar-
Because of impaired host defense mechanisms and
thritis, scleroderma, vasculitis, and systemic
decreased drug penetration into silicotic nodules,
lupus erythematosus), sarcoidosis, glomerulone-
antituberculous therapy should be extended for at phritis, and hepatosplenic silicosis.12,16 However,
least 2 months beyond the typical 6-month course these associations are relatively rare and have not
for patients who demonstrate no cavities on the been well established.
chest radiograph and who have a smear result that
is negative for acid-fast bacilli.14 For patients with Treatment
silicosis who present with active pulmonary TB
with cavities and have smears positive for acid-fast There is no established treatment that can
bacilli, the recommended treatment duration is for prevent or reduce the pulmonary toxicity associ-
11 months rather than 9 months. TB prophylaxis ated with silica exposure. Because pulmonary
should be continued for 12 months with isoniazid fibrosis is irreversible in workers with chronic
alone or for 4 months if a 4-drug regimen consisting silicosis and is directly related to the level of
of isoniazid, rifampin, ethambutol, and pyrazin- silica exposure, any additional silica exposure
amide is used. Close posttreatment follow-up of must be avoided. NIOSH recommends an expo-
patients with silica-mycobacterial infections is sure limit of 50 lg/m3, while OSHA recommends
necessary because of the high relapse rate.14 a PEL of 100 lg/m3 despite the fact that these

Table 2—Pneumoconiosis Chest Radiograph Surveillance Guidelines
Particulate Frequencya
Silica
OSHA Preplacement; every 5 years if ,20 years of exposure; every 2 years if .20 years of exposure;
at employment termination
WHO Preplacement; then after 2–3 years of silica exposure; then every 2–5 years of silica exposure
and thereafter
ACOEM Preplacement; every 3 years if ,10 years of exposure; every 2 years if .10 years of exposure;
at employment termination
Asbestos
OSHA Preplacement; every 5 years if ,10 years of exposure; every 5 years if .10 years of exposure
up to age 35, then every 2 years up to age 45; then annually thereafter or at employment
termination if exposure of .0.1 fiber/mL
WHO Preplacement; every 3–5 years if ,10 years of exposure; every 1–2 years if .10 years of
exposure; annually if .20 years of exposure
Adapted from Muzaffar and Kales.21

a
Frequency of recommended chest radiographs by the OSHA, World Health Organization (WHO), or American College of
Occupational and Environmental Medicine (ACOEM); may be increased at the discretion of the treating physician.
levels have been associated with the develop- dioxide, calcite, and trace metals, such as
ment of silicosis.9,12 There are several NIOSH- cadmium, copper, nickel, iron, lead, and zinc.
approved air-purifying respirators with replace- CWP is distinguished from silicosis partly by the
able N95 filters that have been recommended for unique pathologic changes and the fact that
silica-exposed workers. For the workers who carbon tends to be less fibrogenic than quartz.
have the highest risk and are involved with However, mixed-dust exposures are well docu-
abrasive blasting, the only approved respirator is mented. The Mine Safety and Health Adminis-
the type CE abrasive blasting respirator that tration respirable coal dust PEL is 2 mg/m3,
completely covers the head and operates in a while NIOSH has set a standard of 1 mg/m3
positive-pressure mode. Table 2 lists the recom- (Castranova and Vallyathan16). Coal is ranked
mended chest radiograph surveillance guidelines into 4 types by carbon content, geologic age, and
from various groups for silica-exposed work- presence of contaminating minerals and oxygen.
ers.21 Treatment may be indicated to prevent The 4 types of coal are lignite, subbituminous,
silica-associated complications, as described bituminous, and anthracite. Bituminous coal
above, as well as assistance with pulmonary accounts for nearly 43% of the US coal reserves;
disability that may ensue in the advanced phases it is contaminated with low levels of silica and, in
of silicosis. Lung transplant has been performed the Pittsburgh area, surface-active iron (0.119
in a small number of patients with advanced mg/100 mg), which may account for its higher
silicosis.22 However, lung transplant has a limited pathogenicity.23
role in the treatment of silicosis, given the late age
of onset of severe pulmonary disability. Epidemiology
Coal Workers’ Pneumoconiosis Underground miners, compared with surface

or strip miners, have the greatest risk for the
Definition development of CWP. In the 1950s and 1960s,
there was an increase in mortality rate among
CWP, also known as black lung, is a distinct coal miners in part because of CWP.1,2,16 The
pathologic entity that results from chronic expo- extensive dust-control measures invoked in the
sure to coal dust, graphite, and other forms of 1960s through the 1970s in the United States and
carbon. Some of the mineral and elemental in other industrialized countries resulted in a
contaminants commonly found within coal in- substantial reduction in the prevalence and
clude pyrite, kaolinite, ankerite, quartz, titanium mortality of CWP. It is estimated that .100,000

workers are currently employed in the coal- Table 3—Prevalence of Radiographic-Evident CWP: 1970s
Through Mid-2000s
mining industry in the United States.2,16 As
shown in Table 3, CWP among active miners in Prevalence of CWP, %
Years of
the United States has declined from a rate of from Underground
20% to 35% in the 1970s to a rate of from 3% to Coal Exposure 1970s 1990s 2006
7% in the 1990s but increased to a rate of from 6%
20–24 20 3 6
to 10% in mid-2000s.3 The prevalence of CWP is
25–29 25 3 8
highest in the central Appalachian region but, .30 35 7 10
notably, is not fully explained by the measured
Data from NIOSH.3
direct coal exposure or the coal rank.24 Fortu-
nately, the prevalence of complicated CWP or
because of the greater levels of crystalline silica
PMF has declined from approximately 10% of
and in part because of the greater levels of carbon-
coal workers in the 1970s to approximately 1% in
centered free radicals. Coal mine dust fractured by
the mid-1990s.25 The risk for PMF is directly
grinding contains more free radicals than unfrac-
proportional to the radiographic profusion score
tured dust and is a better predictor of the toxic
and the levels of quartz in the coal being mined.
potential of the dust.23 There is a direct relation-
Pathology ship between the prevalence of CWP in 7 coal mine
regions of the United States and bioavailable iron
The initial lung tissue reaction to coal dust is in the coal.26 As shown in Figure 5, many of the
the formation of a coal macule, and when pathophysiologic events implicated in mediating
combined with surrounding focal emphysema, CWP are similar to those involved with silica.
defines simple CWP. Coal macules are typically Although coal and carbon are not toxic to AMs, the
up to 4 mm and tend to form at the junctions of combination of coal and quartz is. Coal dust is
respiratory bronchioles in the upper lungs (Fig 1, generally less fibrogenic than silica and tends to
B). The macule, consisting of coal dust-laden blunt the effects of quartz.23 In a study of 253 coal
macrophages and fibroblasts, enlarges, loosens miners,27 genetic polymorphisms for genes en-
the connections of the alveolar walls to the coding tumor necrosis factor-a (TNF-a) and
bronchioles, and thereby causes focal areas of lymphotoxin-a were associated with an increased
emphysema. Unlike the concentric collagen risk for CWP. A role for IL-18, a lymphokine that
arrangement in silicotic nodules, the nodules regulates neutrophil activation and the produc-
associated with CWP have haphazardly arranged tion of proinflammatory cytokines and ROS in
collagen bundles filled with dark-staining an- decreasing coal-induced fibrotic lung disease, was
thracotic pigment and lack the birefringent suggested in a longitudinal study of 200 miners.28
particles found in silicotic tissue, which can be These findings suggest that interactions between
seen with polarized light. On the other hand, environmental dusts and certain genes are criti-
coal-induced macules are similar to silicosis in cally involved in determining disease expression
that they can enlarge and coalesce, resulting in in patients with CWP.
masses that encroach on the alveolar ducts and
alveoli. In patients with CWP or silicotic lesions, Clinical Features
the PMF label can be used when these masses are
.1 cm radiographically. In 1831, the first case of CWP was described in a
British coal miner. Although coal was believed to be
Pathogenesis relatively inert and the pulmonary toxicity largely
due to silica, subsequent studies established CWP
CWP and silicosis are both closely related yet as a distinct entity.16 The clinical manifestations of
distinct. The severity of CWP is closely associated CWP that are similar to silicosis include simple
with the levels of coal dust rather than quartz. The CWP, complicated CWP, and PMF. However,
prevalence of CWP is greater in anthracite coal unlike with silica, chronic bronchitis is a more
miners than in bituminous coal miners in part prominent feature, and an accelerated or acute-

onset form of the disease does not occur. Simple occurs independently of the stage of CWP. Coal
CWP is the most common and typically occurs after dust levels have an inverse relationship with
low-dose coal exposure for .20 years. Most FEV1. A study of 722 autopsies on coal miners
patients with simple CWP are relatively asymp- and nonminers in the United States that evalu-
tomatic but can develop cough and sputum ated the relationship between emphysema sever-
production. The diagnosis is based on the occupa- ity and several variables, including (1)
tional exposure history and characteristic chest cumulative coal dust exposure, (2) tobacco, (3)
radiograph findings. Nodules associated with coal age, and (4) race (black), found that each variable
exposure are generally small (ie, 1 to 3 mm), had an additive, independent effect.30 Patients
haphazardly arranged lesions that favor the poste- with complicated CWP or PMF due to coal
rior aspects of the upper lobes but can involve other exposure invariably demonstrate a severe and
lung zones. A lung biopsy is generally reserved for rapidly progressive combined obstructive and
patients with an atypical occupational exposure or restrictive defect with a reduced DLCO.
chest radiograph findings. The onset of dyspnea on
exertion is typically seen in patients with compli- Treatment
cated CWP or PMF. A rim of emphysema sur-
rounding the large nodules is a prominent feature As with silicosis, there is no established
in patients with CWP, and at this stage of the treatment to prevent or reduce the fibrogenic
disease, PFTs generally reveal a mixed obstructive effects of coal exposure and the complicating
and restrictive defect. There is a well-described mycobacterial infections that occur in both
association between CWP and rheumatoid arthritis diseases. An unexplained dichotomy is that the
(Caplan syndrome), so any clinical evidence of risk for lung cancer in coal miners is lower, but in
rheumatoid arthritis should also be carefully patients with silicosis, the risk is higher than that
evaluated. Similar to silicotic masses, central in the general population when adjusted for age
necrosis may develop, raising the specter of a and smoking status.12 Premature death is limited
complicating mycobacterial infection. The presence to patients with complicated CWP or PMF. A 23-
of crackles or clubbing is unusual and suggests an year follow-up study31 of 8,899 coal miners who
alternative cause for the lesion, such as another were initially examined between 1969 and 1971 at
interstitial lung disease, bronchogenic carcinoma, 31 US coal mines showed an increase in mortality
or infection. Cor pulmonale and cyanosis can occur from nonmalignant respiratory diseases (eg,
in the advanced phase of CWP. pneumoconiosis and COPD) but not from lung
As reviewed in detail elsewhere,29 the radio- cancer. Treatment is also centered on the diagno-
graphic findings of coal workers’ pneumoconiosis and prevention of the coal-associated compli-
sis are better detected by high-resolution CT cations that were described previously, as well as
(HRCT) imaging of the chest as compared with assistance with pulmonary disability that may
chest radiography. The characteristic HRCT scan ensue in the advanced phases of CWP. There are
findings in CWP include (1) focal emphysema, small case series showing a potential role for
(2) punctate opacities, (3) subpleural nodules, (4) lung transplant in patients with advanced CWP
PMF, (5) cavitating masses, (6) diffuse interstitial in the absence or presence of PMF.32
pulmonary fibrosis, and (7) bronchiectasis.
As in silicosis, PFT abnormalities correlate Asbestos-Related Diseases
poorly with the presence of nodules as assessed
by means of chest imaging. Patients with early Definition
CWP may show normal volumes, flows, and
DLCO. AS the disease progresses or the levels of Asbestos is a generic term for a group of
coal dust exposure increase, a progressive re- naturally occurring hydrated silicate fibers, the
strictive pattern with a reduced DLCO or a mixed tensile strength and resilient structural and
obstructive/restrictive pattern is often evident chemical properties of which are ideal for a
due to the focal emphysematous changes around variety of construction and insulation purposes.
the coal macule.11,12 Expiratory airflow limitation The word ‘‘asbestos’’, which is derived from the

Greek word for ‘‘inextinguishable’’ or ‘‘un- ma, from the early 1970s until 2000. It is estimated
quenchable,’’ was first used in the late 1300s.33 that the total number of asbestos-associated deaths
However, industrial production of asbestos did in the United States may exceed 200,000 by the year
not occur until the 1850s. All forms of asbestos 2030.39 Given these facts, it is not surprising that
cause nonmalignant inflammatory pulmonary asbestos-related diseases have inundated our legal
diseases (ie, pleural effusions, pleural plaques, system, resulting in recent, very large class-action
rounded atelectasis, and asbestosis) and malig- lawsuits (68,000 individual claims were made in the
nant pulmonary diseases (ie, mesothelioma and year 2000 alone) and the bankruptcy of many old-
bronchogenic carcinoma).34-36 line industrial companies.33
Asbestos is a well-recognized human carcin-
Epidemiology ogen, but whether a threshold level exists that
does not increase the risk for malignancy is
The first cases of asbestos-associated fibrosis unknown.33,36,40 For fibers .5 lm long, with a 3:1
were described in the early 1900s, and the term aspect ratio assessed by means of phase-contrast
‘‘asbestiosis’’ was first established in 1927. Asbes- light microscopy, OSHA has established a PEL of
tos-associated bronchogenic carcinoma in patients 0.1 fiber per milliliter for an 8-h period for all
with asbestosis was well recognized by the mid- fiber types. Epidemiologic studies have convinc-
1950s, and the association with mesothelioma was ingly shown that all types of fibers increase the
established by the 1960s. Despite a dramatic decline malignant risk associated with occupational
in asbestos use since the 1970s, asbestos-induced exposure above the OSHA PEL. There is consid-
pulmonary diseases continue to be a significant erable controversy regarding the malignant risks
health concern for multiple reasons. First, .30 associated with nonoccupational exposure, espe-
million tons of asbestos have been mined, pro- cially to chrysotile, which accounts for .95% of
cessed, and used in the United States since the early global asbestos consumption.33,36 Few well-
1900s.34 Second, an estimated 27 million workers in designed epidemiologic studies have directly
the United States were exposed to aerosolized assessed the risk for malignancy from low-dose
asbestos fibers between 1940 and 1979.37 Third, asbestos exposure. The results from a large-scale,
there is a long interval (called the latency period) retrospective population study41 of 405 hospital-
between fiber exposure and the development of based patients and control subjects indicated that
asbestosis or mesothelioma (15 to 40 years), 5 years of exposure to the current OSHA PEL
requiring long-term, careful follow-up of occupa- would produce a fourfold excess of pleural
tionally exposed workers. Fourth, exposures from mesotheliomas. As reviewed in detail else-
consumer products and from fibers released during where,40 several recent studies have documented
structural renovation are a source of possible more precisely an increased risk from environ-
morbidity and mortality for both occupationally mental asbestos exposure that appears to be
exposed workers and the general population.36,38 about 10 times lower than that observed with
Although the prevalence of asbestosis in the United occupational asbestos exposure.
States is not firmly established, in the year 2000
there were an estimated 20,000 hospital discharges Industries/Occupations at Risk
listing ‘‘asbestosis’’ and 2,000 deaths in which
asbestosis was the primary or contributing cause.38 Asbestos exposure arises from the following
During the decade spanning from 1995 to 2004, three principal sources: (1) mining and milling of
there were more than 13,000 asbestosis deaths in the the fibers, (2) industrial applications of asbestos
United States, with an annual increase in asbestosis (eg, textiles, cement, friction materials, insula-
deaths of nearly 25%.3 Since 1998, asbestosis deaths tion, shipbuilding, repairing brake linings, lag-
have accounted for nearly 50% of all pneumoconi- ging, or pipe cutting), and (3) nonoccupational
osis deaths, which outnumber CWP deaths.3 exposure to airborne asbestos. The development
Surveys in Europe and the United States33 have of asbestosis is directly associated with both the
shown a doubling of the prevalence of asbestos- magnitude and duration of the asbestos expo-
associated pleural disease, including mesothelio- sure.6,34,37 Although a single well-documented

case42 of asbestosis caused by brief inhalational tween animal and human data are in part
exposure has been described, the overwhelming attributed to the confounding effects of cigarette
majority of patients have had significant occupa- smoke, which reduces lung fiber clearance.6
tional asbestos exposure over a prolonged peri- Asbestos-induced lung cancer has been attributed
od. Airborne asbestos levels in public buildings to the ‘‘amphibole hypothesis’’ that fiber structural
are generally several orders of magnitude below characteristics (ie, length, diameter, and aspect
the current OSHA standard, but higher levels ratio) are the basis for lung malignancies.6,36 This
occur during renovation and demolition. Al- concept has been questioned because fiber phys-
though asbestos-induced lung cancer and meso- ical properties alone appear to be insufficient to
thelioma were well recognized in the United account for asbestos pulmonary toxicity, but they
States by the early 1960s, industrial production may partly contribute to lung injury.
continued until 1973 when it reached a peak of Extensive investigations conducted during the
803,000 metric tons.33 By 1998, it had declined to last 20 years have convincingly shown that ROS
16,000 metric tons. and reactive nitrogen species are important second
messengers of toxicity caused by asbestos.6,40,43 The
Pathophysiology mechanisms underlying free radical generation by
asbestos are in part due to reactions occurring on
The toxic effects of asbestos depend on the
the surface of the mineral dusts, by mitochondrial
cumulative dose and the time since the initial
dysfunction, and by the activation of AMs or
exposure. Essentially, all adverse effects of
neutrophils attempting to take up the fibers. Once
asbestos arise from inhalation. There are 2 classes
asbestos fibers are inside macrophages, they are
of asbestos fibers: serpentine and amphibole
coated with iron that is derived from hemosiderin
fibers. Serpentine fibers (eg, chrysotile) are curly
and can be redox activated. All coated fibers are
stranded, curved structures, whereas amphiboles
labeled as ferruginous bodies, while the term
(eg, crocidolite, amosite, and tremolite) are
asbestos body is confined to coated fibers in which
straight, rodlike fibers.
the core fiber is asbestos. Asbestos fibers promote
The physical properties of the different
pulmonary toxicity in a manner similar to that
asbestos fibers have been implicated in the
of silica and coal, as broadly illustrated in Figure 5.
pathogenesis of asbestos-induced diseases for
many years. Amphibole fibers may be more toxic Asbestos-induced AM mitochondrial hydrogen
than the serpentine chrysotile, but this is an area peroxide production via a Rac1-dependent
of considerable controversy because tremolite, mechanism appears important for mediating as-
which is an amphibole, is a frequent contaminant bestosis.44 By means of mechanisms that remain
that has been implicated as a contributor to the uncertain, asbestos-induced mitochondrial ROS
toxicity of chrysotile. Compared with chrysotile, signaling in lung epithelial cells stabilizes p53 and
amphibole fibers accumulate more readily in the promotes p53-dependent transcription of various
distal lung parenchyma, are not cleared as proteins involved in tumor suppression, cell cycle
effectively, and are more durable (their estimated arrest, apoptosis, and cell survival.43 Asbestos- and
half-life in the lungs is on the order of months silica-induced mitochondrial ROS production by
versus decades, respectively).6,36 Chrysotile- AMs and neutrophils activates NALP3 inflamma-
induced asbestosis typically requires a threefold somes, which subsequently augment IL-1b and
higher lung fiber concentration, compared with TNF-a inflammatory signaling.45 Asbestos triggers
amphiboles, but chrysotile injures lung paren- necrotic cell death of human mesothelial cells,
chymal and pleural cells and can induce asbes- resulting in the release of high-mobility group box-
tosis, lung cancer, and mesothelioma in 1 that activates AM TNF-a production; this in turn
humans.6,35 Although fiber length has been augments mesothelial cell nuclear factor jb that can
shown to be important in the fibrogenic and promote cell survival despite DNA damage,
malignant capacity of asbestos in animal and in potentially resulting in the formation of a malig-
vitro models, the results of human studies have nant clone of cells.36 Future studies are required to
been less impressive.6,36 The discrepancies be- determine which of these newly described molec-

ular targets, if any, will prove useful in modulating
asbestosis or asbestos-related mutagenesis.
Benign Asbestos Pleural Effusions
The latent period between asbestos exposure

and the development of a benign asbestos pleural
effusion varies from ,1 year (shortest latency of
all the asbestos-related diseases) to .40 years.
The clinical presentation ranges from being
asymptomatic with total resolution or a blunted
costophrenic angle to pleuritic chest pain associ-
ated with fever, dyspnea, and bloody pleural
fluid. The pleural fluid is usually unilateral, left
sided, and exudative, yet rarely contains ferru-
ginous bodies. The erythrocyte sedimentation
rate is often elevated. A diagnosis can be made
only after the appropriate exposure history, the
exclusion of all other causes (especially malig-
nancy), and close follow-up for 2 to 3 years. Figure 6. Asbestos-induced pleural plaques demonstrated
Although this has not been firmly established, on the diaphragm, parietal pleura, and interlobar fissure.
benign asbestos pleural effusion has no clear Reprinted with permission from ACCP Pulmonary Medicine
prognostic implications for the development of Board Review. 25th ed. Northbrook, IL: American College of
pleural plaques or malignancy.33
useful to better define the extent of the plaques and
Pleural Plaques
to clarify whether confounding processes (eg,
asbestosis, lung mass, fat tissue, or serratus
Pleural plaques occur in 20% to 60% of
anterior and external oblique muscles) contribute
occupationally exposed workers33,46 and in 2%
to the chest radiographic abnormalities. 33
to 6% of nonoccupationally exposed individuals.47
There is no firm evidence that pleural plaques
The most common lesions are circumscribed or
localized pleural plaques, which are discrete areas increase the risk for the development of a
of fibrosis on the parietal pleura. Plaques serve as a mesothelioma or lung cancer. In a review48 of
marker of asbestos exposure and little else. They 13 studies of the relationship between pleural
consist of dense collagenous material that devel- plaques and the risk for lung cancer, 10 of the
ops in the mid-lower ribs and on the diaphragm studies were deemed appropriate to address this
(Fig 6). Electron microscopic studies may reveal issue; in none of the 10 was there a direct
noncoated fibers and, rarely, ferruginous bodies. relationship found. In 1997, an international
Over time, typically .30 years, these lesions expert meeting49 concluded that the presence of
calcify. The frequency with which plaques occur parietal pleural plaques alone was insufficient for
varies widely by sex (male greater than female), attributing lung cancer to asbestos. Only 6.5% of
age (up to 50% of shipyard workers older than 70 234 patients with lung cancer and asbestos
years), and the number of years of occupational exposure had pleural plaques without histologic
and nonoccupational exposure.33 The clinical asbestosis.50 On the other hand, a review51 of 38
consequences of circumscribed plaques are min- asbestos cohort studies showed a direct relation-
imal. In most patients, plaques are an incidental ship between the cumulative asbestosis rate and
finding on a routine chest radiograph. PFT results the rate of excess lung cancers. Thus, patients
are invariably normal unless they are confounded with asbestos-induced pleural plaques without
by another process. Conventional chest CT scans asbestosis have a minimally elevated risk for the
combined with selective HRCT cuts are often development of bronchogenic carcinoma. A

reasonable periodic monitoring program for such War II until the 1970s; the incidence is expected to
patients would include assessing current asbes- peak sometime between 2010 and 2020 because of
tos exposure risks, advising the patient of the the extraordinarily long interval from the time of
importance of smoking cessation, and obtaining exposure to the onset of disease (25–71 years).36,52
regularly scheduled chest radiograph (Table 2). Malignant mesothelioma accounts for nearly 3,000
Diffuse pleural plaques are a more widespread deaths annually in the United States and, during
form of pleural fibrosis involving the visceral and the next 40 years, it is estimated that it will account
parietal pleural surfaces, resulting in blunting of for .100,000 deaths.36 Malignant mesothelioma
the costophrenic angle. These lesions, which can be occurred in nearly 2% of asbestos textile workers
unilateral or bilateral, are relatively infrequent, and, exposed to approximately one fiber per milliliter for
unlike circumscribed plaques, diffuse pleural 50 years and accounts for approximately 8% of the
plaques may result in restrictive pulmonary phys- deaths among asbestos workers.53 In industrial
iology and functional impairment. countries, the yearly incidence of mesothelioma is
two cases per million person-years among women
Rounded Atelectasis and 10 to 30 cases per million person-years among
men, but as high as 270 to 366 cases per million
Rounded atelectasis is a distinct form of person-years in men who have been exposed to
pleural/parenchymal thickening that is charac- crocidolite asbestos.36,54 Although occupational
terized by its major radiographic finding, the asbestos exposure can be documented in 50% to
‘‘comet-tail’’ sign. As pleural fibrosis progresses,
85% of patients with malignant mesotheliomas,
it can entrap the underlying healthy lung and
nonoccupational exposure, radiation, chemical
bronchovascular tissue. These patients present
carcinogens, viruses, and chronic pleural disease
with a pleural-based mass that appears similar to
have also been implicated.36,52 Unlike bronchogen-
bronchogenic carcinoma but can be distin-
ic carcinoma, there is no synergistic interaction
guished from it based on the characteristic
between asbestos and cigarette smoke affecting the
asbestos exposure history, the relative stability
incidence of mesothelioma.
of the lesion during a 2- to 3-year period, other
The typical clinical presentation of a patient
radiographic signs of asbestos exposure, and the
with malignant pleural mesothelioma is an
comet-tail sign pointing toward the hilum on the
elderly (age range, 50-70 years) man (male-
chest CT scan. The uncertain nature of the lesion
female ratio, 5:1) with an insidious onset (median
may occasionally necessitate a biopsy by means
time from symptom onset to diagnosis, 3 months
of percutaneous needle aspiration or, rarely,
video-assisted thoracoscopic surgery. The mech- to 2 years) of nonspecific complaints such as
anisms by which rounded atelectasis occurs are fever, weight loss, night sweats, and fatigue.54
unclear, but the pathways implicated include the Dyspnea (50%-70%), nonpleuritic chest pain
local fusion of the visceral and parietal pleura by (approximately 60%), and cough (approximately
the fibrotic process, the regional shrinkage of 30%) may also be present. Physical examination
connective tissue along the visceral pleura, and/ and chest radiographic findings consistent with a
or the absorption of pleural effusions.33 pleural effusion are seen in 80% to 95% of
patients.33 A mediastinal shift toward the side
Malignant Mesothelioma of the pleural effusion is seen occasionally and
indicates a potentially trapped lung. Chest CT
Malignant mesothelioma is a rare tumor that is scanning is more sensitive than a chest radio-
caused by all forms of asbestos. It occurs in the graph for detecting pleural plaques, differentiat-
following two sites: the parietal pleura and the ing a pleural effusion from a tumor, assessing the
peritoneum. It is much more frequent in the parietal extent of diaphragmatic as well as hilar and
pleura, possibly because inhalation is the typical mediastinal lymph node involvement, and iden-
route of pathogenicity. The incidence of malignant tifying areas of asbestosis. MRI of the chest may
mesothelioma has increased for decades, largely as help distinguish between benign pleural plaques
a result of the extensive use of asbestos from World and malignant mesothelioma.55

The chest radiographic findings of malignant tentiating factor, osteopontin, soluble mesothelin-
pleural mesothelioma, although often very sug- related protein, and others) are useful for
gestive, are not specific enough to establish a discriminating between malignant mesothelioma
definitive diagnosis. Differentiating malignant in asbestos-exposed individuals and other be-
mesothelioma from metastatic adenocarcinoma, nign (eg, asbestosis, pleural plaques) and malig-
benign pleural mesothelioma, or reactive meso- nant conditions (eg, lung cancer) has shown
thelial cells is challenging. No single immuno- significant limitations. The limitations result
histochemical marker or ultrastructural feature is from insufficient sensitivity (approximately
pathognomonic. Misdiagnosis, either overdiag- 34%–73%) and specificity (approximately 95%)
nosis or underdiagnosis, occurs frequently (ap- for this rare disease, resulting in a substantial
proximately 30%).36 A diagnosis of mesothelioma number of false-negative test results, as well as
begins with a strong clinical suspicion based on more false-positive than true-positive test re-
the appropriate occupational exposure history. sults.56-59 A more encouraging role for these
Pleural fluid cytology is diagnostic in only 25% to serum biomarkers, especially mesothelin and
33% of patients, while closed needle pleural megakaryocyte potentiating factor, may involve
biopsy is diagnostic in 21% to 77% of patients, monitoring the course of the patient’s disease
and video-assisted thoracoscopic surgery is often during treatment as well as assessing progno-
necessary.28 A panel of immunohistochemical sis.57-59 Some potentially novel markers of hu-
stains of pleural tissue is often helpful. Adeno- man mesothelioma have been detected with
carcinomas, with which mesothelioma is often complementary DNA microarray technology, in
confused, show periodic acid-Schiff-positive vac- order to identify nearly 300 unique genes
uoles and stain positively with carcinoembryonic expressed in malignant mesothelioma, and by
antigen and Leu-M1 (CD15 antigen). The find- using screening microRNA libraries to suggest a
ings of these stains are typically negative in potential role for microRNA-103.60,61 The trans-
mesotheliomas. On the other hand, mesothelioma lational significance of these recently described
cells generally stain positively for vimentin. biomarkers awaits the outcome of ongoing large
Mesotheliomas may also elevate pleural fluid prospective studies investigating the diagnostic
hyaluronic acid levels, but this test is not always accuracy and the relationship between biomarker
readily available. Newer markers of mesothelioma levels and mortality. A combination of these
include calretinin, a calcium-binding protein that newer pathologic techniques, along with the
strongly stains 88% of malignant mesotheliomas, traditional history, clinical presentation, and
as opposed to adenocarcinoma, in which it binds chest radiographic findings, should establish a
weakly in approximately 50% of tumors.52 Also, definitive diagnosis.
simian virus 40 DNA is detected in about 66% of Unlike with lung cancer, there is no widely
malignant mesotheliomas but not in surrounding accepted staging system for patients with diffuse
normal mesothelial cells.52 Simian virus 40 is not malignant pleural mesothelioma. There are five
necessary for inducing mesotheliomas but may different staging systems, but none of them has
contribute to its development, especially in the been adequately validated in comparative trials
nearly 20% of patients with mesothelioma who involving a sufficient number of patients.33,57
have not knowingly been exposed to asbestos. Some of the favorable prognostic factors identi-
Because of misdiagnosis, pleural fluid cytology is fied include the following: (1) absence of a 5%
considered useful but insufficient to confirm the total body weight loss at the time of diagnosis, (2)
diagnosis of malignant mesothelioma.36 Thus, the tumor confined to the ipsilateral parietal pleura,
gold standard for diagnosis is a tissue biopsy (3) epithelioid cell type, (4) good performance
followed by immunohistochemical analysis and, status, (5) young age, and (6) platelet count
ideally, electron microscopic studies, to confirm ,400,000 cells/lL.
ultrastructural features such as microvilli and No standard therapeutic regimen has been
desmosomes.36 clearly shown to substantially alter the median
Accumulating evidence examining whether survival time, which remains a dismal 6 to 18
biomarkers (eg, mesothelin, megakaryocyte po- months, with a 5-year survival rate of ,5%.33,36,52,57

Single-modality therapy including various chemo- asbestos exposure. Pleural plaques are usually
therapeutic agents, radiation therapy, intrapleural present but may be absent in 10% to 20% of
chemotherapy, intrapleural immunotherapy (eg, patients.34,64 In the early stages of asbestosis, the
interferon-c or IL-2), or surgery (eg, pleurectomy or interstitial and pleural involvement begin in the
extrapleural pneumonectomy) for highly selected mid- to lower-lung zones, resulting in a hazy,
patients rarely prolongs survival beyond several ground-glass appearance that blurs the heart
months.52,54,57 Results from a large phase III border (called the shaggy heart sign) and the
study62 showed that cisplatin, which is the single diaphragm on the chest radiograph.34,64 Neither
most effective chemotherapeutic agent (response the mediastinal nor hilar lymph nodes are
rate, approximately 17% to 23%; median survival enlarged. Honeycombing and upper lobe in-
time, 9 months), is more effective when combined volvement develop in the advanced stages of
with pemetrexed (response rate, 41%; median asbestosis. Because the chest radiographic
survival time, 12 months). Multimodality therapy changes associated with asbestosis may be
with various combinations of chest surgery, che- subtle, an HRCT scan is frequently obtained
motherapy, and radiation has been adapted. In 183 because of its greater sensitivity. The character-
patients who were treated with taxol, carboplatin, istic HRCT scan findings of asbestosis, although
extrapleural pneumonectomy, and radiation ther- nonspecific, include the following: (1) subpleural
apy, the overall median survival time was 17 linear densities parallel to the pleura; (2) paren-
months, and the 5-year survival rate was 14%.63 chymal bands 2 to 5 cm in length, often
However, 2-year and 5-year survival rates of 68% contiguous with the pleura; (3) thickened inter-
and 46%, respectively, were observed for highly lobular septal lines; and (4) honeycombing.64 In a
selected patients with stage I disease and epithelial- study65 of 169 asbestos-exposed workers with
type histopathology. Although select patients may normal chest radiograph findings, HRCT scan
survive longer when undergoing multimodality findings consistent with asbestosis were noted in
therapy, no randomized, multicenter, phase III 57 patients (34%). These workers also had
studies have shown that this approach is superior reductions in both vital capacity and DLCO, and
to any other therapy. an increased dyspnea score, in comparison with
workers who had normal HRCT scan findings.
Asbestosis Pulmonary function abnormalities in patients
with asbestosis demonstrate restricted lung
Asbestosis is a slowly progressive, diffuse volumes and diminished DLCO, but otherwise
pulmonary fibrotic process caused by the inha- spirometry results are normal.34,37,46,66 Abnormal
lation of asbestos fibers. There is a latency period spirometry results (FEV1, ,75% predicted) gen-
of at least 20 to 40 years from the time of initial erally reflect concomitant exposure to cigarette
exposure to the development of respiratory smoke. Although controversial, some groups66
symptoms. The earliest symptom of asbestosis have suggested that asbestos alone may cause
is insidiously progressive exertional dyspnea that airway obstruction in part owing to the large-
often progresses inexorably regardless of further airway inflammation resulting from fiber depo-
asbestos exposure. Cough with sputum produc- sition along the respiratory bronchioles and
tion is generally attributed to exposure to alveolar duct bifurcations. However, this rela-
cigarette smoke rather than asbestos. Patients tionship was not borne out in a study of 3,660
with asbestosis may have bibasilar fine end- asbestos workers who were followed up for more
inspiratory crackles (32%–64%); clubbing (32%– than 25 years after their initial exposure.67
42%); and, in the advanced stages, signs of cor A diagnosis of asbestosis is based on several
pulmonale.34,37 characteristic features and does not require
The chest radiograph usually reveals small histopathologic evaluation for compensation
parenchymal opacities in the lower lung zones purposes.34,37 An American Thoracic Society
with a nodular and/or reticular pattern that is (ATS) expert panel concluded originally in
similar to that seen in patients with IPF. Unlike 1986 37 and again in 200434 that a clinical
with IPF, pleural involvement is a hallmark of diagnosis of asbestosis is established, in the

absence of lung tissue, by the following: (1) a asbestos consumption in .33 countries and
reliable exposure history, (2) an appropriate mortality from asbestos-related diseases (eg,
latency period, (3) characteristic chest radiograph asbestosis, mesothelioma, and lung cancer), the
abnormalities of 1/1 or greater based on the ILO ILO has called for a total worldwide asbestos
scale, (4) reduced lung volumes and/or DLCO, ban.71
and (5) end-inspiratory crackles. The 2004 ATS
statement34 encompassed chest radiograph and Lung Cancer
HRCT scan abnormalities in the clinical defini-
tion and established the role of bronchoalveolar By the mid-1950s, epidemiologic data firmly
lavage (BAL), showing more than one asbestos supported a relationship between asbestosis and
body per milliliter. This is indicative of a high lung cancer. In the mid-1980s, the Environmental
probability of substantial occupational asbestos Protection Agency and the WHO’s International
exposure, whereas asbestos fiber analysis was Agency for Research declared asbestos a proven
de-emphasized. For patients with an atypical human carcinogen. From a 2001 review72 of 23
presentation, the most definitive evidence sup- studies of the associations among asbestos,
porting the diagnosis of asbestosis is lung tissue cigarette smoke, and lung cancer, it was conclud-
demonstrating asbestos bodies in the setting of ed that asbestos causes lung cancer in nonsmok-
diffuse interstitial pulmonary fibrosis. Asbestosis ers despite the small numbers of such workers
can have a patchy distribution that favors the available for study. Moreover, a multiplicative or
lower lung zones, similar to that of IPF. The early synergistic interaction rather than an additive
phase of asbestosis is characterized by peribron- model better described the association between
chiolar fibrosis with normal distal alveoli. In the asbestos and cigarette smoke. This implies that
advanced stages of asbestosis, the fibrotic pro- the combined attributable lung cancer risk
cess, similar to that in IPF, extends into the distal exceeds the sum of the risk of each agent. The
air spaces and is associated with traction bron- mechanisms underlying this synergistic effect are
chiectasis and honeycombing. Conglomerate not fully known but are due in part to impaired
lesions are unusual unless the worker has been lung fiber clearance and enhanced DNA dam-
exposed to a mixed dust-containing silica. age.6,43 Results for early studies suggested that
Asbestosis is generally a slowly progressive tumor location and histology differ in asbestos-
process that culminates in respiratory failure. In and cigarette smoke-exposed individuals, but
seven studies68 involving .2,200 asbestos work- this finding has been refuted by others.50,73,74
ers who were followed up from 1 to 17 years after Asbestos-induced lung cancers can occur in any
their initial diagnosis of asbestosis, progression lobe of the lung, and the distribution of the 4
occurred in 5% to 31% of the patients, as assessed major histopathologic lung cancer types is
by changes in the chest radiograph or PFT similar to the distribution pattern among patients
results. Risk factors predicting the progression with cigarette smoke-induced lung cancer.73,74
of asbestosis include the following: cumulative Considerable controversy surrounds the hy-
asbestos exposure (total amosite/crocidolite fiber pothesis that excess lung cancer risk in those
burden, .100,000 fibers per gram of dry lung), persons with an occupational asbestos exposure
duration of exposure, and crocidolite exposure.68 is limited to workers with asbestosis. There is
Progression of asbestosis as confirmed by means general agreement that histologically and radio-
of HRCT scan is better detected by means of a graphically defined asbestosis, and other forms
reduction in the DLCO than spirometric changes.69 of pulmonary fibrosis as well, significantly
Investigators in study70 of the mortality of 655 increase the risk for lung cancer. Weiss51 re-
male workers with asbestosis found that of the viewed 34 cohort studies and reported a direct
233 workers who died, 20% died from asbestosis, correlation between the rate of asbestosis and
39% died from lung cancer, 9% died from lung cancer, suggesting that asbestosis is a better
mesothelioma, and 32% died from other causes. predictor of excess lung cancer risk than are
Given the long latency between exposure and measures of asbestos exposure. Others75,76 have
disease, as well as the direct relationship between challenged this conclusion, arguing that asbestos

exposure, and not asbestosis, causes lung cancer. mined in open pits. Rock containing talc is crushed
Because it is not necessary to have emphysema to into a fine powder, bagged, and shipped for
implicate cigarette smoke as a cause of lung numerous commercial uses in the manufacturing
cancer, it might not be necessary to have of ceramics, rubber products, chemicals, cosmetics,
asbestosis for implicating asbestos as the attrib- and pharmaceuticals and as a filler in paint, paper,
utable cause of lung cancer. This controversy is soaps, and roofing material.
not likely to be resolved soon because of the
nonuniform definition of asbestosis used in the Epidemiology
various studies (eg, clinical vs histopathologic)
and the uncertain biological scenario, whereby Talc pneumoconiosis, also known as talcosis,
the molecular mechanisms underlying interstitial typically develops in heavily exposed occupational
fibrosis are required to develop a malignancy. workers.2 The first case of talc pneumoconiosis was
Oksa and associates77 showed that lung cancer described in 1896. With modern dust control
developed in 11 of 24 patients with progressive measures in mines and in industrial talc plants,
asbestosis (46%), whereas lung cancer developed talcosis is relatively rare today. Because talc is
in only 5 of 54 patients with stable asbestosis frequently contaminated with other mineral dusts,
(9%). They postulated that the progression of other lung diseases occur in talc-exposed workers.
asbestosis, in addition to cigarette smoke and Although widely used by consumers, talc rarely
asbestos exposure, is an independent predictor of causes disease except in adults exposed to massive
lung cancer risk in patients with asbestosis. amounts of baby powder. Also, talcosis can develop
Asbestos can act at all the critical steps in the in drug abusers who inject or inhale crushed tablets
formation of a malignant clone of cells (eg, containing talc.
initiation, promotion, and progression) and,
therefore is not dependent on the presence of Pathophysiology
fibrosis. Thus, it is unclear whether asbestosis is
simply a marker of high-dose asbestos exposure The toxic manifestations of talc depend on the
or a necessary requirement for attributing an purity of the material to which the workers are
individual’s lung cancer to asbestos. Until more exposed. Nodular lesions in the respiratory bron-
definitive studies have clarified this controversy, chioles similar to those seen in silicosis are
lung cancer attribution should be based on the characteristic, but, unlike in silicosis, talc is rarely
merits of each patient’s carcinogen exposure seen in the nodule, nor are birefringent silica
history combined with the appropriate clinical crystals visible. Multinucleated giant cells can
history and laboratory findings. occur, but focal and diffuse fibrosis occurs in the
later stages. A mixed nodular and diffuse fibrotic
Talc Pneumoconiosis process may be evident pathologically and radio-
logically. In IV drug abusers, talc granulomas may
Definition/Occupations be seen in the interstitium, as well as in the
pulmonary arteries, resulting in pulmonary hy-
Talc is a heterogeneous term that includes pertension and cor pulmonale. Drug abusers may
hydrated magnesium silicates, and it is used also present with very severe emphysematous
commercially to describe mixed materials that changes associated with areas of granulomatous
may contain minimal amounts of talc. Relatively inflammation and fibrosis surrounding the talc.78
pure talc, which is widely used in the cosmetic
industry, is mined primarily in Vermont, the Clinical Features and Treatment
French Pyrénées, and Italy. Less pure talc (approx-
imately 60%) that is contaminated with asbestos, The nodular form of talcosis is similar, both
carbonates, and silica is mined from other areas clinically and radiographically, to silicosis in that
(eg, New York, Texas, and California) and is used patients are typically asymptomatic despite
extensively for a variety of industrial purposes. substantial chest radiographic abnormalities. A
Talc is found near the surface of the earth and is nonproductive cough and dyspnea may develop

many years after the initial exposure. The onset incites an antigen-specific immune response that
of diffuse fibrosis results in cough and dyspnea, can cause a noncaseating granulomatous inflam-
bibasilar inspiratory crackles on examination, matory reaction that is histopathologically simi-
and chest radiographic abnormalities that are lar to that seen in patients with sarcoidosis.
similar to those seen in silicosis and other forms Persistent low-level beryllium exposure results in
of pulmonary fibrosis. PFT abnormalities are chronic berylliosis, which is manifested by
minimal in the nodular form of talcosis but can chronic interstitial fibrosis, often with bullous
demonstrate a restrictive defect with a reduced changes, as well as systemic involvement of the
DLCO once fibrosis occurs. skin, liver, spleen, lymph nodes, myocardium,
There is no proven treatment of talc pneu- kidney, bones, and salivary glands. T lympho-
moconiosis, so the prevention of further exposure cytes from the lungs and blood of patients with
is the key to treatment. There have been berylliosis proliferate when exposed in vitro to
anecdotal reports of a benefit from steroid beryllium salts, which act as an antigen or
therapy in patients with symptoms and talcosis hapten. This reaction serves as an important
whose disease is progressing. early marker for diagnosing berylliosis and has
also been implicated in the pathogenesis of lung
Beryllium Lung Disease fibrosis.2,80 Up to 16% of beryllium workers are
sensitized to beryllium as assessed in the
Definition/Occupations lymphocyte proliferation test.2 An analysis of
blood and BAL cells from patients with chronic
Beryllium is a rare light metal that is extracted berylliosis and healthy subjects revealed the
from beryl ore that is mined in the United States, presence of deficient and dysfunctional Tregs in
Brazil, and China and is refined in the United the lungs of patients with chronic beryllium
States, Japan, and Russia. Beryllium has a very disease.81 In a case-control study of workers at a
high melting point; has a very low density, United States nuclear weapons facility (70 beryl-
elasticity, and coefficient of thermal expansion; lium sensitized, 61 with chronic berylliosis, 255
and is permeable to radiation. These properties control subjects), the genotype with glutamic
make it ideally suited for use in heat shields, rotor acid at position 69 (E69) of the HLA-DBP1 gene
blades, radiograph tubes, and parts for microwave increased the odds of developing beryllium
equipment and nuclear reactors.2,79 Shortly after sensitization and chronic berylliosis.82
beryllium was first used commercially in phos-
phors for fluorescent lights in the United States in Clinical Features and Treatment
the 1930s, its toxic properties were recognized.
Since then, an estimated 800,000 workers have had Acute beryllium disease is now relatively rare
past or current beryllium exposure, resulting in because of improved industrial hygiene methods,
chronic berylliosis in nearly 1% to 21% of the but when it does occur, beryllium acts as a direct
workers.2,79 Beryllium can cause the following two irritant. The diagnosis should be suspected when
types of pathologic conditions: (1) acute pneumo- there is high-level beryllium exposure in associ-
nitis due to short-term, high-level exposure and (2) ation with acute pneumonitis, conjunctivitis,
chronic disease due to long-term, low-level expo- periorbital edema, nasopharyngitis, and tracheo-
sure causing a granulomatous inflammation sim- bronchitis. These patients typically present with
ilar to that of sarcoidosis. Worker exposure to dyspnea, cough, sputum production, chest pain,
beryllium occurs primarily in the aerospace, tachycardia, crackles, and hypoxemia. Chest
nuclear, computer, and electronics industries. radiographs typically reveal diffuse alveolar
infiltrates, while PFT results show a restrictive
Pathophysiology process with a reduced DLCO. Patient treatment
includes eliminating further beryllium exposure;
Acute beryllium pneumonitis is due to direct providing supplemental oxygen if needed; pro-
acute lung injury resulting from the inhalation of viding supportive measures; and, in more ad-
high levels of beryllium particles. Beryllium also vanced forms, providing a therapeutic trial of

Table 4—Some Representative Hard-Metal–Induced Lung Diseases
Agent Histopathology Occupational Exposure
Aluminum Interstitial fibrosis; sarcoidlike granuloma Aluminum miner/refineries

Beryllium Sarcoidlike granulomas; ILD Beryllium miner/aerospace, nuclear, and electronics work
Cadmium Acute pneumonitis; ILD; emphysema Lead or zinc smelter; batteries (brazier disease)
Cobalt Giant-cell ILD; sarcoidlike granuloma; Metal hardener for tungsten carbide (tool grinder,
obstructive airways metal polisher, dental drills)
Iron Dust macule, ILD Iron miner/welder
Mercury Tracheobronchitis; pneumonitis; pulmonary edema Electrical industry; scientific equipment; catalyst work
ILD ¼ interstitial lung disease.
steroids. Most patients fully recover, although the elimination of further beryllium exposure;
chronic berylliosis may develop in up to 25% of often, a course of steroids is administered. Al-
patients.2 though there are no controlled studies demonstrat-
Chronic berylliosis develops after a latent ing their efficacy, most reports have shown that
period ranging from months to as long as 10 removal from further beryllium exposure and the
years after the onset of low-level beryllium use of steroids result in a favorable response both
exposure.2,79 The diagnosis should be suspected clinically and radiographically; however, similar to
in patients with an appropriate exposure history the situation with sarcoidosis, many cases recur
who present with dyspnea (the most common when steroid therapy is discontinued. Data from a
complaint), cough, chest pain, weight loss, large beryllium registry2 involving 689 patients
fatigue, and arthralgias and who have an demonstrated excess mortality from lung cancer
abnormal chest radiograph finding with a reticular- and nonmalignant beryllium disease. Notably, a
nodular infiltrate seen predominantly in the upper recent study85 documented 16 cases of nonoccupa-
lung lobes (although all lobes can be involved). The tional, environmental chronic beryllium disease in
chest radiographic pattern is similar to that seen residents surrounding a beryllium manufacturing
with sarcoidosis, including mediastinal and bilat- facility.
eral hilar adenopathy. A beryllium lymphocyte
transformation test should be performed to docu- Hard-Metal Lung Disease
ment sensitization. Although an estimated 50% of
beryllium-sensitized workers have evidence of Definition/Occupations
chronic beryllium disease at the time of an initial
presentation, a 2005 longitudinal study83 showed As shown in Table 4, hard metals can induce a
that chronic berylliosis will develop in 31% of wide range of lung diseases. Although most hard-
disease-free sensitized workers (especially machin- metal lung diseases arise from occupational expo-
ists) within 3.8 years (range, 1.0–9.5 years), while sure, environmental exposures have been reported
the disease never developed in the remaining 69% (eg, mercury-induced chemical pneumonitis). Met-
during 4.8 years of follow-up. However, there is al-induced pulmonary toxicity can be caused by
insufficient evidence to recommend performing antigen-specific immunologic reactions or nonspe-
routine beryllium lymphocyte transformation tests cific inflammatory responses due to oxidative stress
for screening asymptomatic workers.84 Large cal- similar to that depicted in Figure 5.2,86
cified masses and pleural reactions can be seen,
while nearly one-third of the patients have bilateral Cobalt
hilar adenopathy. PFT results show reduced vol-
umes and DLCO. Although the clinical course of The main components of commercially avail-
chronic berylliosis is variable, most patients have a able hard-metal include tungsten and titanium
slow, inexorable decline that can result in cor carbides (70%–95%), cobalt (5%–25%), and small
pulmonale in nearly one-third of patients. Treat- amounts of various other metals (eg, nickel,
ment options are sparse, but of prime importance is chromium, tantalum, and vanadium). Because

tungsten is inert, cobalt is the primary culprit Siderosis
causing pulmonary toxicity associated with hard- Occupations involving iron exposure (eg, min-
metal exposure. Cobalt is used as a hardener and ing, smelting, welding, and steel making) can lead
binder of metal alloys of, for example, tungsten, to siderosis. It is often a relatively benign condition,
aluminum, chrome, molybdenum, and berylli- usually noted as an incidental finding or as an
um. Cobalt exposure may occur in occupations abnormality on a chest radiograph with dense
such as machinist, metal tool maker, polisher, linear opacities in an asymptomatic iron worker.
grinder, saw sharpener, and dental worker. Occasionally, iron can induce respiratory symp-
Occupational exposure to cobalt is associated toms, restrictive pulmonary physiology, and pul-
with the following three pulmonary manifesta- monary fibrosis in heavily exposed workers.89
tions: (1) airway obstruction that resembles Pathologic findings range from the characteristic
occupational asthma, (2) acute interstitial pneu- iron dust macule to interstitial fibrosis. There is no
monitis with features of hypersensitivity pneu- specific treatment other than the prevention of
monitis, and (3) chronic diffuse interstitial further iron exposure.
fibrosis that can progress to end-stage fibrosis.
Patients with cobalt-induced chronic interstitial Metal Fume Fever
fibrosis present with the insidious onset of
exertional dyspnea, cough, weight loss, and Metal fume fever is a set of flulike symptoms
restrictive pulmonary physiology. Pathologic that occur within 4 to 12 h after the start of the work
findings include desquamative interstitial pneu- shift in metal workers after exposure to high
monitis; giant cell interstitial pneumonitis; and levels of metal fumes, especially zinc oxide. Fumes
varying degrees of bronchiolitis obliterans, inter- of metal oxides of arsenic, boron, cadmium,
stitial fibrosis, and sarcoidlike granulomas. A chromium, copper, magnesium, manganese,
characteristic diagnostic feature is the presence of nickel, and titanium can cause similar symptoms.86
It was initially defined in brass foundry workers in
odd-appearing giant multinucleated cells. An
the mid-1800s and in steel welders in the early
immune mechanism involving suppressor T
1900s. These patients present with fever at temper-
lymphocytes is implicated in mediating cobalt
atures from 1028F to 1048F associated with a
pulmonary toxicity.79,86 Also, genetic factors
metallic taste in the mouth, throat irritation, cough,
involving the allelic substitution of a glutamic
dyspnea, malaise, fatigue, myalgias, arthralgias,
acid in position 69 of the HLA-DPb chain has
sweats, and shaking chills. The syndrome typically
been identified in workers with cobalt-induced
is associated with mild airflow obstruction and
chronic interstitial lung disease.87 Furthermore,
minimal chest radiographic findings, and resolves
the combination of cobalt and other metallic
over a 24- to 48-h period.86 Metal fume fever is due
carbides can induce an oxidative stress on the
to dose-related toxicity rather than immunologic
lungs. Limiting exposure below the PEL of 50 sensitization, since there is no latency period.
mg/m3 is mandatory. Once cobalt-related lung Study results have shown that workers with metal
disease has occurred, the worker should be fume fever have increased levels of various
moved to other sites where no cobalt exposure cytokines (eg, TNF-a, IL-6, and IL-8) in their
can occur. Progression can occur without further bronchoalveolar fluid, presumably released from
cobalt exposure; occasionally, cor pulmonale and AMs, which likely mediate this syndrome.86 An
death may occur many years after the initial unexplained feature of this syndrome is the
exposure. In a 13-year follow-up88 of lung development of tolerance, such that symptoms
function changes in 122 workers exposed to diminish on successive days of exposure but recur
cobalt-containing compounds, pulmonary fibro- after a brief absence away from work.
sis did not develop in one person, whereas a
significant decline in FEV1 occurred only in Acknowledgments
workers who were cigarette smokers; there were
no associations with polymorphisms involving This work was supported in part by a Merit
glutamic acid in position 69. Review grant from the Department of Veterans

Affairs and the NIEHS (RO1ES020357). The author 8. Wu F, Xia Z, Qu Y, et al. Genetic polymorphism of
is grateful for the comments of David Cugell. IL-1A, IL-1, IL-1RN, NFKB1, FAS, and FASL and
risk of silicosis in a Chinese occupational popu-
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Health Effects, Treatment and Control. Vol 11. Charlot- chain. Eur Respir J. 1997;27(10):2741–2743.
tesville, VA: The Michie Co; 1995:103–169. 88. Verougstraete V, Mallants A, Buchet J-P, et al.
76. Finkelstein MM. Absence of radiographic asbes- Lung function changes in workers exposed to
tosis and the risk of lung cancer among asbestos- cobalt compounds. Am J Respir Crit Care Med.
cement workers: extended follow-up of a cohort. 2004;170(2):162–166.
Am J Ind Med. 2010;53(11):1065–1069. 89. Akbar-Khanzadeh F. Short term respiratory func-
77. Oksa P, Klockars M, Karjalainen A, et al. Progres- tion changes in relation to workshift welding
sion of asbestosis predicts lung cancer. Chest. 1998; fume exposure. Int Arch Occup Environ Health.
113(6):1517–1521. 1993;64(6):393–397.

Notes

Chapter 19. Acid-Base Disorders
Objectives: acidosis results from ineffective alveolar ventila-

Review methods of analyzing acid-base disturbances. tion and/or an increase in carbon dioxide
Differentiate anion gap and normal anion gap metabolic production. Treatment involves identification of
acidoses.

the etiology and implementation of corrective
Understand the clinical manifestations of acid-base
disorders. action, which often includes intubation and
Review appropriate treatment for common causes of mechanical ventilation. Respiratory alkalosis
acidosis and alkalosis. results from primary hyperventilation character-
ized by decreased PaCO2. Severe alkalemia
Key words: acid; acidemia; acidosis; alkalemia; alkalosis; requires aggressive treatment directed at the
anion gap; base; strong ion difference
underlying cause with oxygen, analgesia, adjust-
Synopsis:
ment of ventilator settings, sedation, and other
interventions.
Three methods of analysis have been used to describe the
acid-base status of patients: the traditional approach, base
Acid-base disturbances are common findings
excess (BE) approach, and the physicochemical approach. in critically ill and chronically ill patients. The
All methods describe the respiratory component of acid- contribution of acid-base abnormalities to mor-
base changes based on change in PaCO2 but differ in analysis bidity and mortality is unclear but accurate
of the metabolic component. The traditional method relies
on changes in bicarbonate concentration and the anion gap analysis can provide information into underlying
to assess the metabolic component. The BE approach is conditions and potentially guide interventions.
based on nomograms and algorithms based on the amount Accurate evaluation of the acid-base status
of acid or base needed to restore a normal pH. The
requires interpretation of simultaneous measure-
physicochemical approach uses three independent vari-
ables: PaCO2, strong ion difference, and total nonvolatile ments of electrolytes, albumin (alb), and arterial
weak acids. blood gases, as well as knowledge of compensa-
tory physiologic responses.
Metabolic acidoses are commonly characterized

Acid-Base Analysis
by a normal or increased anion gap (AG). An AG Three methods of analysis have been used to
acidosis can exist even with a normal measured describe the acid-base status of patients: the
AG in the presence of hypoalbuminemia or traditional approach, base excess (BE) approach,
pathologic paraproteinemias. Treatment of AG and the physicochemical approach. All of these
metabolic acidoses is directed toward the under- methods describe the respiratory component of
lying condition (ie, insulin for ketoacidosis, acid-base changes based on change in PaCO2 but
dialysis for renal failure). Therapy for a normal differ in how the metabolic component of acid-
AG metabolic acidosis uses a bicarbonate- base disorders is analyzed (Table 1).
containing solution with a low chloride concen- The traditional method relies on analysis of
tration. Metabolic alkalosis results from an changes in bicarbonate concentration and the AG
increase in base in the extracellular fluid or loss to assess the metabolic component. In general, an
of acid. The clinical setting and measurement of increased bicarbonate concentration indicates a
urine chloride (UCl) allows classification into metabolic alkalosis and a decreased bicarbonate
chloride-depleted or chloride-expanded metabol- concentration indicates a metabolic acidosis. The
ic alkalosis. Chloride-depleted alkaloses respond relation of pH and bicarbonate concentration is
to volume replacement. Etiologies associated described by the Henderson-Hasselbalch equa-
with chloride expansion usually indicate imbal- tion: pH ¼ pK þ log HCO3/H2CO3 ¼ 6.1 þ log
ances in the renal-adrenal axis. Respiratory HCO3/0.03 3 PCO2. The Henderson equation

Table 1—Comparison of Components of Acid-Base Analysis Methods
Traditional Base Excess Physicochemical
Respiratory acidosis PaCO2 PaCO2 PaCO2

Respiratory alkalosis PaCO2 PaCO2 PaCO2
Metabolic acidosis HCO3–, anion gap Base excess SID, ATOT
Metabolic alkalosis HCO3– Base excess SID, ATOT
Adapted from Bangalore and Zimmerman.22
shows the interrelation between Hþ, HCO3, and metabolic component of acid-base status, with
PaCO2: Hþ ¼ 24 3 PaCO2/HCO3. An estimation of positive BE indicating metabolic alkalosis and
Hþ concentration can be made from pH. Between negative BE indicating metabolic acidosis.
pH 7.2 and 7.5, Hþ concentration changes by 1 The physicochemical approach, sometimes
mmol/L for each 0.01 unit change in pH (Table referred to as Stewart’s approach, uses three
2). The AG is used to classify metabolic acidoses independent variables to determine acid-base
into increased AG or normal AG type. status: PaCO2, strong ion difference (SID), and
The BE approach for analyzing acid-base total nonvolatile weak acids (ATOT).1,2 Changes in
status is based on nomograms and algorithms dependent variables such as pH, HCO3, OH
developed by Siggaard and Anderson. The and Hþ derive from changes in the independent
degree of metabolic acidosis or alkalosis is variables. The SID is the sum of all strong cation
quantified as the amount of acid or base that concentrations minus the sum of all strong anion
must be added to a sample of whole blood in concentrations according to the following formu-
vitro to restore the pH of the sample to 7.40 while la:
the PaCO2 is held constant at 40 mm Hg. BE has
SIDðmEq=LÞ ¼ Naþ þ Kþ þ Ca2þ þ Mg2þ
been modified to standardize for the effect of ½Cl þ Lactate:
hemoglobin and PaCO2 when the calculations are
applied in vivo as noted in the following This calculation is referred to as the apparent SID
formula: (SIDapp) because there are other unmeasured
ions in the plasma. Usually, the cationic concen-
Standard BE ðmEq=LÞ ¼ 0:9287 3ðHCO3 24:2 tration exceeds the anionic concentration and
þ 14:83 3½pH 7:4Þ:
the plasma SIDapp is approximately þ 40 to
A change in BE describes a change in the 42 mEq/L. The SIDapp decreases when anions
such as lactate, formate, sulfates, ketoacids, and
Table 2—Relationship Between pH and Hþ
fatty acids increase in pathologic conditions.
pH Hþ, mEq/L Plasma proteins such as alb, which carry a
negative charge at physiologic pH, and inorganic
7.65 22 phosphates are the main determinants of ATOT,
7.60 25
7.55 28 but they can also contribute to SID. According to
7.50 32 the physicochemical approach, metabolic acid-
7.45 35 base changes result from changes in SID and/or
7.40 40
7.35 45
ATOT. SID changes with deficits or excess of water
7.30 50 in plasma (associated with changes in Naþ
7.25 56 concentrations) and changes in the concentra-
7.20 63 tions of strong anions (such as Cl).
7.15 71
7.10 79 The effective SID (SIDeff) is an estimate of the
7.05 89 anions needed to balance the excess cations in
7.00 100 order to maintain electroneutrality. SIDeff is
Reprinted with permission from ACCP Pulmonary Medicine derived from PaCO2 and the concentration of
Board Review. 25th ed. Northbrook, IL: American College of weak acids (alb and phosphate) and calculated
Chest Physicians; 2009. by the following formula:
286 Chapter 19. Acid-Base Disorders (Zimmerman)

SIDeff ¼ ð12:2 3Pco2 =10pH Þ
time provides only a snapshot of a complex and
þ 10 3 ½albðg=LÞ3½0:1233 pH 0:631 rapidly changing environment.
þ½ðPo4 in mmol=LÞ3ð0:3093pH 0.469Þ: This chapter will primarily review the
traditional analysis of acid-base problems using
A simplified formula has been suggested to
formulas based on Hþ and HCO3–. Some
approximate SIDeff.1
correlates of the physicochemical approach are
SIDeff ¼ HCO3 þ 0:28 3 albðg=LÞ also mentioned. Primary acid-base disturbances
þ 1:8 3 Po4 ðmmol=LÞ initiate secondary compensatory responses that
Strong ion gap (SIG) is the difference between the are predictable. Compensatory processes help
apparent and SIDeff (SIG ¼ SIDapp SIDeff).3 normalize the arterial pH but usually never
Acidosis is suggested by a positive SIG in return the pH fully to normal. Appropriate
situations where unmeasured anions are in compensatory responses require normal func-
excess and alkalosis is indicated by a negative tioning of lungs and kidneys and failure to
SIG when unmeasured cations are in excess. The develop a compensatory response defines the
normal SIG has a mean value of approximately presence of a second primary disorder (see
0 mEq/L. ‘‘Complex Acid-Base Disorders’’).
The method of acid-base analysis that is
Definitions
more correct or clinically useful continues to be
debated.4–6 Studies have found that the tradi-
The following definitions are used: acidemia,
tional approach using the AG corrected for alb
an increase in Hþ and a decrease in arterial pH;
concentration is equivalent to the physicochem-
alkalemia, a decrease in Hþ and elevation of
ical approach for diagnosis of acid-base disor-
arterial pH; acidosis, a process that, if unop-
ders in intensive care unit patients. Several
posed, will lead to a decrease in pH; and
studies have also found high correlations be-
alkalosis, a process that, if unopposed, will lead
tween the SID, BE, and AG. The physicochem-
to an increase in pH.
ical approach is comprehensive in identifying
acid-base imbalances but is difficult to use at the Metabolic Acidosis
bedside. This method allows identification of the
components contributing to metabolic disorders Metabolic acidosis is a common primary
(strong ions, weak acids, or changes in alb) but acid-base disorder in critically ill patients. How-
the clinical relevance of subtle abnormalities is ever, metabolic acidosis may coexist with other
not clear. The traditional approach using AG acid-base disorders (mixed acid-base disorders)
corrected for alb concentration is easy to apply owing to comorbid acute and chronic conditions
at the bedside but does not account for the effect as well as therapeutic interventions (eg, fluid
of other nonbicarbonate buffers and electrolytes resuscitation, diuretics, mechanical ventilation).
on acid-base status. The BE approach has the Although metabolic acidosis is suggested by a
advantage of readily available results from low bicarbonate concentration, diagnosis re-
arterial blood gas analysis. However, BE cannot quires a careful analysis of additional factors
identify coexisting metabolic processes and does such as alb concentration, unmeasured anions,
not identify the etiology of an acid-base abnor- and coexisting acid-base disorders. Normal
mality. compensatory mechanisms for metabolic acido-
The clinician should understand the limita- sis include increased ventilation leading to
tions and advantages of the acid-base approach decreased PaCO2; exchange of intracellular Naþ
used for patient care. Analysis of acid-base status and Kþ for extracellular Hþ; and increased renal
must be integrated with the clinical history and Hþ excretion with urinary buffers and regenera-
additional laboratory results when determining tion of new bicarbonate (slower process). The
appropriate interventions. Analysis of acid-base expected respiratory compensation can be esti-
status in a critically ill patient at a single point in mated by the following formulas:

Paco2 ðmm HgÞ ¼ 1:5 3 HCO3 þ 8–2; in alb concentration increases the utility of the
traditional method in detecting metabolic
and
acidoses.8,9 Pathologic paraproteinemias lower
DPaco2 ðmm HgÞ ¼ 1:2 3 DHCO3 : the AG because immunoglobulins are largely
During prolonged acidosis, when respiratory cationic. An elevated AG may not always
indicate an underlying acidosis. In patients with
compensation is complete the last two digits of pH
significant alkalemia (usually pH . 7.5), alb is
equal PaCO2 (if pH . 7). The lower limit of normal
more negatively charged, which increases un-
compensation is usually a PaCO2 of 10 mm Hg.
measured anions in the absence of an acidosis.
The traditional method of acid-base analysis
In an uncomplicated AG metabolic acidosis,
focuses on the AG to further characterize
every increase of 1 mEq/L in the AG should
metabolic acidoses. Unmeasured anions (alb,
result in a concomitant decrease of 1 mEq/L in
phosphates, sulfates, and organic acids) in
HCO3–. Deviation from this relationship suggests
healthy persons exceed the unmeasured cations
the presence of another acid-base disorder (mixed
(potassium, calcium, and magnesium), and this
acid-base disorder).10 The difference between
difference results in the AG. The AG can be
these two values has been termed the Dgap (delta
estimated by the following formula:
gap), and can be expressed as follows:
AG ¼ Naþ ðCl þ HCO3 Þ:
Dgap ¼ ðdeviation of AG from normalÞ
Calculation of the AG including potassium [(Naþ ðdeviation of HCO3 from normalÞ:
þ Kþ) (Cl þ HCO3)] can also be used. The
normal AG is usually 8 to 12 – 4 to 6 mEq/L but If the normal AG is assumed to be 12 mmEq/L
the normal range varies with the specific labora- and the normal HCO3– is 24 mEq/L, then the
tory and whether potassium is included in the following equation results:
calculation. The AG can be increased because of a Dgap ¼ ðAG 12Þ ð24 HCO3 Þ:
decrease in unmeasured cations, an increase in
The normal value for Dgap should be zero.
unmeasured anions, or laboratory error in
However, variance in measurements can result
measurement. Conversely, a decreased AG im-
in a Dgap of 0 – 6. If the Dgap is positive, then a
plies an increase in unmeasured cations or a
concomitant metabolic alkalosis exists. If the
decrease in unmeasured anions. Possible etiolo-
decrease in HCO3– is greater than the increase in
gies include paraproteinemias, hypoalbumin-
AG, which results in a negative Dgap, then a
emia, hyponatremia, lithium toxicity, profound
concomitant normal AG acidosis (hyperchlor-
hyperkalemia, hypercalcemia or hypermagnese- emic) may exist. Small deviations of the Dgap
mia, and halide poisoning (bromide and iodide). may not indicate mixed acid-base disorders, and
The AG has several limitations as the sole clinical information must always be considered in
indicator of a metabolic acidosis.7 An AG acidosis the evaluation.
can exist even with a normal AG in patients who The physicochemical approach uses a differ-
are severely hypoalbuminemic or have patholog- ent approach for classifying metabolic acidoses
ic paraproteinemias. In such patients, the normal (decrease in SID): free water excess, increase in
AG may be as low as 4 to 5 mEq/L. For every strong anions (hyperchloremia), and increase in
decrease of 1 g/dL in alb, a decrease of 2.5 to weak acids. A reduction in SID occurs when a
3 mEq/L in AG will occur. The corrected AG can change in extracellular fluid volume is accompa-
be calculated with the following formula: nied by an alteration in the proportional water
AGcorrected ¼ AGobserved þ 2:5 content of the plasma. Hyperchloremia also leads
to acidosis by decreasing the SID.
3 normal alb measured albðg=dLÞ :
Corrections for changes in phosphate concentra- Etiologies
tion have less impact on the AG. Every decrease
of 1 mg/dL in phosphate leads to a decrease of Metabolic acidosis can result from an increase
0.5 mEq/L in AG. Correcting the AG for changes in endogenous acid production that overwhelms

Table 3—Causes of Increased AG Metabolic Acidoses Table 4—Causes of Normal Anion Gap (Hyperchloremic)
Metabolic Acidosis
Ketoacidoses
Diabetes GI loss of HCO3
Alcohol-induced Diarrhea
Starvation Ileostomy
Metabolic errors Proximal colostomy
Lactic acidoses Ureteral diversion
L-Lactic acidosis Renal loss of HCO3
Type A (tissue ischemia) Proximal renal tubular acidosis
Type B (altered cell metabolism) Topiramate
D-Lactic acidosis Carbonic anhydrase inhibitors
Renal failure Ileal bladder
Toxins Renal tubular dysfunction
Acetaminophen Acute tubular necrosis
Cyanide Chronic tubulointerstitial disease
Ethylene glycol Distal renal tubular acidosis, type 1
Iron Amphotericin
Isoniazid Renal transplant
Methanol Distal renal tubular acidosis, type 4
Paraldehyde nonsteroidal antiinflammatory drugs
Propofol Hypoaldosteronism, aldosterone inhibitors
Propylene glycol Addison disease
Salicylates Potassium-sparing diuretic
Valproic acid Pharmacologic ingestion/infusion
Ammonium chloride
Arginine chloride
renal excretion (eg, ketoacidosis), exogenous acid Dilutional acidosis
Sevelamer hydrochloride
input, decreased renal excretion of endogenous
Parenteral nutrition
acids (eg, chronic renal failure), or increased loss
of bicarbonate (eg, diarrhea).11 More common
causes of an increased AG metabolic acidosis are with production of excess pyruvic acid, which
shown in Table 3. Causes of a normal AG may not be cleared owing to inhibition of
acidosis are listed in Table 4. Normal AG pyruvate dehydrogenase. Excess pyruvic acid is
acidoses can also be categorized by the potassi- converted to lactate. Medications and conditions
um level. Hypokalemia (,3.5 mEq/L) is associ- that can result in type B lactic acidosis are listed in
Table 5. For some medications, an elevated lactate
ated with ureteral diversion, diarrhea, proximal
level suggests toxicity and the need to discontin-
colostomy, ileostomy, proximal renal tubular
ue the drug. It is important to distinguish type B
acidosis (RTA), type 1 distal RTA, and parenteral
lactic acidoses from the more clinically ominous
nutrition. Hyperkalemia (.4.5 mEq/L) can be
type A lactic acidoses.
found in hypoaldosterone states, ammonium
chloride administration, and type 4 distal RTA. Table 5—Drugs and Conditions Associated With Type B
Lactic Acidosis
L-Lactic Acidosis: Two types of L-lactic acidosis
exist: type A and type B. Type A lactic acidosis Dobutamine
results from inadequate tissue oxygen delivery Epinephrine
that leads to overproduction of L-lactate through Etomidate
Leukemia
anaerobic glucose metabolism.12 L-lactate often Linezolid
accounts for the unmeasured anion detected by Lorazepam
an increased AG in the critically ill. Type B lactic Lymphoma
Metformin
acidosis is associated with adequate oxygen
Nucleoside reverse transcriptase inhibitors
delivery and results from altered cell metabo- Pentobarbital
lism (usually mitochondrial function), enhanced Propofol
pyruvate production, or inhibition of cyto- Tetracyclines
Thiamine deficiency
chrome oxidase. Beta agonists, including epi- Valproic acid
nephrine and dobutamine, stimulate glycolysis

D-Lactic Acidosis: Anatomic (ileojejunal by- cludes discontinuation of lorazepam and substi-
pass) or functional short bowel (malabsorption) tution of another sedating drug if needed.
can result in overgrowth of D-lactate-producing Propofol: Propofol infusion syndrome is now
bacteria such as Lactobacillus spp Streptococcus being reported more frequently in critically ill
bovis, Bifidobacterium spp and Eubacterium spp.13 adults.17 An AG metabolic acidosis results from
Although D-lactate is not measured by laborato- lactate production. The exact etiology is un-
ry assays, it does contribute to the AG as an known but may be related to mitochondrial
unmeasured anion. Symptoms can occur after utilization of free fatty acids or a genetic
carbohydrate ingestion with absorption of D- predisposition. Reported risk factors include
lactate from the intestine, but can also occur after dose, duration of use, age, sepsis, head injury,
consumption of dairy products or lactobacillus steroid use, and catecholamine infusion. Al-
tablets. D-lactic acidosis can result in transient though the syndrome is usually associated with
neurologic findings such as headache, weakness, doses greater than 4 lg/kg/h and durations
delirium, visual disturbances, dysarthria, ataxia, longer than 48 h, toxicity can occur with lower
cranial nerve palsies, and changes in affect. doses and short-term use. Clinical manifestations
Pyroglutamic Acidosis: Pyroglutamic acid is include arrhythmias, heart failure, rhabdomyol-
another anion, not measured by laboratory ysis, hyperkalemia, acute renal failure, bradycar-
assays, that can result in an AG metabolic dia, and hyperlipemia. An elevated lactate
acidosis.14,15 Pyroglutamic acid (5-oxoproline)
concentration or increase in inotropic/pressor
can be overproduced when glutathione is de-
support in a patient receiving propofol with no
pleted through effects on the c-glutamyl cycle
other obvious etiology can be a clue to propofol
resulting in increased production of c-glutamyl-
toxicity.
cysteine, which is converted to pyroglutamic
acid. This overproduction has been associated
Clinical Manifestations
with acetaminophen use, sepsis, liver dysfunc-
tion, and malnutrition. Additionally, inhibition of
The clinical manifestations of metabolic aci-
5-oxoprolinase by some medications (penicillins,
dosis may primarily reflect the underlying
vigabatrin) can lead to pyroglutamic acidosis.
disorder. Some acute effects of acidosis can be
Acidosis resolves with discontinuation of acet-
related to the change in pH and are listed
aminophen. Administration of N-acetylcysteine
below.18
to replete glutathione stores has been suggested
Cardiovascular: Increased cardiac output; in-
despite lack of evidence.
creased oxygen delivery; decreased systemic
Propylene Glycol: Propylene glycol is a solvent
found in IV formulations of lorazepam (830 mg/ vascular resistance; coronary artery vasodilata-
mL propylene glycol), diazepam, etomidate, tion; arrhythmias (rare); potential decreased
phenytoin, nitroglycerin, esmolol, phenobarbital, responsiveness to catecholamines.
pentobarbital, and other drugs. Use of high-dose Cerebrovascular: Decreased cerebral blood
lorazepam for more than 3 days has been flow; decreased mental status.
identified as a risk for causing acidosis. 16 Metabolic: Insulin resistance; hyperkalemia;
However, toxicity has also been reported with hypercalcemia; increased protein catabolism; cat-
short-term, high-dose use. Accumulation of echolamine stimulation. Metabolic acidosis shifts
lorazepam can occur with doses greater than the oxyhemoglobin dissociation curve to the
0.1 mg/kg/h or in the presence of hepatic or right, which promotes oxygen release at the tissue
renal dysfunction. Signs and symptoms correlate level. However, if acidosis persists, it causes the
with an increased osmolar gap. The clinical RBC concentration of 2–3 diphosphoglycerate to
manifestations of toxicity include CNS depres- fall and restores the oxyhemoglobin dissociation
sion or agitation, renal dysfunction, seizures, curve to baseline.
arrhythmias, and hemolysis. These manifesta- Pulmonary: Increased minute ventilation
tions can mistakenly be attributed to sepsis and (Kussmaul respiration); increase in pulmonary
other inflammatory disorders. Management in- vascular resistance.

Chronic metabolic acidosis can lead to devel- from an increase in base in the extracellular fluid
opment of osteoporosis, osteomalacia, renal or loss of acid and is usually associated with an
osteodystrophy, renal hypertrophy, nephrocalci- increase in HCO3– concentration. In the physico-
nosis, and nephrolithiasis. chemical approach, an increase in the SID due to
a decrease in Cl or water deficit with increase in
Treatment Naþ can result in a metabolic alkalosis. Hypoal-
buminemia is another cause of metabolic alkalo-
Treatment of metabolic acidosis requires sis detected by physicochemical analysis that
appropriate diagnosis of the etiology and correc- may be missed by other approaches. Physiolog-
tion of the underlying disorder. Therapy for a ical compensation is by hypoventilation leading
normal AG metabolic acidosis requires replacing to increased PaCO2. PaCO2 may rise 6 to 7 mm Hg
volume with a bicarbonate-containing solution for every increase of 10 mEq/L in HCO3–. This
that has a low chloride concentration. Treatment response is limited by hypoxemia to a maximum
of most AG metabolic acidoses is well estab- PaCO2 of 50 to 55 mm Hg. A characteristic feature
lished (ie, insulin for ketoacidosis, antidotes for of metabolic alkalosis is that the kidneys contrib-
toxins, dialysis for renal failure). Adjunctive
ute to the process by adding HCO3– to the
therapy with sodium bicarbonate in this setting
circulation and hyperabsorbing filtered HCO3–
is usually not recommended.19 Treatment of
rather than enhancing HCO3– excretion.
lactic acidosis with bicarbonate does not improve
survival. In circumstances when pH , 7.1 is
Etiologies
associated with severe hemodynamic compro-
mise, some studies suggest that bicarbonate may
The etiologies of metabolic alkalosis can be
improve cardiovascular responsiveness. Howev-
divided into those characterized by chloride
er, myocardial performance is often normal or
depletion (hypovolemic) and those character-
increased in the setting of metabolic acidosis.
ized by chloride expansion (hypervolemic).
Potential complications of bicarbonate adminis-
tration frequently outweigh possible benefits
Table 7—Etiologies of Metabolic Alkalosis
(Table 6). Other nonbicarbonate buffers, such as
tris-hydroxymethyl aminomethane, dichloroace- Hypovolemic, Cl– depleted
tate, and carbicarb, may avoid some complica-
tions, but clinical data do not support their use.20 GI loss of Hþ
Vomiting
Gastric suction
Metabolic Alkalosis Cl–-rich diarrhea
Villous adenoma
Metabolic alkalosis is less common than Renal loss of Hþ
Diuretics
metabolic acidemia in the critically ill. It results Posthypercapnia
Hypervolemic, Cl– expanded
Table 6—Potential Complications of Bicarbonate Renal loss of Hþ
Administration Primary hyperaldosteronism
Primary hypercortisolism
Volume overload Adrenocorticotropic hormone excess
Paradoxical CSF/intracellular acidosis Pharmacologic hydrocortisone/mineralocorticoid excess
Respiratory acidosis Renal artery stenosis with right ventricular hypertension
Impaired oxygen delivery (tissue hypoxia) Renin-secreting tumor
Hypokalemia Hypokalemia
Hypocalcemia Bicarbonate overdose
Hypernatremia Pharmacologic overdose of NaHCO3
Hyperosmolality Milk-alkali syndrome
Overshoot alkalemia Massive blood transfusion
Reprinted with permission from ACCP Pulmonary Medicine Reprinted with permission from ACCP Pulmonary Medicine
Board Review. 25th ed. Northbrook, IL: American College of Board Review. 25th ed. Northbrook, IL: American College of
Chest Physicians; 2009. Chest Physicians; 2009.

These etiologies are also referred to as chloride hypoventilation to correct severe metabolic
or saline responsive and chloride or saline alkalosis. Deliberate hypoventilation with seda-
resistant, respectively (Table 7). Hypokalemia is tion in mechanically ventilated patients may be
common to both types of metabolic alkalosis. an option for severe alkalemia. Acetazolamide,
Measurement of UCl is helpful in distinguishing 250 to 375 mg qd or bid, will increase excretion
the two categories: UCl , 20 mmol/L in chlo- of HCO3– but may result in acidemia and
ride depletion and UCl . 20 mmol/L in chlo- worsening hypokalemia because of kaliuresis.
ride expansion. In metabolic alkalosis, UCl is a A single 500-mg dose of acetazolamide may be
more accurate reflection of intravascular volume sufficient.21
than urine sodium because sodium must be
excreted with excess HCO3–. Diuretic use alters Respiratory Acidosis
the utility of UCl for assessing volume status.
Respiratory acidosis results from ineffective
Clinical Manifestations alveolar ventilation and/or an increase in
carbon dioxide production. The associated lab-
Severe metabolic alkalosis is associated with oratory finding is an increased PaCO2. Compen-
a high mortality rate in hospitalized patients. sation includes buffers (primarily intracellular
Cardiovascular: Tachycardia; supraventricular proteins); increased respiratory rate; and in-
and ventricular arrhythmias; decreased coronary creased bicarbonate reabsorption via a slow
artery blood flow; increased cardiac contractility. renal response (.24 to 36 h). The normal
Cerebrovascular: Decreased cerebral blood respiratory response to hypercapnia is an
flow; seizures; altered mental status. increase in alveolar ventilation. The stimulus to
Metabolic: Ionized hypocalcemia; hypokale-
increase ventilation is mediated by changes in
mia; hypophosphatemia; hypomagnesemia; im-
the Hþ of the cerebrospinal fluid (CSF), which
paired enzyme function; stimulation of anaerobic
affects chemoreceptors in the medulla. Because
glycolysis. In contrast to metabolic acidosis,
CSF is essentially devoid of nonbicarbonate
metabolic alkalosis shifts the oxyhemoglobin
buffers, carbon dioxide that diffuses readily
dissociation curve to the left, which increases
across the blood-brain barrier results in a
oxygen affinity for hemoglobin and may impair
marked increase in CSF Hþ. The CSF pH is
oxygen release at the tissue level.
corrected toward normal by a slower rise in CSF
Pulmonary: Hypoventilation.
HCO3– that results from transfer of cerebral or
Treatment blood HCO3–.
A very small increase in plasma HCO3– can
The clinical setting, along with measurement be seen acutely because of titration of intracel-
of UCl, usually allows appropriate classification lular nonbicarbonate buffers. For each increase of
of the metabolic alkalosis. Etiologies associated 10 mm Hg in PaCO2, the HCO3– increases by 1
with chloride depletion respond to volume mEq/L. Acute increases in PaCO2 change the
replacement (saline responsive). Normal saline plasma HCO3– only 4 to 5 mEq/L to a maximum
solution offers more chloride per liter (154 of 30 to 32 mEq/L. If the respiratory acidosis is
mEq/L) than lactated Ringer solution (130 acute, the pH should decrease by 0.08 for each
mEq/L). Etiologies associated with chloride increase of 10 mm Hg in PaCO2. The renal
expansion usually indicate imbalances in the reabsorption of HCO3– is slower and plays a
renal-adrenal axis. Potassium deficiencies minimal role in acute respiratory acidosis. Over
should be corrected as appropriate. Metabolic a period of hours to days, the kidneys compen-
alkalosis should be corrected before weaning in sate with proximal reabsorption of filtered
a patient receiving mechanical ventilation be- bicarbonate and secretion of Hþ in the distal
cause of compensatory hypoventilation. It is tubule, which is trapped by ammonia and
rarely necessary to consider hydrochloric acid excreted. Bicarbonate reabsorption is accompa-
(0.1 N solution) administration or deliberate nied by loss of Cl–. This mechanism provides

adequate, although incomplete, pH compensa- Clinical Manifestations
tion for chronic respiratory acidosis. The transi-
tion from acute to chronic respiratory acidosis is The clinical manifestations of acute respira-
defined by HCO 3 – retention due to renal tory acidosis depend on the absolute increase in
compensation. In chronic respiratory acidosis, PaCO2, the rate of PaCO2 increase, and severity of
the HCO3– increases 3.5 mEq/L for each increase associated hypoxemia. Intentional hypoventila-
of 10 mm Hg in PaCO2. The limit of renal tion (permissive hypercapnia) is well tolerated
compensation in chronic respiratory acidosis is and has little significant impact on hemody-
HCO3– of approximately 45 mEq/L. Higher namics.
values suggest an associated secondary metabol- Cardiovascular: Tachycardia; hypertension;
ic alkalosis. In chronic respiratory acidosis, the supraventricular/ventricular arrhythmias; pe-
pH decreases by 0.03 for each increase of ripheral vasodilation.
10 mm Hg in PaCO2. Cerebrovascular: Somnolence; coma; anxiety or
confusion; psychosis; tremors, myoclonus, or
Etiologies asterixis; headache; cerebral vasodilation with
increased blood flow; increased intracranial
Common causes of acute respiratory acidosis pressure.
include airway obstruction, respiratory center Metabolic: Increased antidiuretic hormone
depression, neuromuscular disorders, and pul- secretion (leads to salt and water retention).
monary disorders (Table 8). Renal: Renovascular vasoconstriction.
Table 8—Etiologies of Respiratory Acidosis Treatment

Airway obstruction
Foreign body Treatment involves the rapid identification of
Tongue displacement the etiology of respiratory acidosis and imple-
Laryngospasm mentation of corrective action. In many circum-
Obstructed endotracheal tube
Severe bronchospasm
stances, intubation and mechanical ventilation are
Obstructive sleep apnea necessary to support alveolar ventilation. Admin-
Respiratory center depression istration of NaHCO3 for acute respiratory acidosis
General anesthesia is not indicated. Remember that NaHCO3 is
Sedative, narcotic drugs
Cerebral injury, ischemia metabolized to carbon dioxide, which may
Increased CO2 production worsen acidosis. In addition, normally function-
Malignant hyperthermia ing kidneys excrete most of the bicarbonate in the
Shivering
acute setting.
Hypermetabolism
High-carbohydrate diet A therapeutic pitfall to avoid in the treatment
Neuromuscular disorders of respiratory acidosis is creation of a posthy-
Drugs or toxins percapnic alkalosis. This condition most com-
Electrolyte disorders
Spinal cord injury
monly occurs when a patient with compensated
Guillain-Barré syndrome chronic respiratory acidosis is overventilated to a
Myasthenia gravis normal or near-normal PaCO2. A high plasma
Polymyositis HCO3– results in alkalemia. Appropriate ventila-
Lung conditions
Restrictive disease tor management and goals should prevent this
Obstructive disease situation.
Hemothorax or pneumothorax
Flail chest
Acute lung injury
Respiratory Alkalosis
Obesity-hypoventilation syndrome
Inappropriate ventilator settings Respiratory alkalosis results from primary
hyperventilation characterized by decreased
Board Review. 25th ed. Northbrook, IL: American College of PaCO2. Compensation includes protein or hemo-
Chest Physicians; 2009. globin release of hydrogen ion and bicarbonate

Table 9—Etiologies of Respiratory Alkalosis mm Hg in PaCO2 in chronic respiratory alkalosis.
However, chronic respiratory alkalosis is unique
Hypoxemic drive
Pulmonary disease with arterial-alveolar gradient among acid-base disorders in that pH may return
Cardiac disease with right-to-left shunt to normal if the condition is prolonged. Persistent
Cardiac disease with pulmonary edema hypocapnia results in decreased renal Hþ secre-
High altitude
Acute and chronic pulmonary disease
tion. Plasma HCO3– decreases 5 mEq/L for each
Emphysema decrease of 10 mm Hg in PaCO2.
Pulmonary embolism
Mechanical overventilation
Etiologies
Stimulation of respiratory center
Neurologic disorders
Pain The etiologies of respiratory alkalosis are
Psychogenic listed in Table 9.
Liver failure with encephalopathy
Sepsis/infection
Salicylates Clinical Manifestations
Progesterone
Pregnancy
Fever
Acute respiratory alkalosis results in neuro-
logic, cardiovascular, muscular, and metabolic
Reprinted with permission from ACCP Pulmonary Medicine abnormalities.
Chest Physicians; 2009. Cardiovascular: Tachycardia; arrhythmias (es-
pecially at pH . 7.6).
Cerebrovascular: Confusion or dizziness; sei-
loss in urine via a slow renal response. Alveolar zures; cerebral vasoconstriction; paresthesias;
ventilation is regulated by several factors: circumoral numbness.
chemoreceptors in the medulla (sensitive to Hþ) Metabolic: Hypokalemia; hypophosphatemia;
and great vessels (sensitive to oxygen), cortical ionized hypocalcemia. In chronic respiratory
input (voluntary control), and pulmonary che- alkalosis, mild hypokalemia (from intracellular
moreceptors and stretch receptors. Any of these shift) and hyperchloremia (from renal retention)
factors, or a combination, may lead to hyper- result.
ventilation. The HCO3– decreases 2 mEq/L for Muscular: Cramps; carpopedal spasms.
each decrease of 10 mm Hg in PaCO2 in acute
respiratory alkalosis. Treatment
Similarly to changes noted in respiratory
acidosis, pH increases 0.08 for every decrease of Severe alkalemia is associated with high
10 mm Hg in PaCO2 in acute respiratory alkalosis, mortality and requires aggressive treatment.
and pH increases 0.03 for each decrease of 10 Therapy is directed at the underlying cause with
Table 10—Mixed Acid-Base Disorders
Acid-Base Disorders Clinical Syndromes
Respiratory acidosis with metabolic acidosis Cardiopulmonary arrest; intoxication with methanol, ethylene glycol;
COPD with lactic acidosis, diabetic ketoacidosis, etc; severe
hypophosphatemia; respiratory failure with renal failure, diarrhea, etc
Respiratory alkalosis with metabolic alkalosis Cirrhosis with diuretic use, vomiting, pregnancy with hyperemesis,
overventilation in patient with COPD
Respiratory acidosis with metabolic alkalosis COPD with diuretic use, vomiting, gastric suction, severe hypokalemia
Respiratory alkalosis with metabolic acidosis Sepsis, salicylate intoxication, renal insufficiency with congestive heart
failure, pneumonia, advanced liver disease with lactic acidosis
Metabolic acidosis with metabolic alkalosis Uremia or ketoacidosis with vomiting, gastric suction, diuretics, etc
Physicians; 2009.

Table 11—Acid-Base Calculations 1. Determine the overall acid-base condition by
measuring pH. Is acidemia or alkalemia
Acid-Base
Disorder Formula
present?
2. Determine if the primary process is metabolic
Respiratory Decrease in pH ¼ 0:08 3 ðPaco102 40Þ (HCO3– deviation) or respiratory (PaCO2 devi-
acidosis ation).
Acute Increase in [HCO3] ¼ DPaco2
10 –3 3. If a respiratory disturbance is present, deter-
Chronic Decrease in pH ¼ 0:03 3 ðPaco102 40Þ mine if it is acute or chronic.
Increase in [HCO3] ¼ 3:5 3 DPaco 10
2
4. If a metabolic disturbance is present, determine
Respiratory Increase in pH ¼ 0:08 3 ðDPaco
10
2Þ if respiratory compensation is appropriate.
alkalosis Decrease in [HCO3] ¼ 2 3 ðDPaco
10
2Þ
5. If a metabolic acidosis is present, calculate the
Acute Increase in pH ¼ 0:03 3 ð40DPaco
10
2Þ
AG.
Chronic Decrease in [HCO3] ¼ 5 7 3 ð40DPaco
10
2Þ
6. If an AG metabolic acidosis is present,
Metabolic AG ¼ [Na] ([Cl] þ [HCO3]) calculate the Dgap to determine if other
acidosis Paco2 ¼ 1.5 3 [HCO3] þ 8 – 2 metabolic disturbances are present.
Dgap ¼ (AG-12) (24 [HCO3])
A summary of useful calculations for acid-
Metabolic Increase in Paco2 ¼ 0.60.7 3 D [HCO3]
alkalosis base evaluation is found in Table 11.

Board Review. 25th ed. Northbrook, IL: American College of Nothing to Disclose
oxygen, analgesia, adjustment of ventilator set-
tings, sedation, and other interventions. whose products or services may be discussed in
this chapter.
Complex Acid-Base Disorders
References
When a single process such as metabolic
alkalosis results in the acid-base disturbance, it is 1. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of
classified as simple. In many patients, multiple metabolic acid-base disturbances in critically ill
acid-base disturbances exist concurrently and are patients. Am J Respir Crit Care Med. 2000;162(6):
labeled complex acid-base disorders (Table 10). 246–251.
Triple acid-base disorders involve two metabolic 2. Morgan TJ. The Stewart approach—one clini-
disturbances with a superimposed primary res- cian’s perspective. Clin Biochem Rev. 2009;30(2):
piratory disturbance. Such conditions may be 41–54.
seen in patients with a chronic acid-base distur- 3. Kellum JA, Kramer DJ, Pinsky MR. Strong ion
bance who have a superimposed mixed distur- gap: a methodology for exploring unexplained
bance. Clues to the presence of a complex anions. J Crit Care. 1995;10(2):51–55.
disorder include a normal pH (with the excep- 4. Dubin A, Menises MM, Masevicius FD, et al.
tion of respiratory alkalosis), PaCO2, and HCO3– Comparison of three different methods of evalu-
deviating in opposite directions, and a pH ation of metabolic acid-base disorders. Crit Care
change in the opposite direction for a known Med. 2007;35(5):1264–1270.
primary disorder. 5. Fidkowski C, Helstrom J. Diagnosing metabolic
Complex disorders require an organized acidosis in the critically ill: bridging the anion
approach to interpretation of acid-base parame- gap, Stewart and base excess methods. Can J
ters for accurate diagnosis. The following con- Anesth. 2009;56(3):247–256.
siderations are one system based on the 6. Morris CG, Low J. Metabolic acidosis in the
traditional acid-base analysis, which may be critically ill, part 2: causes and treatment. Anaes-
useful in determining the disturbances present: thesia. 2008;63(4):396–411.

7. Salem MM, Mujais SK. Gaps in the anion gap. acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):
Arch Intern Med. 1992;152(8):1625–1629. 441–447.
8. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and 16. Arroliga AC, Shehab N, McCarthy K, Gonzales JP.
hypoalbuminemia. Crit Care Med. 1998;26(11): Relationship of continuous infusion lorazepam to
1807–1810. serum propylene glycol concentration in critically
9. Kraut JA, Madias NE. Serum anion gap: it uses ill adults. Crit Care Med. 2004;32(8):1709–1714.
and limitations in clinical medicine. Clin J Am Soc 17. Kam PCA, Cardone D. Propofol infusion syn-
Nephrol. 2007;2(1):162–174. drome. Anaesthesia. 2007;62(7):690–701.
10. Wrenn K. The delta gap: an approach to mixed 18. Levraut J, Grimaud D. Treatment of metabolic
acid-base disorders. Ann Emerg Med. 1990;19(11): acidosis. Curr Opin Crit Care. 2003;9(4):260–265.
1310–1313. 19. Forsythe SM, Schmidt GA. Sodium bicarbonate
11. Schoolwerth AC, Kaneko TM, Sedlacek M, Block for the treatment of lactic acidosis. Chest. 2000;
CA, Remillard BD. Acid-base disturbances in the 117(1):260–267.
intensive care unit: metabolic acidosis. Semin Dial. 20. Gehlbach BK, Schmidt GA. Bench-to-bedside
2006;19(6):492–495. review: treating acid-base abnormalities in the
12. De Backer D. Lactic acidosis. Intensive Care Med. intensive care unit—the role of buffers. Crit Care.
2003;29(5):699–702. 2004;8(4):259–265.
13. Petersen C. D-lactic acidosis. Nutr Clin Pract. 2005; 21. Mazur JE, Devlin JW, Peters MJ, Jankowski MA,
20(6):634–645. Iannuzzi MC, Zarowitz BJ. Single versus multiple
14. Kortmann W, van Agtmael MA, van Diessen J, et doses of acetazolamide for metabolic alkalosis in
al. 5-Oxoproline as a cause of high anion gap critically ill patients. Crit Care Med. 1999;27(7):
metabolic acidosis: an uncommon cause with 1257–1261.
common risk factors. Neth J Med. 2008;66(8): 22. Bangalore D, Zimmerman JL. Acid-base disor-
354–357. ders. Pulmonary, Critical Care, Sleep Update
15. Fenves AZ, Kirkpatrick HM, Patel VV, et al. (PCCSU). 2011;25(lesson 19). www.chestnet.org/
Increased anion gap metabolic acidosis as a result accp/acid-base-disorders?page¼0, 3. Accessed
of 5-oxoproline (pyroglutamic acid): a role for April 13, 2012.

Chapter 20. Hemodynamic Monitoring and Shock
Objectives: hemodynamic monitoring have increased in

Understand the indications, complications, and use of number during the last 10 years but the need
pulmonary artery catheterization. to understand appropriate application and
Apply hemodynamic information to determine appro-
priate clinical management.
interpretation of data from these monitors
Review techniques of estimating cardiac output. remains a constant challenge. Shock is a com-
Outline types, characteristic hemodynamic patterns, and mon condition in intensive care units that uses
management of shock.
more advanced hemodynamic monitoring to
guide interventions. Different types of shock
Key words: cardiac output; hemodynamics; monitoring;
pulmonary artery catheter; sepsis; shock require an understanding of the pathophysiolo-
gy and hemodynamic abnormalities to optimize
Synopsis: outcomes.
Hemodynamic monitoring is an important tool for moni-
toring critically ill patients. Pulmonary artery catheteriza- Hemodynamic Monitoring With
tion (PAC) is an invasive technique that has not been
demonstrated to improve outcomes in a variety of condi-
Pulmonary Artery Catheterization
tions encountered in the intensive care unit. PAC should be
performed by a physician who is skilled in the insertion Pulmonary artery catheterization (PAC)
technique, knowledgeable of complications, and capable of
with a flow-directed, balloon flotation catheter
appropriately interpreting and using the data obtained.
Changes in juxtacardiac pressure or changes in ventricular was introduced into clinical practice in 1970.
compliance alter the interpretation of the pulmonary artery The catheter allowed assessment of cardiac
occlusion pressure (PAOP) as an indicator of preload function and left ventricular filling pressure to
adequacy. Less invasive methods of hemodynamic moni-
toring include arterial pressure waveform analysis, pulsed guide diagnosis and therapy. Because PAC is a
Doppler cardiac output devices, CO2 partial rebreathing monitor, its clinical utility depends on appro-
(applied Fick principle), and bioimpedance. The advantag- priate interpretation of data and institution of
es, disadvantages, and limitations of these techniques must
be taken into account when considering their use in effective therapeutic measures. Some observa-
critically ill patients. Some of these techniques may use tional studies found that use of PAC was
variation in systolic pressure, pulse pressure, or stroke associated with either no reduction in compli-
volume to identify patients who respond to fluids with
improvement in cardiac output. Shock is a syndrome of
cation rates or increased mortality and use of
impaired tissue oxygenation and perfusion that results from resources, in comparison with patients who did
one of the following mechanisms: an absolute or relative not undergo PAC.1–3 Other observational stud-
decrease in oxygen delivery; ineffective tissue perfusion; or
impaired utilization of delivered oxygen. The management
ies did not find an increase in mortality.4,5
of shock requires treatment of the underlying etiology, and Subsequent randomized studies and meta-anal-
the restoration of adequate oxygen delivery and tissue yses of PAC use in high-risk surgical patients,
perfusion through appropriate use of fluids and vasoactive
patients with shock and ARDS, patients with
agents. Septic shock is a common form of shock encountered
in the critically ill patient, and the clinician should be heart failure, and patients admitted to the ICU
familiar with consensus recommendations and the evidence have found no difference in mortality between
supporting interventions.
groups managed with and without PAC.6–13
This section will concentrate on reviewing the
principles of PAC and correct interpretation of
Hemodynamic monitoring can be simple or data rather than on the definitive benefit of
complex and noninvasive or invasive. Some PAC. More detailed information on aspects of
type of hemodynamic monitoring is used in all PAC, including waveform analysis, is available
critically ill patients. Available options for through the Pulmonary Artery Catheterization

Table 1—Indications for PAC Monitoring Table 2—Complications of PAC
Diagnostic Central venous access

Volume status Arterial puncture/damage
Cardiac function Pneumothorax
Type of shock Bleeding
Type of pulmonary edema Air embolism
Cardiac tamponade Neuropathy
Ventricular septal rupture Catheterization procedure
Acute mitral regurgitation Dysrhythmias
Constrictive pericarditis Right bundle-branch block
Therapeutic/preventive Catheter knots
Monitor response to fluids, diuretics, vasoactive drugs, Catheter presence
and positive-pressure ventilation Thrombosis
Monitor high-risk patients perioperatively Infection
Pulmonary artery rupture
Reprinted with permission from ACCP Pulmonary Medicine Balloon rupture
Board Review. 25th ed. Northbrook, IL: American College of Endocardial damage
Chest Physicians; 2009. Pulmonary embolism/infarction
Misinterpretation of data
Education Project, available at http://www. Reprinted with permission from ACCP Pulmonary Medicine
pacep.org. Board Review. 25th ed. Northbrook, IL: American College of
Indications and Complications

of data misinterpretation or misapplication is
unknown.
PAC is without therapeutic purpose with the
rare exception of emergency cardiac pacing. PAC Insertion of the Pulmonary Artery Catheter
should be considered for use when hemodynam-
ic information is needed for optimum care of the The basic multilumen, 110-cm pulmonary
patient, which cannot be supplied by clinical artery (PA) catheter is depicted in Figure 1. The
evaluation or other less invasive modalities. distal lumen opens at the catheter tip, and the
Indications for PAC monitoring that have been proximal lumen (right atrial lumen) opens
suggested are listed in Table 1.14 Many of the approximately 30 cm from the tip. A thermistor
diagnostic uses of PAC have been supplanted by is located 3 to 5 cm from the tip. Adaptations that
the use of echocardiography. allow continuous venous oximetry and right
Various complications are associated with ventricular cardiac output measurements are
PAC, but dysrhythmias, such as premature available. A PA catheter (usually 7F or 7.5F) is
ventricular depolarizations or conduction abnor- preferably inserted aseptically into the subclavi-
malities that occur during passage of the catheter, an vein or internal jugular vein. However, clinical
circumstances of the patient dictate the appro-
are most common (Table 2). Dysrhythmias have
priate selection of the site. Insertion through the
been described in 13% to 78% of patients, and the
femoral vein may require fluoroscopic assistance.
risk is increased in the presence of cardiac
Fluoroscopic guidance may also be necessary in
ischemia, hypotension, hypokalemia, hypocalce-
patients with low cardiac output states, dilated
mia, hypoxemia, and acidosis. When possible, right-heart chambers, severe tricuspid regurgita-
metabolic abnormalities should be corrected tion, or PA hypertension. Ideally, PAC should be
before PAC. In patients with preexisting left performed by a physician who is skilled in the
bundle-branch block, the potential for develop- insertion technique, knowledgeable of complica-
ment of complete heart block exists. This rare tions, and capable of appropriately interpreting
occurrence is more likely when the left bundle- and using the data obtained.
branch block is new and associated with a recent The catheter should be advanced with con-
myocardial infarction. Other complications occur tinuous ECG and pressure monitoring. Once the
at an overall rate of 4% to 7%, but the frequency catheter has passed into an intrathoracic vein, as
298 Chapter 20. Hemodynamic Monitoring and Shock (Zimmerman)

Figure 1. Pulmonary artery catheter. Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed.
noted by respiratory fluctuation in pressures, the the PA occlusion position. The a-wave is absent
balloon should be inflated with 1.3 to 1.5 mL of in atrial fibrillation.
air to facilitate passage through the right heart If particular waveforms are not seen, place-
and into the PA. In the average patient, the ment of the catheter may be incorrect. The
distance from insertion to the right atrium is clinician must always be alert for the possibility
approximately 10 cm from a subclavian ap- of dysrhythmias and abnormal waveform pat-
proach, 10 to 15 cm from the right internal terns. The balloon should be deflated after a PA
occlusion pressure (PAOP) waveform is verified.
jugular vein, and 35 to 45 cm from the femoral
With deflation, a characteristic PA pressure
site. The PA is usually reached within 50 to 55 cm
waveform should be apparent. If a PA pressure
from the internal jugular or subclavian vein and
tracing is not present, continued occlusion of the
within 65 to 70 cm from the femoral vein. Greater
pulmonary vessel (‘‘overwedging’’) is possible
insertion lengths may indicate coiling in the right and requires repositioning of the PAC to prevent
atrium or right ventricle. Characteristic wave- pulmonary infarction. A chest radiograph should
forms and pressures are obtained during passage be obtained after the procedure to evaluate
through the right atrium, right ventricle, and PA proper catheter positioning. Daily chest radio-
(Table 3, Fig 2).15 Atrial pressure waves can graphs should be inspected for distal migration
usually be recorded from the right atrium and of the catheter tip.
Table 3—Components of Hemodynamic Waveforms
Waveform Description
Atrial Pressure and PAOP

a-Wave Atrial contraction; follows P-wave (within PR interval) on ECG in right atrial tracing;
near end of or after QRS in PAOP tracing.
c-Wave Sudden motion of mitral and tricuspid valve rings toward right and left atria at onset
of ventricular systole; follows a-wave but not always present in right atrial tracing
and not visible in PAOP tracing.
v-Wave Venous filling of left and right atria during ventricular systole when mitral and
tricuspid valves closed; near end of T-wave on ECG in right atrial tracing, after T-
wave in PAOP tracing.
x-Descent Atrial relaxation and sudden downward motion of the atrioventricular junction during
early ventricular systole; follows a-wave.
y-Descent Rapid atrial emptying following opening of mitral and tricuspid valves; follows v-wave
Right ventricular Systolic peak with rapid downstroke to end-diastolic pressure; peak systolic wave
occurs after the QRS on ECG but before the T-wave with end-diastole in the T-QRS
period.
PA Systolic peak and diastolic trough with dicrotic notch due to closure of pulmonic valve;
peak systolic wave occurs after the QRS but before the peak of T-wave on ECG; end-
diastolic trough near end of QRS.
Physicians; 2009.

Table 5—Physiologic Data Derived From Hemodynamic
Monitoring
Cardiac index: CO/BSA (normal range, 2.4-4.4 L/min/m2)

Systemic vascular resistance: (MAP CVP)/CO 3 79.9
(normal range, 900-1,400 dynescm5)
Pulmonary vascular resistance: (MPAP PAOP)/CO 3
79.9 (normal range, 150–250 dynescm5)
Stroke volume index: CO 3 1,000 (normal range, 50–100
mL/beat)
Figure 2. Characteristic waveforms and pressures seen Stroke volume index: CI 3 1,000/HR (normal range, 25–45
during insertion of a PAC. A valid pulmonary artery mL/beat/m2)
occlusion pressure is not a straight line but has a-waves Left ventricular stroke work index: SVI X (MAP PAOP)
and v-waves indicative of transmitted left atrial pressure. 3 0.0136 (normal range, 43–61 gm/m2)
Reprinted with permission from ACCP Pulmonary Medicine Right ventricular stroke work index: SVI X (MPAP CVP)
Board Review. 25th ed. Northbrook, IL: American College of 3 0.0136 (normal range, 7-12 gm/m2)
Chest Physicians; 2009. O2 content Hb 3 arterial O2 saturation 3 1.36 þ (PO2 3
0.003) (normal, approximately 19.5 mL/dL)
Arteriovenous oxygen content difference: CaO2 ¼ CvO2
Measurements (normal range, 3–5 mL/dL)
Oxygen delivery: CO 3 CaO2 3 10 (normal range, 800-
1,200 mL/min)
PAC allows measurement of right atrial Oxygen consumption: CO 3 (CaO2 CvO2) 3 10 (normal
pressure, right ventricular pressure (during pas- range, 180–280 mL/min)
Pulmonary shunt (venoarterial admixture): (CcO2 CaO2)/
sage through the chamber), PA pressure, and (CcO2 CvO2) (normal range, ,3% to 5%)
PAOP (‘‘wedge’’ pressure). In addition, cardiac
output and mixed venous oxyhemoglobin satu- BSA ¼ body surface area; CaO2 ¼ arterial O2 content; CcO2 ¼
pulmonary capillary O2 content (assumed equal to alveolar
ration (Svo2) can be directly measured. Normal PO2); CI ¼ cardiac index; CO ¼ cardiac output; CvO2 ¼ mixed
values for these measurements are listed in Table venous oxygen content; Hb ¼ hemoglobin concentration; HR
4. In general, trends in measurements over time ¼ heart rate; MPAP ¼ mean pulmonary artery pressure; SV ¼
stroke volume; SVI ¼ stroke volume index. Reprinted with
are more useful clinically than single values. permission from ACCP Pulmonary Medicine Board Review.
From these primary measurements, other physi- 25th ed. Northbrook, IL: American College of Chest
ologic variables that may be useful in evaluation Physicians; 2009.
and management of patients can be calculated.

These equations and values are listed in Table 5. ventilation, especially with positive end-expira-
Large variations in intrathoracic pressure due tory pressure (PEEP), can cause difficulty in
to labored spontaneous respiration or mechanical interpreting measurement of vascular pressures.
To minimize these effects, vascular pressures are
Table 4—Normal Values Obtained From PAC measured at end-expiration. Digital readouts of
mean PAOP are not adequate in patients with
Variables Normal Range rapid or labored breathing because more time
points than end-expiration will be averaged.
Right atrial pressure, 2–8
mm Hg Visual assessment of the pressure tracing allows
Right ventricular more accurate determination of PAOP. Discon-
pressure, mm Hg nection from the ventilator or a decrease in PEEP
Systolic 20–30
Diastolic Same as right atrial pressure
in order to measure hemodynamic variables is
PA pressure, mm Hg not recommended. Either of these actions alters
Systolic 20–30 hemodynamic conditions and may result in
Diastolic 5-15
deterioration of clinical status.
PAOP, mm Hg 6-12 (must be less than
diastolic PA pressure)
SvO2, % 65–75 PAOP
Board Review. 25th ed. Northbrook, IL: American College of The measurement of PAOP has been a major
Chest Physicians; 2009. reason for use of PAC. Accurate measurement is

alveolar pressure exceeding pulmonary venous
pressure. Balloon inflation converts zone 2 to
zone 1 conditions by stopping blood flow and
allowing collapse of the vessel distal to the
balloon. Thus, PAOP reflects alveolar pressure
rather than left atrial pressure in these zones. In
zone 3, PA and venous pressures exceed alveolar
pressures, and capillaries remain open, provid-
ing the necessary connection between the cathe-
ter tip and left atrium. With supine positioning,
most of the lung is in zone 3, and flow-directed
catheters usually enter these areas. Placement in
non-zone 3 areas or conversion of zone 3 to other
zones can occur with hypovolemia, change in
Figure 3. Catheter tip placement can occur in various west patient position, or application of positive-pres-
zones of the lung. Reprinted with permission from ACCP
sure ventilation. It has been estimated that if the
American College of Chest Physicians; 2009. PAOP changes .50% of a change in PEEP, the
catheter tip is likely to be in a non-zone 3
position.
essential for correct physiologic interpretation of
The PA diastolic pressure is sometimes used
data.16 The correct position of the catheter for
to estimate the PAOP if wedging is unsuccessful.
determination of PAOP can be confirmed by
The PAOP is usually only 1 to 3 mm Hg less than
using the following criteria: (1) Mean PAOP
the PA diastolic pressure in individuals with a
should be less than or equal to the PA diastolic
normal heart rate and pulmonary vasculature.
pressure, and less than the mean PA pressure. (2)
With tachycardia (.120 to 130 beats/min) or
The waveform should be characteristic of left
pulmonary hypertension (eg, chronic lung dis-
atrial pressures with an a-wave and v-wave. A ease or hypoxemia), the difference in the two
damped waveform, straight line, or waveform measurements may be large and vary over time.
deflections only related to respiratory changes Appropriate interpretation of the measure-
are not acceptable. Balloon inflation and deflation ments obtained with a PAC requires an under-
should consistently result in disappearance and standing of the physiologic assumptions. The
reappearance of the PA pressure tracing. (3) A PAOP is obtained to reflect left ventricular filling
free-flowing column of fluid or continuous flush pressure (left ventricular end-diastolic pressure).
excludes catheter obstruction. (4) Blood gas Balloon occlusion of a branch of the PA interrupts
analysis of a sample withdrawn from the flow and allows transmission of pressure back
presumed PAOP position should usually have from the pulmonary veins and, ultimately, from
an oxygen saturation greater than or equal to the left atrium. In general, the PAOP approxi-
systemic arterial blood. mates left atrial pressure in the absence of any
The correct catheter position is necessary to mechanical disruption of the large pulmonary
interpret the PAOP as a reflection of left atrial veins. Pressures within the left atrium are a
pressure.17,18 The pulmonary vascular system reflection of the pressure within the left ventricle
distal to the catheter tip must be patent and at end-diastole. Left ventricular end-diastolic
provide a blood-filled connection with the left pressure is a major determinant of left ventricular
atrium. Left atrial pressures cannot be estimated end-diastolic volume, or preload. However,
in the upper lung (zone 1), where alveolar preload is also determined by compliance of the
pressure usually exceeds PA and venous pres- ventricle (pressure-volume relationship) and
sures (Fig 3). These conditions close pulmonary transmural ventricular distending pressure (in-
capillaries, and blood flow does not occur. In the tracavitary pressure less juxtacardiac pressure).
central lung area (zone 2), flow is determined by Figure 4 illustrates these principles. Changes in
the PA pressure and alveolar pressure, with juxtacardiac pressure, as with PEEP therapy (or

Table 6—Conditions That Alter Pressure and Volume
Relationships
PAOP overestimates LVEDP

Mitral valve obstruction
Atrial myxoma
Mitral valve regurgitation
Pulmonary venous obstruction/vasoconstriction
Intracardiac shunt (left to right)
Non-zone 3 catheter position
Tachycardia
PAOP underestimates LVEDP
Aortic regurgitation
Decreased left ventricular compliance
PAOP and LVEDP do not reflect preload (LVEDV)
Positive-pressure ventilation
Abnormal left ventricular compliance
Vasoactive drugs
Dilated right ventricle
Figure 4. Pulmonary artery occlusion pressure as an LVEDP ¼ left ventricular end-diastolic pressure; LVEDV ¼
indicator of preload. PAOP may be associated with different left ventricular end-diastolic volume. Reprinted with per-
left ventricular volumes, or preload, depending on whether mission from ACCP Pulmonary Medicine Board Review. 25th
juxtacardiac pressure is elevated (A), as may occur with ed. Northbrook, IL: American College of Chest Physicians;
PEEP therapy, or whether ventricular compliance is de- 2009.
creased (C), as may occur with ischemia. B, Normal
ventricular compliance and juxtacardiac pressure. Reprinted
embolism and hypoxia) and pharmacologic
with permission from ACCP Pulmonary Medicine Board
Review. 25th ed. Northbrook, IL: American College of Chest alterations (eg, prostaglandin administration
Physicians; 2009. and sympathetic stimulation) affect the pulmo-
nary venous resistance. In such cases, the PAOP
auto-PEEP), or changes in ventricular compli- may underestimate the degree to which elevated
ance, as with ischemia or vasoactive agents, alter pulmonary capillary pressure contributes to the
the interpretation of the PAOP as an indicator of development of pulmonary edema.
preload adequacy. The effect of PEEP on juxta-
cardiac pressure depends on lung and chest wall Thermodilution Cardiac Output
compliance. Usually, PEEP causes a decrease in
left ventricular transmural pressure despite an Determination of cardiac output by thermodi-
increase in measured PAOP. Overall, measured lution involves the injection of normal saline
PAOP will overestimate left ventricular end- through the proximal port (right atrium) with
diastolic pressure with PEEP, but the extent is detection of a temperature change by the therm-
difficult to determine precisely. In addition, istor at the distal end of the catheter. The volume
mitral or aortic valve dysfunction alters the and temperature of injectate and the area under
association of PAOP with left ventricular end- the thermodilution curve enable the cardiac
diastolic pressure (Table 6).19 The PAOP as a output to be calculated. Thermodilution cardiac
measure of preload does not reliably predict fluid output generally has a good correlation with the
responsiveness.20,21 Fick or dye dilution technique. However, even
The PAOP is an indirect assessment of under the best circumstances, this measurement
pulmonary capillary pressure but does not equal has a reliability of –10%. To ensure optimum
pulmonary capillary pressure. The pulmonary accuracy, the following steps should be taken: (1)
capillary pressure exceeds left atrial pressure and carefully measure the temperature and volume of
PAOP by a variable degree depending on the injectate; (2) obtain the average of three
vascular resistance in the pulmonary venous separate measurements at least 1 min apart; (3)
system. A normal PAOP may be present despite inject the solution over 2 s at the same phase of
high pulmonary capillary pressures if marked respiration, which preferentially is end-expiration;
resistance exists. Physiologic (eg, pulmonary (4) use room temperature injectate except for

patients who are severely hypothermic (,308C) when rapid changes in vascular resistance occur
and who require iced injectate; a temperature (eg, hemodynamic instability).
difference of 108C is necessary for accurate
measurements; and (5) inspect graphic display Transesophageal Doppler Ultrasonography
of cardiac output thermodilution curve for rapid
upstroke and gradual, smooth return to baseline. This technique determines the velocity of
Falsely low measurements may be obtained in the blood in the descending thoracic aorta during
presence of tricuspid regurgitation and falsely ventricular systole.26 Stroke volume is estimated
elevated results in the presence of intracardic from this velocity and a measurement of aortic
shunts or distal catheter position. Measurements diameter (direct measurement or nomogram).
may be unreliable in the presence of atrial Proper positioning is necessary for accurate
fibrillation because of poor reproducibility. measurements and requires training and experi-
ence.
Less Invasive Hemodynamic
CO2 Partial Rebreathing
Monitoring
Monitors using this technique are based on the
Multiple methodologies have been developed
Fick principle applied to CO2. Determinations are
for measuring cardiac output, stroke volume, or
made of CO2 production and arterial CO2 content
fluid responsiveness that are less invasive than
during normal and rebreathing conditions. Pa-
PAC. These methods include arterial pressure
tients must be receiving controlled mechanical
waveform analysis, pulsed Doppler cardiac
ventilation with sedation because a change in
output devices, CO2 partial rebreathing (applied
minute ventilation during the rebreathing period
Fick principle), and bioimpedance.22,23 Studies of
in spontaneously breathing patients reduces the
the reliability, validity, and clinical utility of less
accuracy of the cardiac output estimation. Inaccu-
invasive techniques report variable results.24,25 rate measurements also result with low minute
The advantages, disadvantages, and limitations ventilation, high shunt fraction, high cardiac
of the various techniques suggest that a single output, and hemodynamic instability.
method may not be applicable to all patients.
Further clinical investigations are needed to Bioimpedance
determine the optimal method of assessing the
hemodynamic status of critically ill patients. Electrical bioimpedance methods rely on
changes in thoracic or body impedance, associ-
Pulse Contour Analysis ated with cyclic changes in blood flow due to
cardiac activity to estimate cardiac output.
Analysis of the arterial pressure waveform is Electrodes can be placed on the skin or mounted
used to compute stroke volume, with initial on an endotracheal tube, depending on the
calibration of cardiac output by transpulmonary device.
thermodilution or indicator dilution (eg, lithium
chloride) or by use of a proprietary cardiac Fluid Responsiveness
output algorithm. The pulse contour methodol-
ogy is based on changes in the pulse pressure The clinically relevant issue in many critically
waveform. The pulse pressure varies with the ill patients is whether additional fluids will
stroke volume and changes in vascular compli- improve stroke volume or cardiac output rather
ance. An elevated pulse pressure variation may than a specific measurement of preload (PAOP,
predict fluid responsiveness in critically ill central venous pressure [CVP]). In septic pa-
patients. These techniques are not reliable when tients, a CVP ,8 mm Hg and PAOP ,12 mm Hg
the arterial waveform is poorly defined, arrhyth- were poor predictors of fluid responsiveness.20,21
mias are present, or an intraaortic balloon pump In patients receiving mechanical ventilation,
is used. Accuracy may also be compromised respiratory changes in stroke volume or a

correlate due to lung-heart interactions have reflect changes in cardiac output, decreases in
been proposed as a way to assess fluid respon- arterial oxygen saturation (hypoxemic lung dis-
siveness. Patients who respond to fluids with ease) or hemoglobin concentration, as well as
improvement in cardiac output may demonstrate increased tissue oxygen consumption (fever,
significant variation in systolic pressure, pulse hypermetabolism, shivering, seizures, pain, or
pressure, or stroke volume, measured by several work of breathing), can result in decreases in
of the less invasive techniques mentioned SvO2. A normal SvO2 in a stable patient usually
above.27,28 Various thresholds of 10% to 15% indicates that tissue oxygen needs are being met.
variation in one of these parameters have been An exception to this rule is in sepsis and certain
suggested to identify a patient as a responder to poisonings (eg, cyanide), in which tissue hypoxia
fluids. There are limitations in the accuracy of may exist with normal or elevated Svo2.
these measurements in the following circum- In many critically ill patients without PAC,
stances: spontaneous breathing, hemodynamic central venous catheterization allows measure-
instability, arrhythmias, tidal volume ,8 mL/kg, ment of central venous oxyhemoglobin satura-
and right ventricular dysfunction. This type of tion (ScvO2) either continuously or intermittently.
assessment is best suited to patients with regular The ScvO2 is usually 2% to 3% less than SvO2 in
cardiac rhythms who are receiving mechanical healthy individuals because the lower body
ventilation with sedation, which limits applica- extracts less oxygen. However, in patients with
bility. Passive leg raising has also been used to shock, this relationship is altered owing to
identify patients likely to respond to fluid.29
increased oxygen consumption by the GI tract.
Raising the legs to a 45-degree angle mimics fluid
Under such conditions, the ScvO2 is 5% to 7%
infusion by shifting blood from the lower
higher than SvO2, but both values usually change
extremities to the intrathoracic compartment.
in parallel.
An increase in blood pressure, stroke volume,
or inferior vena cava diameter suggests the need
Hemodynamic Monitoring in Clinical
for additional intrathoracic volume.
Conditions
Mixed Venous Blood Measurements
Myocardial Infarction and Heart Failure
Measurements of mixed venous oxyhemo-
PAC allows estimation of left ventricular
globin saturation (SvO2) are obtained by with-
drawing blood from the distal port of the PA preload by PAOP, measurement of cardiac
catheter with the balloon deflated. At least 2.5 to output, and calculation of systemic vascular
3 mL of blood must be eliminated to allow for resistance (SVR) to guide institution and titration
catheter dead space before removal of blood for of fluids and inotropic or vasopressor agents in
analysis. Blood should be removed slowly in patients with myocardial infarction complicated
patients receiving high fraction of inspired by shock. Less invasive techniques may also
oxygen levels or PEEP to avoid contamination provide estimates of PAOP, cardiac output, and
with oxygenated capillary blood. Inaccurate left ventricular function. The recognition of
measurements also occur in the presence of ischemic right ventricular dysfunction has impli-
severe mitral regurgitation, left-to-right cardiac cations for treatment different from those of left
shunts, and distal tip placement. PA catheters ventricular dysfunction. The characteristic find-
that provide continuous measurement of Svo2 ings with PAC in acute right ventricular dys-
make use of fiberoptic reflectance oximetry. function include an elevated right atrial pressure
The SvO2 reflects the balance between tissue that equals or exceeds PAOP, a steep y-descent,
O2 delivery and O2 consumption.30 The four and a right ventricular pressure tracing with a
variables that determine SvO2 are cardiac output, diastolic dip and plateau (square root sign). The
arterial oxygen saturation, hemoglobin concen- right atrial pressure may increase during inspi-
tration, and tissue oxygen consumption. Al- ration (Kussmaul sign) or with the hepatojugular
though this measurement is often used to reflux maneuver.

PAC has been used in patients with heart associated with elevated right atrial and right
failure to optimize inotropic and vasodilator ventricular end-diastolic pressures. A prominent
therapy. The randomized trial of PAC use in early v-wave is seen in the right atrial pressure
patients with severe symptomatic heart failure tracing with PAC, and the x-descent may be
(ejection fraction ,30%) failed to show any absent or diminished. A steep y-descent is
benefit and was associated with a greater present. In severe tricuspid regurgitation, the
incidence of in-hospital adverse events. The right atrial pressure tracing may resemble the
benefit of PAC in cardiogenic shock has not been right ventricular pressure tracing.
evaluated in clinical trials.
Intracardiac Shunt
Shock
The presence of an intracardiac shunt may be
PAC or less invasive techniques may be determined by using PAC to obtain blood
helpful in the diagnosis of shock not due to samples for PO2 determination from the right
myocardial infarction. Characteristic hemody- atrium, right ventricle, and PA, or by using PAC
namic patterns that use filling pressures, cardiac with oximetry. This assessment may be helpful in
output, and/or SVR are usually sufficient to distinguishing acute ventricular septal defect
distinguish cardiogenic, distributive, hypovole- from acute mitral regurgitation in myocardial
mic, and obstructive shock (see below). infarction. A step-up in oxygen content (10%)
between the right ventricle and right atrium
Mitral Regurgitation indicates a ventricular septal defect. With devel-
opment of an acute ventricular septal defect, the
Chronic mitral regurgitation is best diag- right atrial pressure, PA pressure, and PAOP are
nosed by echocardiography. Acute valvular elevated.
decompensation may occur in myocardial infarc-
tion, and PAC information will often distinguish Acute Massive Pulmonary Embolism
mitral regurgitation from other complications if
echocardiography is not readily available. Ele- Massive pulmonary embolism can produce a
vated left atrial pressure and PAOP are noted, clinical presentation similar to cardiogenic shock.
and tall, peaked v-waves are seen in the PAOP Although rarely needed as a diagnostic tool, PAC
tracing. A bifid PA waveform composed of the will demonstrate elevated systolic and diastolic
PA systolic wave and the v-wave may be seen. PA pressures in massive pulmonary embolism
Regurgitant flow makes accurate assessment of but no elevation in PAOP. The mean PA pressure
the PAOP difficult if not impossible. In such rarely exceeds 40 mm Hg unless there is a
circumstances, the a-wave on the PAOP tracing chronic component of pulmonary hypertension.
can be used to estimate left ventricular end-
diastolic pressure. The pressure tracing should be Acute Cardiac Tamponade
examined together with a simultaneous ECG
tracing. The v-wave occurs at the end of the T- Echocardiography is most commonly used to
wave on ECG, with the PA waveform occurring diagnose pericardial effusion and its hemody-
earlier in the cardiac cycle. Prominent v-waves namic effects on myocardial function. In those
can also be noted when the left atrium is instances in which echocardiography is not
distended and noncompliant owing to left available, or when there is a question of
ventricular failure from any cause. hemodynamic impact of pericardial effusion,
PAC may be helpful particularly with focal
Tricuspid Regurgitation effusions. The characteristic hemodynamic pat-
tern of acute cardiac tamponade includes eleva-
Tricuspid regurgitation usually occurs in the tion and equalization of right-sided and left-
setting of pulmonary hypertension and right sided filling pressures (right atrium and PAOP)
ventricular dilation. Tricuspid regurgitation is and a prominent systolic x-descent and blunted

Table 7—Classification of Shock the right atrial tracing along with a systolic x-
descent and prominent early diastolic y-descent.
Hypovolemic
Hemorrhagic (trauma and GI bleed)
Nonhemorrhagic (eg, external loss, interstitial fluid Restrictive Cardiomyopathy
redistribution)
Distributive The hemodynamic pattern in restrictive car-
Sepsis
Adrenal crisis diomyopathy is similar to that in constrictive
Neurogenic (spinal shock) pericarditis. Differentiation of the two conditions
Anaphylaxis may be very difficult. Left-sided filling pressures
Thyroid storm
Cardiogenic tend to be higher than right-sided filling pres-
Myopathic (eg, ischemia, cardiomyopathy) sures in restrictive cardiomyopathy. In addition,
Mechanical (eg, valvular lesions, septal defects) the diastolic pressure plateau is usually less than
Arrhythmias
Obstructive
one-third of the right ventricular systolic pres-
Massive pulmonary embolism sure.
Tension pneumothorax
Cardiac tamponade
Constrictive pericarditis
Shock
Reprinted with permission from ACCP Pulmonary Medicine Shock is a syndrome of impaired tissue
oxygenation and perfusion that results from one
of the following mechanisms: an absolute or
relative decrease in oxygen delivery; ineffective
y-descent on the right atrial pressure tracing. The
tissue perfusion; or impaired utilization of
right atrial pressure declines in inspiration in delivered oxygen. Shock results when the oxygen
contrast to right ventricular infarction and balance is disturbed and oxygen demands exceed
constrictive pericarditis. supply. Although hypotension is often present in
shock states, BP may be normal or even slightly
Constrictive Pericarditis increased owing to compensatory vasoconstric-
tion. Additional clinical manifestations in shock
Constrictive pericarditis produces equaliza- are related to tissue hypoperfusion, the compen-
tion and elevation of right-sided and left-sided satory responses initiated by shock, and the
filling pressures similar to cardiac tamponade. In underlying etiology of shock.
addition, constrictive pericarditis usually pro- Shock is usually classified into four catego-
duces an early diastolic dip, followed by a ries: hypovolemic, distributive, cardiogenic, and
pressure plateau in the right and left ventricular obstructive (Table 7). However, most patients
pressure tracings. An inspiratory increase in with shock demonstrate features of more than
pressure (Kussmaul sign) can often be seen in one type of shock (ie, mixed shock). For example,
Table 8—Hemodynamic Patterns of Shock
Type of Shock SVR CO CVP PAOP SvO2 or ScvO2
Distributive
Septic or N (rarely) or N or N or N
Neurogenic or or N
Hypovolemic
Cardiogenic
Obstructive
Cardiac tamponade
Pulmonary embolism or N
CO ¼ cardiac output; N ¼ normal, ¼ increase; ¼ decrease. Reprinted with permission from ACCP Pulmonary Medicine Board
Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.

Table 9—Vasoactive Agents in Shock
Drug Usual IV Dose a b1 b2 Dopaminergic
Dopamine 1–2 lg/kg/min 1þ 0–1 þ 0–1 þ 3þ

2–10 lg/kg/min 2þ 1–2 þ 0–1 þ 3þ
10–30 lg/kg/min 3þ 1–2 þ 0–1 þ 3þ
Dobutamine 2–30 lg/kg/min 0–1 þ 3þ 1þ 0
Norepinephrine 0.5–80 lg/min 3þ 2þ 0 0
Epinephrine Low: 0.005–0.02 0 3þ 2þ 0
lg/kg/min
High: .0.02 2þ 3þ 1–2 þ 0
lg/kg/min
Phenylephrine 20–200 lg/min 3þ 0 0 0
Vasopressin 0.01–0.04 U/kg/min 0 0 0 0
Physicians; 2009.
a patient who is in septic shock will likely have a transfusion and oxyhemoglobin saturation by the
hypovolemic component before resuscitation in administration of supplemental oxygen and
addition to the decreased SVR that is character- mechanical ventilation as needed. Therapeutic
istic of distributive shock. intervention with fluids, vasopressor agents,
The different types of shock are characterized inotropic agents, and, rarely, vasodilators (car-
by hemodynamic patterns (Table 8) that assist diogenic shock) is used to optimize BP and
with diagnosis and the determination of appro- cardiac output.
priate management. Specific measurements may Fluids: Most types of shock benefit from
not always be available, and clinical findings in a initial volume resuscitation. Even patients with
specific patient may be variable owing to the cardiogenic shock may require fluids to increase
specific etiology of shock, the underlying cardiac ventricular filling pressures in order to optimize
function, the duration of shock, and degree of myocardial performance (the Frank-Starling
resuscitation. principle). Isotonic crystalloid solutions or col-
loid solutions are equivalent as long as an
Management of Shock
appropriate quantity is administered to achieve
hemodynamic goals. In general, crystalloids
The management of shock requires treatment
require two to three times greater volume than
of the underlying etiology, and the restoration of
colloids to achieve similar goals. Hypotonic
adequate oxygen delivery and tissue perfusion.
crystalloids should not be used for volume
Oxygen delivery is optimized with interventions
that achieve an appropriate BP, cardiac output, resuscitation. Colloid solutions have the potential
and oxygen content of arterial blood (Table 5). advantage of achieving adequate volume resus-
The first goal is a minimum BP to maintain blood citation more quickly and with smaller volumes.
flow to the heart and vital organs while other Some studies have suggested that hetastarch
components of oxygen delivery are addressed. solutions may be associated with more renal
An initial mean arterial pressure (MAP) of 65 dysfunction and increased mortality, but the
mm Hg is usually recommended, but the specific different properties of specific hetastarch solu-
goal for an individual patient should aim to tions preclude extrapolation of the results to the
optimize tissue perfusion without increasing entire class of fluids.31 Therapy with titrated
myocardial oxygen demand. Once a minimum boluses of fluids (500 to 1,000 mL of crystalloid
BP is achieved, oxygen delivery is improved by and 300 to 500 mL of colloid) is recommended in
increasing cardiac output, hemoglobin concen- patients who are in shock, with close monitoring
tration, or oxyhemoglobin saturation. Hemoglo- of the response until the hemodynamic goals are
bin concentration can be increased by blood achieved.

Vasoactive Agents: Vasoactive medications for
30%, or dobutamine infusion to a maximum
the treatment of shock include agents with
of 20 lg/kg/min.
vasopressor, inotropic, and/or vasodilator ef-
fects. Some agents have combined effects (vaso- Infection Issues
pressor and inotropic), and effects may vary with
Begin therapy with IV antibiotics as soon as
the dose. An agent should be selected by the
possible but always within 1 h of recognizing
physiology of the type of shock, the effect
the presence of severe sepsis and septic shock.
desired, and the specific assessment of the
Reassess the antibiotic regimen daily to opti-
patient.32–34 Clinical trials have not established
mize efficacy, prevent resistance, avoid toxicity,
the superiority of a single agent or combination
and decrease costs.
of agents on outcomes in shock. Common
Consider using combination therapy for 3 to
vasoactive agents, dosing ranges, and adrenergic
5 days and deescalate therapy when suscepti-
effects are listed in Table 9. In general, agents
bilities are known.
with predominantly a-adrenergic properties will Implement source control measures as soon as
have greater vasopressor effects, and agents with
possible after initial resuscitation.
greater b-adrenergic properties will have more
inotropic and chronotropic effects. Therapy with
Hemodynamic Support
potent vasopressor agents will generally result in
increases in afterload, MAP, and preload, with Use crystalloids or colloids for fluid resuscita-
decreases in cardiac output and relative brady- tion. The role of albumin for resuscitation is
cardia. Agents with potent inotropic effects being further defined.36
increase myocardial contractility, cardiac output, Maintain MAP at 65 mm Hg.
and heart rate, and may decrease BP. Norepinephrine and dopamine are the initial
vasopressors of choice. Dopamine use is
Severe Sepsis and Septic Shock associated with more arrhythmic adverse
events than norepinephrine use.34
Consensus guidelines have been developed Epinephrine, phenylephrine, or vasopressin
and revised for the management of severe sepsis should not be the initial vasopressor.37
and septic shock.35 The clinician should be Epinephrine is the first alternative therapeutic
familiar with these recommendations and the agent to be used when BP is poorly responsive
evidence supporting interventions. The consen- to norepinephrine or dopamine.
sus guidelines will be updated in 2012 and
additional information can be found at http:// Adjunctive Therapy
www.survivingsepsis.org. Recommendations of
Consider therapy with IV hydrocortisone
particular interest are listed below. Recommen-
dation grades are not included owing to pending when hypotension responds poorly to ade-
release of the revised guidelines. quate fluid resuscitation and vasopressors.38
An adrenocorticotropic hormone stimulation
Initial Resuscitation test is not recommended to identify patients
who should receive hydrocortisone.
Initiate resuscitation immediately in patients
with hypotension or lactate concentration of
Supportive Care
.4 mmol/L.
Resuscitation goals are CVP of 8 to 12 mm Hg; After initial resuscitation, transfuse RBCs when
MAP of 65 mm Hg; urine output of 0.5 mL/ hemoglobin concentration decreases to ,7 g/
kg/h; ScvO2 of 70% or SvO2 of 65%. dL to target a hemoglobin concentration of 7 to
If the goals for ScvO2 and Svo2 are not 9 g/dL.
achieved, consider therapy with additional Use IV insulin to control hyperglycemia after
fluid, transfusion to a hematocrit value of stabilization.

Control glucose concentration to a target value 10. Sandham JD, Hull RD, Brant RF, et al. A
of ,150 mg/dL by using a protocol for insulin randomized, controlled trial of the use of pulmo-
adjustment. nary-artery catheters in high-risk surgical pa-
tients. N Engl J Med. 2003;348(1):5–14.
11. Harvey S, Stevens K, Harrison D, et al. An
Nothing to Disclose
evaluation of the clinical and cost-effectiveness
of pulmonary artery catheters in patient manage-
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randomised controlled trial. Health Technol Assess.
2006;10(29):iii–iv, ix-xi, 1–133.
this chapter.
12. Harvey S, Young D, Brampton W, et al. Pulmo-
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2647. septic shock. N Engl J Med. 2008;358(9):877–887.
29. Boulain T, Achard J-M, Teboul J-L, Richard C, 38. Sprung CL, Annane D, Keh D, et al. Hydrocorti-
Perrotin D, Ginies G. Changes in BP induced by sone therapy for patients with septic shock. N
passive leg raising predict response to fluid Engl J Med. 2008;58(2):111–124.

Chapter 21. Community-Acquired Pneumonia:
Advances in Management
Objectives: Epidemiology
Identify the common pathogens causing community-
acquired pneumonia. Community-acquired pneumonia (CAP) affects
Identify the risk factors for mortality to improve site-of- 5.6 million adults annually in the United States
care decisions. and causes 1.7 million hospitalizations per year.1
Improve antibiotic selection in the empiric therapy of
community-acquired pneumonia. Pneumonia is the eighth-leading cause of death
Recognize the risk of avian influenza and community- in the United States, accounting for .60,000
acquired methicillin-resistant Staphylococcus aureus. deaths annually.2 It is the cause of 46% of all
deaths from infectious disease.3 Admission to an
Key words: community-acquired methicillin-resistant ICU was required in 10% to 20% of patients
Staphylococcus aureus; CURB-65; Patients Outcome Research
Team score; Streptococcus pneumoniae hospitalized with pneumonia. The mean length
of stay for pneumonia was 5 days, and the 30-
Synopsis: day rehospitalization rate was as high as 20%.2 In
Community-acquired pneumonia (CAP) is a very common the United States, there were approximately 4.2
condition often leading to hospitalization. Patients admitted million ambulatory care visits for pneumonia in
to hospital (and the ICU) have a mortality rate that varies
2006. While causative pathogens are identified in
from 10% to 30%. Streptococcus pneumoniae is the commonest
pathogen independent of the severity of illness. In most ,50% of cases,4 the specific organisms that
clinical settings, atypical organisms (Mycoplasma pneumo- require coverage include typical organisms such
niae, Chlamydia pneumonia, and Legionella spp) are the next as Streptococcus pneumoniae, Haemophilus influen-
most common. Only a minority of patients require hospi-
talization, and several severity-of-illness tools have been zae, and Moraxella catarrhalis. Atypical organisms,
developed that can aid in the decision to admit a patient to including Mycoplasma pneumoniae, Chlamydia
the hospital. Several tools have been developed to assist in pneumoniae, and Legionella pneumophila, may have
the decision to admit a patient directly to the ICU.
Biomarkers such as procalcitonin, C-reactive protein, and
a presentation that is more subacute, with
cardiac biomarkers are being actively investigated to nonproductive cough and a chest radiograph
separate viral from bacterial infections, limit the duration that appears characteristically worse than the
of antibiotic therapy, and serve as prognostic indicators.
patient’s clinical appearance, but this is not
There is reasonable evidence to suggest that atypical
coverage is useful and is associated with reduced mortality uniform by any means and does not allow
and shortened lengths of stays for seriously ill patients. clinical identification from patients with infection
There is considerable concern regarding the emergence of from usual organisms.5
community-associated methicillin-resistant Staphylococcus
aureus (MRSA) as a potential pathogen in CAP. As
diagnostic tools improve, viral pneumonia is being diag- Etiology
nosed more frequently. Seasonal and pandemic influenza
continue to be important clinical issues. There is emerging
Using the Infectious Diseases Society of
evidence to suggest that pneumococcal vaccination with a
23-valent polysaccharide vaccine is not particularly helpful, America/American Thoracic Society (IDSA/
but a new protein conjugate vaccine may be more useful. ATS) CAP guideline as a framework, patients
The diagnosis of pneumonia considerably alters long-term with CAP are stratified based on an assessment
prognosis even after correcting for comorbidities and
severity of illness. of the need for a specific site of therapy
(outpatient, inpatient ward, or ICU), the presence
of comorbidities, and the likelihood for drug-
resistant S pneumoniae (DRSP), enteric gram-
negative organisms, and Pseudomonas aeruginosa.6
Not every patient should be considered at risk

Table 1—Organisms Associated With Community-Acquired the risk of macrolide failures.12 All patients with
Pneumonia CAP could potentially be infected with C pneumo-
Patient Type Etiology
niae, M pneumoniae, and/or Legionella spp (the
‘‘atypical’’ pathogens), either alone or as part of a
Outpatient S pneumoniae mixed infection; and thus therapy for these
M pneumoniae pathogens should be considered in all patients.13
H influenzae
C pneumoniae
A meta-analysis14 has suggested that clinical
Respiratory viruses outcomes are satisfactory when outpatients are
Inpatient (non-ICU) S pneumoniae treated with b-lactams alone without atypical
M pneumoniae coverage. However, most of the trials selected for
C pneumoniae
H influenzae this meta-analysis were for antibiotic registration
Legionella spp purposes, and the patients were highly selected.
Aspiration These trials examined late clinical outcomes and
Respiratory viruses
differences in rates of recovery could easily be
Inpatient (ICU) S pneumoniae
S aureus missed by this analysis. This meta-analysis ap-
Legionella spp plied only to outpatients and does not speak to the
Gram-negative bacilli appropriate management of hospitalized patients
H influenzae
with CAP. There are considerable data to suggest
Adapted from Mandell et al.6 that atypical coverage (either with macrolides or
fluoroquinolones) is associated with better clinical
for infection with DRSP. Specific risk factors have outcomes, including reduced lengths of hospital
been identified, and there are regional differences stay and mortality.15,16
in resistance rates. The role of enteric gram- When patients with CAP are admitted to the
negative organisms in CAP is controversial, but ICU, the organisms responsible include S pneumo-
these organisms do not need to be considered niae, Staphylococcus aureus, Legionella spp, and
unless specific risk factors are present; one of enteric gram-negative organisms.17 P aeruginosa
these risk factors includes residence in a nursing has been recovered from some patients with severe
home. CAP, but this organism should only be considered
S pneumoniae is the most common pathogen when patients have well-identified risk factors
and may even account for pneumonia in patients present. In a prospective study, Arancibia and
who have no pathogen identified by routine coworkers18 identified that probable aspiration,
diagnostic testing (Table 1). It is the most previous hospital admission, previous antimicro-
common pathogen found independent of sever- bial treatment, and the presence of pulmonary
ity of disease.7 Although the incidence of DRSP is comorbidity were independent predictors of gram-
increasing, available data show that mortality in negative pneumonia. Similarly, pulmonary comor-
patients with CAP is adversely affected by drug- bidity and previous hospital admission were
resistant pneumococci only when minimum independent predictors of pneumonia caused by
inhibitory concentration values to penicillin are P aeruginosa. In a prospective study involving over
4 mg/L.8 The impact of organisms at lower 5,000 patients in Germany,19 Enterobacteriaceae or
levels of resistance remains uncertain. Some P aeruginosa was found in less than 2% of patients;
studies have been unable to detect treatment these could be identified by demonstrating certain
failures when patients with drug-resistant strains risk factors that included cardiac and cerebrovas-
of S pneumoniae are treated with antibiotics that cular disease for Enterobacteriaceae and, for P
do not have in vitro activity against the pathogen.9 aeruginosa, chronic respiratory disease and enteral
Treatment failures have been described among tube feeding.
patients with infection treated with macrolides In a prospective observation study involving
when pneumococci exhibit macrolide resistance 193 patients with CAP,20 39% had a pathogen
and fluoroquinolones when pneumococci exhibit identified. Of these pathogens, 15% were viruses,
fluoroquinolone resistance.10,11 The mechanism of 20% were bacteria, 4% were mixed, and the rest
macrolide resistance does not appear to influence were unknown. Influenza, human metapneumo-
312 Chapter 21. Community-Acquired Pneumonia: Advances in Management (Grossman)

Table 2—Microorganisms Associated With Specific Conditions
Condition Commonly Encountered Pathogen(s)
Alcoholism S pneumoniae and anaerobes

COPD and/or smoking S pneumoniae, H influenzae, M catarrhalis, and Legionella spp
Nursing home residency S pneumoniae, gram-negative bacilli, H influenzae, S aureus,
anaerobes, and C pneumoniae
Poor dental hygiene Anaerobes
Epidemic Legionnaires’ disease Legionella spp
Exposure to bats or soil enriched with bird droppings Histoplasma capsulatum
Exposure to birds Chlamydia psittaci
Exposure to rabbits Francisella tularensis
HIV infection (early stage) S pneumoniae, H influenzae, and M tuberculosis
HIV infection (late stage) Above þ P carinii, Cryptococcus, and Histoplasma spp
Travel to southwestern United States Coccidioides spp
Exposure to farm animals or parturient cats Coxielle burnetii (Q fever)
Influenza active in community Influenza, S pneumoniae, S aureus, S pyogenes, and H influenzae
Suspected large-volume aspiration Anaerobes (chemical pneumonitis, obstruction)
Structural disease of lung (bronchiectasis, cystic P aeruginosa, Burkholderia cepacia, and S aureus
fibrosis, etc.)
Injection drug use S aureus, anaerobes, M tuberculosis, and S pneumoniae
Airway obstruction Anaerobes, S pneumoniae, H influenzae, and S aureus
virus, and respiratory syncytial virus accounted culture and Gram stain are not required. All
for most viral infections. Compared with bacte- admitted patients with CAP should have an
rial infection, patients with viral infection were assessment of gas exchange (oximetry or arterial
older, were more likely to have cardiac disease, blood gas), routine blood chemistry and blood
and were more frail. There were few clinically counts, and a collection of two sets of blood
meaningful differences in presentation and no cultures. The standard recommendation for
differences in outcomes according to the pres- blood cultures has been challenged.22 The risk
ence or absence of viral infection. Using nucleic of bacteremia is increased among patients who
acid amplification techniques in patients with have underlying liver disease, who demonstrate
CAP, at least one respiratory virus was found in hypotension (systolic BP ,90 mm Hg), tachycar-
about one-third of patients, significantly higher dia (pulse rate 125/min), or extremes of
than in noninfected controls.21 Coronaviruses temperature (,358 C or 408 C), and who exhibit
were most frequently discovered. These studies certain abnormal laboratory values (BUN 30
suggest that viral infections are common in mg/dL, sodium ,130 mmol/L, WBC count
adults with pneumonia, raising issues of inci- ,5,000/lL or .20,000/lL). The risk of bacter-
dental nosocomial transmission. emia is significantly decreased among patients
who have received prior antibiotics. If a decision
Diagnosis support tool was used, whereby no blood
cultures would be drawn if the risk of bacteremia
Patients should be investigated for the was low, one blood culture if the risk of
presence of microorganisms when the usual bacteremia was moderate, and two blood cul-
empiric regimen would not be sufficient, espe- tures if the risk of bacteremia was high, then 88%
cially when the patient has clinical or epidemi- of bacteremias would be detected and 38% fewer
ologic considerations suggesting the presence of blood cultures would be drawn.22 If a drug-
unusual organisms (Table 2).6 All patients with resistant pathogen or an organism not covered by
CAP should undergo chest radiography to usual empiric therapy is suspected, then sputum
establish the diagnosis and the presence of culture should be obtained and a Gram stain be
complications (pleural effusion, multilobar dis- used to guide interpretation of culture results.
ease).6 All outpatients should have a careful Routine serologic testing is not recommended for
assessment of disease severity, but sputum any population with CAP. For patients with

severe CAP, Legionella and pneumococcal urinary Other routinely obtained biomarkers can be
antigen should be measured, and aggressive used to judge severity of illness. In a retrospec-
efforts at establishing an etiologic diagnosis tive cohort study30 of 500 consecutive patients
should be made, including the collection of hospitalized with CAP, an abnormal platelet
bronchoscopic samples of lower respiratory count ,100,000/L (thrombocytopenia) and/or
secretions in selected patients, although the .400,000/L (thrombocytosis) were strongly as-
benefit of such efforts has not been proven.6 sociated with 30-day mortality, whereas no
In a randomized, controlled trial,23 routine association was observed for leukocyte count.
implementation of urine antigen detection tests Almost 3,000 patients with CAP diagnosed in an
did not have outcome-related or economic ED and discharged home were followed to
benefits to hospitalized patients with CAP. identify the impact of initial hypoxemia. Com-
Narrowing the antibiotic treatment according to pared with patients with higher blood oxygen
the urine antigen results actually resulted in a saturations, those discharged with saturations
higher risk of clinical relapse. ,90% had significantly higher rates of 30-day
mortality and hospitalization.31 Admission hy-
Admission Decision and Severity-of-Illness poglycemia was also associated with a higher in-
Determination hospital mortality, and the outcome was not
affected by treatment for diabetes.32
The admission decision can be difficult, and Admission to the ICU is needed for patients
prognostic scoring rules (the Patients Outcome with severe CAP. The need for mechanical
Research Team pneumonia severity index [PSI]; ventilation or vasopressor support are clear
British Thoracic Society rules; and CURB-65, indications for ICU admission, but a combination
CRB-65, and CURB [Confusion, elevated Urea, of at least three minor criteria of those listed
increased Respiratory rate, decreased BP] crite- below were also suggested by the IDSA/ATS
ria) are adjunctive tools to support, but not guideline committee, although these were not
replace, this process.24–27 These tools were devel- evidence-based.6 The minor criteria were:
oped to predict mortality but have been adapted
Respiratory rate .30 breaths/min
to aid in the admission decision. The CURB
Confusion/disorientation
criteria include respiratory rate 30/min, dia-
Uremia (BUN .20 mg/dL)
stolic BP 60 mm Hg, blood urea .7.0 mmol/L
Leukopenia (WBC ,4,000 cells/lL)
(BUN .19.1 mg/dL), and confusion. In a meta-
Systolic BP ,90 mm Hg
analysis, including 23 studies examining more
Multilobar infiltrates
than 22,000 patients, PSI had the highest sensi-
PaO2/FIO2 ratio 250
tivity and lowest specificity for mortality, CRB-65
Thrombocytopenia (platelets ,100,000 cells/
was the most specific (but least sensitive) test, and
lL)
CURB-65/CURB were between the two.28 All of
Hypothermia (core temp ,368 C)
these tools have good negative predictive values
Decreased BP requiring aggressive fluid resus-
for mortality in populations with a low preva-
citation
lence of death but are less useful with regard to
positive predictive values. Another meta-analy- The presence of any three minor variables
sis29 concluded that there were no significant had a positive predictive value of 53% and a
differences in overall test performance among negative predictive value of 92% for ICU care.33
PSI, CURB-65, and CRB-65 for predicting mortal- Subsequently, a retrospective analysis of prospec-
ity from CAP. In general, hospitalization is tively acquired data acquired from an electronic
needed if patients have multiple risk factors for health record indicated that using four minor
a complicated course (high PSI or CURB-65 criteria improved the performance of the score to
scores). Patients may also need to be hospitalized a positive predictive value to 81% and main-
for a variety of nonmedical reasons, and such tained the negative predictive value at 92%.34
social factors should also be incorporated into the Patients who have two of four criteria from the
admission decision process. modified British Thoracic Society rule also have

more severe illness and should be considered for marker of bacterial infection indicating a need for
ICU admission. antibiotics.37 It may also predict bacteremia and,
Several other tools to predict the need for ICU among patients with very low procalcitonin levels,
admission have also been developed.35,36 Two of may reliably indicate that blood cultures are not
these, SMART-COP and CUROX-80, are de- required.38 It may allow a clinician to reduce the
scribed below. When comparing the modified duration of antibiotic therapy, especially in pa-
IDSA/ATS severity rule (using four of the minor tients with mild-to-moderate disease.39 Its abso-
criteria) to these other two ICU prediction rules, lute level is related to severity of disease, but its
the IDSA/ATS criteria demonstrated significant- ability to improve mortality prediction is variable.
ly better performance in predicting the need for Consecutive C-reactive protein measurements
ICU admission than the other two scores. may be useful in the first week in follow-up of
SMART-COP utilizes additional clinical and antibiotic treatment for severe CAP and delayed
laboratory variables and weighs hypotension, normalization of C-reactive protein levels is
hypoxemia, and acidosis more heavily. associated with a higher risk of having received
inappropriate antibiotic treatment.40
SMART-COP:
A study of adult hospitalized patients with
S Systolic BP ,90 mm Hg 2 points CAP41 examined genomic pneumococcal bacte-
M Multilobar chest radiograph involvement 1 point rial load detected in blood by polymerase chain
A Albumin ,3.5 g/dL 1 point reaction, as a predictor of outcome. The primary
R Respiratory rate: age-adjusted 1 point
endpoints were the development of septic shock
T Tachycardia 125/min 1 point
C Confusion (new onset) 1 point and the need for mechanical ventilation. The
O Oxygen low: age-adjusted 2 points secondary outcomes were the development of
P Arterial pH ,7.35 2 points acute kidney injury, ARDS, and in-hospital
mortality. A positive real-time polymerase chain
The maximum score is 11. Patients demon-
reaction assay finding was associated with
strating a score of 0 to 2 points have a low risk of
increased mortality, increased risk for shock,
needing intensive respiratory or vascular sup-
and an increased need for mechanical ventila-
port. Those with a score of 3 to 4 points have a
tion. The intensity of bacteremia was associated
moderate risk (1 in 8). Patients with scores
with a poor outcome. This is a sensitive tool to
ranging from 5 to 6 points have a high risk (1
identify pneumococcal infection and may have a
in 3), and those with scores 7 points have a very
role as an objective prognostic marker. This could
high risk (2 in 3).
also play a role in future trials of adjuvant
A second rule, called CUROX-80, involves
therapy.
five variables, listed below.36 The presence of two
Cardiac biomarkers including atrial natriuretic
of these variables would be sufficient to warrant
peptide,42 midregional pro-atrial natriuretic pep-
ICU admission.
tide,43 and adrenomedullin44 have been examined
CUROX-80: in patients with CAP. They indicate cardiovascular
dysfunction in septic patients and may predict
Confusion outcomes in septic patients admitted to an ICU.
Urea .30 mg/dL Their role may be become more prominent because
Respiratory rate .30/min
of the well-documented increased rate of cardiac
X-ray multilobar bilateral
complications that occurs among patients with
PaO2 ,54 or PaO2/FiO2 ,250 mm Hg
CAP.45,46
Age 80
Treatment
Role of New Biomarkers
Patients should initially be treated empirically
Procalcitonin, a calcitonin precursor that is based on the likely pathogens for each of the sites
elevated in infection as well as in trauma, burns, of care, although when culture results become
and neuroendocrine tumors, has been used as a available, organism-specific therapy may be pos-

Table 3—Outpatient Treatment Table 4—Inpatient Treatment
1. Previously healthy and no use of antimicrobials within Inpatient, non-ICU

the previous 3 mo A respiratory fluoroquinolone
A macrolide A b-lactam plus a macrolide
Doxycyline Inpatient, ICU
2. Presence of comorbidities such as chronic heart, lung, A b-lactam (cefotaxime, ceftriaxone, or ampicillin-
liver, or renal disease; diabetes mellitus; alcoholism; sulbactam) plus either azithromycin or a respiratory
malignancies; asplenia; immunosuppressing conditions fluoroquinolone (for penicillin-allergic patients, a
or use of immunosuppressing drugs; or use of respiratory fluoroquinolone and aztreonam are
antimicrobials within the previous 3 mo (in which case recommended)
an alternative from a different class should be selected) Special concerns
A respiratory fluoroquinolone (moxifloxacin, If Pseudomonas is a consideration:
gemifloxacin, or levofloxacin [750 mg]) An antipneumococcal, antipseudomonal b-lactam
A b-lactam plus a macrolide (piperacillin-tazobactam, cefepime, imipenem, or
3. In regions with a high rate (.25%) of infection with meropenem) plus either ciprofloxacin or levofloxacin
high-level (minimum inhibitory concentration, 16 g/mL) (750 mg); or
macrolide-resistant S pneumoniae, consider use of The above b-lactam plus an aminoglycoside and
alternative agents listed above in (2) for patients without azithromycin; or
comorbidities (moderate recommendation; level III The above b-lactam plus an aminoglycoside and an
evidence) antipneumococcal fluoroquinolone (for penicillin-
allergic patients, substitute aztreonam for above b-
Adapted from Mandell et al.6 lactam)
sible for some patients. All populations should be Adapted from Mandell et al.6
treated for the possibility of atypical pathogen
patients (Table 4). The recognition that the use of
infection (Table 3) although a clear benefit has not
antibiotics in the previous 3 months is a
been identified in all studies.14,47 For outpatients
significant predictor of antibiotic resistance to
or non-ICU inpatients with risk factors for these
that class helps drive the empiric therapy
other organisms, therapy should be with either a
decision to another class of antibiotics.10 Retro-
b-lactam/macrolide combination or an antipneu-
mococcal fluoroquinolone alone (Table 3). Al- spective studies15,50 have suggested that combi-
though both regimens appear therapeutically nation antibiotic therapy (usually a b-lactam plus
equivalent, particularly among inpatients, in the a macrolide) is superior to single-agent therapy
outpatient treatment of the more complicated (usually a b-lactam alone) among severely ill
patient, an antipneumococcal fluoroquinolone patients with bacteremic pneumococcal pneumo-
may be more convenient than a b-lactam/macro- nia. In a prospective international observational
lide combination (Table 4). All admitted patients study,51 combination antibiotic therapy was
should receive their first dose of antibiotic therapy superior to monotherapy but only for severely
as soon as possible after arrival at the hospital.48 ill patients. Whether a respiratory fluoroquinolone
While a 4-h door-to-needle time has been the is equivalent to two agents cannot be ascertained
recommended standard, it is not clear that every from the available data. In order to compare
patient must be treated that quickly; the diagnosis clinical outcomes of patients with CAP, treated
of pneumonia often takes .4 h to establish, and with and without atypical coverage, a secondary
treatment should not be started until other analysis was performed using two comprehensive
diagnostic possibilities have been excluded. Link- international databases.52 Patients treated with
ing antibiotic administration to a very tight time atypical coverage had decreased time to clinical
frame may lead to overdiagnosis of pneumonia stability, decreased length of stay, decreased total
and inappropriate administration of antibiotics.49 mortality, and decreased CAP-related mortality. A
In the ICU-admitted patient, current data do retrospective cohort study was conducted in
not support the use of an antipneumococcal patients with pneumonia and clinical criteria of
fluoroquinolone alone, and therapy should be severe sepsis.53 Severe sepsis was present in 30.1%,
with a b-lactam plus either a macrolide or of whom 43.9% received macrolides. In a multi-
fluoroquinolone, using a regimen with two variable analysis, the use of macrolide was
antipseudomonal agents in appropriate, at-risk associated with decreased mortality at 30 days

and at 90 days, even in patients with severe sepsis Blood specimen for culture drawn prior to
with macrolide-resistant pathogens. The mecha- antibiotic administration in the hospitalized
nism of this is uncertain. These findings would patient;
support empiric therapy for all hospitalized Administration of antibiotics with activity
patients with CAP, with a regimen that covers against all likely causative pathogens, prefera-
atypical pathogens. bly the least expensive efficacious regimen;
Most patients with CAP will have an ade- Counseling patients regarding smoking cessa-
quate clinical response within 3 days; when the tion;
patient has met appropriate criteria, a switch to Switching from IV to oral antibiotics if clini-
oral therapy should be made.54,55 Criteria for cally improving and hemodynamically stable,
switch include improvement in cough and with discharge within 24 h of switching to oral
dyspnea, afebrile (,37.88 C) on two occasions 8 therapy;
h apart, decreasing WBC count, and functioning Chest radiography within 24 h of hospital
GI tract with adequate oral intake. Even if the admission;
Employment of methods to increase vaccina-
patient is febrile, a switch in therapy can occur if
other clinical features are favorable. If the patient tion rates against influenza and pneumococ-
has met criteria for a switch, oral therapy can be cus; and no discharge home for patients who
started, and the patient can be discharged on the are unstable on the day of discharge.62,63
same day if other medical and social factors
permit. Switch therapy is simpler and quicker if a Prognosis
respiratory fluoroquinolone is used rather than a
b-lactam/macrolide combination. Outcomes are In a meta-analysis,4 the overall mortality rate
identical to patients staying in the hospital longer among 33,148 patients with pneumonia reported in
to complete their course of therapy.56 127 studies was 13.7%, ranging from 5.1% in a
Because of the persistent high morbidity and population that included both hospitalized and
mortality associated with pneumonia, investiga- ambulatory patients, to 13.6% for hospitalized
tors have been examining the role of adjunctive patients. In the elderly, the mortality rate was
therapy other than antibiotics. Neither cortico- 17.6%, while among nursing home patients it was
steroids nor tifacogin (a recombinant human 30.8% and among those admitted to the ICU it was
tissue factor pathway inhibitor) were found to 36.5%. When S pneumoniae was responsible, the
be effective in randomized, controlled trials.57,58 mortality rate was 12.3%, a rate similar to that seen
when no pathogen could be identified (12.8%).
Quality Indicators Certain pathogens such as P aeruginosa, other gram-
negative organisms (such as Klebsiella pneumoniae),
Length of stay has been shown to be related and S aureus had higher associated mortality rates.
to three quality-of-care measures: initial admin- An episode of CAP in young adults without
istration of antibiotics in the ED, appropriate significant comorbidity is not a predictor of poor
antibiotic selection, and shortened door-to-nee- medium-term survival.64 Increasing age, comorbid
dle time.59–61 Initiation of antibiotic therapy in cerebrovascular and cardiovascular disease, an
the ED led to shorter hospital stays for CAP by altered mental status, and increasing blood glucose
approximately 2 days in one report.60 are independent predictors of decreased medium-
The following have been listed as quality term (up to 3 years) survival.
indicators in the assessment of care of the CAP Treatment failure rates with guideline-driven
patient: empiric therapy have been reported as high as
15%. Risk factors for treatment failure that have
Antibiotics administered in a timely way, been identified include liver disease, pneumonia
within either 4 h or 8 h of hospital admission; risk class, leukopenia, multilobar CAP, pleural
Oxygen assessment or therapy within 8 to 24 h effusion, and radiographic signs of cavitation.65
of hospital arrival; Independent factors associated with a lower risk

of treatment failure include influenza vaccina- is quite distinct from hospital-acquired MRSA
tion, initial treatment with fluoroquinolones, and from an epidemiologic, genetic, and clinical
a concurrent diagnosis of COPD. Failure of perspective. Community-acquired MRSA tends
empiric therapy increases the mortality of CAP to be less resistant to antimicrobial agents than
11-fold after adjustment for risk class. Modifica- hospital-acquired MRSA strains, and it almost
tion of these risk factors is possible and should always contains a type IV Staphylococcus cassette
encourage prospective randomized trials. chromosome mec type IV gene and the genes for
In a prospective observational study of 2,457 Panton-Valentine leukocidin, an extracellular
patients,66 57 (2.3%) died 48 h after admission. cytotoxin that is a virulence factor for primary
Overall mortality was 7.7%. Independent factors skin infections and pneumonia. While commu-
associated with early deaths were increased age, nity-acquired MRSA is not common, it may cause
altered mental status at presentation, multilobar pneumonia that is typically characterized by a
pneumonia, shock at admission, pneumococcal short duration of illness and focal necrotizing
bacteremia, and discordant empiric antibiotic infiltrates. MRSA strains that produce the Pan-
therapy. Currently, early mortality is relatively ton-Valentine leukocidin toxin can cause severe
low and is caused by pneumonia-related factors. pneumonias characterized by leukopenia, he-
Because pneumococcal bacteremia and discor- moptysis, and extensive necrosis of lung tissue.73
dant antibiotic therapy, mainly due to lack of The disease may be rapidly progressive, so
coverage against P aeruginosa, are significant risk consideration of this entity is important in the
factors, appropriate early intervention may im- management of severely ill patients with CAP.74
prove clinical outcome. Some patients may have a more benign course.75
A prognostic index was derived in 1,117 adult In general, these strains are usually suscep-
patients with CAP and was validated among 646 tible in vitro to vancomycin, linezolid, trimetho-
consecutive patients discharged from hospitals at a prim-sulfamethoxazole, doxycycline, and
later time.67 In the derivation cohort, pre-illness fluoroquinolones. In addition, they are often
functional status Charlson index and severity upon susceptible to clindamycin, but the presence of
admission were independently associated with 90- in vitro inducible resistance should be deter-
day mortality, and a scoring system was developed. mined before the drug is administered. The
The 90-day mortality was 0.7% in the low-risk initial choice in most published series has been
group, 3.5% in the intermediate-risk group, and IV vancomycin, although linezolid appears to be
17.3% in the high-risk group. The results in the at least equivalent to vancomycin in the treat-
validation cohort were very similar. The prognostic ment of nosocomial MRSA pneumonia.76 The
index accurately stratified patients hospitalized for efficacy of treatment with trimethoprim-sulfa-
CAP into low-, intermediate-, and high-risk groups methoxazole in systemic infections due to MRSA
for 90-day mortality upon discharge. Another was comparable to vancomycin, and it has been
study indicated that CAP was associated with effective alone and in combination with rifampin
decreased long-term survival, even after correcting in patients with soft-tissue infections due to
for comorbidities.68 community-acquired MRSA.
Outcomes can be improved if currently
available guidelines are followed. The risk of Streptococcus pneumoniae
clinical failure and mortality are reduced when
clinicians adhere to current guidelines.69,70 S pneumoniae is the most common organism
found in patients with CAP.2 This is true
Emerging Threats independent of the site of care (outpatient,
hospitalized in a ward bed, or in the ICU).7 It is
Community-Acquired Methicillin-Resistant also the most frequent organism associated with
S aureus (MRSA) bacteremia. In a secondary analysis of the
Community-Acquired Pneumonia Organization
Community-acquired MRSA has emerged as database of hospitalized patients with CAP and
a cause of CAP over the past several years.71,72 It pneumococcal bacteremia and patients with CAP

and negative blood culture findings, investiga- significant difference between the intervention
tors modeled all-cause mortality and CAP- and nonintervention arms among all patients.
related mortality using logistic regression analy- Efficacy could be demonstrated in some sub-
sis and time to clinical stability and length of groups, for instance, younger patients with
hospital stay using Cox proportional hazards severe airflow obstruction and in patients with
models.77 The multivariable regression analysis COPD aged less than 65 years and in those with
revealed a lack of association of pneumococcal severe airflow obstruction, but was ineffective
bacteremic CAP and time to clinical stability, among the other groups of COPD patients. In a
length of hospital stay, all-cause mortality, and database analysis of 62,918 adults hospitalized
CAP-related mortality. This suggests that factors with CAP,81 12% had a record of prior pneumo-
related to severity of disease are confounders of coccal vaccination. Vaccine recipients were less
the association between pneumococcal bacter- likely to die of any cause during hospitalization
emia and poor outcomes and that the presence of than were individuals with no record of vacci-
pneumococcal bacteremia, by itself, should not nation, even after adjustment for the presence of
be a contraindication for de-escalation of therapy comorbid illnesses, age, smoking, and influenza
in clinically stable hospitalized patients with vaccination and under varying assumptions
CAP. Combination therapy has been identified about missing vaccination data. Vaccination also
as more effective among critically ill bacteremic lowered the risk of respiratory failure and other
patients but not in less ill patients.51 complications and reduced median length of stay
by 2 days, compared with no vaccination.
Role of Pneumococcal Vaccination
However, in a meta-analysis involving 22 trials
involving 101,507 participants,82 pneumococcal
Pneumococcal polysaccharide vaccines have
vaccination did not appear to be effective in
been available for more than 50 years and have
preventing pneumonia, even in populations for
progressed from 2-valent vaccines to the current
whom the vaccine is currently recommended.
23-valent vaccine. The 23-valent vaccine includes
There was significant heterogeneity among trials,
serotypes accounting for 72% to 95% of invasive
and those trials with the most rigorous design
pneumococcal disease, depending on the geo-
were negative. One-half of patients discharged
graphic area.78 Current recommendations sug-
from the hospital after pneumonia die or are
gest that PPSV23 should be administered to
adults aged 19 to 64 years with chronic or subsequently hospitalized with a vaccine-
immunosuppressing medical conditions, includ- preventable infection within 5 years.83 PPSV23
ing asthma.79 Adults aged 19 to 64 years who was not associated with a reduced risk of death
smoke should receive PPSV23 and smoking or hospitalization.83
cessation guidance. All persons should be vacci- Several reports have shown a reduction in the
nated with PPSV23 at age 65. Those who received overall incidence of invasive pneumococcal
PPSV23 before age 65 for any indication should disease after the introduction of 7-valent protein
receive another dose of the vaccine at age 65 or conjugate vaccine, PCV7,84,85 and, in some
later if at least 5 years have passed since their studies, the rate increase has been associated
previous dose. Those who receive PPSV23 at or with an increase of infections caused by non-
after age 65 should receive only a single dose. PCV7 serotypes.86,87 A new 13-valent conjugate
While these recommendations have been widely vaccine has been approved for use in children
circulated, the evidence to support them has been and, for the first time, in adults greater than 50
questioned. There have been conflicting results of years with chronic illnesses and all adults greater
the efficacy of the vaccine and observational than 65 years. While no outcome data are
studies and controlled trials have frequently currently available, the enhanced immunogenic-
shown different outcomes. In a randomized ity of this vaccine and the demonstrated superi-
controlled trial in 596 patients with COPD,80 the ority of the 7-valent vaccine over PPSV23 have
role of pneumococcal vaccination in preventing given the regulatory authorities enough reassur-
pneumonia was determined. There was no ance to approve this vaccine. A cost-effectiveness

study indicated a favorable outcome compared cocirculated in the United States, with the
to PPSV23.88 predominant virus varying over time and by
region.94 Influenza A predominated in all regions
Influenza during January and early February, and more than
80% of subtyped influenza A viruses from Novem-
Influenza A viruses are classified into sub- ber and December were influenza A/H3N2.
types on the basis of two surface proteins: Multiple studies show that influenza vaccine
hemagglutinin (HA) and neuraminidase (NA). is efficacious, with higher efficacy demonstrated
Three subtypes of HA (H1, H2, and H3) and two against laboratory-confirmed influenza than clin-
subtypes of NA (N1 and N2) are recognized ically defined outcomes without laboratory con-
among influenza A viruses that have caused firmation. 95 With a good match, influenza
widespread human disease. Since 1977 the vaccination has been shown to prevent influenza
human H3N2 and human H1N1 influenza A illness in approximately 70% to 90% of healthy
subtypes have contributed to influenza illness to children and adults and to reduce incidence by
varying degrees each year. Immunity to the HA about half in the elderly.96 Systematic reviews
and NA proteins reduces the likelihood of have also demonstrated that influenza vaccine
infection and lessens the severity of disease if decreases the incidence of pneumonia, hospital
infection occurs. Influenza viruses are transmit- admission, and death in the elderly97,98 and
ted from person to person primarily through reduces exacerbations in persons with COPD.99
contact with infected respiratory secretions, The impact of the influenza vaccine may be
especially airborne droplets generated by cough- exaggerated. Clinical, laboratory, and functional
ing and sneezing. It is estimated that between 5% data were prospectively collected on 1,813 adults
to 10% of the population becomes infected with with CAP admitted to hospital outside of influ-
influenza each year.89 Rates of influenza infection enza season.100 The cohort consisted of 352
are highest in children, but rates of serious illness vaccine recipients and 352 matched control
and death are highest in older persons (.65 subjects. Influenza vaccination was associated
years) and persons with underlying medical with a 51% mortality reduction outside influenza
conditions.90 In 2009, more than 99% of circulat- season. Adjustment for age, sex, and comorbidi-
ing influenza viruses identified in the United ties did not alter these findings. More complete
States were 2009 H1N1 influenza (previously adjustment for confounding factors (eg, function-
referred to as novel influenza A [H1N1]). The al and socioeconomic status) markedly attenuated
clinical presentation of patients with uncompli- these benefits. This would suggest that previous
cated 2009 H1N1 influenza virus infection was observational studies may have overestimated the
generally similar to seasonal influenza and mortality benefits of influenza vaccination.
included abrupt onset of fever, cough, sore
throat, myalgias, arthralgias, chills, headache, Avian Influenza
and fatigue. In the case of pandemic (H1N1)
influenza, hospital admissions and severe out- Avian influenza is an infectious disease of
comes occurred in all age groups and in a much birds caused by type A strains of the influenza
younger population than seasonal influenza virus. Migratory waterfowl, most notably wild
typically does.91 The risk of a severe outcome ducks, are the natural reservoir of avian influen-
was associated with the presence of one or more za viruses, and these birds are also the most
underlying medical conditions, age of 20 years or resistant to infection. Domestic poultry, including
more, and a delay in hospital admission.92 There chickens and turkeys, are particularly susceptible
was no evidence of a beneficial effect of to epidemics of rapidly fatal influenza. H5N1
corticosteroids in patients with ARDS secondary variants demonstrated a capacity to directly
to influenza pneumonia, but very early cortico- infect humans in 1997, and they have done so
steroid therapy was harmful.93 again in Vietnam in January 2004. The spread of
In the 2011–2012 influenza season, influenza infection in birds increases the opportunities for
A/H3N2, pH1N1, and influenza B viruses direct infection of humans. If more humans

acquire infection over time, the likelihood also Other/research contracts: GSK, Novartis. The
increases that humans with concurrent infection ACCP Education Committee has reviewed these
with human and avian influenza strains could relationships and resolved any potential conflict
serve as a ‘‘mixing vessel’’ for the emergence of a of interest.
novel subtype with sufficient human genes to be
easily transmitted from person to person. Such References
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1373–1381. 353(13):1374–1385.

Chapter 22. Hospital-Acquired and Ventilator-Associated
Pneumonia
Objectives: arises .48 to 72 h after endotracheal intubation

Identify the key respiratory pathogens causing hospital- among patients treated in an ICU setting.1–4
acquired pneumonia/ventilator-associated pneumonia. Health-care-associated pneumonia (HCAP) re-
Develop a systematic approach to the diagnosis of
fers to patients admitted to hospital with
hospital-acquired pneumonia/ventilator-associated
pneumonia. pneumonia who may have received IV therapy
Improve the initial therapeutic choices for the manage- at home, wound care, or specialized nursing care
ment of hospital-acquired pneumonia/ventilator-associ- through a health-care agency, family, or friends
ated pneumonia.
or had self-administered IV medical therapy in
the 30 days before pneumonia.5 They may have
Key words: clinical pulmonary infection score; hospital-
attended a hospital or hemodialysis clinic or
acquired pneumonia; Pseudomonas aeruginosa; Staphylococcus
aureus; ventilator-associated pneumonia received IV chemotherapy in the 30 days before
pneumonia. They may also have been admitted
Synopsis: to an acute care hospital for 2 or more days in the
Hospital-acquired pneumonia, ventilator-associated pneu- 90 days before pneumonia or resided in a
monia, and health-care-associated pneumonia (HCAP) are nursing home or a long-term care facility.
common hospital infections associated with significant
morbidity and mortality. The concept of HCAP is not
universally accepted as being useful. The most common
Epidemiology
pathogens are Staphylococcus aureus and enteric gram-
negative organisms. The diagnosis is usually suspected HAP is the second most common nosocomial
clinically based on fever, purulent tracheobronchial secre- infection in the United States and is associated
tions, elevated white blood cell count, and an abnormal
chest radiograph. Pneumonia follows the aspiration of
with high mortality and morbidity.1 Hospital
oropharyngeal contents into the lung. This is usually length of stay increases by an average of 7 to 9
preceded by colonization of the oropharynx by pathogenic days per affected patient and is associated with
hospital-associated organisms. There is considerable con- costs .$40,000 per patient.3,6 HAP occurs at a
troversy regarding the need for invasive procedures to
confirm the diagnosis. Broad-spectrum coverage is usually rate of between 5 and 10 cases per 1,000 hospital
recommended, as most studies have indicated that inade- admissions, with the incidence increasing by as
quate initial therapy is one of the most powerful predictors much as 6- to 20-fold in patients receiving
of a poor outcome. Once a pathogen has been defined, step-
mechanical ventilation.3,7,8
down to a more limited spectrum of antibiotic(s) has been
recommended. There are many measures that have been HAP accounts for up to 25% of all ICU
identified that can reduce the incidence of pneumonia, and infections and for .50% of the antibiotics
many have been bundled into discrete processes of care. prescribed.9 VAP occurs in 9% to 27% of all
These bundles do reduce pneumonia incidence but have not
been shown to reduce mortality.
intubated patients.3,6 The risk of VAP is highest
early in the course of hospital stay and then
abates somewhat. The risk has been estimated to
be 3%/day during the first 5 days of ventilation,
Definitions 2%/day during days 5 to 10 of ventilation, and
1%/day after this.10 Nosocomial pneumonia is
Pneumonia that develops 48 h after admission, less common when cases are managed with
which was not incubating at the time of noninvasive ventilation.11–13
admission to hospital, is defined as hospital- Previous guidelines14 identified that early-
acquired pneumonia (HAP).1 Ventilator-associat- onset pneumonia was frequently caused by
ed pneumonia (VAP) refers to pneumonia that community pathogens. Early-onset HAP and

Table 1—Risk Factors for MDR Pathogens Causing HAP, creasing particularly among patients with diabe-
HCAP, and VAP tes mellitus, head trauma, and those hospitalized
Antimicrobial therapy in preceding 90 days
in ICUs.27,28 Rates of polymicrobial infection vary
Current hospitalization of 5 days widely but appear to be increasing and are
High frequency of antibiotic resistance in the community especially high in patients with ARDS.29–31
or in the specific hospital unit The etiology of HAP and the frequency of
Presence of risk factors for HCAP
Hospitalization for 2 days in the preceding 90 days specific MDR pathogens vary by hospital, patient
Residence in a nursing home or extended-care facility population, exposure to antibiotics, type of ICU
Home infusion therapy (including antibiotics) patient, and changes over time.32,33 Local sur-
Long-term dialysis within 30 days
veillance data are crucial in monitoring the
Home wound care
Family member with MDR pathogen emergence of MDR pathogens and should drive
Immunosuppressive disease and/or therapy the formulation of local guidelines. Anaerobic
lung infection may follow aspiration in non-
Board Review. 25th ed. Northbrook, IL: American College of intubated patients but is very uncommon in
Chest Physicians; 2009. patients with VAP.22,34
Elderly residents of long-term care facilities
VAP, defined as occurring within the first 4 days have been found to have a spectrum of patho-
of hospitalization, are more likely to be caused by gens that more closely resemble late-onset HAP
antibiotic-sensitive bacteria. Late-onset HAP and and VAP.5,24,25 This observation has led to the
VAP (5 days) are more likely to be caused by development of the term health-care-associated
multi-drug-resistant (MDR) pathogens and are pneumonia. This designation purportedly identi-
associated with increased patient mortality and fies patients from health-care facilities who are at
morbidity. However, patients with early-onset increased risk for infection with resistant patho-
HAP who have received antibiotics or who have gens.35 However, a study examining the perfor-
had hospitalization within the past 90 days have mance of the HCAP designation to predict
similar pathogens to those patients with late- pneumonia caused by resistant pathogens did
onset HAP or VAP and should be treated not perform very well.36 In contrast, a decision
similarly (Table 1).15 rule based on variables independently associated
The crude mortality rate for HAP may be as with resistant organisms (immunosuppression,
high as 3% to 70%, but the mortality related to long-term care admission, and prior antibiotics)
HAP or ‘‘attributable mortality’’ has been esti- performed moderately well.36 Patients with
mated to be between 33% and 50% in several culture-positive HCAP have a greater severity
case-matching studies of VAP.16 Increased mor- of illness shown by more ICU admissions, greater
tality rates are associated with bacteremia, hospital mortality, and longer hospital lengths of
especially with Pseudomonas aeruginosa or Acine- stay and are more likely to be treated with an
tobacter species, medical rather than surgical inappropriate initial antimicrobial regimen com-
illness, and treatment with ineffective antibiotic pared with culture-negative patients.37 Despite
therapy.16,17 Strangely, some studies18–20 using these observations, culture-positive HCAP is not
similar methodology have not identified any associated with hospital mortality by multivari-
attributable mortality due to VAP. ate analysis. In a Spanish study, patients with
HCAP were older, had greater comorbidity, and
Etiology were more commonly classified into high-risk
pneumonia severity index classes.38 The most
The most frequent isolated pathogens from common causative organism was Streptococcus
respiratory secretions are aerobic gram-negative pneumoniae in both groups. Staphylococcus aureus
bacilli, such as P aeruginosa, Escherichia coli, and gram-negative bacilli were slightly more
Klebsiella pneumoniae, and Acinetobacter spe- frequent in HCAP. In the German CAPNETZ
cies.3,17,21–26 Infections due to gram-positive network study, nursing home pneumonia pa-
cocci, such as Staphylococcus aureus, particularly tients had similar microbiological findings to
methicillin-resistant S. aureus (MRSA), are inpatients over age 65 years with community-
328 Chapter 22. Hospital-Acquired and Ventilator-Associated Pneumonia (Grossman)

acquired pneumonia, and potential multidrug the oropharynx, but the importance of these
resistant pathogens were very rare.39 Rello and routes is debated.52,53
colleagues examined the role of health-care-
associated pneumonia as a designation among Diagnosis
patients admitted with bacteremic pneumococcal
pneumonia.40 In doing so, they removed the role The standard diagnostic criteria in VAP
of bacterial resistance and inappropriate antibi- include at least two of the following three
otic administration as a cause of the poor findings: fever, leukocytosis, and purulent tra-
outcome usually associated with this designa- cheal secretions, usually with abnormal findings
tion. They identified that mortality was still on chest radiographic studies. When these
increased, but differences in age, comorbidities, conditions occur, the likelihood of VAP is high.54
and criteria for ICU admission accounted for this. The presence of a radiographic infiltrate in a
These studies suggest that the original rationale patient with fever, leukocytosis, or purulent
for this designation (presence of resistant path- tracheobronchial secretions has high diagnostic
ogens) is debatable and certainly not predictable sensitivity but low specificity. When all four
throughout the world. criteria are present, specificity improves but
Rates of nosocomial Legionella pneumophila sensitivity drops to ,50%, which is clinically
vary considerably between hospitals, and disease unacceptable.54 The only study examining inter-
occurs more commonly with serogroup 1 when observer diagnostic reliability found no major
the water supply is colonized or there is ongoing differences between individual physicians or
construction.41,42 Nosocomial virus and fungal those grouped by level or training.54
infections are uncommon causes of HAP and Pugin and coworkers55 developed the clinical
VAP in immunocompetent patients. Outbreaks of pulmonary infection score (CPIS), which com-
influenza have occurred sporadically, and the bines clinical, radiographic, physiologic (Pao2/
risk of infection can be substantially reduced fraction of inspired oxygen), and microbiologic
with widespread effective infection control, data into a single numerical result in order to
vaccination, and use of anti-influenza agents.43–45 improve the specificity of clinical diagnosis.
When the CPIS exceeded 6, a good correlation
Pathogenesis with positive quantitative culture findings of
bronchoscopic and nonbronchoscopic BAL spec-
The severity of the patient’s underlying imens was seen. These findings have not been
disease, prior surgery, exposure to antibiotics, reproduced by other investigators, but the
other medications, and exposure to invasive accuracy of the CPIS score is improved if a Gram
respiratory devices and equipment may lead to stain of a deep respiratory tract culture is added
airway colonization and contribute to the path- to the evaluation.56,57
ogenesis of HAP and VAP.46,47 Aspiration of These findings suggest that the presence of
oropharyngeal pathogens or leakage of secretions abnormal clinical manifestations, combined with
containing bacteria around the endotracheal tube abnormal radiographic findings, can be used for
cuff are the primary routes of bacterial entry into initial screening for VAP. However, the lack of
the lower respiratory tract.48–50 Inhalation or specificity with this method suggests that addi-
direct inoculation of pathogens into the lower tional procedures are needed, such as cultures of
airway, hematogenous spread from infected IV lower respiratory tract secretions.
catheters, and bacterial translocation from the GI All patients with suspected VAP should have
tract lumen are uncommon pathogenic mecha- blood cultures collected, recognizing that a
nisms.47 Infected biofilm in the endotracheal positive result can indicate the presence of either
tube, with subsequent embolization to distal pneumonia or extrapulmonary infection.58 A
airways, is another source of entry of infected diagnostic thoracentesis to rule out a complicat-
material into the lung.51 The stomach and sinuses ing empyema or parapneumonic effusion should
may be potential reservoirs of nosocomial path- be performed if the patient has a large pleural
ogens that contribute to bacterial colonization of effusion or if the patient with a pleural effusion

Table 2—Initial Empiric Antibiotic Therapy for HAP or lead to treatment for more organisms than
VAP in Patients With No Known Risk Factors for MDR diagnostic techniques based on quantitative
Pathogens, Early Onset, and Any Disease Severity
cultures.63,68–70
Potential Pathogens Recommended Antibiotic Nonbronchoscopic sampling can reliably ob-
tain lower respiratory tract secretions for quan-
Streptococcus pneumoniae Ceftriaxone; or levofloxacin, titative cultures if bronchoscopic sampling is not
Haemophilus influenzae moxifloxacin, or ciprofloxacin
Methicillin-sensitive or ampicillin/sulbactam, or
immediately available.70 The use of a broncho-
Staphylococcus aureus ertapenem scopic bacteriologic strategy has been shown to
Antibiotic-sensitive enteric reduce 14-day mortality but not the 28-day
Gram-negative bacilli mortality, compared with a clinical strategy, in
Escherichia coli
Klebsiella pneumoniae one study of suspected VAP.62 Three other
Enterobacter species smaller studies demonstrated no advantage of
Proteus species an invasive diagnostic approach. A meta-analysis
Serratia marcescens
of these trials indicated that an invasive ap-
Reprinted with permission from ACCP Pulmonary Medicine proach did not alter mortality (odds ratio 0.89,
Board Review. 25th ed. Northbrook, IL: American College of 95% confidence interval 0.56–1.41).71 Invasive
testing, though, affected antibiotic utilization. A
randomized controlled trial comparing the utility
appears toxic. Samples of lower respiratory tract of bronchoscopic lavage with quantitative culture
secretions should be obtained from all patients of BAL fluid or endotracheal aspirate with
with suspected HAP and should be collected nonquantitative culture of the aspirate identified
before antibiotic changes. Samples can include an no significant difference in the 28-day mortality
endotracheal aspirate, BAL sample, or protected rate (the primary outcome), the rate of targeted
specimen brush sample.59–61 A sterile culture of therapy, days alive without antibiotics, hospital
respiratory secretions in the absence of a new or ICU length of stay, or maximum organ
antibiotic in the past 72 h virtually rules out the dysfunction scores.72 Delays in the initiation of
presence of bacterial pneumonia, but viral or appropriate antibiotic therapy can increase the
Legionella infection are still possible. If these mortality of VAP, and, thus, therapy should not
patients have clinical signs of infection, an be delayed for the purpose of performing
extrapulmonary site of infection should be diagnostic studies in patients who are clinically
investigated.62 unstable.73,74
A reliable tracheal aspirate Gram stain can be
used to direct initial empiric antimicrobial Therapy
therapy and may increase the diagnostic value
of the CPIS. 62 The presence of a new or Initial empiric therapy should be selected
progressive radiographic infiltrate plus at least based on the absence or presence of risk factors
two of three clinical features (temperature .388C, for MDR pathogens. These risk factors include
leukocytosis or leukopenia, and purulent secre- prolonged duration of hospitalization (5 days),
tions) represent the most accurate clinical criteria admission from a health-care-related facility, and
for starting empiric antibiotic therapy.57 If a recent prolonged antibiotic therapy (Table 1).35
clinical strategy is used, reevaluation of the Choice of specific agents should be dictated by
decision to use antibiotics based on the results local microbiology, cost, availability, and formu-
of semiquantitative lower respiratory tract cul- lary restrictions (Tables 2, 3).75,76 It has been
tures and serial clinical evaluations, by day 3 suggested that patients with health-care-related
or sooner, is appropriate.63–67 Singh and co- pneumonia should be treated for potentially
workers65 demonstrated that a modified CPIS drug-resistant organisms regardless of when
of 6 for 3 days is an objective criterion to select during the hospital stay the pneumonia begins.
low-risk patients for early discontinuation of Inappropriate therapy (failure of the etiologic
empiric treatment of HAP. Tests that identify pathogen to be sensitive to the administered
pathogens on the basis of qualitative cultures will antibiotic) is a major risk factor for excess

Table 3—Initial Empiric Therapy for HAP, VAP, and HCAP in Patients With Late-Onset Disease or Risk Factors for MDR
Pathogens and All Disease Severity
Potential Pathogens Combination Antibiotic Therapy
Pathogens listed in Table 2 and MDR pathogens Antipseudomonal cephalosporin (cefepime, ceftazidime); or
Pseudomonas aeruginosa antipseudomonal carbepenem (imipenem or meropenem); or
Klebsiella pneumoniae (extended-spectrum b-lactam/b-lactamase inhibitor (piperacillintazobactam) plus
b-lactamase positive) antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin;
Acinetobacter species or aminoglycoside (amikacin, gentamicin, or tobramy-cin)
MRSA plus linezolid or vancomycin
Legionella pneumophila
Physicians; 2009.
mortality and length of stay for patients with doses to ensure maximum efficacy.81 Initial
HAP, and antibiotic-resistant organisms are the therapy should be administered to all patients
pathogens most commonly associated with inap- through IV with a switch to oral/enteral therapy
propriate therapy.77 In selecting empiric therapy in selected patients with a good clinical response
for patients who have recently received an and a functioning intestinal tract. Highly bio-
antibiotic, an effort should be made to use an available agents, such as the fluoroquinolones
agent from a different antibiotic class because and linezolid, may be easily switched to oral
recent therapy increases the probability of inap- therapy in such patients. Combination therapy
propriate therapy and can predispose to resis- should be used if patients are likely to have
tance to that same class of antibiotics.78 Initial infection with MDR pathogens.35 No data have
antibiotic therapy should be administered documented the superiority of this approach
promptly because delays in administration may compared with monotherapy, except to enhance
add to excess mortality resulting from VAP.74,75,79 the likelihood of initially appropriate empiric
Twice-weekly quantitative surveillance cultures therapy. If patients receive combination therapy
of endotracheal aspirates may assist in the early with an aminoglycoside-containing regimen, the
prescription of appropriate antibiotic treatments aminoglycoside can be stopped after 5 to 7 days
for patients who acquire VAP.80 This strategy in responding patients.82 Monotherapy with
may improve clinical outcomes, potentially may selected agents can be used for patients with
reduce antibiotic resistance in patients in critical severe HAP and VAP in the absence of resistant
care units and related complications, and may pathogens.77 Patients in this risk group should
reduce hospitalization costs. Antibiotic selection initially receive combination therapy until the
based on the available results of pre-VAP results of lower respiratory tract cultures are
endotracheal aspirate cultures was adequate in known and confirm that a single agent can be
38 of 40 patients (95%) in a recent small study.80 used. If patients receive an initially appropriate
In contrast, had the American Thoracic Society/ antibiotic regimen, therapy can be shortened
Infectious Diseases Society of America guide- from the traditional 14 to 21 days to periods as
lines35 and Trouillet et al.15 guidelines been used, little as 7 days, provided that the etiologic
empiric antibiotic treatment would have been pathogen is not P aeruginosa, and that the patient
adequate in 68% and 83% of patients, respective- has a good clinical response.83
ly. The main reason for the inadequate coverage If P aeruginosa pneumonia is documented,
using the published guidelines was the failure of combination therapy is recommended. The prin-
the guidelines to predict appropriate coverage of cipal justification is the high frequency of
highly resistant pathogens. Before this strategy development of resistance on monotherapy.81,82
can be widely adopted, prospective randomized Although combination therapy will not necessar-
trials are needed to confirm this observation. ily prevent the development of resistance, com-
Empiric therapy of patients with severe HAP bination therapy is more likely to avoid
or VAP requires the use of antibiotics at optimal inappropriate and ineffective treatment of pa-

tients.81 If Acinetobacter spp are documented to be during this time unless there is rapid clinical
present, the most active agents are the carbape- decline. Nonresponse to therapy is usually
nems, sulbactam, colistin, and polymyxin. There evident by day 3, using an assessment of clinical
are no data documenting an improved outcome parameters.62,64 Serum procalcitonin may act as a
if these organisms are treated with a combination prognostic marker in VAP, with elevated levels
regimen.84 In an randomized, controlled trial, 100 while on therapy predicting a poor outcome.92
patients with VAP mainly caused by MDR Serum-procalcitonin-guided therapy lowers an-
Acinetobacter baumannii and/or P aeruginosa were tibiotic exposure and is noninferior with respect
randomized to nebulized colistimethate sodium to outcomes.93 The responding patient should
(CMS) equivalent to 75 mg of colistin base in 4 have deescalation of antibiotics, narrowing ther-
mL of NSS every 12 h or nebulized saline until apy to the most focused regimen possible on the
systemic antibiotic therapy of VAP was ended.85 basis of culture data. The nonresponding patient
Parenteral therapy was given at the discretion of should be evaluated for noninfectious mimics of
the attending physician. While the therapy pneumonia, unsuspected or drug-resistant or-
appeared to be safe, there was no additional ganisms, extrapulmonary sites of infection, and
clinical benefit identified. If extended-spectrum complications of pneumonia and its therapy.
b-lactamase-positive Enterobacteriaceae are iso- Diagnostic testing should be directed to which-
lated, third-generation cephalosporins should be ever of these causes is likely.94
avoided, and carbapenems should be consid- Sixty episodes of VAP treated with appropri-
ered.86 Linezolid is an alternative to vancomycin ate therapy (H influenzae, 15 episodes; methicil-
for the treatment of MRSA VAP. A subset analysis lin-sensitive S aureus, 15 episodes; P aeruginosa,
of two prospective randomized trials87,88 has 15 episodes; and methicillin-resistant S aureus, 15
indicated that linezolid is at least as good as episodes) and 30 episodes with initial inappro-
vancomycin. This agent may be preferred if priate therapy, all due to P aeruginosa, were
patients have renal insufficiency or are receiving compared in a prospective observational study.95
other nephrotoxic agents, but more data are A significant delay in the resolution of hypox-
needed. A meta-analysis of eight randomized, emia was observed in VAP episodes due to
controlled trials comparing linezolid to glyco- MRSA and P aeruginosa with inappropriate
peptide antibiotics for suspected MRSA pneu- antibiotic therapy when compared with the
monia in 1,641 subjects .12 years of age could remaining pathogens. MRSA VAP was associated
not identify any advantage of linezolid, although with longer respiratory support independent of
the two treatments were equally safe.89 The the appropriateness of initial antibiotic therapy.
authors concluded that treatment choice should More aggressive management may be required
depend on local availability, antibiotic resistance for these difficult to treat pathogens.
patterns, preferred routes of delivery, and cost
rather than presumed differences in efficacy. Prevention
Antibiotic restriction can limit epidemics of
infection with specific resistant pathogens. Het- In a meta-analysis of randomized controlled
erogeneity of antibiotic prescriptions, including trials examining the role of antiseptics to prevent
formal antibiotic cycling, may be able to reduce nosocomial pneumonia, 14 studies involving
the overall frequency of antibiotic resistance. 2,481 patients were included, 12 investigating
However, the long-term impact of this practice the effect of chlorhexidine (2,341 patients), and
is unknown.90,91 two of povidone-iodine (140 patients).96 Antisep-
A serial assessment of clinical parameters tic use was associated with a significant risk
should be used to define the response to initial reduction of ventilator-associated pneumonia.
empiric therapy.62,64 Modifications of empiric Chlorhexidine application was shown to be
therapy should be made on the basis of this effective whereas the effect resulting from povi-
information in conjunction with microbiologic done-iodine trended in the same direction but
data. Clinical improvement usually takes 48 to 72 was not significant. The addition of electric
h, and thus therapy should not be changed toothbrushing to standard oral care with 0.12%

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Notes

Chapter 23. Hypoxemic Respiratory Failure
Objectives: mechanisms can cause a significant elevation in

Examine the causes of hypoxemic respiratory failure. PaCO2 (hypercapnia) and/or a reduction in PaO2
Review the pathophysiology, diagnostic criteria, clinical (hypoxemia). The normal range of PaO2 varies
features, and epidemiology for acute lung injury (ALI)
and ARDS.
with age as a result of the loss of effective alveoli
Examine management strategies for ALI/ARDS, includ- during advancing age and can be approximated
ing mechanical ventilation, medical management, and from the following equation: PaO2 ¼ 100.1 0.32 3
rescue therapy for refractory hypoxemia. (age in years). This equation assumes the
Key words: acute lung injury; acute respiratory distress individual is breathing ambient air and is near
syndrome; hypoxemia; mechanical ventilation sea level. PaO2 will decline progressively with
Synopsis:
increasing altitude above sea level as a result of
declining barometric pressure and thus lower PO2
Hypoxemic respiratory failure has a variety of causes and
mechanisms that produce a life-threatening state that often
of inhaled gas.
requires high levels of supplemental oxygen and mechanical
ventilation. Acute lung injury (ALI) and the more severe Hypoxemia and Hypoxia: Mechanisms and
subset ARDS are characterized by pulmonary inflammation Measurement
and development of high protein content pulmonary edema
that causes severe hypoxemia. Management of ALI/ARDS
focuses on managing the underlying causative condition(s) Hypoxemia usually arises as a result of
while providing mechanical ventilation designed to mini- disrupted alveolar ventilation (V̇) and/or perfu-
mize further lung injury by using lower tidal volumes and
avoiding excessive alveolar distending pressures while also
sion (Q̇) that causes relative impaired or absent
minimizing repetitive alveolar collapse and recruitment with ventilation of perfused alveoli. The range of V̇/Q̇
higher levels of positive end-expiratory pressure (PEEP). mismatching of the 300 million or so alveoli runs
Additional supportive measures include minimizing accu-
the spectrum from absence of ventilation (shunt-
mulation of lung water, which is associated with delayed
recovery. Selected interventions for ARDS often improve like) to absence of perfusion (dead space). In
oxygenation and thus may have a role in rescue therapy for fewer cases, hypoxemia is the result of true
severe hypoxemia, including use of the neuromuscular shunting of venous blood that admixes with
blocking agent (NMBA) cisatracurium for the first 48 h of
ARDS, prone positioning, titrating PEEP to higher than oxygenated blood, producing hypoxemia. These
customary levels, administration of inhaled nitric oxide conditions cause an increased gradient between
(INO), use of airway pressure release ventilation (APRV), calculated alveolar PO2 (PAO2) and measured
high-frequency oscillatory ventilation (HFOV), and extracor-
poreal membrane oxygenation (ECMO). It is important to
PaO2, as calculated in the equation PAO2 PaO2
recognize that many of these interventions, including INO, ¼ (barometric pressure 47 mm Hg) 3 0.21
APRV, and HFOV, have no evidence of improving important PaCO2/RQ PaO2, where 47 mm Hg represents
outcomes such as survival or ICU length of stay. Other the partial pressure of water vapor and RQ is
interventions such as use of NMBA, prone positioning, high
PEEP, ECMO, and moderate-dose corticosteroids have some respiratory quotient (generally regarded to be 0.8
evidence for improved outcomes—particularly for patients to 1.0). While breathing ambient air at sea level,
with severe ARDS—but remain controversial. Future re- PAO2 ¼ 150 (PaCO2/0.8), and PAO2 PaO2 should
search will help define optimal management.
be ,10 to 15 mm Hg. In contrast, generalized
alveolar hypoventilation without V̇/Q̇ mismatch
can result in hypercapnia plus hypoxemia with a
Hypoxemic Respiratory Failure normal PAO2 PaO2. Supplemental oxygen is
often administered for hypoxemia, and in this
Pulmonary Gas Exchange setting the relative degree of hypoxemia is more
The disruption of gas exchange as a result of accurately estimated using the ratio of PaO2 to
one or more of numerous pathophysiologic FIO2, or PaO2:FIO2 (the P/F ratio) than with

PAO2 PaO2. In the presence of diffuse parenchy- as being associated with improved outcomes,
mal lung disease, PaO2:FIO2 ratios ,300 and ,200 consideration of use of rescue therapies for
mm Hg are general thresholds for moderate and refractory hypoxemia, and supportive care. Gener-
severe hypoxemia, respectively. al considerations for initial evaluation and stabili-
Although hypoxemia represents low oxygen zation and support of oxygenation and ventilation
tension in blood, tissue hypoxia can occur through in hypoxemic respiratory failure are discussed
various mechanisms that impair oxygen delivery here, whereas issues more directly related to
or utilization from a cellular perspective. Reduc- ALI/ARDS such as evidence-based interventions
tions in oxygen delivery include hypoxemic and rescue therapy for refractory hypoxemia are
hypoxia from reduced oxygen tension in arterial addressed within that section below.
blood; anemic hypoxia, in which reduction in Initial Evaluation and Stabilization: Basic life-
oxygen content of blood is due to reduced oxygen- support measures including management of the
carrying capacity via loss of hemoglobin or airway and breathing should be rapidly initiated.
hemoglobin dysfunction and circulatory hypoxia, Life-threatening respiratory distress will often
in which depressed cardiac output or vascular require urgent endotracheal intubation and me-
factors impair oxygen delivery to tissue. Finally, chanical ventilation. Assessment of oxygenation
metabolic forms of hypoxia occur at the cellular and ventilation by arterial blood gas analysis is
level when oxygen utilization is disrupted. useful and pulse oximetry may provide contin-
uous display of oxygenation including response
Clinical Manifestations and Causative to therapy. Initial evaluation should also include
Conditions of Hypoxemia timely detection and management of urgent
conditions such as airway obstruction or tension
A variety of symptoms and clinical signs may pneumothorax.
accompany hypoxemia including dyspnea, tachy- Supplemental Oxygen and Artificial Ventilation:
pnea, tachycardia, hypertension, cardiac arrhyth- Supplemental oxygen can be administered by a
mias (including bradycardia progressive to variety of interfaces including face mask, face
asystole in extreme cases) tremor, anxiety, deliri- tent, and nasal cannula with higher effective FIO2
um, and agitation. Often additional clinical man- being delivered with a tight-fitting nonrebreather
ifestations are present that reflect the underlying mask. Mechanical ventilation, with delivery of
causative condition(s). The onset of clinical man- positive-pressure breaths for alveolar ventilation
ifestations can be more gradual, as with slow as well as positive end-expiratory pressure
progression of long-standing illness, or may be (PEEP) for alveolar recruitment and distention
abrupt from rapidly progressive cardiopulmonary can be provided using a ventilator and delivered
disease. Common clinical conditions are associat- via an endotracheal or tracheostomy tube or with
ed with hypoxemic respiratory failure are listed in a tightly fitting mask applied to the face or nose.
Table 1. Among these associated clinical condi- The addition of PEEP is particularly effective for
tions, acute lung injury (ALI)/ARDS represents a improving oxygenation in the setting of diffuse
continuum of a syndrome of parenchymal lung lung disease and poorly compliant lungs as seen
disease characterized by high-protein alveolar in ALI/ARDS and similar conditions. Details
edema and diffuse inflammation that usually has regarding positive-pressure ventilation, includ-
a specific underlying cause(s). ing noninvasive positive-pressure ventilation, are
discussed more extensively in other chapters.
Management Principles for Hypoxemic
Respiratory Failure ALI and Acute Respiratory Distress
Syndrome
Care of the patient who has hypoxemic
respiratory failure includes initial evaluation and Definitions
stabilization, assessment and management of the
underlying conditions, support of oxygenation and ARDS was first described in 1967 as the
ventilation, application of interventions identified acute onset of hypoxemic respiratory failure
340 Chapter 23. Hypoxemic Respiratory Failure (Sessler)

Table 1—Common Clinical Conditions Associated With ARDS (PaO2:FIO2 ,200 mm Hg at entry to the
Hypoxemic Respiratory Failure study) to a less severe category. ICU mortality
ALI/ARDS
rates validated the greater accuracy of PEEP-
Pulmonary edema
influenced reclassification, with 6% mortality if
Diffuse alveolar hemorrhage PaO2:FIO2 .300 mm Hg, 20% if PaO2:FIO2 ¼ 200 to
Pulmonary embolism 300 mm Hg, and 46% if PaO2:FIO2 remained ,200
Interstitial lung disease mm Hg after applying high PEEP. Finally,
Infectious pneumonia
Pneumonitis clinician interpretation of chest radiographs for
Neoplasm patients with possible ALI varies widely.5 Al-
Pulmonary contusion though increased alveolar capillary leak for
Atelectasis
protein as well as pulmonary inflammation—
Emphysema
Asthma factors that might more accurately reflect the
Chronic bronchitis pathophysiology of ALI than other criteria—have
Bronchiolitis been demonstrated in research settings, such
Reprinted with permission from ACCP Pulmonary Medicine measurements are not availability for wide-
Board Review. 25th ed. Northbrook, IL: American College of spread clinical use.
Clinical Features
accompanied by diffuse pulmonary infiltrates in
the absence of a cardiac failure and following an Clinical features of ALI/ARDS at the onset of
inciting event.1 Although broadly debated, spe- illness include manifestations of hypoxemia as
cific diagnostic criteria based upon readily described above as well as signs and symptoms
available information form the basis for the related to the underlying cause(s). It is notewor-
American–European consensus conference defi- thy that the manifestations that are directly
nitions, the essential elements of which are related to ALI/ARDS can change over time. In
displayed in Table 2.2 It is noteworthy that the early phase of ARDS, progressive hypoxemia
exclusion of left atrial hypertension as the cause and increased work of breathing due to devel-
for pulmonary edema is inexact. For example, opment of pulmonary edema typically results in
hypoxemia that is partially responsive to sup-
measurement of pulmonary capillary wedge
plemental oxygen, and even frank respiratory
pressure (PCWP)—or more properly, ‘‘pulmo-
distress and ventilatory failure. The pace of onset
nary artery occlusion pressure’’—is infrequently
varies but in general is faster with aspiration
performed in current practice and elevations in
lung injury (90% of cases of ARDS develop
PCWP may reflect volume expansion in the
within 48 h of insult) than sepsis (75% within 48
setting of ALI due to sepsis-induced capillary
h) or trauma (65% within 48 h).6 Some patients
leak rather than heart failure per se. In the ARDS
recover quickly with effective transport of sodi-
Network randomized controlled trial (RCT) that um and water from alveoli and reepithelializa-
compared fluid management guided by intra- tion with type II pneumocytes, whereas others
vascular pressures from a central venous catheter lapse into a condition characterized by ongoing
or a pulmonary artery catheter, 29% of patients inflammation and disorganized fibrosis.7 This
with ALI had PCWP .18 mm Hg, nearly all of fibroproliferative phase of ARDS is often herald-
whom had normal or elevated cardiac output.3 ed by ongoing fever, leukocytosis, and acute
Similarly, although PaO2:FIO2 ratio ,200 mm Hg alveolar inflammation with predominance of
is accepted as consistent with ARDS and ,300 neutrophils on bronchoalveolar lavage.8
mm Hg with ALI, the severity of hypoxemia is The chest radiograph typically demonstrates
influenced by the level of PEEP. Villar and bilateral infiltrates that are patchy or confluent
colleagues4 demonstrated that remeasuring PaO2: and are often described as alveolar or ground
FIO2 ratio after applying PEEP at 10 cm H2O (or glass. In contrast to cardiogenic pulmonary
higher if the patient was already receiving a edema, features such as cardiomegaly, pleural
higher amount) reclassified 42% of patients with effusions, and widening of the vascular pedicle

Table 2—American European Consensus Criteria for ALI Causes of ALI/ARDS
and ARDS (All Features Must Be Present)
1. Acute onset (,7 d) The causes of ALI/ARDS are often catego-

2. Hypoxemia rized based upon the mechanism of injury: direct
a. ALI: PaO2:FIO2 ,300 mm Hg (or epithelial) or indirect (or vascular). The more
b. ARDS: PaO2:FIO2 ,200 mm Hg
3. Diffuse bilateral pulmonary infiltrates on frontal chest common causes are listed in Table 3 using this
radiograph consistent with pulmonary edema; infiltrates categorization. When one considers comprehen-
can be patchy and/or asymmetric
sive epidemiology studies, sepsis, pneumonia,
4. Absence of left atrial hypertension based upon clinical
assessment or PCWP ,18 mm Hg if measured trauma, and aspiration of gastric contents ac-
count for the majority of cases.11,12
Chest Physicians; 2009. Pathophysiology of ALI/ARDS
are not prominent. Although these infiltrates The acute phase of ALI/ARDS is character-
usually appear diffuse on chest radiograph, ized by the accumulation of protein-rich edema
cross-sectional CT scan imaging reveals hetero- fluid within the lung interstitial spaces and the
geneity of infiltrates.9 Often there is consolidation alveoli as a result of increased permeability of the
involving dependent lung units with areas of alveolar capillary endothelium and the alveolar
near-normal-appearing lung and atelectatic lung epithelium and a highly inflammatory lung
units in mid and upper lung zones, as seen in injury.7,13 Net fluid accumulation is influenced
Figure 1. Interestingly, upon moving the patient by the influx of fluid and proteins as well as
from supine to prone position, rapid migration of clearance, which is normally primarily from
consolidation and infiltrates to the ventral lung lymphatic drainage of peribronchovascular ede-
units, which are now in a dependent position, ma fluid. Epithelial disruption is a primary cause
can be demonstrated by CT scan. Further, of alveolar flooding and injury to type I
variations in mechanical ventilation including pneumocytes contributes to impaired transport
PEEP have significant visible impact on lung of sodium, chloride, and water from alveoli.
parenchymal characteristics as viewed using CT Further, surfactant is inactivated and diluted. As
scan imaging.10 Table 3—Common Causes of ALI/ARDS
Direct causes
Pulmonary infection
Aspiration injury (gastric contents, near drowning,
blood, toxins)
Inhalation injury (smoke, toxins)
Trauma (contusion)
Embolism (amniotic fluid, fat, air)
Reexpansion injury
Reperfusion injury
Indirect causes
Severe sepsis
Shock
Nonpulmonary trauma
Transfusion-related lung injury
Cardiopulmonary bypass
Anaphylaxis
Medications (opioids, salicylates, amiodarone, tocolytics,
Figure 1. Computed tomographic section of chest in a chemotherapy)
patient with ARDS that demonstrates dependent consoli- Acute pancreatitis
dation and areas of normal lung and atelectatic lung in the
mid and anterior zones. Reprinted with permission from Reprinted with permission from ACCP Pulmonary Medicine
ACCP Pulmonary Medicine Board Review. 25th ed. North- Board Review. 25th ed. Northbrook, IL: American College of
brook, IL: American College of Chest Physicians; 2009. Chest Physicians; 2009.

epithelium is sloughed, hyaline membranes are annually. This same study reported in-hospital
formed. mortality rates of 38.5% and 41.1% for ALI and
The injury to epithelium and endothelium is ARDS, respectively, using data collected in 1999
interwoven with an inflammatory injury. Neutro- and 2000. Of note, mortality rates tend to be lower
phils migrate out of vasculature into interstitium in ALI/ARDS from trauma compared with cases
and alveoli, where they release inflammatory arising after sepsis or gastric aspiration. An
mediators, proteases, and oxidants. Neutrophils analysis of published reports16 suggests that
are recruited and activated in part because of mortality rates for ALI/ARDS have declined
release by alveolar macrophages of cytokines about 1% per year from 1994 to 2006. Mortality
such as TNF-a, IL-1, IL-6, and IL-8. Other cellular rates in recent large RCTs of patients with ALI
sources of mediators are also important, because reveal 30- to 60-day mortality rates of only 25% to
ALI/ARDS occurs in neutropenic patients. It is 30%.
worth noting that injurious mechanical ventila- Pulmonary function tends to return to near
tion during ALI is associated with more inflam- normal over the ensuing 12 months for survivors,
mation as reflected by higher levels of with residual reduced diffusing capacity and
proinflammatory cytokines in the airspaces and exercise-induced hypoxemia seen in some pa-
in circulating blood. In a small RCT, Ranieri and tients. In contrast, quality of life is often impaired
colleagues14 showed increased levels among after ARDS and the causative event(s), with a
patients who received larger tidal volumes (VT) high proportion of patients having neuropsycho-
and modest levels of PEEP in comparison to logical problems and neuromuscular weakness
patients who received ventilation with low VT as prominent components.17,18 At 5 years after
and high PEEP. Fibroblasts are activated to ARDS, pulmonary function was normal to near
produce extracellular matrix in ALI. Fibrin is normal, median 6-min walk distance was 76% of
abundant as is collagen—particularly in a state of predicted, and a variety of physical and psycho-
prolonged inflammation and fibrosis. Many logical problems persisted or had developed,
patients quickly progress to a recovery phase negatively impacting quality of life for patients
characterized by phagocytosis of apoptotic neu- and caregivers.19
trophils, clearance of sodium by the sodium
pump of type II epithelial cells, and water efflux An Overview of Management of ALI/ARDS
via aquaporins. The presence of alveolar and
interstitial edema, fibrosis, and inflammation Management of ALI/ARDS incorporates
contributes to stiff, poorly compliant lungs. Many treatment of the underlying cause; support for
alveoli are not functional gas exchange units gas exchange; supportive and preventative mea-
because they are filled with fluid and/or inflam- sures such as adequate nutrition and prophylaxis
matory exudates or are prone to collapse and thus against deep venous thrombosis, stress gastric
contribute to shuntlike gas exchange resulting in ulceration, and ventilator-associated pneumonia;
refractory hypoxemia. application of evidence-based strategies for ven-
tilation and medical care of ALI/ARDS; and
Epidemiology of ALI/ARDS rescue therapies for refractory hypoxemia in
selected cases. There is a long history of
Epidemiologic estimates of the incidence of proposed therapies for ARDS, many subjected
ALI and ARDS vary widely from 1.5 to 75 per to large-scale RCTs. Yet few interventions have
100,000 annually, but are highly dependent upon been demonstrated to improve key outcomes
the population studied, the definitions used, and such as survival or reduced duration of mechan-
other factors. Some of the best data regarding US ical ventilation and ICU length of stay (LOS).20
cases comes from studies done in Seattle, in which There is general agreement that use of lung
Rubenfeld et al15 estimated crude incidence of protective ventilation, including limiting tidal
79.8 and 58.7 per 100,000 for ALI and ARDS, volume (VT) to 6 mL/kg of predicted body
respectively. Extrapolated to the US population, weight (PBW), is a key component of contempo-
190,600 and 141,500 cases are estimated to occur rary management.21 Some interventions improve

physiologic parameters, like oxygenation, that additional information about VALI and mechan-
have relevance for clinical management. Inter- ical ventilation in ARDS.
estingly, there is not consistent concordance Although earlier RCTs21 that compared low-
between physiologic improvement and enhanced tidal-volume positive-pressure ventilation with
outcome. Despite considerable investigation conventional ventilation in patients with ALI/
some interventions such as systemic corticoste- ARDS were not conclusive, the pivotal trial
roids, prone positioning, and high levels of PEEP performed by the ARDS Network investigators
remain controversial. Management will be disin 861 patients with ALI/ARDS demonstrated a
cussed as ventilatory management and medical 10% absolute reduction in mortality. Patients
management. randomized to receive VT of 6 mL/kg PBW also
had more ventilator-free and organ failure-free
Ventilatory Management of ALI/ARDS days compared with patients who received 12
mL/kg PBW VTs. Interestingly, there was no
Ventilatory management goals for ALI/ significant difference in the incidence of baro-
ARDS include enhancing the likelihood of traumas between groups. Meta-analysis26 of six
survival, avoidance of ventilator- and airway- RCTs comparing lung protective ventilation to
related complications, reducing the duration of conventional ventilation confirmed hospital and
mechanical ventilation and critical illness, sup- 28-day mortality benefits with the caveat that
porting gas exchange, and relieving distress and overall mortality was not significantly different if
excessive work of breathing. Key principles of plateau inspiratory airway pressure (Pplat) was
ventilatory management are guided by observa- ,31 cm H2O in the control group. ARDSNet
tions from results of clinical and animal-model recommendations for mechanical ventilation in
investigations and imaging studies that help to ARDS included the following: (1) use volume-
correlate structure and function.22 First, multiple assist control mode; (2) set inspiratory flow at
lines of evidence demonstrate that effective more than patient demand (usually .80 L/min);
alveolar volume is reduced substantially in (3) start with VT ¼ 8 mL/kg PBW and reduce VT
ARDS—mimicking baby lungs in size—and that by 1 mL/kg until 6 mL/kg PBW is reached; (4)
overdistention of functional alveoli impairs gas aim for Pplat ,30 cm H2O; (5) increase respira-
exchange and induces a state of inflammatory tory rate, to a maximum of 35 breaths/min, to
lung injury, so-called ventilator-associated lung achieve pH ¼ 7.3–7.45; (6) consider adding IV
injury (VALI).23 Alveolar overdistention is typi- bicarbonate if necessary to achieve pH goals; and
cally produced by creation of excessive trans- (7) adjust FIO2 and PEEP to achieve PaO2 ¼ 55 to
pulmonary distending pressure during positive- 80 mm Hg or SpO2 ¼ 88% to 93% according to
pressure breath delivery. Second, many alveoli Table 4. Note that PBW (in kg) can be calculated
are prone to collapse either throughout the as 50 þ 2.3 3 (height in inches 60) for men and
respiratory cycle or as lung volume and airway 45.5 þ 2.3 3 (height in inches 60) for women.
pressure decrease during exhalation—so-called Ventilator procedures utilized in recent ARDS
atelectrauma. Recruiting these alveoli and main- Network RCTs apply these parameters, but also
taining them in an open state improves gas permit modes other than volume assist control to
exchange and reduces VALI related to injury be used, allow VTs as large as 8 mL/kg PBW for
caused by repetitive alveolar collapse and re- severe dyspnea as long as Pplat remains ,30 cm
cruitment. Third, high concentrations of oxygen H2O, support use of either PEEP:FIO2 Table 4 or 5
are typically necessary to achieve sufficient with possible preference for the higher PEEP
cellular oxygenation but if administered for table for patients who have substantial increase
prolonged periods are associated with pulmo- in oxygenation with higher PEEP, and have
nary fibrosis in animal models. Thus, current additional minor differences.
ventilatory strategies for ARDS focus on using The results are compelling for adoption of a
small VTs sufficient PEEP to splint open alveoli, low-tidal-volume approach to mechanical venti-
and supplemental oxygen.24,25 Also see the lation; however, examination of actual clinical
chapter on mechanical ventilatory support for practice at ARDS Network hospitals and other

Table 4—Adjustments to PEEP and FIO2 During Mechanical Ventilation for ALI/ARDS According to the ARDS Network
FIO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0
PEEP, cm H2O 5 5 8 8 10 10 10 14 14 14 18 24
PEEP is increased in increments of 2 cm H2O, FIO2 by 0.1. Adapted from Esan et al.44
hospitals years after publication of ARDSNet well as better outcomes. Ranieri et al14 also
results indicates that clinicians often do not demonstrated reduced levels of proinflammatory
reduce lung volumes adequately. In fact, in one cytokines in the air spaces as well as circulating
three-center study27 only 16% of patients with blood with open lung ventilation. PEEP respon-
ALI/ARDS had VT ,8 mL/kg PBW. Barriers to siveness is highly variable as judged by physio-
adoption include clinician reluctance to relin- logic parameters and anatomic measures like CT
quish control of the ventilator; lack of recognition scan imaging.31 As a result of these observations
of ARDS; and concerns for contraindications, and the evidence from animal models of lung
discomfort, and impaired gas exchange.28 Higher injury that higher PEEP may protect against
rates of compliance can be achieved by utilizing a injury from repetitive alveolar collapse and
written protocol.29 Use of nomograms to easily recruitment (called atelectrauma by some) three
identify hypoxemia that reaches the threshold for large (.500 subjects each) multicenter RCTs32–34
ALI or ARDS (Fig 2) and that quickly converts designed to compare a high PEEP strategy to
height in inches or centimeters to PBW and to the traditional ARDSNet PEEP have been completed.
target tidal volume of 6 mL/kg (Fig 3) may help All studies were similar in that PEEP averaged
raise awareness and streamline the process of about 7 to 10 cm H2O in the low PEEP arm and
providing lung protective ventilation. 10 to 16 cm H2O in the high PEEP arm over the
It is noteworthy that the original ARDSNet 6
mL/kg VT approach (described above) actually
led to slightly worse oxygenation compared with
12 mL/kg VT. This contrasts with other smaller
studies, such as those by Amato et al30 and
Ranieri and coworkers14 in which a low-tidal-
volume ventilation coupled with a more aggres-
sive PEEP strategy, so-called open lung ventila-
tion, was associated with better oxygenation as
Figure 3. Table to identify tidal volume that corresponds to 6

mL/kg of PBW based upon patient gender and height in
inches or centimeters. Find the cell that most closely
matches the height in inches or centimeters for a male (left)
or female (right) and identify the corresponding tidal
Figure 2. Graph of PaO2 vs FIO2 to easily identify if
volume listed in the same row. The PBW is also listed for
oxygenation criteria are present for ALI or ARDS. Find the
point where the horizontal line for measured PaO2 intersects the corresponding heights. Calculations are based upon the
the vertical line for FIO2 and determine if this point is within following equations. Male: PBW (in kg) ¼ 50 þ 2.3 3 (height
the area that defines ARDS or ALI without ARDS. Reprinted in inches 60). Female: PBW (in kg) ¼ 45.5 þ 2.3 3 (height in
with permission from ACCP Pulmonary Medicine Board inches 60). Reprinted with permission from ACCP
Review. 25th ed. Northbrook, IL: American College of Chest Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
Physicians; 2009. American College of Chest Physicians; 2009.

no difference in barotraumas (Table 6). In
contrast, among patients who had ALI without
ARDS (ie, 200 mm Hg ,PaO2:FIO2 ,300 mm Hg),
patients randomized to higher PEEP had trends
for higher hospital mortality and fewer ventila-
tor-free days (Table 6). Thus, a higher PEEP
strategy appears to be advantageous for ARDS
but not for ALI without ARDS.
The fashion by which one determines optimal
PEEP in ARDS has been widely debated. The
goal is to achieve optimal alveolar recruitment
and retention in order to enhance gas exchange
and avoid atelectrauma while avoiding alveolar
overdistention that can cause volutrauma, in-
Figure 4. PEEP vs PaO2/FIO2 ratio on day 3 in the low PEEP creased dead space ventilation, and barotrauma.
and high PEEP arms of four RCTs. Data from Meade et al,32
Mercat et al,33 Brower et al,34 and Talmor et al.36 Excessive PEEP can also have adverse cardio-
vascular consequences by reducing cardiac out-
course of the first week of ARDS. PaO2:FIO2 ratios put and therefore oxygen delivery, as well as
were uniformly higher (Fig 4) and rescue therapy creating hypotension and organ hypoperfusion.
for hypoxemia employed less frequently in Clinical parameters potentially of value include
patients randomized to the more aggressive changes in oxygenation, evidence of alveolar
PEEP strategy in these studies. None of the recruitment (or derecruitment), increased dead
studies demonstrated a difference in rates of space ventilation, and reduced cardiac output.
mortality or barotrauma events; however, more The most common approach is a simple PEEP:
FIO2 table (Tables 4 and 5) in which either PEEP
organ failure-free and ventilator-free days were
or FIO2 is adjusted in response to measured
seen with higher PEEP in the study by Mercat
oxygenation using PaO2 or SpO2, as used in the
and colleagues.33
ALVEOLI and LOVS RCTs.32,34 There may be
Subsequently, a number of meta-analyses of
advantages, however, to patient-specific adjust-
these three RCTs have been published, with the
ments that typically rely upon evidence of
analysis by Briel and colleagues35 being most effective alveolar recruitment. For example,
informative because individual patient data Mercat et al33 increased PEEP progressively as
rather than pooled data were analyzed and long as Pplat remained ,28 to 30 cm H2O and
patients with more severe disease (ARDS) were oxygenation improved. In a subsequent study,
compared with those with milder oxygenation Talmor36 and coinvestigators used esophageal
deficits (ie, ALI without ARDS). They demon- pressure as a surrogate for pleural pressure to
strated that patients randomized to higher PEEP guide setting PEEP while avoiding excessive
had significantly better oxygenation, less rescue transpulmonary pressure. They demonstrated
therapy for hypoxemia, more ventilator-free better oxygenation and lung compliance, along
days, and lower hospital and ICU mortality, but with a trend for lower mortality, without increas-
Table 5—Adjustments to PEEP and FIO2 During Mechanical Ventilation for ALI/ARDS According to the Increased Recruitment
Arm of the Express Trial
FIO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

PEEP, cm H2O 5–10 10–18 18–20 20 20 20–22 22 22–24
PEEP is adjusted upwards according to the table, unless Pplat . 30 cm H2O while the patient is receiving volume assist-
control ventilation with VT ¼ 6 mL/kg PBW. PEEP is increased in increments of 2 cm H2O, FIO2 by 0.1. Note that a trend for
higher mortality was noted for patients with PaO2:FIO2 . 180 mm Hg, thus this strategy is not recommended for ALI without
ARDS (ie, PaO2:FIO2 . 200 mm Hg). Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed.

Table 6—Meta-analysis of Individual Patient Data for High PEEP vs Low PEEP Strategies in ARDS and ALI Without ARDS
ARDS ALI Without ARDS
Higher PEEP, % Lower PEEP, % P Higher PEEP, % Lower PEEP, % P
Hospital death 34 39 .049 27 19 .07

ICU death 30 37 .001 20 17 .71
Pneumothorax 8 7 .13 4 5 .33
Ventilator-free days 12 7 .004 17 19 .07
Rescue therapy 14 21 ,.001 4 7 .25
Adapted from Briel et al.35
ing barotrauma in this pilot study. It is notewor- creased transiently in most studies.46 Recent
thy, however, that extending this research meth- work highlights different approaches to recruit-
od to widespread clinical practice is challenging. ment maneuvers. A shorter duration—10 s—of
Some experts examine the contour of the airway high-pressure (40 cm H2O) inflation appears to
pressure-time waveform during constant-flow be sufficient to recruit alveoli, while avoiding the
ventilation in a volume-targeted mode, which transient hemodynamic deterioration that occurs
they call the stress index, as an indication of the at 20 to 30 s.47 Staircase recruitment48 and
likelihood of further alveolar recruitment.37 A prolonged moderate pressure recruitment49 fol-
concave downward shape that is considered lowed by PEEP titration have been recently
‘‘stress index ,1’’ implies further capacity for demonstrated to effectively recruit alveoli and
alveolar recruitment and thus setting a higher increase lung compliance such that lower PEEP
PEEP, as shown in Figure 5. In contrast, a concave can be used to maintain good gas exchange.
upward shape to the pressure-time waveform Application of a recruitment maneuver such as
indicates excessive pressure as the breath is applying an inspiratory pressure at 40 cm H2O
delivered—‘‘stress index .1’’ and low likelihood for 40 sec may be reasonable after ventilator
of further alveolar recruitment. Interestingly,
these investigators demonstrated lower levels of
proinflammatory cytokines using this patient-
specific approach to set PEEP, as compared with
using a PEEP:FIO2 table.37 Imaging of lung
parenchyma with CT scan38 or ultrasound39 can
reveal evidence of response to PEEP. Although
most experts recommend escalation of PEEP,
some favor starting with high PEEP (ie, 20 cm
H2O) and decreasing it.40–42
Recruitment maneuvers are used by some
clinicians to open alveoli that are then splinted
open with PEEP, but their use remains contro-
versial.43 A wide variety of techniques have been Figure 5. Stress index based upon airway pressure-time
graphic display while receiving volume-targeted ventilation
utilized to provide sustained high-pressure in- with square wave flow. Stress index ,1 (left) is represented
flation including applying airway pressure of 30 by concave downward airway pressure vs time curve and
to 40 cm H2O for 30 to 40 s, intermittent sigh, signifies opportunity for increasing PEEP without causing
alveolar overdistention. Stress index .1 (right) is represent-
extended sigh, and intermittent PEEP ined by concave upwards airway pressure vs time curve
crease.44,45 In a Cochrane review of 1,170 patients depicting increasing airway pressure as the breath is
with ARDS/ALI in seven clinical trials, recruit- progressively delivered and implies that alveolar overdis-
ment maneuvers were associated with no differ- tention is likely if PEEP is increased. A flat contour of rising
pressure vs time as breath is delivered is consistent with
ence in 28-day mortality, risk of barotrauma, or stress index ¼ 1 (middle). Reprinted with permission from
blood pressure, although oxygenation was in- Esan et al.44

disconnection with the accompanying loss of release ventilation (APRV) is also applied to this
alveolar distention in ARDS patients who are mode, typically when a very long inspiratory
PEEP responsive and have poor oxygenation. plateau and a very brief (,0.8 sec) exhalation
PEEP should be reduced decrementally, if possi- phase is used.53–55 However, terminology has
ble postrecruitment. Further study may confirm been variable in published literature, and APRV
value via recent additional observations. has been used to describe bilevel ventilation with
Although the pivotal ARDSNet study pre- 1:1 I:E ratio in some European studies.56 There is
scribed using the volume-assist control mode,21 weak evidence from retrospective studies that
application of a pressure-targeted mode, as done traditional APRV (ie, very long inspiratory time)
by Amato et al30 in his lung protective strategy, is may permit use of less sedation because breaths
of interest to clinicians. A pressure-targeted are permitted even during the long inspiratory
mode may permit more fine-tuning of Pplat, phase57; however, prospective studies are needed
PEEP, and inspiratory time to improve oxygen- to confirm this. There is evidence that unrestrict-
ation while also adhering to VT 6 mL/kg PBW ed spontaneous breathing, particularly if the
and acceptable Pplat.50,51 The open ventilation breaths are not pressure supported, promotes
mode tested by Meade and colleagues incorpo- better aeration of dependent juxtadiaphragmatic
rated pressure-targeted ventilation with inspira- lung zones.58–60 Investigators have demonstrated
tory to expiratory ratio (I:E) up to 1:1, higher better gas exchange with measured decreases in
Pplat to a maximum of 40 cm H2O, higher PEEP shunt fraction and dead space, as well as
(discussed above), and recruitment maneuvers increased cardiac index, with the addition of
after disconnection from the ventilator.32 With unsupported spontaneous breaths throughout
this approach, they demonstrated superior oxy- ventilation using APRV with 1:1 I:E ratio.61,62
genation and fewer deaths due to refractory Although oxygenation may be improved with
hypoxemia, but no difference in mortality, APRV, there are few data and no adequately
barotrauma, or ICU LOS compared with tradi- powered RCTs that address important outcomes
tional ARDSNet ventilation. A significant limita- such as survival, ICU LOS, or barotrauma rates
tion of using pressure-targeted ventilator modes with this technique. Further, the very short
in ALI/ARDS is the loss of control over the VT, exhalation time may be inadequate to fully
and thus increased likelihood of violating the empty the lungs, particularly if bronchospasm
important goal of using low-tidal-volume venti- or secretions impede exhalation—potentially
lation. For the same inspiratory pressure and leading to life-threatening auto-PEEP. If a longer
inspiratory time settings, a more vigorous inspi- inspiratory time is used, I prefer using an
ratory effort or improvement in lung compliance expiratory time of 1 s in order to reduce the
will result in larger and potentially excessive VT. likelihood of this potentially dangerous situation
Systematic review of RCTs of pressure-limited vs from occurring. Finally, APRV may present
volume-limited ventilation has been hampered increased risk for violation of the low-tidal-
by lack of large studies that limit differences in volume ventilation strategy because tidal volume
ventilation to pressure vs volume targeting (1) is not precisely controlled during pressure
without imbalances related to tidal volume targeted breaths, (2) may increase with improv-
and/or PEEP.52 When open-lung strategies (pres- ing lung compliance, (3) may increase with
sure-limited þ higher PEEP) are included, sys- superimposed spontaneous breaths, and (4)
tematic review suggest reduced mortality but may be poorly detected.63
increased use of paralytic agents with pressure- High-frequency oscillatory ventilation (HFOV)
targeted modes compared with volume-limited is perhaps the ultimate form of lung protective
ventilation.52 ventilation for ARDS, because VT of ,150 mL are
A modification of pressure-targeted con- delivered at rates greater than 180 breaths/
trolled ventilation that permits inspiratory efforts min.64,65 The largest RCT performed in adults
to occur and be pressure-supported regardless of with ARDS showed equivalency of HFOV to
the phase of ventilation is called bilevel or conventional ventilation regarding gas exchange
biphasic ventilation. The term airway pressure and outcomes but was performed when larger (10–

12 mL/kg PBW) VT were utilized.66 A recent meta- approach. There was no difference in mortality
analysis67 identified six RCTs totaling only about between groups but more electrolyte disorders
350 adult and pediatric patients and found (hypernatremia, hypokalemia, alkalosis) oc-
superior oxygenation on days 1 and 3 with HFOV, curred in the conservative management group.
fewer treatment failures, and lower mortality The research protocol for conservative fluid
(P ¼ .03) for all studies but no difference in management is complex, however. Each of 20
mortality (P ¼ .07) when lung protective ventila- separate management cells is defined by the
tion was mandated or when limited to adults central venous pressure (CVP) range and one or
(P ¼ .07). The results of multicenter RCTs compar- more of the following clinical characteristics: (1)
ing HFOV to conventional lung protective venti- presence or absence of shock (mean arterial
lation that are underway will inform decision pressure , 60 mm Hg or any need for vasopres-
making regarding HFOV. It is noteworthy that sor), (2) urinary output (,0.5 mL/kg/h vs .0.5
HFOV adds significant complexity to patient mL/kg/h), (3) ineffective circulation (cardiac
management, including adjusting frequency, am- output ,2.5 L/min/m2 or cold, mottled skin
plitude, airway pressure, bias gas flow, and with delayed capillary refill time), (4) or effective
inspiratory time, often to subjective (ie, thigh circulation. A simplified version (by collapsing
wiggle) and counterintuitive (ie, decrease frequen- several CVP ranges into one CVP range and
cy to reduce hypercapnea) targets. Deep sedation elimination of the ‘‘ineffective circulation’’ pa-
and neuromuscular blockade (NMB) is typically rameter because this was rarely present) is
required,68 and pulmonary auscultation, bron- presented in Table 7. Of note, 75% of interven-
choscopy, and transport out of ICU may be tions performed during the study were when the
compromised. Its use should be limited to centers patient was stable, that is, normotensive and
with experience and immediately available on-site nonoliguric; this is the opportune time to
expertise to troubleshoot problems. eliminate excessive fluid by diuresis. Retrospec-
tive analysis of a large cohort of ARDS patients
Nonventilatory Management of ALI/ARDS identified a correlation between negative fluid
balance on day 4 with independently lower
Many pharmacologic interventions, as well as hospital mortality.72 Work by other investiga-
other nonventilatory treatment strategies, have tors73,74 suggests that the addition of albumin
been used in uncontrolled settings or tested in infusion to patients with ALI and low (,5 mg/
RCTs,69,70 most with negative results. Some dL) serum protein as they are receiving furose-
experimental therapies are not commercially mide diuresis leads to improved oxygenation,
available, and thus are not discussed. Rather, fluid balance, and hemodynamics.
we will focus on readily available interventions Nutrition: Many factors influence nutritional
that have been subjected to evaluation in RCTs. A management of critically ill patients who are
number of interventions such as inhaled nitric mechanically ventilated. Many patients have
oxide (INO) and prone positioning will be feeding intolerance and are at risk for becoming
considered within the context of rescue therapy malnourished. There is evidence that providing
for refractory hypoxemia. at least minimal or trophic nutrition can help
Conservative Fluid Management: Typical man- preserve intestinal epithelium and enhance im-
agement of a patient with ALI results in a net mune function. However, some data has sug-
positive fluid balance of about 1 L per day.70 gested that permissive underfeeding is
There is evidence from a large multicenter RCT71 associated with better outcomes. Recently, the
from the ARDS Network investigators that a ARDS Network investigators75 randomized 1,000
protocol-directed conservative approach to fluid patients to either trophic enteral feeding or full
management for patients with ALI leads to enteral feeding over the first 6 days of mechan-
shorter duration of mechanical ventilation (more ical ventilation. Full-feeding patients received
ventilator-free and ICU-free days) without neg- more calories but had more gastrointestinal
atively impacting renal function, when compared distress (vomiting, high gastric residual volumes,
with a liberal fluid management conventional constipation). However, there were no differenc-

Table 7—Conservative Fluid Management Strategy for ALI
CVP Range, mm Hg Shock Present Shock Absent, Oliguric Shock Absent, Nonoliguric
9 Vasopressors Diuretica Diuretica

4–8 Fluid bolus Fluid bolus Diuretica
4 Fluid bolus Fluid bolus KVO fluids
Shock ¼ mean arterial pressure ,60 mm Hg or use of any vasopressor. Oliguric ¼ urine output ,0.5 mL/kg/h. KVO ¼ keep-
vein-open IV fluid rate.
a
Diuretics are not given if a vasopressor was used within 12 h.
es in important outcomes such as mortality, four RCTs demonstrated the lack of benefit of
LOSs, or secondary infections. corticosteroids given in high doses and for short
ALI/ARDS is an inflammatory disorder in duration in preventing the development of ARDS
which oxidants also play a role in lung injury. in high-risk patients; this form of therapy has
Altering the fatty acids incorporated into tissue been abandoned. More recently, interest has
lipids can modify the nature of lipid inflamma- shifted to longer duration, modest-dose cortico-
tory mediators that are subsequently released. steroids, particularly for ARDS that is persistent
The arachidonic acid metabolites, in particular, beyond 7 days. Most RCTs that have addressed
are proinflammatory and may contribute to the question have been small and/or suffered
worsening lung injury. A meta-analysis of three from methodological concerns.
smaller RCTs76 demonstrated that enteral admin- The largest and most methodologically sound
istration of a nutrition product that contains study80 was a multicenter RCT performed by the
eicosapentaenoic acid (EPA), gamma-linoleic ARDS Network investigators with randomiza-
acid (GLA), and antioxidants to patients with tion of 170 patients with ARDS that has persisted
ARDS is associated with better oxygenation, for 7 to 28 days to methylprednisolone (MP) 2
along with more ventilator-free days, more organ mg/kg/day in four divided doses with gradual
dysfunction-free days, more ICU-free days, and taper, or placebo. Randomization to MP was
better survival. These studies have been criti- associated with no difference in 60-day or 180-
cized for serious methodological flaws and day mortality, but more ventilator-free days
several multicenter RCTs of patients with ARDS through day 28 (P , .001) and day 180 (P ¼ .04);
were recently completed. A Spanish multicenter shorter duration of mechanical ventilation
RCT77 showed shorter ICU LOS but no difference (P ¼ .006); more ICU-free days (P ¼ .02), less
in oxygenation, duration of mechanical ventila- cardiovascular organ failure (P ¼ .04), pneumo-
tion, organ dysfunction, or survival for mechan- nia (P ¼ .05), and shock (P ¼ .03), as well as better
ically ventilated septic patients who received an PaO2:FIO2 ratio (P ¼ .05) and lung compliance
EPA–GLA diet compared with control diet. The (P ¼ .05). More frequent severe myoneuropathy
ARDS Network investigators78 demonstrated was noted (P ¼ .001) but no difference in pro-
significantly fewer ventilator-free days, fewer spectively diagnosed myoneuropathy (P ¼ .67) or
ICU-free days, fewer nonpulmonary organ fail- total cases of myoneuropathy was found when
ure-free days and trends for higher 60-day all were combined (P ¼ .20). In a secondary
hospital mortality with EPA þ GLA þ antioxidant analysis81 of the data, treatment with MP was
nutritional supplementation compared with con- not associated with increased risk of neuromy-
trols. Because of this demonstrated concern for opathy (OR: 1.5; 95% CI: 0.7–3.2). Although this
harm, diets rich in EPA, GLA, and antioxidants was widely considered to be the most rigorous
should be avoided in ARDS. RCT addressing corticosteroids in ARDS, critics
Corticosteroids: The use of glucocorticoids in identified the study design flaws, which included
the treatment of ALI/ARDS as a condition rapid discontinuation (over 2 days) of MP after
characterized by intense inflammatory and dis- the patient was extubated or developed suspect-
ordered fibrotic repair spans decades and has ed septic shock because it likely contributed to
never been free of controversy.79 In the 1980s, rapid deterioration in respiratory or cardiovas-

cular status. Subset analysis of the ARDS In a 2008 consensus statement from the
Network data80 suggests that survival may be American College of Critical Care Medicine,
worse with corticosteroids among subjects en- administration of moderate-dose glucocorticoids
rolled .14 days after onset of ARDS (P ¼ .02). in the management of patients with early severe
However, it is worth noting that those random- ARDS and before day 14 in patients with
ized to placebo had an extraordinarily low 60- unresolving ARDS is suggested as a weak
day mortality rate of 8%, compared with that of recommendation based upon moderate-quality
MP (35%), as well as mortality rates of patients evidence (2B).85 Although this management
enrolled between 7 and 14 days (36%, 27%) and strategy is rather polarizing among experts, most
that the subset sample size was small (n ¼ 25 in agree that if corticosteroids are administered to
the late-stage MP subset), raising questions about treat ARDS, several caveats apply: (1) use low-to-
the validity of harm being attributable to moderate dose (1–2 mg/kg/d MP to start, then
corticosteroids in this subgroup. Nevertheless, taper), long-course (up to 28-day) therapy, (2)
the authors conclude (and I concur) that cortico- initiating therapy .13 days after onset of ARDS
steroids should not be initiated to treat unresolv- should be avoided, (3) active infection surveil-
ing ARDS after day 13 until more data are lance should be performed during MP therapy,
available. and (4) concomitant administration of neuro-
The role of low-dose MP early in ARDS has muscular blocking agents (NMBAs) should be
been examined as well. Meduri and colleagues8 avoided.79
investigated the impact of low-dose (1 mg/kg/ b-Agonist Therapy: There is experimental
day, then taper over up to 28 days) MP vs placebo evidence that b-adrenergic receptor agonists
begun early (,72 h) in severe ARDS in 91 accelerate resolution of pulmonary edema and
patients. They reported lower mortality, shorter smaller studies showed some promise. In a
duration of mechanical ventilation, shorter ICU preliminary study of patients with ARDS,86 IV
LOS, and lower rate of infections in patients salbutamol resulted in significantly lower lung
randomized to MP, although the 2:1 randomiza- water and lower Pplat, but a higher incidence of
tion scheme and crossover of nonresponders at supraventricular arrhythmias. However, two
10 days are significant methodological concerns. recently completed large multicenter RCTs87,88
Meta-analysis of RCTs and cohort studies demonstrated lack of efficacy and safety concerns
demonstrated favorable outcomes with cortico- with aerosolized and IV b-agonists in ARDS/
steroids compared with placebo, including lower ALI. In particular, IV salbutamol was associated
mortality (P ¼ .01) for all studies combined but with significantly higher mortality than placebo
only a trend (P ¼ .08) in RCTs. Meta-analysis82 and the study87 of 326 patients with ARDS was
also found corticosteroids to be associated with terminated early, effectively eliminating this
shorter duration of mechanical ventilation therapy from clinical consideration. Aerosolized
(P ¼ .03), less organ failure (P , .001), better albuterol was associated with a trend for pro-
oxygenation (P ¼ .01), and no difference in longed mechanical ventilation (ie, fewer ventila-
frequency of any adverse events. Interpretation tor-free days, P ¼ .087), more tachycardia, and no
of this meta-analysis must be tempered by the difference in mortality, and thus is not recom-
significant heterogeneity among studies. Propo- mended.88
nents of corticosteroids in ARDS argue that
administration of low-to-moderate-dose therapy Rescue Therapy for Refractory Hypoxemia
for longer duration, up to 1 month, is crucial to
avoid relapse.83 When RCT data are limited to The incidence of refractory and/or life-
patients with unresolving ARDS who had dura- threatening hypoxemia in ALI/ARDS is not
tion of 1 to 13 days before corticosteroids were known, although refractory hypoxemia was seen
initiated and who received treatment for at least in about 10% and rescue therapies (INO, prone
1 week, a meta-analysis by Meduri et al84 shows positioning, and/or almitrine) were used in 10%
better survival with MP (P ¼ .01), although the to 35% of patients in several recent multicenter
population is limited to 245 subjects. RCTs for mechanical ventilation in ALI/ARDS.

Although most patients with fatal ALI/ARDS die all of these studies and thus the impact of other
of multiple organ failure, some deaths are the NMBA on ARDS outcomes is unknown. It may
result of refractory hypoxemia. Typically these be that the specific NMBA is important because
patients have oxygen desaturation with minimal prolonged paralysis or acquired quadriplegic
movement, suctioning, or other minor stimula- myopathy has been only rarely describe with
tion that is very slow to recover. A number of the cisatracurium and its clearance primarily by
interventions discussed earlier have been associ- enzymatic, non-end organ mechanism of Hof-
ated with significantly improved oxygenation mann degradation may be important.95,96 The
acutely, such as increased PEEP, APRV, HFO, and mechanism underlying this benefit is uncertain
recruitment maneuvers.44 Additionally, several but may be related to improved synchrony
nonventilatory interventions are commonly used between the patient and ventilator, reduced
as rescue therapy for refractory and life-threat- barotrauma, and perhaps reduced pulmonary
ening hypoxemia, including NMB, INO, and inflammation.97,98
prone positioning.89 When NMBAs are used, the lowest effective
NMBA: The administration of an NMBA in dose is recommended and the duration of
ALI/ARDS can result in improved oxygenation, therapy should be as brief as possible, that is,
primarily when there is persistent patient- ,48 h. Concomitant administration of corticoste-
ventilator asynchrony. The frequency with which roids is to be avoided because of the increased
NMBAs are used in ARDS is highly variable, likelihood of persistent weakness due to acute
ranging from 25% to 55% of patients in recent quadriplegic myopathy under these circumstanc-
large multicenter RCTs and prospective surveil- es. Additional precautions when using NMBAs
lance studies.32–34,89,90 The dosage of NMBA can include administering adequate sedative and
be titrated to achieve a range of effects, from analgesic medications, monitoring clinically
synchronous breathing with the ventilator to and/or with peripheral nerve stimulation, peri-
apnea or even cessation of all movement. odically discontinuing the medication and re-
Evidence of improved outcomes with NMBs in evaluating, avoiding drug interactions, and
ARDS comes primarily from work by a group of providing eye protection and proper position-
French investigators. In preliminary studies they ing.96,99
demonstrated better oxygenation, reduced in- INO and Pulmonary Vasodilators: Nitric oxide
flammation in the lungs and circulation, and is a gas with vasodilator properties in minute
trends for lower mortality.91,92 quantities (ie, 5–20 parts per million [ppm]).
Recently, Papazian and colleagues93 led a Mechanistically INO is an attractive interven-
French multicenter RCT in which 340 patients tion—nitric oxide is delivered by inhalation to
were randomized to receive the nondepolarizing alveoli, which are ventilated, and then diffuses
benzylisoquinolinium NMBA, cisatracurium, or into capillaries, feeding these alveoli and thus
placebo for the first 48 h of severe (PaO2:FIO2 ratio increasing their perfusion while not entering
,150 mm Hg) ARDS. Mortality was significantly nonfunctional alveoli.100 Increasing perfusion to
lower (P ¼ .05) at 28 days with a trend for lower all alveoli, such as with an IV vasodilator, would
90-day mortality (P ¼ .08) with cisatracurium. indiscriminately increase perfusion, thus poten-
Further, randomization to cisatracurium was tially increasing the proportion of blood flow to
associated with more ventilator-free days shuntlike alveoli, worsening oxygenation. Addi-
(P ¼ .04) and fewer pneumothoraces (P ¼ .01) tionally, nitric oxide is inactivated quickly and
with no difference in ICU-acquired paresis. It is thus does not produce vasodilatation of systemic
noteworthy, however, that the survival benefit vessels that might result in systemic hypotension.
was limited to the most severely hypoxemic In clinical studies INO increases PaO2 and
(PaO2:FIO2 , 120 mm Hg) patients. Whether decreases pulmonary artery pressure. In dose-
these results are widely generalizable is not ranging studies,101 these effects tend to peak at
known. Meta-analysis of studies by Papazian et about 20 ppm concentrations. RCTs demonstrate
al93 and Gannier et al92 confirms 28-day mortality improved oxygenation in the majority of pa-
benefit.94 Cisatracurium was the NMBA tested in tients, sometimes dramatically, but the effects

tend to decline over 2 to 4 days.102 None of the patients, the incidence of new or worsening
multicenter RCTs103,104 have shown that the pressure sores often increases, the likelihood of
administration of INO to patients with ALI/ airway obstruction increases, and the likelihood
ARDS improves chances of survival or reduces of accidental removal of critical tubes and lines
ventilator time. This is confirmed in meta- during position change is present. RCTs demon-
analyses.102,105 Potential adverse effects of INO strate a significant increase in oxygenation with
include methemoglobinemia and increased levels proning, which returns towards baseline oxygen-
of nitrogen dioxide—neither common unless ation when the patient is returned to the supine
high doses of INO (80 ppm) are used. 104 position. Several large multicenter RCTs108–112
Interestingly, a higher rate of kidney injury was failed to demonstrate improvement in survival or
found among patients randomized to INO in a reduction in LOS, although Mancebo et al110
multicenter RCT104 and confirmed in meta- noted a trend for improved survival and in post
analyses102,105 Thus, there is no evidence that hoc analysis Gattinoni and coworkers108 ob-
routine administration of INO in ARDS is of served improved mortality among the sickest
value and the role of INO is largely as rescue quartile of patients, both by severity of illness
therapy for refractory and life-threatening hyp- and by severity of hypoxemia. A recent meta-
oxemia.89,106 Because the acquisition cost is quite analysis113 of seven RCTs totaling 1,675 adult
high, use of INO should be carefully considered patients revealed no effect of proning on mortal-
and unless a clinically important improvement in ity (P ¼ .39); however, when analysis was con-
life-threatening hypoxemia is demonstrated, it
fined to ARDS patients, ICU mortality was
should be discontinued in a timely fashion.
significantly lower (P ¼ .048). Of note, the four
Other inhaled vasodilators are being adminis-
recent studies included in this subanalysis
tered to patients with ARDS as less expensive
employed the longest proning durations and
alternatives to INO; however, none have been
used lung protective ventilation. Prone position-
extensively investigated for safety and efficacy in
ing can be useful for severely hypoxemic patients
this setting.89 Inhaled prostacyclin is probably
with ALI/ARDS but a healthy respect for the
most widely utilized but safe and reliable delivery
challenging process and use of measures to
can be challenging. There is some evidence for
safeguard against complications is necessary.
improved oxygenation with these agents. For
Safe proning in patients with severe ARDS (ie,
example, aerosolized alprostadil was associated
PaO2/FIO2 , 100 mm Hg) is feasible at centers
with increases in PaO2:FIO2 ratios of 55 mm Hg and
84 mm Hg at 4 and 24 h in 15 patients with that frequently apply this technique.114
ARDS.107 More investigation, including studies Extracorporeal Membrane Oxygenation (ECMO):
that address outcomes, is needed. ECMO can provide cardiopulmonary rescue via
Prone Positioning: Placing a hypoxemic pa- artificial heart and lung support. In this tech-
tient who has ALI/ARDS in the prone position nique, blood is removed from the patient and is
improves oxygenation in the majority of patients. circulated through an artificial lung where blood
Principal mechanisms by which this occurs is oxygenated and CO2 removed. This oxygenat-
include: (1) more uniform distribution of venti- ed blood is admixed with the patient’s blood,
lation, with more ventilation of dependent lung which, in the setting of profound hypoxemic
units, thereby more effectively matching ventila- respiratory failure, has venous oxygen levels even
tion and perfusion; (2) lifting the weight of the after passing through the lung; thus, sufficient
heart off of the left lower lobe, as the heart is now flow through the membrane oxygenator is neces-
in a dependent position; and (3) promoting more sary to achieve satisfactory PaO2, particularly in
effective drainage of secretions from the airways. high cardiac output states like sepsis. The
Moving the patient from supine to prone and application of ECMO to hypoxemic respiratory
maintaining the patient in the prone position for failure is typically by veno-venous connections,
an extended time period carries new concerns whereas ECMO applied for heart failure is veno-
and potential complications. For example, deeper arterial. Veno-venous ECMO is used in centers
sedation is needed and NMB is required in more with the capability to provide the equipment and

expertise as a rescue option for profound respi- Nonventilatory measures include avoidance of
ratory failure.115 excessive lung water. Ancillary interventions
The CESAR trial, a British multicenter such as use of NMBAs, INO, prone positioning,
study,116 is the only large RCT performed in the higher PEEP, APRV, HFOV, and ECMO have
era of lung protective ventilation that provides been demonstrated to improve oxygenation in
evidence regarding the value of ECMO in broad most patients and may be useful to combat life-
application to patients with ARDS. The investi- threatening hypoxemia in select cases. Future
gators randomized 180 patients with severe research will help define the role for novel
ARDS to transfer to a designated ECMO center interventions and new treatment strategies.
or be managed conventionally at their hospital.
Patients randomized to an ECMO center had Nothing to Disclose
significantly better (P ¼ .03) 6-month survival
without disability, but only a trend for lower The author has disclosed that no relation-
mortality. Interpretation of these results must be ships exist with any companies/organizations
with the knowledge that only 76% of patients whose products or services may be discussed in
referred to an ECMO center actually received this chapter.
ECMO and that there were important shortcom-
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Notes

Chapter 24. Mechanical Ventilatory Support
Objectives: proper MV influences not just gas exchange, but also

survival and other important outcomes.
Review the determinants of oxygenation and ventilation.
Compare the different modes of mechanical ventilatory
support.
Examine the role and methods for noninvasive positive
pressure ventilation. Physiology of Ventilation and
Examine the value of monitoring and ventilator graphics Mechanical Ventilation
in understanding patient-ventilator asynchrony.
Describe the complications associated with mechanical
ventilatory support, including auto-PEEP (positive end- Delivery of a breath occurs when there is a
expiratory pressure) and ventilator-associated lung change in transpulmonary pressure, which is the
injury. pressure differential between the mouth and the
Review the importance of patient-focused ventilation, pleural space. During a spontaneous breath,
particularly differentiating ventilation strategies for
obstructive lung disease and for ARDS. respiratory muscle contraction causes chest wall
Review the rationale and results of studies supporting a expansion and diaphragmatic descent that cre-
lung protective ventilation strategy for acute lung ates negative pressure within the pleural space.
injury/ARDS. Entering through the trachea, inspired gas moves
Examine structured protocols on liberation from me-
chanical ventilation and the endotracheal tube. via bulk flow down the pressure gradient
through the conducting bronchi and bronchioles
Key words: intrinsic positive end-expiratory pressure;
to the respiratory units where gases move by
mechanical ventilation; noninvasive ventilation; respiratory diffusion within respiratory bronchioles and
failure; weaning alveoli, then by diffusion through the alveolar-
capillary membrane to the pulmonary capillaries.
Synopsis: Negative pressure ventilators simulate the action
Mechanical ventilatory support is used as a key component of the respiratory muscles by creating subatmo-
of the management of both hypoxemic respiratory failure spheric pressure surrounding the chest, thus
and hypercapnic respiratory failure—topics discussed in
expanding the thoracic cavity in a manner that
more detail in other chapters. The principal techniques for
providing artificial ventilation have changed over the past is physiologically similar to spontaneous breath-
century. Negative pressure support achieved widespread ing. Loss of effective diaphragm movement in the
use in the polio epidemic in the 1920s with the Drinker ‘‘Iron negative pressure ventilation system, however,
Lung,’’ followed by introduction of other negative pressure
yields less efficient alveolar ventilation and gas
devices. However, positive pressure ventilation, typically
delivered through an artificial tracheal airway, has achieved distribution.
broad acceptance, while negative pressure ventilation is Similar to spontaneous breathing and nega-
rarely used in current practice. While the patient-ventilator tive pressure ventilation, positive pressure ven-
interface for positive pressure ventilation is most often an
tilators generate transpulmonary pressure,
endotracheal tube or tracheostomy tube, the less invasive
approach of using a tightly fitting full oronasal or nasal favoring bulk flow of gases down the trachea
mask has achieved widespread use for selected forms of and the conducting airways. However, this is
respiratory failure. Advances in mechanical ventilator created by positive pressure within the airway,
technology during the past 50 years have included efficient
forcing air down the trachea, sufficient to
demand valves for triggered ventilation delivery, comput-
erized integration of physiologic measurements and gas overcome pleural pressure to achieve gas deliv-
delivery parameters, accurate gas blending systems, and ery to respiratory lung units. It is noteworthy that
advanced monitoring and safety systems that have resulted pleural pressure is often actually a positive
in more options for the clinician to match mechanical
pressure at rest as a result of the resistive forces
ventilation to patient needs, better patient-ventilator inter-
actions, and greater patient safety. Recent experience with associated with chest wall, abdominal, or pleural
mechanical ventilation (MV) for ARDS illustrates that factors. Common examples of elevated pleural

pressure include large pleural effusion or pneu- common component of respiratory failure and
mothorax, increased chest wall thickness and/or the most straightforward solution is to increase
rigidity from obesity or burn eschar, and dia- the FIO2. Adjustments in airway pressure can
phragmatic elevation from pregnancy, ascites, have an important impact on oxygenation, as
obesity, or intraabdominal hypertension. For well, particularly for patients who have extensive
example, a plateau airway pressure of 30 cm parenchymal lung disease. Considerable ventila-
H2O may be associated with a transpulmonary tion-perfusion mismatching with a large compo-
pressure of only 20 cm H2O in a patient who is nent of underventilated or shuntlike alveoli
obese and has a pleural pressure of þ10 cm H2O. contributes greatly to hypoxemia and is often
Distribution of inspired gases within the responsive to increases in airway pressure
thorax differs between spontaneous breathing through alveolar recruitment and retention.
and controlled positive pressure ventilation, Positive end-expiratory pressure (PEEP) is typi-
particularly when in the supine position. With cally added at low levels (ie, 5 cm H2O) to help
positive pressure ventilation, gases are delivered splint open alveoli even in the absence of diffuse
preferentially to zones of least resistance—gen- lung disease; however, PEEP is generally in-
erally, the more anterior lung units. In contrast, creased to recruit and retain alveoli that are
diaphragmatic descent in spontaneous ventila- prone to cyclic collapse as airway pressures
tion more effectively inflates the inferiorly and decrease during exhalation. While alveolar dis-
dependently positioned juxtadiaphragmatic lung tention throughout the respiratory cycle is best
units, improving ventilation-perfusion matching accomplished by applying higher levels of PEEP,
of these units. Techniques to enhance ventilation other adjustments that increase mean airway
of these lung units, via spontaneous breathing pressure (MAP)—particularly by increasing the
and by prone positioning, often yield improved duration of inspiratory distending pressure, that
oxygenation. is, inspiratory time (Ti)—can improve alveolar
ventilation and oxygenation. Excessive alveolar
Positive Pressure Ventilation pressure can be detrimental, however, by (1)
overdistending functional alveoli, thus increas-
While the notion of forcing gas down the ing dead space; (2) increasing intrathoracic
trachea to inflate the gas exchange lung units pressure, thereby reducing venous return, cardi-
with oxygen-enriched gas is a seemingly straight- ac output, and oxygen delivery; (3) overstretch-
forward concept, there are many variables to be ing alveoli, producing ventilator-associated lung
considered for safe and effective mechanical injury; and (4) causing alveolar rupture, produc-
ventilation. Principles of mechanical ventilation ing air-leak barotrauma. Ventilation can be
will be discussed in the context of the primary conceptualized by understanding the parameters
derangements of respiratory failure, key param- related to delivery of individual breaths, the
eters of positive pressure ventilation, conven- frequency of breath delivery, and how conven-
tional modes of ventilation in widespread use, tional modes of ventilation differ regarding
additional commercially available modes of breath delivery.
ventilation, and specialized modes and tech-
niques. Breath Delivery and Principal Modes of
Mechanical Ventilation
Oxygenation and Ventilation
Volume and Pressure-Targeted Breaths: As dis-
A conceptual framework for understanding played in Figure 1, each breath the patient
the key determinants of oxygenation and venti- receives can be defined by the three ‘‘Ts’’: (1)
lation during mechanical ventilation is displayed the ‘‘target’’ for delivery, that is, volume or
in Figure 1. While achieving acceptable oxygen- pressure; (2) the ‘‘trigger’’ or signal to initiate
ation and ventilation is certainly interrelated, the breath; and (3) the ‘‘termination’’ criteria that
approaching the issues separately can be useful signal the end of the inspiratory phase and
to emphasize key elements. Hypoxemia is a beginning of the expiratory phase, traditionally
362 Chapter 24. Mechanical Ventilatory Support (Sessler)

ous breaths are only pressure-targeted in con-
ventional modes. The patient interacts with the
ventilator via sensors that are in-line pressure or
flow transducers that respond to the patient’s
spontaneous efforts. Data suggest that flow-
triggered sensors are more sensitive to the
patient’s efforts than are the demand sensors
triggered by changes in pressure, unless the
pressure transducer is positioned at the distal
end of the endotracheal (ET) tube. However,
clinically available sensors are positioned inside
the ventilators, and thus the pressure or flow
signal is dampened by the dead space of the
ventilator tubing that connects the ET tube to the
ventilator. Depending on the sensitivity and
responsiveness of the ventilator, respiratory
muscular efforts may not be sensed by the
ventilator, thus causing poor ventilator/patient
interaction. This asynchrony increases the im-
posed work of breathing (WOB) that the patient
has to generate to initiate a breath.
Figure 1. Mechanical ventilation parameters that influence Volume-Targeted Breaths: In volume-targeted
oxygenation and ventilation. Oxygenation, if modified by breaths, a tidal volume (VT) is chosen and the
adjusting FIO2 and parameters that change MAP. Ventilation
breath is delivered by applying an inspiratory
is determined by breath characteristics, ventilator mode,
and respiratory rate, including minimum mandatory flow rate (flow limitation) and pattern of delivery
breaths and additional patient breaths. Each breath can be (square wave, sine wave, or decelerating or ramp
defined by the delivery target (pressure or volume) and the pattern). Typical flow rates vary from 30 to 80 L/
signals to initiate and to terminate the breath. There are
three types of breaths as defined by initiation and
min, with higher flows resulting in shorter Ti and
termination signals: VIM, PIM, and PS. The mode deter- shorter inspiratory to expiratory (I:E) ratio, but
mines the type of breaths that can be mandatory and those higher peak inspiratory pressure (PIP). Similarly,
that are in addition to the minimum set rate. PIM ¼ patient- square wave flow results in shorter Ti and higher
initiated mandatory breath; VIM ¼ ventilator-initiated
mandatory breath. Reprinted with permission from ACCP PIP, while the decelerating pattern has the
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: opposite effects. Collaboration with a skilled
American College of Chest Physicians; 2009. respiratory therapist is important for fine-tuning
these parameters. The breath is terminated and
called cycling. Breath characteristics can be exhalation permitted after the set VT has been
clinician determined (ie, mandatory breath) or delivered. In some volume-targeted modes, the
influenced by clinician settings and patient effort inspiratory time is also set and exhalation begins
(ie, pressure-supported breath). These parame- after Ti is concluded. The airway pressure that is
ters differ in the common modes of ventilation generated in order to deliver the breath varies,
(Table 1). An important concept is that manda- increasing to a peak pressure as the lung is
tory breaths are ‘‘guaranteed,’’ both in terms of a inflated. Airway pressures are dependent upon
minimum number of breaths each minute, as the ventilator settings as well as lung and chest
well as delivery of a predetermined volume or a wall mechanics. For example, higher PIP can be
predetermined pressure and inspiratory time. In caused by bronchospasm, ET tube obstruction, or
contrast, spontaneous breaths are dependent tension pneumothorax with no change in set flow
upon patient effort for both breath initiation as or VT, but may also be the result of faster flow
well as breath duration. Mandatory breaths can rates or larger tidal volume without new pulmo-
be volume- or pressure-targeted while spontane- nary dysfunction.

Table 1—Comparison of Principal Modes of Ventilation
Mode of Ventilation Assist Control SIMV Spontaneous/PSV
Mandatory breaths Yes Yes No

Spontaneous breathsa No Yes Yes
Volume or pressure Either volume or pressure Mandatory: either volume or Pressure
pressure
Spontaneous: pressure only
Advantages Stabilization mode Comfortable mode
Disadvantages Respiratory alkalosis, air Less comfortable Unreliable ventilation if apnea,
trapping with weakness, deterioration in
tachypnea lung mechanics
Physicians; 2009.
a
Spontaneous breaths are all patient initiated and termination of inspiration (and thus inspiratory time) is patient determined.
Pressure-Targeted Breaths: In contrast to vol- mode or synchronized intermittent mandatory

ume-targeted breaths, pressure-targeted (or pres- ventilation (SIMV) mode. Mandatory breaths can
sure-limited) breaths do not guarantee delivery also be patient initiated (ie, patient-initiated [or
of specific tidal volume. The inspiratory pressure assisted] mandatory breath; see Fig 1). This
(Pi) and the Ti will determine the VT. The Pi is set feature promotes patient comfort by recognizing
by the clinician in all conventional pressure- a patient’s inspiratory effort and delivering a
targeted modes, but inspiratory time can be mandatory breath that has the same clinician-
clinician determined (as in a mandatory breath) determined characteristics as if ventilator initiat-
or patient determined (as with a spontaneous ed. The ventilator can be set up to recognize
breath). If the Pi and Ti are held constant but lung inspiratory flow or negative pressure within the
mechanics change, the tidal volume may be circuit. The threshold for either of these param-
larger or smaller. For example, resolution of eters (flow or pressure) can be adjusted to avoid
pulmonary edema would improve lung compli- overly sensitive triggering that may result in
ance, which would result in a larger tidal volume ‘‘autotriggering,’’ or insensitive critieria that can
for the same Pi and Ti, whereas new onset of contribute to increased WOB and ineffective
bronchospasm would be associated with a trigger asynchrony. The AC and SIMV modes
smaller tidal volume from increased airway differ in the number of mandatory breaths
resistance. permitted. With the AC mode, a minimum
Breath Initiation (Trigger), Breath Termination, frequency (eg, 10 breaths/min) is set; however,
Breath Frequency, and Principal Modes of Ventila- all additional breaths that the patient triggers are
tion: The frequency of breath delivery is depen- also mandatory breaths. In contrast, with SIMV,
dent upon the signal(s) to initiate the breath, the the number of breaths that are mandatory is
mode of ventilation, the minimum set rate for always determined by the clinician-set minimum
mandatory breaths, and patient effort. The frequency. Any additional breaths are treated as
influence of ventilator mode on respiratory ‘‘spontaneous’’ breaths that may be pressure
frequency and type of breaths is compared in ‘‘supported’’ (see scenarios C and D in Table 2
Table 1 and illustrated in hypothetical cases in for examples). For SIMV, ventilator manufactur-
Table 2. For ventilator-initiated (or controlled) ers apply different algorithms that determine
mandatory breaths, the breath is initiated when a whether an inspiratory effort triggers an assisted
clinician-determined time interval has been mandatory breath or a spontaneous pressure-
reached. For example, if a frequency of 10 supported breath. For example, with some
breaths/min is set, a new breath will be initiated ventilator models, delivery of a mandatory
every 6 s. Among the conventional modes of breath is followed by a ‘‘refractory period’’
ventilation (Table 1), the frequency of mandatory during which a patient’s inspiratory effort will
breaths can be set with the assist control (AC) trigger a spontaneous breath but not a manda-

Table 2—Hypothetical Examples of Varying the Drive to Breath, Number of Patient Inspiratory Efforts, and Clinician-Selected Parameters on Breath Types and
Characteristics in Principal Modes of Ventilation
Modes
Assist Control (10/min) Assist Control (10/min) SIMV (10/min) SIMV (10/min) Spontaneous
Mandatory: Pressure, Mandatory: Volume, Supported:
Scenario Parameter Pressure Volume Supported: Pressure Supported: Pressure Pressure
A. Baseline, 12 Mandatory breaths 12 total, mix of controlled 12 total, mix of 10 total, mix of 10 total, mix of 0
inspiratory efforts/ and assisted controlled and controlled and controlled and
min assisted assisted assisted
ACCP Pulmonary Medicine Board Review: 26th Edition

Spontaneous breaths 0 0 2 2 12
B. Apnea Mandatory breaths 10 controlled, 0 assisted 10 controlled, 0 assisted 10 controlled, 0 10 controlled, 0 0
assisted assisted
C. Thirty patient Mandatory breaths 30 total, most assisted 30 total, most assisted 10 total, 0–10 10 total, 0–10 0
inspiratory efforts/ since tachypneic since tachypneic controlled, the rest controlled, the rest
min assisted assisted
D. set f to 2/min; Mandatory breaths 12 total, 2 controlled, 10 12 total, 2 controlled, 10 2 total, probably all 2 total, probably all 0
there are 12 patient assisted assisted controlled controlled
inspiratory efforts/
min
E. Pulmonary edema Tidal volume Decreases No change Decreases No change Decreases
develops
Peak airway pressure No change Increases No change Increases No change
Five examples of ventilator modes are presented (assist control-pressure, assist control-volume, SIMV-pressure, SIMV-volume, spontaneous/PSV). The rate is set at 10/min for
all except the spontaneous mode. Five scenarios are presented in which a different number of patient inspiratory efforts are made (A, B, C), or the set rate is reduced to 2/min
(D), or pulmonary edema develops (E). For the first four scenarios, the expected effect on mandatory and spontaneous breaths is depicted. In scenario E, the effect on tidal
volume and peak airway pressure is illustrated. Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest
Physicians; 2009.
365
tory breath. Finally, in the spontaneous mode, could result in an increase in airway pressure
patient effort determines both the onset and owing to auto-PEEP and dynamic hyperinflation
termination of each breath, thus controlling both (scenario D in Table 2).
the frequency of breathing and the inspiratory SIMV: Intermittent mandatory ventilation
time (which generally varies from breath to (IMV) was originally developed as a bridge
breath). These spontaneous breaths are usually between controlled mandatory ventilation and
pressure supported. The spontaneous mode with spontaneous breathing. With controlled manda-
all breaths receiving pressure support (PS) is tory ventilation, all breaths are ventilator-initiated
widely referred to as pressure support ventila- mandatory breaths and patient inspiratory efforts
tion (PSV). In the spontaneous mode, VT typically do not result in any airflow or ventilation—an
varies from breath to breath and will also change uncomfortable sensation. With IMV, the patient’s
with alterations in lung mechanics. inspiratory effort promotes delivery of a sponta-
Summary and Comparison of Principal Modes of neous breath from a reservoir bag that contains
Ventilation: AC, SIMV, and Spontaneous Modes: The gas with the same FIO2 as for mandatory breaths.
three principal modes of ventilation are com- The size of the breath is determined by patient
pared and contrasted in Table 1. An international effort and lung mechanics. Most modern venti-
prospective surveillance study of .5,000 adults lators use ‘‘synchronized’’ IMV, which allows the
receiving mechanical ventilation showed that patient to initiate a mandatory breath (ie, an
among these modes, AC was the most commonly ‘‘assisted’’ mandatory breath), or initiate a spon-
applied mode, with approximately 60% of taneous breath. Current ventilators allow sup-
patients with acute exacerbation of COPD and port of the spontaneous breaths with a
60% of patients with ARDS receiving AC predetermined pressure (ie, a PS breath). Thus,
ventilation.1 Only 12% to 15% of COPD or ARDS with SIMV, there is a combination of controlled
patients received SIMV with or without PS, while mandatory, assisted mandatory, and pressure-
nearly 10% of COPD patients had PSV, and 10% supported spontaneous breaths. Whether an
to 15% of ARDS patients received pressure- assisted or supported breath is produced is
controlled ventilation (PCV). The effect of hypo- dependent upon the timing of the inspiratory
thetical changes in respiratory frequency or effort. Over the course of a minute, the total
respiratory drive and changes in lung mechanics number of mandatory breaths, including both
on ventilatory parameters for the three principal controlled and assisted breaths, cannot exceed
modes are displayed in Table 2. the preset frequency. While the original intention
AC VENTILATION: AC ventilation may be of SIMV was to speed the transition from full
volume- or pressure-targeted and all breaths ventilatory support to spontaneous breathing by
have the same settings (VT for volume targeted, gradually decreasing the number of mandatory
Pi and Ti for pressure targeted). The clinician sets breaths, clinical trials actually have demonstrated
the minimal number of breaths per minute. In that SIMV is inferior to PSV for ‘‘weaning.’’
addition, inspiratory efforts trigger the ventilator Patient comfort can be impaired in this mode as
to supply additional mandatory breaths. Usually well, with the patient receiving three different
AC ventilation is used when the operator desires breath types.2
to minimize the WOB that the patient has to SPONTANEOUS VENTILATION/PSV: Spontaneous
perform. AC ventilation cannot be used effec- ventilation requires patient effort for initiation of
tively as a weaning mode per se, since all breaths all breaths. Additionally, the termination of all
the patient takes are mandatory breaths that are breaths is determined by reduction in inspiratory
associated with minimal WOB regardless of the effort that is reflected in a drop in flow below a
minimum frequency setting (see scenario C in preset percentage of peak flow. This has been
Table 2). Since all breaths are mandatory breaths, called ‘‘flow-cycled’’ termination. If PEEP is
hyperventilation in this setting can be detrimen- applied, then CPAP is present, as the patient’s
tal because of the resulting high minute ventila- airway pressure is positive during inspiration
tion and associated respiratory alkalosis, but also and expiration. Most clinicians now augment
in the potential for ‘‘stacking’’ of breaths, which spontaneous breaths with pressure support,

usually in the 5 to 25 cm H2O range—often WOB.3,4 Some of the more common modes are
referred to as PSV. With PSV, flow commences discussed below.
when a pressure or a flow sensor is triggered. PCV: PCV is a controlled mode of ventilation
The duration of the added pressure support is (no spontaneous breaths) that is most often used
determined by the spontaneous inspiratory flow, for the ventilatory management of ARDS, partic-
related to patient inspiratory effort. PSV cycles ularly with extended duration of the inspiratory
off when the spontaneous inspiratory flow phase in excess of expiratory phase, so-called
decreases to a preset level (usually approximately inverse ratio ventilation or PC-IRV.5 Traditionally,
25% of the peak flow). The amount of pressure the I:E ratio is usually 1:2 to 1:4. PC-IRV uses I:E
can be adjusted to achieve comfortable breathing, ratios of 1:1, with ratios of 3:1 occasionally
with acceptable VT and respiratory rate (frequen- used. PCV is similar to pressure-targeted AC or
cy, f). PSV is generally considered to be a SIMV, but without assisted or spontaneous
comfortable mode of ventilation for the alert breaths. With PCV, the ventilator rapidly
patient. Additionally, the amount of PS can be achieves the clinician-set inspiratory pressure,
reduced, thus placing a greater requirement on which is usually delivered in a decelerating
the patient for WOB during transition from waveform. The operator sets the duration of
ventilatory support to spontaneous breathing. inspiration (and thus the VT varies) by varying
In the past, PSV was a popular approach to the Ti (time cycled) or by setting the I:E ratio.
weaning. The patient was placed on spontaneous Inspiratory flow from the ventilator to the patient
mode and the PS level sequentially lowered, will continue until the preset Ti or the I:E ratio
increasing the amount of patient WOB. The has occurred. In the time-cycled mode, if the
patient with adequate respiratory muscle preset pressure is achieved early in the inspira-
strength and reserve experienced minimal tory cycle, an inspiratory hold will occur. The
change in the breathing pattern (f, VT, and increase in MAP seen with PC-IRV can be
thoracoabdominal synchrony) as the PS level effective for alveolar recruitment and retention
was reduced. However, if the patient is not ready and has been associated with better oxygenation.
to assume all the required WOB, f will increase Outcome studies have not demonstrated higher
and VT will decrease as the PS level is sequen- survival rates or short duration of mechanical
tially diminished. In current approaches to ventilation with PC-IRV. The major disadvantage
liberation from the ventilator, PSV (5 to 8 cm of PCV, particularly PC-IRV, is the need for heavy
H2O) is often used to overcome the added WOB sedation, since spontaneous breaths are not
that accompanies the resistance of breathing supported. A second disadvantage is that deliv-
through the ET tube during a spontaneous ered VT, and minute ventilation, can change
breathing trial. Since mandatory breaths are not significantly as lung mechanics change. Lung
provided in this mode, reliance on the patient for volumes can increase substantially with improv-
initiating each breath, as well as having sufficient ing lung compliance.
respiratory drive and respiratory muscle strength Bilevel Ventilation and Airway Pressure Release
to achieve adequate minute ventilation, is an Ventilation (APRV): Bilevel (also called ‘‘biphas-
important limitation to consider if the patient is ic’’) ventilation is, in essence, a modification of
likely to become apneic or weak. Further, as with SIMV in which mandatory breaths are pressure
any pressure-targeted mode, deterioration in targeted and PS can be used to augment
lung mechanics can result in hypoventilation spontaneous breaths. The unique feature of
despite previously effective PS settings. Bilevel ventilation is that spontaneous breaths
can be performed throughout the respiratory
Additional Commercially Available Modes of cycle. Thus, in contrast to other pressure-targeted
Ventilation modes including SIMV, AC, and PCV, the patient
can take spontaneous breaths even during a
A variety of ventilator modes have been prolonged lung inflation. Mandatory breaths are
designed to improve patient-ventilator interac- delivered by increasing airway pressure to a new
tions, improve oxygenation, and/or decrease higher level of pressure for a set time, and

exhalation occurs when airway pressure is
decreased to the PEEP level. This higher level
of pressure is often called PEEPHIGH and the
traditional PEEP level called PEEPLOW, thus the
term Bilevel. The frequency is set with a specific
number of mandatory breaths (like SIMV), and
like SIMV or AC, mandatory breaths can be
ventilator initiated (ie, controlled) or patient
initiated (ie, assisted). Pressure support can be Figure 2. APRV. Graphic display of airway pressure (top)
applied to augment spontaneous breaths, but as a and flow (bottom) vs time during APRV with PEEPLOW ¼ 5
safety feature, the amount of PS is added relative cm H2O, PEEPHIGH ¼ 25 cm H2O, PS ¼ 25 cm H2O, resulting
to the PEEPLOW level in most ventilators. For in small breath while at PEEPHIGH. Arrow A depicts
example, as is seen in Figure 2, PEEPLOW is 5 cm continued expiratory flow at the time the second mandatory
breath begins, consistent with incomplete emptying of the
H2O and PEEPHIGH is 25 cm H2O, and the plateau
previous breath and a high likelihood of auto-PEEP.
airway pressure is 25 cm H2O. The augmentation
of a spontaneous breath with 25 cm H2O PS PEEP is probably considerably higher as a result
would raise the peak pressure of spontaneous of intrinsic- or auto-PEEP that develops from
breaths taken during the expiratory phase tran- incomplete exhalation. In European clinical stud-
siently to 30 cm H2O (ie, 5 cm H2O PEEP þ 25 cm ies, Bilevel ventilation with I:E ratio of 1:1 and no
H2O PS). Spontaneous breaths taken while at the
PS for spontaneous breaths was associated with
high PEEP of 25 cm H2O in our case would only
improved gas exchange and patient comfort.12,13
be augmented to the 30 cm H2O limit; thus, an
Importantly, while APRV is considered to be an
effective PS pressure of only 5 cm H2O is
effective rescue therapy for severe hypoxemia in
provided. Many clinicians prefer that spontane-
ARDS, there is a paucity of outcome studies that
ous breaths not be supported with PS. Some
demonstrate improved outcomes for APRV. An
clinicians consider Bilevel ventilation to be a
international cohort study comparing APRV and
potentially attractive mode for severe ARDS,
AC in cases matched with a propensity score
combining the advantages of ventilation with
found no differences in any important outcome.15
pressure-targeted prolonged inspiratory breaths,
Similarly, a pilot randomized clinical trial (RCT)
yet permitting spontaneous ventilations at any
time in the respiratory cycle, and potentially of APRV vs low tidal volume ventilation via
reducing the requirement for sedation and conventional modes in 63 trauma patients found
neuromuscular blockade.6–8 Additionally, spon- no differences in important outcomes.16 An
taneous breathing, particularly when breaths are important concern for the very brief expiratory
not pressure supported, promotes better aeration time is the abrupt development of potentially
of dependent juxtadiaphragmatic lung zones.9–11 life-threatening auto-PEEP caused by increased
Outcome studies that support Bilevel ventilation expiratory resistance from retained secretions or
for ARDS are lacking, however. bronchospasm. Evidence for incomplete empty-
The term airway pressure release ventilation ing of the preceding breath is seen in Figure 2, as
has different connotations depending upon lo- continued expiratory flow is present when the
cale. Bilevel ventilation with I:E ratio of 1:1 has next inspiration begins (arrow A), indicating a
been called APRV in some European studies12,13; high likelihood of auto-PEEP. Finally, as is true
however, in the United States, the term airway for any pressure-limited ventilator mode, VT can
pressure release ventilation is generally applied increase dramatically as lung compliance im-
to pressure-targeted ventilation with a very long proves, potentially violating the low tidal volume
inspiratory time and a very brief (ie, ,0.8 s) ventilation strategy in ARDS. I express the
expiratory time.14 Exhalation to a set PEEP of potential safety concerns of APRV as ‘‘auto-PEEP
zero is used by some clinicians, allowing exha- and tidal volume creep.’’
lation during this ‘‘airway pressure release.’’ Pressure-Regulated Volume Control (PRVC): The
However, it is important to consider that actual PRVC mode, also called volume control plus

(VCþ), AutoFlow, adaptive-pressure control, and nosis.25–28 ASV is recommended by experts for
adaptive support ventilation by various ventila- this scenario.29
tor manufacturers, combines some of the ele- Proportional-Assist Ventilation (PAV): PAV was
ments of volume-targeted assist control and designed to deliver positive pressure ventilation
pressure-limited assist control.17 All breaths are in proportion to respiratory resistance and
mandatory and can be patient or time triggered elastance.30 PAV incorporates a feedback loop
(ie, assisted or controlled, respectively) and are from the spontaneous breathing pattern to better
pressure limited and time cycled. However, the proportion subsequent positive pressure breaths.
clinician sets the goal VT and the inspiratory time, This requires real-time, ongoing measurement of
and the ventilator resets inspiratory pressure, these parameters with rapid adjustments of PAV
based upon the most recent breaths, in order to to keep pace with changes in patient effort and
deliver the goal VT.18 For example, if the VT is resistance, which can be significant even when
lower than target, subsequent breaths will have there are no clinical changes in the patient’s
higher inspiratory pressure to achieve target VT. status. If the patient generates greater effort,
If target VT is exceeded, subsequent breaths will ventilator support is increased. PAV is set to
have lower inspiratory pressure.4 Some investi- overcome a selected proportion of the WOB. PAV
gators find that this mode may reduce time for can reduce the sense of breathlessness and
weaning from mechanical ventilation.19 WOB31 and may reduce frequency of ineffective
Volume-Assured Pressure Support Ventilation triggering in comparison to PSV.32 Modifications
(VAPSV): Similar to PRVC, this mode is pressure to PAV allow better integration of measurements
limited but volume assured. However, in con- of elastance and resistance to prevent excessive
trast, to PRVC, VAPSV applies to spontaneous support, which might result in high pressure or
breaths. All breaths are patient triggered, pres- volume, in situations with rapidly changing lung
sure limited, and flow cycled, similarly to mechanics.33 More studies are needed to dem-
conventional PSV; however, inspiratory pressure onstrate outcome benefits for PAV.
is adjusted on the basis of patient effort to Neurally Adjusted Ventilatory Assist (NAVA):
achieve a goal tidal volume. Initially described Initiation and cycling of breaths with conven-
for delivery to intubated patients with acute tional ventilator modes relies upon changes in
respiratory failure,20 VAPSV is used with greater pressure or flow within the ventilator circuit.
frequency as a mode for noninvasive positive Normally, patient-initiated changes in pressure
pressure ventilation (NPPV) in the management and flow are the result of neural stimuli to
of patients with hypercapnic respiratory failure respiratory muscles that lead to muscle contrac-
from COPD or obesity hypoventilation syn- tion, which changes the relative pleural pressure,
drome.21–24 producing changes in intrathoracic pressure and
Adaptive Servo-Ventilation (ASV): ASV is a volume, and ultimately, changes in pressure and
novel mode of ventilation used via NPPV, flow from the ventilator—events that take time to
particularly for Cheyne-Stokes respiration and occur. NAVA links ventilator actions directly to
central sleep apnea (CSR-CSA) associated with neural stimulus to respiratory muscles, allowing
congestive heart failure. With ASV, the airway greater synchronization of patient and ventila-
pressure is adjusted breath to breath in order to tor.34 A special nasogastric tube with an array of
supply higher airway pressure during periods of electrodes is positioned to detect the electrical
hypopnea and apnea, and reduced airway activity of the diaphragm (EAdi). During an
pressure during periods of hyperventilation. It inspiratory effort the EAdi is measured and
has been demonstrated to be superior to CPAP multiplied by a ‘‘gain factor’’ to achieve the
and to Bilevel positive airway pressure for desired airway pressure by the ventilator, pro-
improving sleep disorder breathing in some portional to the electrical activity of the dia-
studies. Among patients with congestive heart phragm. As EAdi intensity diminishes, a
failure and CSR-CSA, a variety of studies suggest threshold is reached whereupon positive airway
that use of ASV is associated with better quality pressure ceases and the breath cycles off. Various
of life, fewer cardiac events, and better prog- safeguards are incorporated into NAVA to

prevent excessive ventilation. NAVA has been (Glasgow coma scale score .10), lack facial
demonstrated to reduce WOB, to improve pa- trauma or deformity, and have adequate clear-
tient-ventilator synchrony, and to reduce dynam- ance of respiratory secretions.40 Correction of
ic hyperinflation and ineffective triggering.35,35–37 profound hypoxemia is often not possible with
NPPV, even with additional sources of supple-
NPPV mental oxygen. During NPPV, one must avoid air
leaks, eye irritation, and nasal abrasions. Careful
NPPV is used in a variety of settings of attention by respiratory therapists and bedside
respiratory failure; however, its use is quite nurses, including establishing a good mask fit,
variable among practitioners. Although histori- and careful titration of airway pressures to
cally, noninvasive ventilation included negative tolerance, will help with success of NPPV.41 It is
pressure ventilation and positive pressure venti- particularly important to continuously reevaluate
lation, the latter approach has gained greater tolerance of NPPV and to identify in a timely
acceptance, while the former is rarely used.38 fashion impending failure of NPPV. Experts
NPPV is delivered through a tight-fitting orona- recommend that if NPPV has not resulted in
sal or nasal mask; however, experts suggest using definitive improvement within 2 h of onset,
an oronasal mask rather than a nasal mask for endotracheal intubation and conventional venti-
patients with acute respiratory failure.39 It can be lation should be strongly considered.42 Signs of
delivered via a pressure-targeted or volume- improvement include reduced respiratory dis-
targeted mode, delivered by using a conventional tress (ie, less tachypnea and use of accessory
ICU ventilator or a portable ventilator specifi- muscles, better thoracoabdominal coordination),
cally designed for bilevel positive airway pres- or physiologic improvement as determined by
sure support. The mask is connected to the arterial blood gas analysis or breathing pattern
ventilator via a single inspiratory and expiratory analysis. It is worth considering that many
line fitted with a special exhalation valve or by studies are modest in size, patients enrolled
dual lines such as used with conventional represent a small percentage of patients with
mechanical ventilation. Most commonly, the acute respiratory failure at those centers, and
operator sets the inspiratory positive airway blinding subjects and investigators to the inter-
pressure as well as the expiratory positive airway vention is impossible.
pressure. These setting are analogous to PS and NPPV has been used in many forms of
PEEP, respectively. This bilevel ventilator can be respiratory failure. Among the many proposed
used in a spontaneous mode or in a spontane- indications, acute hypercapnic respiratory failure
ous/timed mode that is the equivalent of SIMV in the patient with COPD has the strongest
plus PSV. Being a pressure-targeted mode of evidence base for recommendation. Several
ventilation, bilevel NPPV does not guarantee multicenter RCTs have demonstrated lower
delivery of a constant VT or minute ventilation. A intubation rates, shorter duration of mechanical
limitation to NPPV is that the monitoring ventilation, and improved survival. Additional
systems in conventional ventilators may be too indications with demonstration of improved
sensitive to air leaks that occur around the mask. outcomes include treatment of cardiogenic pul-
Recently, bilevel pressure devices have incorpo- monary edema, fever and pulmonary infiltrates
rated more sophisticated alarm systems to in immunocompromised hosts, postextubation
circumvent this problem. respiratory distress due to upper airway obstruc-
It is important to recognize that the patient tion, and persistent weaning failure with extuba-
who requires emergent endotracheal intubation tion to NPPV. In 2011, a Canadian group led by
is a poor candidate for NPPV, such as those with Keenan39 published clinical practice guidelines
overt respiratory distress, or cardiopulmonary for use of NPPV, representing the most recent
arrest. Additionally, suitable candidates for comprehensive recommendations. Among pa-
NPPV are those who are hemodynamically tients with acute respiratory failure, they make
stable, have sufficiently alert mental status 1A recommendations (strong recommendation

based upon high-quality evidence) for the use of at low risk and those who do not have COPD (2C
NPPV in patients with a severe exacerbation of recommendations). The role of NPPV for ‘‘rescue’’
COPD (pH , 7.35 with relative hypercarbia), therapy for extubation failure is less well estab-
and for cardiogenic pulmonary edema and lished. In fact, Esteban and colleagues45 demon-
respiratory failure in the absence of shock or strated higher mortality with NPPV for recurrent
acute coronary syndrome requiring acute coro- respiratory failure post extubation in a multicenter
nary revascularization. Mask CPAP is also RCT of 221 patients with mixed causes of acute
recommended for cardiogenic pulmonary ede- respiratory failure. Importantly, only about 10% of
ma. They suggest (2B recommendation) that patients had COPD as the reason for mechanical
NPPV be used in immunosuppressed patients ventilation. The Canadian clinical practice guide-
who have acute respiratory failure and for lines recommend against use of NPPV for post-
respiratory failure after abdominal or lung- extubation recurrent respiratory failure in the
resection surgery (2C recommendations). After absence of COPD (2C recommendation) and offer
careful analysis of published studies, these no recommendations for NPPV in this setting for
experts make no recommendations for use of patients with COPD because of insufficient evi-
NPPV in acute respiratory failure due to asthma dence.39
exacerbation, acute lung injury, severe commu-
nity-acquired pneumonia without COPD, chest Monitoring During Mechanical
trauma with or without respiratory distress, or Ventilation
for patients who are hypoxemic and undergo
bronchoscopy. Airway pressures, volumes, flow, and other
The use of NPPV to facilitate early liberation variables can be monitored during ventilation.46
from mechanical ventilation or to ‘‘rescue’’ a patient Monitoring incorporates continuous measure-
who has postextubation respiratory distress has ment of key parameters, display of numerical
been investigated. In a 2010 meta-analysis of 12 and graphic data to enhance visual inspection,
clinical trials with 530 patients who predominantly establishment of thresholds that define accept-
had COPD, weaning by NPPV was associated with able limits for key parameters, and use of visual
lower mortality, fewer cases of ventilator-associat- and audible alarms that alert clinicians of
ed pneumonia (VAP), and shorter duration of ICU breaches in established thresholds. Key safety
and hospital length of stay (LOS), although measurements include low ventilation or low
weaning duration was similar to traditional ‘‘inva- pressure alarms that might indicate ventilator
sive airway weaning.’’43 However, in the largest disconnection or loss of airway, apnea alarms,
study44—a 2012 multicenter RCT of 208 patients and high airway pressure alarms. Elevation of
with chronic hypercapnic respiratory failure who PIP is important to detect and should prompt
failed one spontaneous breathing trial (SBT)— investigation of potential causes. The following
patients who were randomly assigned to undergo equation provides clues as to reasons for elevated
extubation directly to NPPV had similar survival, PIP: PIP ¼ flow 3 resistance þ plateau pressure
ICU and hospital lengths of stay, tracheostomy (Pplat), where Pplat ¼ VT/compliance þ PEEP.
rates, and overall reintubation rates as did patients Thus, PIP elevation might be caused by increased
extubated to supplemental O2 and patients who airway resistance, in which case the Pplat would
underwent traditional ‘‘weaning.’’ Patients ran- be unchanged. Common causes of increased
domly assigned to supplemental O2 or to tradition- airway resistance include bronchospasm and ET
al ‘‘weaning’’ were permitted to undergo rescue tube narrowing by secretions or patient biting of
NPPV. Keenan and colleagues39 suggest that NPPV the tube. Elevation of both PIP and Pplat is
be used to facilitate early liberation from MV in typically produced by parenchymal lung disease
patients who have COPD, and after planned (pulmonary edema, pneumonia, auto-PEEP),
extubation in patients who are considered to be at pleural disease (pneumothorax), chest wall ab-
high risk of recurrent respiratory failure (2B normality (obesity), or elevated abdominal pres-
recommendations), but against its use for patients sure (ascites, pregnancy).

Patient-Ventilator Asynchrony
Close examination of graphic display of

airway pressure, flow, and volume vs time can
provide important clues as to patient-ventilator
asynchrony, the likelihood that auto-PEEP is
present, and the mode and settings of positive Figure 4. Double-trigger patient-ventilator asynchrony.
pressure ventilation.47–49 Major components of Graphic display of flow and pressure over time demon-
strates three conventional breaths followed by a double-
mechanical ventilation in which asynchronies triggered breath (arrows). See text for definition. Reprinted
occur is during triggering of a breath, during with permission from ACCP Pulmonary Medicine Board
inspiratory flow, and during cycling. Some of the Review. 25th ed. Northbrook, IL: American College of Chest
more commonly recognized forms of patient- Physicians; 2009.
ventilator asynchrony include ineffective trigger- breaths separated by a very brief expiratory
ing, double-triggering, autotriggering, and flow phase (,½ of the preceding inspiratory time;
asynchrony. Ineffective triggering is considerably see Fig 4). Often, the patient’s ventilatory
more common than the others, with double- demand is high and the set inspiratory time is
triggering second in frequency in prospective too brief, leading to a drop in airway pressure
studies.50–52 early in exhalation that triggers an immediate
Triggering asynchronies are common and second positive pressure breath. Double-trigger-
important to recognize.53 An example of ineffec- ing can result in excessively large VT, which can
tive triggering is displayed in Figure 3, with the violate a low tidal volume ventilation strategy.54
arrow corresponding to the event. Ineffective Flow asynchrony most often occurs during
triggering occurs when an inspiratory effort by flow-targeted volume-limited ventilation when
the patient does not create change in airway the set flow rate is lower than the patient’s
pressure or flow of sufficient magnitude to desired flow. Evidence for this can be seen on the
initiate a positive pressure breath. The character- pressure-time graphic display as a concave
istic findings seen on the graphic display include upwards shape that is the result of the patient’s
a transient peak in flow and concomitant dip in inspiratory effort decreasing the magnitude of
airway pressure (that is the result of the patient’s positive pressure during breath delivery. This is
inspiratory effort) that does not result in a illustrated in Figure 5A, arrows. Figure 5B
triggered positive pressure breath. The most illustrates graphic display of airway pressure vs
common cause of ineffective triggering is auto- time, with a normal contour after flow has been
PEEP, often in the setting of COPD. Worsening increased. Cycling asynchrony is typically the
airflow obstruction, tachypnea, high trigger result of the duration of breath delivery that is
sensitivity, and excessive pressure support can too short or too long as compared with the
exacerbate auto-PEEP. Double-triggering is iden- patient’s desired breath delivery time.55 Figure
tified by the presence of two positive pressure 6A demonstrates evidence of mandatory breaths
with a longer inspiratory time than the patient
desires. Accordingly, the final 0.3 s of the breath
has evidence that the patient has begun to
attempt to exhale while the ventilator continues
to deliver the breath. One can see an increase in
airway pressure (arrow A) and expiratory flow
(arrow B) despite continued positive pressure
Figure 3. Ineffective trigger patient-ventilator asynchrony. applied by the ventilator. This is an example of
Graphic display of flow and pressure over time demon- delayed termination or delayed cycling in which
strates two conventional breaths followed by an ineffective ventilator-set termination is late when compared
trigger in which patient inspiratory effort (arrows) does not
with the patient’s desired cycling. This can be
trigger a breath. Reprinted with permission from ACCP
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: corrected by shortening the inspiratory time
American College of Chest Physicians; 2009. (typically in pressure-targeted AC or SIMV) as

Figure 5. Flow asynchrony. A, Graphic display of airway Figure 6. Delayed termination asynchrony. A, Graphic
pressure (top) and flow (bottom) vs time in SIMV mode. The display of airway pressure (top) and flow (bottom) vs time
second and third breaths are mandatory flow-targeted in the pressure-targeted AC mode. Evidence of delayed
volume-limited breaths; the flow-time display reveals peak termination or delayed cycling is illustrated in airway
flow of 40 L/min with decelerating ramp, and pressure-time pressure vs time in which an increase in airway pressure is
display shows a concave upwards configuration (arrows) seen in the final 0.3 s of inspiration (arrow A), accompanied
consistent with inadequate flow, that is, flow asynchrony. B, by expiratory flow during the final 0.3 s of breath delivery
Graphic display of airway pressure (top) and flow (bottom) (arrow B). B, Graphic display of airway pressure (top) and
vs time in SIMV mode. The first and third breaths are flow (bottom) vs time in pressure-targeted AC mode. The
mandatory flow-targeted volume-limited breaths; the flow- duration of the inspiratory phase is shorter by 0.3 s, in
time display reveals peak flow of 70 L/min with deceler- comparison to A, and the evidence of delayed termination is
ating ramp, and the pressure-time display shows a flat no longer present.
configuration consistent with resolution of flow asynchrony.
proactively in order to prevent them, recognize

illustrated in Figure 6B, or increasing flow, thus
them in a timely fashion, and manage them
shortening the duration to achieve the target
appropriately. Some of the more common com-
volume (as in volume-targeted AC or SIMV).
plications are listed in Table 3. Several complica-
Patient-ventilator asynchronies are associated
tions require additional discussion.
with worse outcomes but it is not yet clear whether
this is cause and effect or a marker for higher Pulmonary Barotrauma
risk.56,57 Recognition of common patient ventila-
tor asynchronies is an important goal for educa- Air leaks typically develop from rupture of
tion of physicians, respiratory therapists, and ICU alveoli, particularly alveoli that abut fixed struc-
nurses because recognition can lead to corrective tures such as bronchi and vessels. With continued
actions.46,52,58,59 There is evidence, however, of a leaking, such as with positive pressure ventilation,
significant knowledge gap.60 Technologic aids for air tracks in a path of least resistance, often along
automated detection may help to optimize pa- the bronchovascular bundles towards the hila of
tient-ventilator synchrony.61,62 the lung, then rupturing into mediastinum, then
through the thoracic inlet to produce subcutaneous
Complications of Positive Pressure emphysema. Eventually, air ruptures into the
Ventilation pleural space, producing a pneumothorax. It is
important to recognize lesser forms of barotrauma,
Complications of mechanical ventilation and such as subcutaneous emphysema or pneumome-
artificial airways are important issues to address diastinum, so that adjustments can be made to

Table 3—Complications of Mechanical Ventilation and phragm in a flattened, mechanically disadvan-
Artificial Airways taged position that contributes to smaller VT,
Oxygen toxicity
which in turn promotes tachypnea and thus
Pulmonary barotrauma: air leak exacerbates air trapping by further reducing
Pneumothorax exhalation time. Auto-PEEP is also a common
Pneumomediastinum/pneumopericardium/ cause of ineffective triggering patient-ventilator
subcutaneous emphysema
Pulmonary interstitial emphysema and air cysts asynchrony because the patient must overcome
Systemic air embolism the auto-PEEP with a drop in intrathoracic
Dynamic hyperinflation and auto- or intrinsic-PEEP pressure of sufficient magnitude to be sensed
Hemodynamic compromise
by the ventilator. When extreme, hypotension
Alveolar overdistention
Altered diaphragm/chest wall position and function, can progress to frank shock and even to
impairing ventilation cardiopulmonary arrest, typically with pulseless
Ventilator-associated lung injury electrical activity. Mechanisms include reduced
Volutrauma
Atelectrauma
venous return, plus a component of altered right
Biotrauma and left heart chamber filling, and increased right
Multiple-organ dysfunction ventricular afterload from the increased intratho-
Ventilator-associated pneumonia racic pressure.
Tracheomalacia
Trauma and dysfunction of vocal cords A common scenario is that of the patient with
Trauma to lip, teeth, oral cavity, nose, pharynx airflow obstruction who is tachypneic in the
Unplanned extubation setting of positive pressure ventilation; this leads
Endotracheal tube malposition
to insufficient exhalation time and progressive
Bronchial intubation
Esophageal intubation hyperinflation and auto-PEEP. Another situation
Tracheostomy bleeding, stoma problems, decannulation is the use of very short exhalation time (ie, ,1 s),
Gastrointestinal bleeding from stress ulceration/gastritis such as with APRV, in which even mild bron-
Reprinted with permission from ACCP Pulmonary Medicine chospasm or respiratory secretion retention can
Board Review. 25th ed. Northbrook, IL: American College of impair exhalation, producing incomplete empty-
Chest Physicians; 2009. ing. Unexpected auto-PEEP can occur in patients
without obvious risk factors. Finally, manual
ventilation with a bag is often performed too
reduce ventilatory pressures and halt the progres-
rapidly and with uncontrolled tidal volumes,
sion to pneumothorax.
thus causing transient hyperinflation. A manual
rate of 8 to10 breaths/min is generally recom-
Dynamic Hyperinflation and Auto-PEEP
mended. Development of serious hyperinflation
Avoidance of overinflation of the lung relies can be subtle and can be recognized by wheezing
upon delivery of appropriately sized tidal during exhalation, persisting up to the next
breaths delivered with appropriate transpulmo- positive pressure breath; respiratory efforts
nary pressure, plus allowance of full exhalation (chest movement) without ventilator triggering;
before initiating the next breath.63 Failure to characteristic findings of ineffective trigger on
adhere to these concepts increases the likelihood ventilator graphics; hyperinflation on chest ra-
of developing dynamic hyperinflation from diograph; or a decrease in the VT if the patient is
overinflation and auto-PEEP (also called intrin- receiving positive pressure ventilation in a
sic-PEEP or occult PEEP) from failure to fully pressure-targeted mode. Auto-PEEP is not di-
deflate (ie, ‘‘stacking’’ breaths). Both are poten- rectly measured during conventional ventilation,
tially dangerous conditions that might contribute thus the designation occult PEEP. One can
to respiratory compromise and hemodynamic temporarily occlude the exhalation port, by
compromise. Hyperinflation can overdistend pressing a button on most modern ventilators,
alveoli, increasing the likelihood of rupture as creating a no-flow state that allows equilibration
well as compressing the alveolar capillaries, thus of the pressure in the ventilator tubing (where
converting functional alveoli to dead space. the pressure is sensed) with the pressure deep
Additionally, hyperinflation can place the dia- within the lung. Total PEEP is measured, and

subtracting the extrinsic (or set) PEEP yields an
estimation of intrinsic- or auto-PEEP. This is
illustrated in Figure 7. Often the presentation is
dramatic, with hypotension and falling oxygen
saturation. Life-threatening hyperinflation can be
immediately treated by disconnecting the ET or
tracheostomy tube from the ventilator, thus
allowing passive exhalation—that may take 15 s
or more—and preventing delivery of additional
breaths. This is often followed by rapid and
dramatic improvements in blood pressure and Figure 7. Incomplete exhalation and demonstration of
intrinsic-PEEP (auto-PEEP). Graphic display of airway
oxygenation. More definitive treatment includes pressure (top) and flow (bottom) vs time demonstrates
bronchodilators, sedation to reduce spontaneous ongoing expiratory flow (small arrow, yellow line is below
respirations, and ventilator adjustment to in- zero flow line) at the time each exhalation ends as a new
crease expiratory time (reduce respiratory rate, breath is delivered. To measure total PEEP (and thus
estimate intrinsic-PEEP [auto-PEEP] at the end of exhalation
lower VT, and perhaps increase inspiratory flow of the first breath), the circuit is closed, such that flow
rate). If the patient is breathing spontaneously becomes zero (large arrow, white line) and pressure
and has auto-PEEP-induced ineffective trigger equilibrates, at which time total PEEP (PEEPTOT) is
measured (14 cm H2O in this case) and extrinsic (set) PEEP
breaths, extrinsic PEEP can be increased to a level
subtracted to calculate intrinsic-PEEP (PEEPI) of 11 cm H2O.
that is several cm H2O less than the measured
auto-PEEP to reduce the magnitude of pressure
drop the patient must generate to trigger a extent, in patients who do not satisfy criteria for
breath. The magnitude of inspiratory effort by ALI/ARDS. Figure 8 is an illustrated depiction of
the patient can be measured by using an the major pathophysiologic and altered gas-
esophageal balloon that displays changes in exchange events documented in ALI, and super-
pleural pressure during these efforts. imposes similar effects of MV on the lung, as
derived from animal model research and human
Ventilator-Associated Lung Injury studies. The similarities are striking. Initially
shown in animal models, but more recently in
There is considerable experimental evidence patients with ALI, the application of low tidal
from animal models and accumulating evidence volumes—6 mL/kg of predicted body weight in
from patients that mechanical ventilation can be man—is associated with reduced inflammation,
injurious, producing alveolar trauma and a less lung injury, shorter duration of MV, and
systemic inflammatory response.64 It is hypoth- improved survival. Further, many studies dem-
esized that excessive alveolar volume, coupled onstrate that the application of PEEP at a level
with increased transalveolar pressure, results in above the lower inflection point prevents the
shearing forces that disrupt the fragile alveolar cyclic alveolar collapse and reduces lung injury
architecture. These deleterious effects are and inflammation.
thought to be worse when there is local inhomo-
geneity of ventilation. This has been called
volutrauma, since experiments in animal models
Patient-Focused Mechanical
identify alveolar distention, rather than the Ventilation
distending pressure per se, as the most important
parameter. Additionally, the cyclical inflation and The goals of MV include improving hypoxemia
deflation of alveoli produces damage and in- and hypercapnia, relieving suffering and distress
flammation, so called atelectrauma. The subse- such as dyspnea, providing respiratory support
quent mechanical damage to lung tissue activates during circumstances with impaired drive to
inflammatory mediators that act as a pulmonary breathe (ie, general anesthesia), and applying
source for multiple-organ failure in patients with evidence-based strategies to promote survival and
acute lung injury (ALI) or ARDS, and to a lesser timely recovery. Lung protective strategies and

some patients with respiratory failure have
ARDS or have significant airflow obstruction
from an exacerbation of asthma or COPD—
conditions that require specific ventilatory strat-
egies that differ substantially by difference in
pulmonary physiology. Ventilatory strategies for
severe airflow obstruction and for ALI/ARDS are
compared in Table 4.
Mechanical Ventilation During Airflow

Obstruction
Status asthmaticus as well as acute exacerba-

tion of COPD is associated with marked limita-
tion of expiratory airflow. Such a state increases
the likelihood of developing dynamic hyperin-
flation (elevated end-inspiratory pressure and
volume) and auto-PEEP (elevated lung volume
and intrathoracic pressure at the end of exhala-
Figure 8. Hypothetical depiction of the pathophysiology of
tion), as discussed above.63 Additionally, such
acute lung injury and adverse effects of mechanical
ventilation as related to components of lung injury. VALI hyperinflation increases the likelihood of devel-
¼ ventilator-associated lung injury. Reprinted with permis- oping barotrauma. Ventilatory management in-
sion from ACCP Pulmonary Medicine Board Review. 25th ed. cludes adjusting the ventilator to prevent
development of dynamic hyperinflation and
auto-PEEP, and early recognition and timely
permissive hypercapnia supersede goals of nor- management of worsening of airflow obstruction.
malization of gas exchange. One can conceptualize Key tenets of management include providing
stages of respiratory failure and MV support as sufficient sedation (and possibly neuromuscular
stabilization, maintenance, and recovery. blockade) to control tachypnea, reducing the set
respiratory rate ( f ) in order to provide an
Initiating Mechanical Ventilation expiratory phase of sufficient duration to allow
near-complete emptying, and using small VT.65
Mechanical ventilation may be required Of note, reducing the respiratory rate from 20/
when there is a failure of oxygenation or min to 10/min will more than double the
ventilation. Life-threatening respiratory distress expiratory time. Examination of the flow-vs-time
or cardiopulmonary arrest requires immediate graphics and examining the patient’s chest for
attention and emergent endotracheal intubation, continued wheezing as one progressively in-
followed by initiation of mechanical ventilation. creases the expiratory time can help identify
NPPV should be considered for many patients when flow is near completion. Minute ventilation
with progressive respiratory insufficiency, partic- declines significantly with these measures and
ularly those with respiratory failure due to development of hypercapnia is commonplace.
COPD exacerbation or cardiogenic pulmonary Interestingly, since reductions in VT and f can
edema who have suitably alert mental status and reduce the severity of alveolar hyperinflation and
hemodynamic stability. Caveats regarding pa- dead space ventilation, the rise in PCO2 can be
tient selection and early monitoring and man- blunted as the number of perfused alveoli
agement for the response to NPPV are discussed. increases. Many clinicians have become comfort-
A strategy for providing full ventilatory able with permissive hypercapnia with pH into
support that will provide adequate ventilation the 7.2 to 7.1 range, although a safe lower limit is
and oxygenation is usually sufficient. However, not well defined. Follow-up of patients who were

Table 4—Comparison of Ventilatory Strategies for Severe Airflow Obstruction and for ALI/ARDS With ARDSNet Guidelines
or Alternative Strategies Supported by Results of RCTs
Severe Airflow ALI/ARDS: ALI/ARDS:

Variable Obstruction ARDS Network Strategy Alternative Strategies
FIO2 To achieve SpO2 ¼ 88%-93% To achieve SpO2 ¼ 88%-93% To achieve SpO2 ¼ 88%-93%
or PaO2 ¼ 55–80 mm Hg or PaO2 ¼ 55–80 mm Hg or PaO2 ¼ 55–80 mm Hg
per PEEP-FIO2 Table
Mode of ventilation Varies Assist control Assist control
Pressure or volume Either Volume Pressure
Target VT ,8 mL/kg PBWa 6 mL/kg PBW 6 mL/kg PBW
Total rate, breaths/ Low (10–12) 25, to 35 if needed 25, to 35 if needed
min
I:E target 1:5 1:2 to 1:1 1:3 to 3:1
PEEP Minimalb Modest, use PEEP-FIO2c More aggressive, use PEEP-
FIO2c
Target Pplat ,30 cm H2O ,30 cm H2O ,40 cm H2O
Recruitment No No Yes, after ventilator
maneuvers disconnection
Sedation/NMB Yes, sufficient to prevent Yes Yes (less sedation if Bilevel
tachypnea, avoid NMB if mode used)
possible
Permissive OK, PCO2 may be very high OK, pH . 7.3 OK, pH . 7.3
hypercapnia
NMB ¼ neuromuscular blockade; SpO2 ¼ saturation by pulse oximetry. Adapted with permission from ACCP Pulmonary
Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.
a
PBW in kg: male ¼ 50 þ 2.3 3 (height in inches – 60), female ¼ 45.5 þ 2.3 3 (height in inches – 60).
b
Consider adding PEEP if significant auto-PEEP is present and there is WOB from failure to trigger dyssynchrony. PEEP
should be set approximately 2 cm H2O below auto-PEEP.
c
See Table 5.
allowed to remain hypercapnic showed no long- pressures are associated with ALI. Computed
term deleterious effects. Permissive hypercapnia tomographic examination of the lungs of patients
is contraindicated in patients with intracranial with ARDS reveals small volume of normal or
hypertension (in whom hypercapnia could in- atelectatic lung, supporting the notion of ‘‘baby’’-
duce cerebral vasodilation and worsen the sized lungs in ARDS. Some earlier RCTs demon-
intracranial pressure) and in patients with an strated improved outcomes in ARDS when
irritable myocardium (in whom hypercapnia patients received ventilation with lower tidal
may induce cardiac arrhythmias). Some clini- volumes (and other ventilatory adjustments)
cians administer intravenous bicarbonate in an compared with conventional volumes, but no
attempt to maintain a pH . 7.2 or so, but others difference was found in some RCTs.
do not. If a pressure-targeted mode is used, care In the year 2000, publication of the results of
must be taken to monitor VT, for as the airflow the ARDS Network pivotal RCT—which docu-
obstruction improves, VT is likely to increase mented significantly lower mortality among
significantly. patients who received VT of 6 mL/kg predicted
body weight (PBW), compared with those who
Mechanical Ventilation for ALI/ARDS received 12 mL/kg—has set the standard for
mechanical ventilation for ALI/ARDS.66 There
This topic is reviewed in detail in the chapter were also more ventilator-free and organ failure-
‘‘Hypoxemic Respiratory Failure.’’ Considerable free days but no difference in the frequency of
experimental evidence from various animal barotrauma or in oxygenation. The key compo-
models has demonstrated that larger tidal vol- nents of the ARDSNet approach to giving
umes and higher plateau or transpulmonary ventilation to patients with ALI/ARDS are

Table 5—PEEP-FIO2 Values for Table 4
Recommended for ALI without ARDS (PaO2/FIO2 ¼ 200–300 mm Hg)
FIO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.8 0.9 1.0 1.0
PEEP,
cm
H2O 5 5 8 8 10 10 10 14 14 14 18 24
Recommended for ALI without ARDS (PaO2/FIO2 , 200 mm Hg)
FIO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 10

PEEP,
cm
H2O 5–10 10–18 18–20 20 20 20–22 22 27–24
PEEP is increased in increments of 2 cm H2O, FIO2 by 0.1. Adapted with permission from ACCP Pulmonary Medicine Board
Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.
summarized in Table 4. The ARDSNet approach traditional ARDSNet ventilation and 10 to 16

to mechanical ventilation for ARDS has been cm H2O with the higher PEEP strategy. All
widely endorsed as an evidence-based corner- groups received tidal volumes of 6 mL/kg
stone of management of critically ill patients. PBW. In the ALVEOLI study, Brower and the
However, several groups of investigators, includ- ARDSNet investigators75 demonstrated better
ing ARDS Network investigators, have demon- oxygenation but no difference in mortality,
strated in subsequent ‘‘real-life’’ studies, years ventilator-free days, or barotrauma. A meta-
after publication of ARDSNet results, that clini- analysis of these three studies, which examines
cians are not consistently using low tidal vol- individual patient data, concludes that patients
umes. In one three-center study, only 16% of with ARDS (PaO2/FIO2, ,200 mm Hg) benefit
patients had VT , 8 mL/kg PBW, with virtually from higher PEEP, with better oxygenation, more
none at ,6 mL/kg.67 Barriers to adoption ventilator-free days, and lower hospital and ICU
include lack of willingness to relinquish ventila- mortality, whereas patients who have ALI with-
tor control, recognition of ARDS, and concerns out ARDS (PaO2/FiO2, 200–300 mm Hg) tend to
for contraindications, discomfort, and impaired have worse outcomes.76 Other work suggests
gas exchange.68 Improved compliance with low that esophageal pressure monitoring can help
tidal volume ventilation was strongly associated individualize the setting of PEEP to improve gas
with use of a written protocol in one study.69 exchange but is cumbersome to perform.77 Use of
Based upon an earlier study by Amato and a static pressure volume curve or a stress index
coworkers,70 more recent smaller studies by display78 may be of value in selecting best PEEP
Ranieri et al71 and Villar et al,72 as well as other but is also more difficult to perform when
sources of evidence, have addressed some of the compared with a FIO2:PEEP table (see Chapter
finer points of mechanical ventilation for ARDS/ 23 for more information). Clinicians typically
ALI, including use of higher PEEP, use of a escalate PEEP, on the basis of oxygenation, but
pressure-targeted rather than a volume-targeted some experts recommend staring with high
mode, and the addition of recruitment maneu- PEEP, such as 20 cm H2O, and deescalating.79
vers. There are now three large-scale (.500 Evidence for use of recruitment maneuvers is less
subjects in each) RCTs that address using a compelling, with only transient improvement in
higher PEEP level, stratified by oxygenation, oxygenation and potential for transient hemody-
compared directly to the original ARDSNet study namic compromise in one large RCT. A Cochrane
parameters and PEEP levels.73–75 In all studies, review of prospective trials showed only tran-
PEEP averaged about 7 to 10 cm H2O in sient improvement in oxygenation and no impact

on outcomes with recruitment maneuvers.80 Use Weaning and Liberation From
of a recruitment maneuver (typically 40 cm H2O Ventilation
inflation held for 40 s) seems most likely to help
when performed after ventilator disconnection Weaning and Liberation: Evolving Concepts
and loss of alveolar distention. While the original
ARDS Network low-tidal-volume study used Traditionally, separation of the patient from
volume-limited AC ventilation, some experts mechanical ventilation has primarily been a
favor pressure-targeted ventilation,81,82 although process of progressively reducing the proportion
definitive studies that compare only pressure vs of ventilation that is supported artificially, that is,
volume targeting during low tidal volume weaning from the ventilation, while increasing
ventilation are lacking.83 The use of APRV in the WOB that the patient undertakes until it is
ARDS is discussed above and in the chapter judged that the patient is capable of breathing
‘‘Hypoxemic Respiratory Failure.’’ independently, at which time the ET tube is
High-frequency oscillatory ventilation removed. Different approaches have been used,
(HFOV) has been used successfully for severe most commonly, progressively reducing PS in the
ARDS.84–86 Typically, 180 to 300 small breaths per PSV mode, decreasing the mandatory breath rate
minute (3–5 Hz) are delivered with HFOV, in SIMV mode, or increasing the duration of
although rates as high as 15 Hz have been spontaneous breathing trials in AC.2 As a result
reported.87 Oxygenated humidified gas flows of clinical trials, clinicians now focus on identi-
(called bias flow) in front of the oscillating fying the patient who, by successfully passing a
membrane that exerts both positive (inflation) number of conditions, has a high likelihood of
and negative (deflation) pressure. Oxygenation breathing independently of the ventilator and
will be determined by the FIO2 of the gas and the tolerating removal of the ET tube, without the
MAP, which is altered by adjusting the resistance gradual reducing ventilatory support. Despite
valve at the end of the bias-flow circuit and the the transition to identifying the ability to breathe
bias-flow rate. Alveolar ventilation, and thus CO2 independently, the general process is still com-
removal, is influenced by the power with which monly called weaning. Historically, measures of
the diaphragm moves, the so called deltaP, the respiratory muscle strength, endurance, and gas
set frequency, and the percentage inspiratory exchange, such as negative inspiratory force,
time. Counterintuitively, the slower the frequen- vital capacity, minute ventilation, maximum
cy, the more CO2 is exhaled. Typical starting voluntary ventilation, respiratory rate, or f/VT,
settings might include MAP ¼ MAP on conven- were relied upon. Modern programs assess more
tional ventilation þ 5 cm H2O, bias flow of 40 L/ diverse factors such as hemodynamic stability,
min, frequency of 4 Hz, inspiratory time of 33%, mental status, oxygenation, and respiratory
and power of 80 cm H2O. Management differs endurance. Effective programs to liberate the
from conventional ventilator management. For patient from mechanical ventilation incorporate
example, power is often adjusted to achieve evidence-based structured techniques that im-
wiggling of the thighs, deescalation from HFOV prove frequency and consistency of measure-
to conventional ventilation is often subjective, ments and actions, are multidisciplinary and
and simple things, such as lung auscultation, are team based, and incorporate criteria to proceed
altered. Physician and respiratory therapist ex- to the next step; thus, they eliminate unnecessary
pertise is crucial for safe and effective HFOV delays, integrate clinical judgment, and have
operation. While often effective in cases of been demonstrated to improve outcomes. The
severely hypoxemic patients, evidence of superi- concepts and criteria are based on the patho-
or efficacy from multicenter RCTs is lacking. A physiology of respiratory failure and also recog-
meta-analysis of a mix of adult and pediatric nize the importance of nonpulmonary organ
RCTs totaling only 350 patients demonstrated dysfunction in readiness to proceed. Duration
superior oxygenation but no clear outcome of the process and difficulty in liberation from
benefits.88 Additional studies are underway. mechanical ventilation vary widely among pa-

Table 6—Components of Protocols for Discontinuation of Ventilation
Parameter Measures
Medical stability Presence of shock, use of vasopressors, pH

Mental status Use of continuous sedative infusion, sedation scale criteria
Oxygenation FIO2, PEEP, PaO2/FIO2
Lung mechanics f/VT, pH
Ventilatory endurance SBT
Secretion clearance Cough strength, sputum volume/suction frequency
Airway patency Cuff-leak test
Miscellaneous factors Condition improving, patient confidence for extubation success
f/VT ¼ frequency to tidal volume ratio (also called rapid shallow breathing index, RSBI). Adapted with permission from ACCP
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest Physicians; 2009.
tients and can be classified as simple weaning (ie, noting, however, that strict adherence to overly
extubation within the first day of weaning conservative criteria can actually delay weaning
attempts), difficult weaning (ie, 1–7 days of and/or extubation.
weaning), and prolonged (ie, .7 days of wean-
ing) affecting 55%, 39%, and 6% of patients, Evidence-Based Consensus Recommendations
respectively, in an international cohort of 4,968
patients undergoing mechanical ventilation.89 In December 2001, a collective task force made
up of representatives from the American College of
Protocol-Based Liberation From Mechanical Chest Physicians, American Association for Respi-
Ventilation ratory Care, and American College of Critical Care
Medicine published evidence-based guidelines for
In 1996, Ely and colleagues90 developed a weaning and discontinuation of mechanical venti-
multistep protocol to identify resolution of lation.92 Table 6 summarizes key recommendations
respiratory failure and, in an RCT, demonstrated regarding all aspects of the process. They offer
faster weaning, shorter duration of ventilation, specific recommendations for assessment of dis-
and fewer complications (unplanned extubation, continuation potential (ie, screening) as follows: (1)
prolonged ventilation, reintubation, and trache- evidence for some reversal of the underlying cause
ostomy). This protocol incorporated daily screen- for respiratory failure; (2) adequate oxygenation
ing of all patients receiving mechanical (Pa O 2 /F IO 2 . 150–200; PEEP , 5–8 cm H 2 O;
ventilation by respiratory therapists for hemody- FIO2 , 0.4-0.5) and pH . 7.25; (3) hemodynamic
namic stability, cessation of sedative infusions, stability (no active myocardial ischemia or clinical-
adequate oxygenation, low PEEP level, adequate ly significant hypotension); and (4) capability to
cough, and adequate respiratory muscle strength initiate an inspiratory effort. These recommenda-
as judged by f/VT , 105 while breathing without tions serve as a solid basis for current recommen-
support. Patients who successfully passed this dations; however, newer data allow us to re-
screening protocol underwent a 2-h SBT with 5 address these and other parameters.
cm H2O CPAP or T-tube—those who passed
were deemed likely (85% likelihood) to be Components of Protocols to Assess
successfully extubated. This protocol has served Discontinuation of Ventilation
as a basic template for many weaning protocols
(specific criteria) and structured approaches There are many factors that can influence the
(daily performance by respiratory therapists success a patient has for tolerating withdrawal of
and nurses). Most, but not all, published reports ventilatory support and removal of the ET tube.93
of such protocols have demonstrated shorter Some of the parameters and criteria that can
duration of ventilation, shorter ICU LOS, cost affect this process are listed in Table 6, and
savings, and/or other benefits.91 It is worth several deserve additional comment. There is

considerable evidence that mental status is an SBT: The SBT is widely considered to be the
important determinant of timely recovery from pivotal test, incorporating assessment of lung
mechanical ventilation, since overly sedated mechanics and endurance.92 The patient is given
patients may have impaired drive to breathe low-level ventilatory support intended to over-
and inability to protect the airway once the ET come the added WOB associated with breathing
tube is removed. Level of consciousness is through the ET tube, or without any support for a
assessed in protocols indirectly by the presence period of 30 to 120 min, and observed for
or absence of ongoing continuous infusion of deterioration in vital signs or ventilatory failure.
sedatives, or directly with a sedation scale. There is, however, considerable variability in
Shorter duration of mechanical ventilation has several parameters with different criteria for the
been demonstrated in numerous prospective mode and settings of ventilatory support, duration
studies that use strategies to reduce overseda- of SBT, and termination (failure) criteria.103 While
tion, including daily interruption of sedation, T-tube, ‘‘flow-by,’’ CPAP, or PSV is often used as
intermittent (rather than continuous) sedative low-level ventilatory support, automatic tube
and opioid administration, and matching patient compensation (ATC) is emerging as a form of
characteristics to drugs.94,95 In one study,96 the ‘‘smart’’ PSV. ATC is designed to provide enough
combination of a daily awakening trial plus an pressure support to overcome the resistance of
SBT was superior to SBT alone. The combination breathing through an artificial airway. This pres-
of poor cough, high sputum volume, and poor sure is recalculated every 5 ms and is based upon
mental status is a particularly worrisome combi- the tube size and type (ET vs tracheostomy) plus
nation, even if the patient is capable of passing an instantaneous flow measurement. Thus, higher
SBT. In one study,97 80% of patients who met this pressure is provided if the tube has a smaller
combination of findings underwent reintubation. diameter or if flow is faster. In one study,104 ATC
In a 2011 survey of Australian intensivists, the was superior to CPAP for overall success (SBT
most highly rated predictors of extubation completed and extubation for .48 h).
success were effective cough and level of Airway Patency and Postextubation Stridor:
consciousness, along with respiratory rate.98 Although clinicians have long recognized the
Adequacy of oxygenation after extubation is importance of postextubation stridor in extuba-
important to predict; however, some protocol tion failure, recent research has helped clarify
criteria may inadvertently delay extubation if too risk factors, evaluation, and potential manage-
restrictive. For example, some protocols require ment. Postextubation stridor is observed in 5% to
FIO2 , 0.4, PEEP , 5 cm H2O, and/or PaO2/ 30% of patients, depending upon the patient
FIO2 . 200, yet many patients who have oxygen- population. Those who develop stridor tend to be
ation that does not reach these thresholds (ie, sicker, have longer-duration intubation, and are
PO2 ¼ 95 mm Hg on FIO2 of 0.5) will have more likely to have had a difficult intubation
adequate oxygenation post extubation. In fact, and/or self-extubation.105 By deflating the ET
oxygenation criteria (PaO2/FIO2 . 180 mm Hg) tube cuff and detecting airflow around the tube
were the most common weaning criteria never (either by measurement using comparison of
passed in a large cohort of patients who were volume exhaled through the tube before and
successfully extubated.99 In 1991, Yang and after cuff deflation, or simply hearing a leak), one
Tobin100 found f/VT to be a reliable measure of increases the ability to predict absence of post-
lung mechanics and good predictor of successful extubation stridor.105 Typically, exhaled volume,
discontinuation. However, some patients, partic- while administering a mandatory tidal volume of
ularly smaller individuals and those with paren- 10 mL/kg PBW or so, with the cuff inflated, and
chymal lung disease, may have a more rapid, then again with the cuff deflated, allows a simple
shallow pattern of breathing. Investigators have estimation of the ‘‘leak’’ around the tube, which
demonstrated that incorporating f/VT , 105 as a can be expressed as a percentage or total gas
screening criterion delayed weaning.101 Some exhaled or ‘‘cuff leak.’’ Leak .18% was identified
protocols use higher thresholds (ie, ,125)102 or as being a good predictor (85% sensitive, 72%
omit f/VT from their protocol. specific) of postextubation stridor in one study,

Table 7—Recommendations for Evaluation of Ability to Tolerate Discontinuation of Ventilation and Extubationa
Screening criteria
1. Is patient hemodynamically stable (not in shock, no more than minimal vasopressor
requirement)?
2. Is underlying cause of respiratory failure improving?
3. Is the patient alert or does he or she have easy arousal (opens eyes to voice) and
cognition (follows simple commands)? Perform daily interruption of sedation for patients
for whom this is feasible.
4. Is cough strength moderate or better and suctioning frequency no more than every 2 h?
5. Is PaO2/FIO2 .150 and PEEP ,8 cm H2O?
6. Is f/VT ,125? Consider eliminating f/VT.
Cuff-leak test
1. Is air movement around ET tube with cuff deflated .15%? If cuff leak is ,25%, consider
administering methylprednisolone (see text).
SBT
1. Does patient tolerate breathing on minimal support for 60 min? Consider using
automatic tube compensation as mode of ventilatory support during SBT, if available.
Physicians; 2009.
a
All intubated patients receiving mechanical ventilation should undergo screening. Those who pass criteria but fail mental
status testing (screening criteria 3) should undergo interruption of sedation (discontinue all intravenous sedative and opioid
drugs) and repeat screening criteria. Patients who pass the screening criteria should have a cuff-leak test performed. If cuff leak
is ,25%, methylprednisolone should be administered (40 mg IV every 6 h 3 4). Patients who pass screening criteria and cuff-
leak testing should undergo SBT testing; if SBT is passed, patients should be extubated.
although thresholds of .15% to 25% have been key components in a multidisciplinary team-based
identified by others. Administration of methyl- approach that promotes efficiency. Interestingly,
prednisolone (MP)(40 mg every 6 h 3 4 doses) to computerized weaning that is integrated within
patients with poor cuff leak (,24%) was effective mechanical ventilators is being explored as a means
in reducing likelihood of postextubation stridor of standardizing and streamlining the process, with
(6% vs 30% with no MP) in one study.106 In shorter duration of MV and shorter ICU LOS
another study,107 giving MP at a dose of 20 mg demonstrated in one study.110 The authors’ recom-
every 4h 3 4 doses before extubation was mendations for specific components and caveats
effective in reducing postextubation stridor in related to these parameters are listed in Table 7.
unselected patients (ie, no cuff-leak threshold Asking patients whether they are confident that
was used). In a 2009 Cochrane review,108 use of they will remain extubated may be worthwhile,
prophylactic corticosteroids reduced postextuba-
since patient prediction was highly accurate, with
tion stridor and reduced reintubation when
an odds ratio of 9.2 in one study.111 It is worth
administered as multiple doses begun 12 to 24
acknowledging that knowledge regarding weaning
h before extubation to adults at high risk for
and extubation continuous to evolve, that some
postextubation stridor. Recent work109 associates
recommendations are based upon opinion and
reduced inflammation, as judged by the balance
lower-level evidence, and that clinical skills play an
of proinflammatory and antiinflammatory circu-
important and complementary role. An important
lating cytokines, as a potential mechanism for the
beneficial effects of corticosteroids. component of the weaning process is to recognize
that the patient who fails this evaluation repeatedly
Recommendations for Weaning and Liberation and/or who fails extubation should undergo
evaluation for possible causes of failure such as
All patients receiving endotracheal intubation those listed in Table 8. As discussed previously,
and mechanical ventilation should undergo daily there is some evidence that extubation of high-risk
evaluation to determine their potential for discon- patients who have acute respiratory failure from
tinuation of ventilation. This should be a struc- COPD, with immediate institution of NPPV, can
tured, evidence-based protocol that incorporates improve outcomes. It is important to recognize that

Table 8—Modifiable Factors Related to Failure of Weaning uation of MV in the patient with a tracheostomy
From Mechanical Ventilation
is generally by traditional weaning. This is
Unresolved precipitating process
typically accomplished by progressively increas-
Reversible airflow obstruction ing the duration of periods without ventilatory
Increased endotracheal tube resistance support, often using oxygen delivered directly
Excessive respiratory secretions
via the tracheostomy tube, omitting the ventilator
Impaired mental status
Respiratory depressant medications circuit.
Excessive sedative and opioid medications
Metabolic alkalosis Summary and Conclusions
Electrolyte imbalance
Hemodynamic instability
Ischemic heart disease Mechanical ventilation is a lifesaving modal-
Infection and sepsis ity for treating respiratory failure and for
Malnutrition
Overfeeding providing gas exchange support. There are many
Neuromuscular disorders subtleties in effective management, which in-
Psychologic factors clude adopting a patient-focused approach,
Reprinted with permission from ACCP Pulmonary Medicine using evidence-based strategies for mechanical
Board Review. 25th ed. Northbrook, IL: American College of ventilation, as well as discontinuing ventilation
Chest Physicians; 2009. and avoiding complications related to mechani-
cal ventilation and the artificial airway.
this strategy has considerably less support in the
absence of COPD. Nothing to Disclose
Tracheostomy
Tracheostomy has been available for many
years as a surgically placed artificial airway that
this chapter.
permits longer-term placement as compared with
ET tube. Tracheostomy is considered to be more
stable, more comfortable, and can allow lower
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Chapter 25. Hypercapnic Respiratory Failure
Objectives: increases in proportion to the metabolic rate, as

Understand the determinants of PaCO2 and the types of with fever and exercise. Carbohydrate utilization
physiologic derangements that lead to hypercapnia. also increases the respiratory quotient (or V̇CO2/
Review specific neurologic and muscular disorders that
oxygen consumption) as compared with fat and
cause respiratory failure.
Discuss respiratory muscle function and the assessment protein metabolism, producing more carbon
of respiratory muscle strength. dioxide for each calorie expended. In patients
Outline the types of situations in which an imbalance with limited ventilatory reserve, an increase in
between the work of breathing and energy supply to
respiratory muscles leads to fatigue.
V̇CO2 may culminate in an increase in PaCO2.
Discuss how hypercapnia may occur when excessive
concentrations of inspired oxygen are administered to Reduced V̇A
susceptible persons.
Key words: hypercapnia; neuromuscular diseases; respira- Any disorder causing a reduction in V̇A will
tory failure; respiratory muscles increase PaCO2. This occurs with three types of
pathophysiologic derangements:
Synopsis:
V̇E(the product of respiratory rate and VT) is
This chapter will present the types of physiologic derange-
ments that lead to hypercapnia and explore and explain the reduced.
determinants of PaCO2. Specific neurologic and muscular VT is reduced. Even if the overall VE is normal
disorders that can cause respiratory failure will be reviewed, or high, the portion of each breath that is
and respiratory muscle function and strength will be
discussed. Excessive oxygen administration may worsen distributed to anatomic or physiologic dead
preexisting hypercapnia, particularly in patients with space (dead space fraction, or V̇D/VT) increas-
COPD, and the contributing mechanisms will be presented. es, and V̇A is reduced. If V̇E does not increase
proportionally, PaCO2 increases. This occurs
commonly in patients with rapid, shallow
breathing pat terns.
Components of the Respiratory System V̇D/VT increases, with normal or high V̇E and
VT. An extreme example would be a patient
The respiratory system can be considered as two
with fixed V̇E who has a massive pulmonary
distinct parts: the lungs and a ventilatory pump.
embolism. Here, although V̇E and VT remain
Disorders of the lungs interfere with gas ex-
the same, the increase in V̇D/VT that results
change, manifested mainly by hypoxemia. Disor-
from the newly underperfused lung units
ders of the pump impair ventilation, manifested
reduces V̇A and increases PaCO2.
by hypercapnia. Arterial carbon dioxide is related
to carbon dioxide output (V̇CO2) by metabolism
and is removed by alveolar ventilation (V̇A). V̇A is Disorders of Ventilation
the total minute ventilation (V̇E) minus dead space
ventilation (V̇D). PaCO is determined by the Central Control
following: PaCO2 ¼ K(V̇CO2/V̇A), where K ¼ 0.863
mm Hg; (V̇A ¼ V̇E V̇D ) or, rearranged, PaCO2 ¼ The medullary central controller sends sig-
K{V̇CO2/V̇E[1 V̇D/tidal volume(VT)]}. nals that set the respiratory rate and VT. This
center receives inputs from higher CNS centers,
Increased V̇co2 peripheral chemoreceptors, and receptors in the
lungs, chest wall, and airways. The carbon
Hypercapnia may occur when V̇CO2 increases dioxide sensor (chemoreceptor) is located in the
without a corresponding increase in V̇A V̇CO2 medulla and responds to changes in pH of

extracellular fluid. Oxygen sensors in the carotid accounted for the increasing incidence of tetanus
body and aortic body sense changes in PO2. and wound botulism in California since 1997. In
Disorders of central respiratory control include surgical wound infection, contraction of the
the following: (1) congenital central hypoventila- muscles surrounding the wound could be the
tion syndrome (or Ondine curse) and inborn first sign. The disease is preventable through
failure of autonomic control of breathing, linked vaccination; patients with tetanus should be
to mutations in the PHOX2B gene; (2) central treated with wound care, tetanus immune
sleep apnea; (3) overdoses with narcotics or globulin to neutralize remaining exotoxin, sup-
sedatives; (4) diseases of the medulla (infarct, port of ventilation and hemodynamics, and
tumor); (5) hypothyroidism; (6) metabolic alka- medications to suppress muscle rigidity.
losis, in which the PaCO2 usually increases 0.7 to ALS is characterized by the presence of
0.8 mm Hg for every 1.0 mEq/L increase in dysarthria, tongue atrophy and fasciculations,
plasma bicarbonate; and (7) rabies. amyotrophy (muscle atrophy), extremity fascic-
Rabies is a viral infection transmitted in the ulations, weakness, and hyperreflexia. The diag-
saliva of infected mammals that causes an nosis of ALS is confirmed with electrophysiologic
encephalomyelitis that is almost always fatal. In studies. Although new cases of poliomyelitis are
North America, bats are implicated in transmis- almost unheard of in developed nations, late
sion in .90% of cases. The virus may involve the manifestations may occur many years after the
entire nervous system in infected persons, and primary infection. The ‘‘postpolio syndrome’’
respiratory failure may occur from either central may occur in up to half of the survivors of
respiratory depression or ascending spastic pa- paralytic poliomyelitis, with the onset of new
ralysis, which occurs in 20% of cases. Postexpo- weakness or abnormal muscle fatigue, muscle
sure prophylaxis with rabies immune globulin atrophy, or generalized fatigue. Muscle weakness
and rabies vaccine is recommended for the may even lead to respiratory failure in a few
unvaccinated person who is exposed to bat patients.
saliva. Because the consequences of rabies are
so devastating, postexposure prophylaxis should Peripheral Neuropathy
be considered even if a bite cannot be reasonably
excluded. Disorders of the peripheral nerves commonly
cause hypercapnic respiratory failure. Guillain-
Motor Neurons Barré syndrome (GBS) is the most common cause
of acute generalized paralysis after the virtual
Interruption of transmission impulses from elimination of poliomyelitis around the world.
the respiratory centers to the respiratory muscles There are at least four subtypes of GBS; the most
also leads to hypoventilation. Motor neuron common is an acute, inflammatory demyelinat-
diseases include the following: (1) spinal cord ing polyradiculopathy; others are acute motor
injury, especially at the C3 level; (2) tetanus; and and sensory neuropathies (alone or together),
(3) diseases involving the anterior horn cells, acute pandysautonomic forms, and overlap
including amyotrophic lateral sclerosis (ALS) syndromes. GBS is believed to be the result of
and poliomyelitis. In tetanus, the anaerobe an aberrant T-cell response to a previous infec-
Clostridium tetani may inoculate a disruption of tion, leading to a macrophage-mediated destruc-
the skin barrier and elaborate the exotoxin tion of myelin. Most cases involve either a flulike
tetanospasmin, which reaches the spinal cord illness or gastroenteritis within the previous 6
by retrograde axonal transport and blocks the weeks, and approximately one-fourth of patients
release of inhibitory transmitters. Trismus is with GBS, especially those with axonal forms of
often the first symptom, which progresses to the disease, have had a recent infection with
spastic paralysis, especially of the laryngeal and Campylobacter jejuni.
respiratory muscles, causing respiratory failure The lipopolysaccharide of C jejuni cell walls
that may persist for several months. Subcutane- shares similar antigens with peripheral nerve
ous injection of heroin, or ‘‘skin popping,’’ has gangliosides. Patients usually present with
390 Chapter 25. Hypercapnic Respiratory Failure (Rosen)

ascending paralysis, paresthesias, and hypoflexia Neuromuscular Junction
or areflexia. The disorder usually is diagnosed by
finding electromyography (EMG) evidence of Disorders/particulars interfering with trans-
conduction block in motor nerves. Cerebrospinal mission of impulses at the neuromuscular junc-
fluid studies typically show few or no cells, tion include the following:
increased protein after 1 to 2 weeks, and Myasthenia Gravis: In this disease, binding of
circulating or cerebrospinal fluid antiganglioside IgG antibodies to the postsynaptic acetylcholine
antibodies in some patients. Plasmapheresis and receptor induces complement-mediated recep-
infusion of c-globulin appear to be equally tor destruction and skeletal muscle weakness.
effective, and the combination of both treatments Most cases are idiopathic, but the disease may
confers no additional benefit. There is no be induced by penicillamine and transiently
established role for therapy with corticosteroids exacerbated by corticosteroids. The diagnosis is
in this disorder. supported by the following: (1) impaired neu-
Critical illness polyneuropathy (CIP) is an romuscular transmission on EMG, with decre-
acute sensory-motor disorder that mainly affects mental response to repetitive stimulation; (2)
the lower limbs of critically ill patients. It may be clinical response to cholinergic agents (edropho-
the consequence of microcirculatory damage nium); and (3) the presence of acetylcholine
caused by decreased perfusion or endothelial receptor antibodies in the serum (85%–90% of
injury from a systemic inflammatory cytokine patients with generalized weakness). Myasthe-
response. Critical illness myopathy (CIM) is an nia gravis is associated with both benign and
acute myopathy that causes weakness and malignant thymoma. Treatments include cholin-
paralysis in critically ill patients and that usually ergic drugs, corticosteroids for mild to moderate
occurs with CIP. Because CIP and CIM usually disease (and sometimes with other immunosup-
overlap, the term critical illness polyneuromyop- pressive agents), and plasma exchange or IV Ig
athy is often used. Sepsis, multiorgan failure, and for patients with severe weakness. Plasma
hyperglycemia often are cited as risk factors but exchange and IV Ig are equally effective in
cannot be confirmed because of methodologic exacerbations of myasthenia gravis, and the role
limitations of investigations into these disorders. of these treatments in chronic disease is un-
These patients often present with ‘‘weaning proven. Even in the absence of thymoma,
problems’’ after sepsis resolves, typically with thymectomy is generally recommended for
flaccid paresis that spares the cranial muscles, patients with generalized myasthenia gravis
muscle atrophy, and reduced or absent deep who are between puberty and 60 years of age
tendon reflexes. EMG shows axonal neuropathic because it is associated with a greater likelihood
and/or myopathic patterns, and muscle biopsies of remission or improvement.
(when performed) show denervation atrophy. If Eaton-Lambert Syndrome: This paraneoplastic
the patient survives the critical illness, the disorder often is associated with small cell
syndrome may resolve over a period of weeks carcinoma of the lung. Weakness is mainly
to months, but many patients remain perma- proximal and spares the ocular and bulbar
nently disabled. There is no specific treatment, muscles. Unlike myasthenia, EMG in Eaton-
but efforts to prevent this disorder include Lambert syndrome shows an incremental pattern
minimizing the use of corticosteroids, and some with repetitive stimulation.
studies have suggested that rigorous glycemic Organophosphates: Organophosphates, a com-
control is associated with a reduced incidence. ponent of some insecticides, inhibit cholinester-
Unusual causes of neuropathy include diph- ase.
theria, porphyria, and tick paralysis. Exposure to Botulism: The spores of Clostridium botulinum
toxins also may cause severe neuropathy and generate a potent neurotoxin that causes a
paralysis. For example, fugu, a puffer fish, potentially lethal, descending flaccid paralysis.
elaborates a potent neurotoxin, and ingestion of Patients typically present with oculomotor pal-
improperly prepared fugu sushi accounts for sies, progressing to facial muscle paralysis and
approximately 50 deaths in Japan each year. difficulty swallowing, and then limb and

respiratory muscle weakness and paralysis. Respiratory Muscles
Although botulism is best known to be acquired
by ingestion of preserved food containing pre- The respiratory muscles perform the work of
formed toxin, a similar syndrome may occur breathing. The diaphragm is the most important
when the organism is inoculated into a wound or inspiratory muscle, responsible for 60% to 90% of
other devitalized tissue; it may also be acquired work of breathing at rest. Contraction of the
by inhalation, making it a potential bioterrorist costal component displaces abdominal viscera
weapon. Similar to tetanus, a dramatic increase downward and lifts the lower rib cage; the crural
in reported cases of wound botulism was linked component displaces abdominal viscera down-
to subcutaneous or IM injection of ‘‘black tar’’ ward. The external intercostals, scaleni, and
heroin in California. Like Eaton-Lambert syn- sternocleido-mastoids comprise the accessory
drome, there is augmentation of muscle action muscles of inspiration and are used when V̇E is
potential with repetitive nerve stimulation, al- increased or when the diaphragm is weak or
though to a lesser degree. The diagnosis is fatigued. Contraction of these muscles elevates
established by identifying the toxin in the serum, the rib cage.
stool, or wound, or the organism in stool or The expiratory muscles (internal intercostal
wound. Treatment includes debridement, botuli- and abdominal) are not used during resting
num antitoxin, and supportive care. breathing because exhalation is passive. Howev-
Prolonged Muscle Weakness: Prolonged muscle er, they contract actively when V̇E is increased
weakness after nondepolarizing neuromuscular and are essential to the cough reflex. The internal
blocking agents is common. Discontinuing intercostals depress the ribs, and the abdominal
mechanical ventilation may be delayed, and muscles depress the lower ribs and pull the
weakness may persist for months. Two types of abdominal wall inward.
neuromuscular dysfunction occur. Persistent
Muscle Weakness
blockade of the neuromuscular junction may
occur as the result of accumulation of the drug
Weakness is defined as a reduced capacity of
or active metabolites, especially in patients with
a rested muscle to generate an expected force.
renal failure. This occurs more commonly with
Weakened inspiratory muscles may be incapable
aminosteroid agents (pancuronium and vecuro-
of performing the work of breathing, leading to
nium), in which renal excretion of active
hypercapnia. Expiratory muscle weakness im-
metabolites is important, than with the benzyl-
pairs the cough reflex, promoting retention of
isoqunolone agents (atracurium, doxacurium, secretions and pneumonia. Causes of muscle
and cisatracurium), which are inactivated spon- weakness are listed in Table 1.
taneously in the blood. The second is an acute, As part of normal aging, respiratory muscle
generalized, necrotizing myopathy that clinical- strength generally declines in parallel with
ly resembles and may be indistinguishable from overall muscle performance. Malnutrition causes
CIM in the absence of these agents, except that all muscles, including those of respiration, to
patients generally have intact sensation, usually become atrophic and weak, causing predisposi-
have greater creatine kinase levels, and normal tion to respiratory failure. Respiratory muscles
nerve conduction. This complication is most may become weak as the result of denervation,
common in patients who are receiving high myopathy, and endocrinopathies. Metabolic dis-
doses of corticosteroids along with neuromus- orders, including severe abnormalities in serum
cular blocking agents, including the benzyliso- potassium, magnesium, and phosphate, may
qui-nolones. Treatment is supportive, but interfere with contractile function, causing inad-
patients may be incapacitated for months after equate V̇E and hypercapnia. When acidosis
recovery from the acute illness. Minimizing the impairs the contractile force of respiratory
dose and duration of paralytic agents and muscles, a positive feedback loop of respiratory
corticosteroids is the best way to prevent this muscle weakness and respiratory acidosis may
complication. be established.

Table 1—Causes of Respiratory Muscle Weakness balloon catheter, and pleural pressure measured
in the esophagus.
Aging
Malnutrition
Respiratory Muscle Fatigue
Denervation
Myopathy
Muscular dystrophy Fatigue is defined as a reduced capacity to
Polymyositis generate an expected force, which is corrected
Drug induced (neuromuscular blocking agents,
corticosteroids)
with rest. Fatigue can be classified as central,
Endocrinopathy (hyperthyroidism, Cushing syndrome) transmissional, and contractile. Central fatigue
Metabolic describes a reversible decrease in central neural
Hypokalemia respiratory drive caused by overuse of muscles. It
Hyperkalemia
Hypophosphatemia may be motivational when strength can be
Hypomagnesemia restored by voluntary effort and nonmotivational
Hypermagnesemia when strength is not restored by increased effort
Acidosis
but the muscle responds normally to electrical
Hyperinflation
stimulation. Central fatigue is probably a conse-
quence of reflex inhibition, influenced by afferent
Hyperinflation places the inspiratory muscles and cortical signals, perhaps endogenous opioids.
at mechanical disadvantage, largely because of a Transmission fatigue is a reversible, exertion-
reduction in muscle length. Inspiratory muscle induced impairment of neural transmission; its
weakness with hyperinflation is more pronounced pathophysiology and significance are unknown.
in acute disorders such as severe asthma than in Contractile fatigue is a reversible impairment
COPD. With time, remodeling of sarcomeres in contractile response to neural impulses not
restores them to normal length, and the propor- caused by drugs or alteration in length/tension
or force/velocity relationships. It occurs when
tion of slow-twitch muscle fibers increases. These
energy demands on contracting muscles exceed
adaptive responses improve contractile function
the energy supply. Energy demand is a function
and increase resistance to fatigue. Also, many
of the work of breathing (V̇E, compliance, and
patients with COPD lose weight; these patients
resistance) and the efficiency of the respiratory
have increased circulating levels of tumor necrosis
system. Fatigue typically occurs when the ten-
factor-a, which promotes muscle wasting and
sion time index is .0.15. The tension-time index
weakness. The benefits of lung volume reduction
is defined as follows: Pdi/maximal Pdi 3 TI/TT,
surgery in patients with severe COPD are
where TI ¼ duration of inspiration, and TT ¼ dura-
probably attributable to enhanced ventilatory tion of one respiratory cycle.
pump function; lung volume reduction surgery Put more simply, fatigue occurs when P
reduces hyperinflation and air trapping, improv- breath/MIP 3 TI /TT is excessive, where P
ing diaphragm mechanics and increasing VA. breath ¼ inspiratory pressure for a given breath,
and MIP ¼ maximal inspiratory pressure. There-
Assessment of Respiratory Muscle Strength fore, a weak muscle (where maximal Pdi and
MIP are reduced) is more likely to fatigue and fail
In clinical practice, the strength of respiratory than a normal muscle.
muscles usually is measured with maximal The efficiency of inspiratory muscle contrac-
pressures at the mouth against a closed airway tion is impaired by lung volume, the presence of
(maximum inspiratory pressure, maximum expi- neuromuscular disease, and malnutrition. Body
ratory pressure). The gold standard measure- position also influences contractile efficiency;
ment, used more in scientific investigations than inspiration requires less effort in the upright
in clinical practice, is transdiaphragmatic pres- position because the abdominal contents are
sure (Pdi) during a maximal inspiratory effort. displaced downward by gravity, unloading the
Pdi is calculated as the difference between diaphragm. Patients with lung disease and an
abdominal pressure, measured with a gastric increased work of breathing usually are more

comfortable in an upright compared with supine (1) increased physiologic dead space (this factor
position. This is especially true for patients with is an important one, but the precise explanation
massive obesity, when assuming the supine for this phenomenon is not completely under-
position may precipitate respiratory arrest be- stood) (2) attenuation of hypoxic ventilatory
cause the diaphragm cannot overcome the drive (patients with chronic hypercapnia become
intolerable load imposed by the weight of the insensitive to increments in PaCO2); and (3) the
abdominal contents. Haldane effect, in which oxygen releases CO2
The energy supply to muscles varies directly bound to hemoglobin, increasing PaCO2.
with blood flow. Shock often culminates in
respiratory failure because blood flow and oxygen Primary Disorders of the Chest Wall
supply to contracting respiratory muscles are
reduced. In cardiogenic shock, hypercapnic respi- Severe kyphoscoliosis, obesity, thoracoplasty,
ratory failure occurs because pulmonary edema and pleural thickening all may cause hypoven-
increases the work of breathing, and impaired tilation by one of two general mechanisms, which
hemodynamic function reduces blood flow to the can be categorized as ‘‘can’t breathe’’ and ‘‘won’t
respiratory muscles. Hypoxemia may compro- breathe.’’ Significant increase in the work of
mise oxygen supply to respiratory muscles, but breathing caused by severe mechanical derange-
hypoxemia alone does not usually cause muscle ments of the chest wall may lead to reduced VTS
fatigue; oxygen consumption can be maintained and increased V̇D/VT (can’t breathe). Many
by increased cardiac output and augmented patients with chest wall restriction have central
oxygen extraction from capillary blood. carbon dioxide nonresponsiveness, either as a
When respiratory muscles are fatigued, the primary disorder or to compensate for increased
EMG power spectrum is shifted, with increased work of breathing (won’t breathe). In acute
low-frequency and decreased high-frequency illness, respiratory muscle fatigue imposed by
components. Dyspnea and tachypnea are com- increased work of breathing may precipitate
mon. Respiratory alternans, the alternating recruit- frank hypercapnic respiratory failure.
ment and derecruitment of the diaphragm and The interplay of increased work of breathing
other inspiratory muscles, often precedes the onset and diminished respiratory drive is a prominent
of paradoxical abdominal motion with respiration. feature of the obesity-hypoventilation syndrome
Treatment of fatigue depends on correcting (OHS), defined as a combination of obesity (BMI
the underlying disorders and rest. If the underly- . 30 kg/m2) and hypercapnia (PaCO2 . 45 mm
ing condition that provoked muscle fatigue is not Hg) during wakefulness in the absence of other
readily reversible, the patient will require me- known causes of alveolar hypoventilation. In
chanical ventilation until adequate rest is many patients, severe obesity is associated with
achieved. Pharmacologic approaches to improve chronic daytime hypercapnia and hypoxemia,
respiratory muscle function have been investigat- erythrocytosis, and right ventricular failure. Most
ed. Although aminophylline, digoxin, and dobu- (but not all) patients with OHS also have
tamine have all been demonstrated to increase the obstructive sleep apnea, but only a minority of
contractility of the diaphragm, their clinical utility obese patients with obstructive sleep apnea have
in patients with respiratory muscle fatigue is OHS. Patients with OHS have a blunted central
unproven. Similarly, the role of strength and drive in response to hypercapnia and hypox-
endurance training of the respiratory muscles emia, possibly related to decreased circulating
has been under investigation for decades, but levels or receptor hyporesponsiveness to leptin, a
there is still no good evidence to support its use. hormone that acts on the hypothalamus to
suppress appetite and probably also on central
Hypercapnia With Oxygen Administration respiratory centers to maintain hypercapnic
ventilatory responses. Obesity-related upper air-
Excessive oxygen administration may worsen way narrowing, dependent atelectasis, and ex-
preexisting hypercapnia, especially in patients cessive loading of respiratory muscles may all be
with COPD. Mechanisms include the following: contributing factors.

Acknowledgment Deem S, Lee CM, Curtis JR. Acquired neuromuscular
disorders in the intensive care unit. Am J Respir Crit
This chapter is reprinted with permission Care Med. 2003;168(7):735–739.
from the ACCP Pulmonary Medicine Board Review. Hermans G, Wilmer A, Meersseman W, et al. Impact
25th ed. Northbrook, IL: American College of of intensive insulin therapy on neuromuscular com-
Chest Physicians; 2009. plications and ventilator dependency in the intensive
care unit. Am J Respir Crit Care Med. 2007;175(5):
Relationship Disclosed 480–489.
Horowitz BZ. Botulinum toxin. Crit Care Clin. 2005;
The author has disclosed the following 21(4):825–839.
relationship: Product/procedure/technique that
Hughes RAC, Cornblath DR. Guillain-Barré syn-
is considered research and is NOT yet approved
drome. Lancet. 2005;366(9497):1653–1666.
for any purpose: B glucan in PCP. The ACCP
Jubelt B, Agre JC. Characteristics and management of
Education Committee has reviewed these rela-
postpolio syndrome. JAMA. 2000;284(4):412–414.
tionships and resolved any potential conflict of
interest. Latronico N, Peli E, Botteri M. Critical illness
myopathy and neuropathy. Curr Opin Crit Care.
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Review of the physiology of each component of the Muscle weakness occurred in 20 of 69 patients who received
integrated systems that control breathing, with cases both a neuromuscular blocking agent and corticosteroids,
illustrating disorders of these systems. compared with none of the 38 patients who received
corticosteroids alone. Weakness correlated with the dura-
Laghi F, Tobin MJ. Disorders of the respiratory
tion of paralysis, and the incidence of weakness was not
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reduced in patients who received atracurium, compared
Very thorough review of the role of respiratory muscles in
with those who received pancuronium or vecuronium.
acute respiratory failure; specific neuromuscular diseases;
and the influence of chest wall, systemic diseases, and Pujar T, Spinello IM. A 38-year-old woman with
surgery on respiratory muscle function. heroin addiction, ptosis, respiratory failure and
proximal myopathy. Chest. 2008;134(4):867–870.
Weinberger SE, Schwartzstein RM, Weiss JW. Hyper-
Concise review with table summarizing the differential
capnia. N Engl J Med. 1989;321(18):1223–1231.
diagnosis of neuromuscular diseases that cause respiratory
Concise summary of mechanisms, specific disorders, and
failure.
therapeutic strategies.
Schweickert WD, Hall J. ICU-acquired weakness.
Chest. 2007;131(5):1541–1549.
Neuromuscular Disorders
Schwendimann RN, Burton E, Minagar A. Manage-
ment of myasthenia gravis. Am J Ther. 2005;12(3):
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failure in tetanus: case report and review of a 25-year
These articles are cited because they are relatively current
experience. Chest. 2002;122(4):1488–1492.
and offer detailed discussions regarding neuromuscular
Centers for Disease Control and Prevention. Human disorders that may cause respiratory failure.
rabies: Alberta, Canada, 2007. MMWR. 2008;57(8):
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197–200.
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Describes clinical picture, management, and prevention
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strategies. The upsurge in diagnoses has been attributed to subcuta-
Cherington M. Clinical spectrum of botulism. Muscle neous drug injection (skin popping). Abscess formation and
Nerve. 1998;21(8):701–710. devitalized tissue provide a favorable milieu for growth of

the organism. This article also provides a concise review of Hypercapnia After Oxygen Administration
other paralytic diseases discussed in this chapter.
Aubier M, Murciano D, Milic-Emili J, et al. Effects of
Respiratory Muscles the administration of O2 on ventilation and blood
gases in patients with chronic obstructive pulmonary
American Thoracic Society/European Respiratory disease during acute respiratory failure. Am Rev Respir
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American Thoracic Society and European Respiratory hypercarbia with oxygen therapy in patients with
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Comprehensive review of mechanisms. This study uses a computer model of the pulmonary
circulation with data from the study of Aubier et al to
Cohen CA, Zagelbaum G, Gross D, et al. Clinical
evaluate the factors contributing to hypercarbia after
manifestations of inspiratory muscle fatigue. Am J
oxygen administration in patients with COPD. The
Med. 1982;73(3):308–316.
discussion offers a lucid explanation of the pathophysiology
Progression of clinical findings leading to respiratory
of this phenomenon.
failure.
Robinson TD, Freiberg DB, Regnis JA, et al. The role of
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hypoventilation and ventilation-perfusion redistribu-
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exacerbations of chronic obstructive pulmonary dis-
Lando Y, Boiselle PM, Shade D, et al. Effect of lung ease. Am J Respir Crit Care Med. 2000;161(5):1524–1529.
volume reduction surgery on diaphragm length in These studies explore the mechanisms of hypercapnia after
severe chronic obstructive pulmonary disease. Am J oxygen administration in patients with COPD. The former
Respir Crit Care Med. 1999;159(3):796–805. shows that increased wasted ventilation is the major factor,
Polkey MI, Moxham J. Clinical aspects of respiratory whereas the latter holds that both increased dead space and
muscle dysfunction in the critically ill. Chest. 2001; reduced total ventilation are responsible.
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Reviews respiratory muscle physiology, evaluation of OHS
muscle dysfunction, and disorders that lead to prolonged
ventilator dependency. Kessler R, Chaouat A, Schinkewitch P, et al. The
Roussos C, Macklem PT. The respiratory muscles. N obesity-hypoventilation syndrome revisited: a pro-
Engl J Med. 1982;307(13):786–797. spective study of 24 consecutive cases. Chest. 2001;
Develops the concept of ‘‘pump failure,’’ reviewing the 120(2):369–376.
physiology and clinical features of muscle mechanics, Most patients with OHS also have obstructive sleep apnea.
energetics, and fatigue. In addition to daytime hypercapnia, OHS is likely
associated with pulmonary hypertension and severe hyp-
Shade D, Cordova F, Lando Y, et al. Relationship oxemia.
between resting hypercapnia and physiologic param-
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These three studies from the same center show that lung Thorough review of physiology and complications of
volume reduction surgery increases the length of the obesity with a broad discussion of critical illness in
diaphragm and improves its strength, the changes correlate these patients.
with postoperative improvements in exercise capacity and Mokhlesi B, Tulaimat A. Recent advances in obesity
maximum voluntary ventilation, and patients with hyper- hypoventilation syndrome. Chest. 2007;132(4):
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function and V̇E improve. Reviews pathophysiology and treatment options.

Chapter 26. Respiratory Symptoms
John D. Buckley, MD, MPH, FCCP
Objectives: various forms of irritation. Cough is initiated by

Recognize and characterize respiratory symptoms en- various receptors located almost everywhere in
countered by pulmonologists. the chest (not just the lungs) and upper airway.
Describe the physiologic and disease mechanisms of
Often referred to as a reflex arc, cough begins
respiratory symptoms.
Outline diagnostic approaches to specific respiratory with irritation of cough receptors (Table 2), which
symptoms including cough, dyspnea, chest pain, wheez- trigger afferent signals leading to the cough center
ing, and hemoptysis. in the medulla and higher cortical centers. The
Describe relative importance of respiratory symptoms in
identifying their underlying cause. brain responds by sending efferent signals via
Interpret respiratory symptoms in the context of other phrenic, vagal, and spinal nerves to the dia-
clinical data. phragm and thoracic muscles to coordinate a
cough. The force of a cough seems predominantly
Key words: chest pain; cough; dyspnea; hemoptysis;
wheeze
dependent on the magnitude and type of irrita-
tion, along with vital capacity. While tracheosto-
Synopsis: mies prevent a pressure build-up behind a closed
Symptoms related to respiratory diseases are among the glottis and reduce the sudden release of a forceful
most common reasons for which patients seek outpatient cough, this appears far less important than a deep
medical attention. Unfortunately, most respiratory symptoms
lack diagnostic specificity. However, understanding known
breath and strong musculature. For example,
epidemiology and pattern recognition can help establish an think of intubated patients who can expectorate
accurate clinical diagnosis. The Centers for Disease Control sputum across the room when the connection of
and Prevention data show that cough led all specified the endotracheal tube is removed.
principal reasons for visit, ahead of prenatal examinations,
well-baby visits, back pain, hypertension, and diabetes. Unfortunately, the cough itself can cause
Supporting these findings are diagnostic codes used by problems. Many patients presenting to a pulmo-
physicians in the United States during 2008 identifying nologist will state that their cough does not
diseases of the respiratory system as accounting for 10.9% of
outpatient visits, more than any other organ system.
bother them as much as it bothers others. Other
problems associated with cough are listed in
Table 3. In some situations, the cough is self-
perpetuating by irritating or preventing healing
Cough of the upper airway mucosa, even if the root
cause has subsided. This last possibility is not
Some estimates suggest cough is the reason for well-defined but may contribute to unusually
greater than 30 million patient visits to US
prolonged cough after some upper respiratory
physicians annually (Table 1).1 Most of these
infections. The type of mucus produced by a
episodes are acute, less than 3 weeks in duration,
cough, if any, is rarely diagnostic of the under-
and dominated by viral infections that are self-
lying cause. Nonetheless, particular characteris-
limited.2 Pulmonologists are rarely involved with
tics of the mucus have a historical association
acute cough in the clinical setting but commonly
outlined in Table 4.
encounter patients with cough that is subacute (3–8
weeks) or chronic (.8 weeks). Separating cough
into these three temporal periods is a very useful
Acute Cough
initial step in diagnosing and treating these patients
While the most common form, acute cough is
Mechanism and Characteristics of Cough also the least studied. Viral infections are most
likely the leading cause of acute cough and are
It is important to remember that cough is a typically both mild and self-limiting. Treatments
primarily protective mechanism in response to should focus on symptom relief, with avoidance

Table 1—Primary Diagnosis of Outpatient Visits, Classi- Table 3—Problems Caused by Cough
fied by Major Disease Category
Syncope
Principal Reason for Visit Distribution, % Vomiting
Barotrauma/mediastinal emphysema
Diseases of the respiratory system 10.9 Incontinence (bowel and bladder)
Circulatory 8.0 Surgical wound dehiscence
Musculoskeletal 7.4 Petechia, subconjunctival hemorrhage
Injury and poisoning 6.7 Musculoskeletal injury/rib fracture
Mental disorders 6.1
Endocrine, metabolic, immunity 5.8
Neoplasms 4.5
whooping cough associated with pertussis gets
Skin 3.7
Infectious diseases and parasites 3.5 its name from the loud, unique, stridorous
Digestive 2.6 inspiration heard typically just before a coughing
spell.
Information adapted from CDC.1
Diagnostic tests for B pertussis include poly-
merase chain reaction and antibody testing
of antibiotics except in the less common cases of
against the pertussis toxin, but these tests are
bacterial superinfection. However, other causes probably best reserved for epidemiologic pur-
of acute cough must be considered, some of poses rather than individual patients because of
which are life-threatening (Table 5). suboptimal sensitivity and specificity. Diagnosis
is predominantly based on history and physical
Subacute Cough examination with awareness of local outbreaks.
Treatment of suspected pertussis usually
Classically associated with Bordetella pertussis, involves a macrolide or trimethoprim/sulfa-
subacute cough is associated with the middle, or methoxazole, but this probably only helps if
paroxysmal, phase. This postinfectious phase administered in the first or second week of
follows the catarrhal and precedes the convales- symptoms. Treatment of close contacts, especially
cent phases. The exact prevalence of subacute those not vaccinated, should be considered.
cough during outbreaks of pertussis varies Unfortunately, by the time patients present to a
among case series from 25% to 50%, but it is pulmonologist, the infectious period has usually
likely higher because of the underrecognized passed, and antibiotics probably have little value.
prevalence of adult pertussis. Despite wide- In these situations, antitussives, pertussis immu-
spread DTaP vaccination programs for children, noglobulin, b2-agonists, and even corticosteroids
many parents have not pursued childhood have been proposed therapies.3
vaccines, which may explain a resurgence of this
condition. Currently, the Centers for Disease Chronic Cough
Control and Prevention recommends booster
vaccines for adolescents and adults in the Tdap By far, the most common cough presenting to
combination. Both forms of vaccine protect pulmonologists is chronic. Unfortunately, neither
against pertussis, tetanus, and diphtheria. The the nature, timing of the cough, nor the absence
or presence of sputum production are useful
Table 2—Cough Receptors clues to the diagnosis.2 Cough lasting longer than
8 weeks is dominated by three conditions that
Mechanical receptors may occur in isolation (75%) or in combination
Touch (mucus, saliva, food, foreign body) (25%).4 These include upper airway cough
Displacement (abscess, submucosal adenopathy)
Chemical receptors
syndrome (UACS), gastroesophageal reflux dis-
Acid ease (GERD), and asthma. The next three most
Temperature (hot and cold) common causes are chronic bronchitis, bronchi-
Capsaicin ectasis, and nonasthmatic eosinophilic bronchitis.
Transient receptor potential vanilloid type 1
Transient receptor potential ankyrin type 1 Together, these six conditions explain nearly 95%
of all chronic cough.
398 Chapter 26. Respiratory Symptoms (Buckley)

Table 4—Mucus Characteristics and Historical Associations
Cough Characteristics Association
Mucus characteristic
Pink, frothy Pulmonary edema
Copious, frothy, salivalike Bronchioloalveolar form of adenocarcinoma
Thick, mucoid, with casts Asthma
Malodorous Anaerobic infection
Yellow/green Infection
Rust-colored Pneumococcal pneumonia
Brownish (chocolate/anchovy paste) Amoebic lung abscess
Caseous TB
Purulent, intermittent blood, and influenced by posture Bronchiectasis
Temporal feature
Early morning Smoking
Nocturnal Asthma, pulmonary edema
Sound
’’Whooping’’ sound during inspiration that precedes cough Pertussis infection
’’Barking’’ sound during cough Laryngotracheal infections: viruses, pertussis, diptheria
UACS of chronic sinusitis. Newer antihistamines may

help in allergic rhinitis, but not other forms of
Upper airway cough syndrome is a relatively rhinosinusitis, most likely because they lack
new term recommended by the American College substantive anticholinergic properties. Inhaled
of Chest Physicians’ 2006 Cough Guideline nasal decongestants should be used no more than
Committee to replace postnasal drip syndrome, 5 days to avoid rhinitis medicamentosa.
primarily because the exact mechanisms behind Allergic rhinitis often responds to a variety of
this syndrome remain unclear. Postulated mech- interventions including antigen avoidance mea-
anisms include several patterns of local inflam- sures, nearly all antihistamines, and leukotriene
mation and irritation of afferent receptors in the
antagonists, usually with improvement in the
upper airway. Various forms of rhinitis and
first week. Inhaled corticosteroids and cromolyn
sinusitis outlined in Table 6 have been suspected
often take several weeks to work and allergen
of causing UACS, and a response to specific
immunotherapy even longer. Of all medical
therapy is probably the most useful diagnostic
therapies, inhaled corticosteroids appear the
strategy (Table 7). After avoidance measures of
potential environmental factors, an empiric most effective, but patient education is essential
course of a first-generation antihistamine com- to ensure compliance during the 3 to 4 weeks
bined with a decongestant is typically recom- necessary to achieve full medical benefit.
mended before extensive investigation. Failure to
Table 6—Potential Causes of UACS
respond to this therapy may suggest the presence
Rhinitis
Table 5—Causes of Acute Cough Allergic
Drug-induced (nonsteroidal antiinflammatory drugs,
Viral infection antihypertensives)
Bacterial infection Nonallergic rhinopathy (formerly known as vasomotor
Aspiration/inhalation injury rhinitis)
Pulmonary embolism Environment (irritant)
Pulmonary edema Sinusitis
Early manifestations of diseases more likely associated Inflammatory
with chronic cough Bacterial
Asthma Acute
GERD Chronic
UACS Other (anaerobic bacteria, fungi)

Table 7—Therapies for UACS Table 8—Nonpharmacologic Antireflux Behaviors
Antihistamines (old and new) Elevate the head of bed by 6 to 8 inches.

Leukotriene antagonists Avoid eating for several hours before sleeping.
Decongestants Reduce weight in overweight persons.
Steroids (systemic and topical) Avoid tight-fitting clothes.
Intranasal ipratropium Avoid caffeine, nicotine, and chocolate.
Intranasal corticosteroids Avoid coffee, including decaffeinated type.
Saline lavage (Neti pot) Eat multiple small meals rather than fewer large meals.
Chronic rhinosinusitis (CRS) is a heteroge- some for patients with cystic fibrosis, diabetes, or
neous disorder for which two of the following other forms of immune system compromise.
four cardinal symptoms should be present for at Chronic fungal infections are often associated
least 12 weeks; it should be refractory to typical with mild immunocompromised states and often
therapies.5 involve bony erosions.
Nasal obstruction GERD
Facial pain/pressure
Decreased sense of smell GERD has been implicated in nearly 40% of
Mucopurulent drainage patients with chronic cough, either as the sole
Chronic cough may be part of CRS, but the cause or in combination with other etiologies,
other symptoms dominate. Approximately one- and often without the traditional symptoms of
third of CRS cases are associated with nasal dyspepsia and heartburn. The mechanism likely
polyps, and when present, asthma and aspirin varies from patient to patient, but may include
sensitivity should be considered (Samter triad).6 components of acid reflux, nonacidic gastric
Allergic fungal rhinosinusitis comprises about reflux, and posterior pharyngeal or tracheal
10% of CRS cases, and while also associated with aspiration of gastroesophageal material, and/or
nasal polyps, sinus opacification is typically seen may trigger vagally mediated distal esophageal-
with thick, inspissated mucus comprised of bronchial reflex mechanisms. The resulting
degranulated eosinophils and fungal hyphae. cough itself may aggravate GERD, creating a
Therapy for CRS involves topical corticoste- perpetuating cycle.
roids, whose use is supported by several ran- A 24-hour pH distal esophageal probe may
domized clinical trials.7 Nasal saline irrigation be the most sensitive and specific diagnostic test
(sprays or use of a Neti pot) may provide for GERD, but there are limitations. An acidic
additional benefit. Neti pots have recently gained distal esophageal environment may not be the
popularity as a home remedy, with a history primary component of GERD-associated chronic
dating back centuries (Neti likely originated from cough. Patient unwillingness, cost, and the lack
the Sanskrit term for nasal cleansing). There have of uniform interpretation of 24-hour esophageal
been highly publicized cases of homemade saline pH monitoring all make it less than ideal.
solutions carrying dangerous strains of bacteria, Instead, clinicians often initiate empiric therapy
supporting the recommendation of sterile saline as a diagnostic strategy. The ACCP’s guidelines
preparations. Intranasal ipratropium, alone or in on GERD-associated chronic cough suggest an
combination with antihistamines and/or cortico- empiric course of therapy for GERD when other
steroids, may relieve symptoms of rhinorrhea common causes, including asthma and UACS,
and cough, but data are limited. are not present.
Infections can complicate all forms of CRS Behavioral modification may have excellent
and are difficult to identify and treat. Gram- results and includes activities listed in Table 8.
positive (specifically Staphylococcus aureus), gram- The list of foods and beverages associated with
negative, and anaerobic bacteria have all been GERD is extensive and highly individualized.
implicated when CRS is associated with infec- Identifying specific foods may require patient
tion, with gram-negative organisms more worri- journals of dietary intake and symptoms. Phar-

macologic therapy may include antacids, hista- Angiotensin-Converting Enzyme Inhibitors
mine-2 antagonists, proton-pump inhibitors, and (ACEIs)
in extreme situations, surgical fundoplication.
Up to 20% of patients taking ACEIs may
Asthma develop cough, with symptoms beginning any-
time between hours to months after the first dose.
Chronic cough may be the only symptom The exact mechanism is not fully understood but
associated with underlying asthma, particularly likely involves bradykinin and substance P.
in children, and this is traditionally known as Genetic predisposition is noted in some women
cough-variant asthma. Often the airflow limita- and African Americans. Improvement typically
tions are not severe or even present, but the occurs with discontinuation of the medication,
cough symptoms can be very problematic for which appears to be a class effect and not dose
patients.8 The use of bronchoprovocation tests to related. After an initial concern that angiotension
diagnose cough-variant asthma should be done receptor blockers might also cause chronic
with caution, given a 22% false-positive rate cough, prospective clinical trials have demon-
demonstrated in one clinical trial.4 In an appro- strated that cough develops at a rate similar to
priate clinical setting, a trial of asthma therapy that associated with diuretics.11
with an inhaled corticosteroid and/or broncho-
dilator may be the best diagnostic approach, Other
although nonasthmatic eosinophilic bronchitis
would likely respond similarly. Other causes of chronic cough will be covered
in their separate chapters. Several are listed in
Nonasthmatic Eosinophilic Bronchitis Table 9.
Like cough-variant asthma, nonasthmatic Clinical Approach to Chronic Cough

eosinophilic bronchitis is typically associated
with symptoms of cough and sputum eosino- In general, the initial evaluation of a patient
philia, but differs by involving neither variable with chronic cough should include a detailed
airflow limitations nor airway hyperresponsive- history, physical examination, and chest radio-
ness.9 Sputum eosinophilia is declared when graph. Chest CT scans are rarely helpful when
eosinophils comprise more than 3% of non- the chest radiograph is unremarkable. If smoking
squamous cells in a sputum sample induced by or ACEIs are involved, discontinuation is the first
nebulized hypertonic saline. Performing a bron- step. Beyond this, empiric treatment of a sus-
chial wash or mucosal biopsy is usually unnec- pected etiology may be all that is needed rather
essary. Therapy involves avoidance of known than more extensive testing. If the response to
triggers and inhaled corticosteroids. Therapeutic empiric therapy is inadequate, then more specific
courses of at least 2 weeks in duration are usually testing for the suspected cause may be useful.
necessary and systemic steroids can usually be There are several important considerations
avoided. The role of antihistamines and leuko- when assessing patients whose condition does
triene antagonists remains largely unknown. not respond to initial treatments: (1) optimal
therapy and patient compliance are essential
Chronic Bronchitis before moving on to other diagnoses; (2) diag-
nostic tests have well-recognized limitations and
A cough productive of sputum is the hall- both positive and negative results should be
mark of chronic bronchitis, occurring 3 months of interpreted with caution; (3) there may be
the year for two consecutive years. A smoking multiple etiologies of a patient’s chronic cough
history or exposure to environmental irritants and maintaining optimal therapy of all partially
should be present, and avoidance measures help effective therapies is necessary to recognize all
nearly all patients with cough, half of whom contributing causes; and (4) educating patients
experience improvement in the first month.10 about chronic cough may help uncover impor-

Table 9—Unusual Causes of Chronic Cough
Other Causes of Cough Characteristic Features
Bronchiectasis Cough is often very productive and a symptom of an acute exacerbation, often
improving with antibiotics.
Malignancy An unusual cause of chronic cough, but common presenting symptom of lung
cancer
Benign tumors and foreign bodies When suspected, this is the rare indication for bronchoscopy in chronic cough.
ILD, (especially IPF and sarcoidosis) While cough is a common symptom of underlying ILD, concomitant conditions
including GERD and aspiration may be the actual cause of the cough.
Autonomic dysfunction of vagus nerve Often associated with patchy sweat dysregulation, anisocoria from a tonic pupil,
(eg, Holmes-Adie syndrome) and impaired deep tendon reflexes (particularly the Achilles)
Habitual Very uncommon cause and should only be implicated after extensive evaluation
including behavioral modification and psychiatric evaluation
External otitis/impaction Irritation of the auricular branch of vagus nerve
ILD ¼ interstitial lung disease; IPF ¼ idiopathic pulmonary fibrosis.
tant clues to the diagnosis and involving them in outside of areas with high prevalence of tuber-
decisions regarding empiric treatment may help culosis. Table 10 provides a framework for the
improve compliance. Reassuring patients that a most common causes of massive hemoptysis.
diagnosis and successful treatment are achieved Not all patients with massive hemoptysis
for 90% to100% of patients can help alleviate the require intubation. However, any patient in
associated stress often present in this chronic distress or with oxygenation or ventilation
condition. difficulties with active bleeding likely warrants
intubation, preferably with a large bore endotra-
Hemoptysis cheal tube that may permit subsequent bron-
choscopy. Antitussives may play a role at
Expectoration of bloody or blood-tinged reducing violent coughing that can aggravate
sputum can be a very concerning symptom for hemoptysis, but they also reduce a patient’s
patients. Often the source is the nasal passage or ability to clear the airway, making their use
esophagus, warranting a much different ap- controversial. Both oxygenation and ventilation
proach than if the blood originates from the problems can occur either in isolation or together,
larynx, trachea, or lower airways. Making this and no single therapeutic strategy applies to all
distinction is an important early step in the patients. The need for aggressive hemodynamic
approach to these patients. support is probably less common and likely
The minimum amount of expectorated blood related to hypoxia and acidosis. While a chest
necessary to be classified as massive hemoptysis radiograph may be useful at identifying the
varies in different case series from 200 to 600 source, it often fails to identify the actual source
mL/24 h. Massive hemoptysis can be life- in a reliable manner. Parenchymal air space
threatening, more from its risks of asphyxiation disease should be interpreted with caution, as
than exsanguination. Some estimates have sug- they may simply represent blood originating
gested that as little as 60 mL of blood occluding from another site rather than the true source of
an airway can lead to death. The common causes the blood. A more useful imaging is CT
of massive hemoptysis are different from those of angiography, which provides better definition of
nonmassive hemoptysis and have evolved over airways, lung parenchyma, mediastinal struc-
time. Fifty years ago, pulmonary tuberculosis tures, and the pulmonary vasculature. Correcting
was the most common cause of massive hemop- any coagulopathy is essential, including particu-
tysis, and in a large 2009 case series from Hong lar attention to the use of platelet-inhibiting
Kong, it continues to be the most common cause. medications. Aspirin, nonsteroidal antiinflamma-
However, malignancies, bronchiectasis, and oth- tory drugs, and clopidogrel all interfere with
er infections probably now play a larger role platelet function but not number, and a platelet

transfusion may be necessary despite a normal Table 10—Causes of Massive Hemoptysis
platelet count.
Tumors
In many situations, early bronchoscopy is Bronchogenic lung cancera
warranted for several reasons: to locate the Bronchial adenomas
source of blood, to potentially tamponade a Metastatic cancer
distal pulmonary source, or to guide placement Carcinoid
Broncholithiasis
of an endotracheal tube (ETT).12 If the upper Infection
airway is identified as the source of massive Aspergillomaa
hemoptysis, a standard ETT positioned with its Necrotizing pneumoniaa
TBa
inflated cuff distal to the lesion may protect both
Fungal
lungs from blood spillage. When this is not Abscess
possible, urgent consideration of tracheostomy or Septic emboli
other surgical intervention is warranted. When Vascular
Large vessel
the source of bleeding appears to be isolated to Arteriovenous malformation
one lung, there are several ETT strategies that Pulmonary embolism
may help. A double-lumen ETT can permit Severe pulmonary hypertension
independent control of each lung, allowing Aortic aneurysm
Vasculitis and autoimmune
tamponade of the source lung, while preserving Granulomatosis with polyangiitis
ventilation of the healthy lung, but proper Systemic lupus erythematosus
positioning requires specific knowledge and Goodpasture syndrome
Other pulmonary diseases
experience. If a double-lumen tube is not an
Bronchiectasis (all causes)a
option, a single-lumen tube may be advanced Cystic fibrosis
sufficiently far into the nonbleeding lung’s Diffuse alveolar hemorrhage
mainstem bronchus to allow inflation of the cuff Idiopathic pneumonia syndrome
Trauma
in that bronchus. This can protect the healthy Blunt or penetrating injuries
lung from blood spilling over from the source Foreign bodies
lung. Pulmonary artery catheter erosion
Bronchoscopy
If the source of bleeding is distal to the
Lung biopsy
trachea, identifying the ‘‘guilty’’ side is important Percutaneous tracheostomy
for two other reasons. First, placing the patient in Other
the lateral decubitus position with the source Mitral stenosis
Drugs (anticoagulants, cocaine, chemotherapy)
side down may reduce spillage of blood into the Amyloidosis
healthier lung. Second, it targets vascular or Endometriosis
surgical interventions. Management of massive hemoptysis involves several key
While many of the above steps may result in components
Ensure a secure airway
cessation of the hemoptysis, more definitive Provide respiratory and hemodynamic support
therapy is necessary if the bleeding recurs or is Identify the source
expected to recur. Selective bronchial artery Correct any coagulopathy
Assess for specific interventions
embolization is playing an increasingly valuable
Endobronchial
role in the management of massive hemoptysis, Vascular
and the number of centers experienced in this Surgical
procedure continues to grow.13 Even though a
Denotes more common causes in the United States.
lungs have several vascular supplies and are at
risk for multiple causes of massive hemoptysis,
embolizing the appropriate bronchial artery can spinal artery originates off a bronchial artery and
achieve control of bleeding in up to 75% of embolization can result in paralysis. Historically,
patients. It becomes essential for the bronchos- this potential complication has been quoted in up
copist to identify the site of bleeding as specif- to 10% of embolization procedures, but improve-
ically as possible to guide the interventional ment in equipment and techniques has likely
radiologist. In a minority of patients, the anterior decreased its incidence.

Surgical interventions are typically the final ,4 cm, more than 40 pack-years of smoking, and
option but may be the only truly definitive self-reported history of COPD.14 In addition, the
therapy for many conditions, including myceto- relationship of wheezing to the severity of
mas and necrotizing pneumonias. obstruction in asthma is poor, on the premise
Nonmassive hemoptysis also has a lengthy that with very severe obstruction, airflow is
differential diagnosis similar, but not identical, to insufficient to generate the sound of a wheeze.15
massive hemoptysis. While recent epidemiologic Stridor is a specific type of wheeze usually
studies do not exist, the key difference is that associated with extrathoracic airway diseases
bronchitis (acute or chronic) appears to be the such as laryngeal edema, epiglottitis, and head
most common cause of hemoptysis in the United and neck cancer. While the pitch and tone are not
States, but is rarely the cause of massive clearly different from other wheezes, it is
hemoptysis. The evaluation of nonmassive he- typically noted during inspiration when the
moptysis is similar to that of massive hemoptysis variable extrathoracic obstruction becomes more
but typically with less urgency. If the hemoptysis prominent.
is of a week’s duration or less, and appears Spirometry can be a useful test to determine
associated with signs and symptoms of bronchi- the location of wheezing, and it may be helpful to
tis, conservative management and observation categorize the numerous diseases associated with
may be all that is necessary. For patients at higher wheezing by the three anatomic locations often
risk for cancer, or if the evaluation does not suggested by spirometry: (1) upper airway,
suggest bronchitis, obtaining a chest radiograph extrathoracic; (2) upper airway, intrathoracic;
and even chest CT scan or bronchoscopy may be and (3) small airways (,2 mm in diameter).
important. Details of these spirometric features are covered
in the chapter on pulmonary function testing.
Wheezes
Dyspnea
Wheezes are generally understood to be
adventitial breath sounds described as a whis- Like pain, dyspnea is a symptom that exists if
tling or musical sound, and thought to be declared as such by the patient and is present in
generated by airflow through abnormally nar- up to 50% of patients admitted to the hospital
rowed airways. The exact mechanism remains and 25% presenting to outpatient clinics. It is
uncertain, but fluttering walls of airways and/or distinctly separate from hypoxia, tachypnea, and
movement of secretions likely play a key role. hypercapnea and can result from an incredibly
These sounds can be characterized by pitch, complex and poorly understood set of mecha-
timing of when they start and stop in the nisms. While dyspnea often accompanies these
respiratory cycle, whether monophonic or poly- objective findings, there are situations where it
phonic, and location of greatest intensity. In does not. One example of discordance is in
theory, a monophonic wheeze may suggest a COPD, where significant spirometric changes in
pathologic process involving a single airway response to bronchodilator therapy did not
(often the trachea or upper airway), while correlate with the dyspnea score.16 This impor-
polyphonic wheezes may suggest multiple air- tant distinction has helped clinicians and re-
ways with varying degrees of secretions and searchers move away from selecting purely
airway narrowing. Several prospective studies objective outcome variables and placing addi-
have attempted to identify characteristics of tional emphasis on the symptom of dyspnea.
wheezes that predict specific clinical conditions, Dyspnea is a very common symptom, with
but none has demonstrated significant positive patients using a variety of terms that may shed
predictive value. light on the underlying etiology. Common
In a multicenter trial studying the clinical descriptions are included in Table 11. In labora-
examination of 309 adults, the presence of tory studies, terms including chest tightness and
wheezes was only useful in making the diagnosis constriction are much more likely to suggest
of COPD when combined with laryngeal height airflow limitations than dyspnea encountered

Table 11—Common Patient Terms for Dyspnea Table 12—Common Conditions Associated With Dyspnea
Chest constriction/tightness In Primary Care In Pulmonary Clinic

Out of breath
Cannot take a deep breath Asthma Asthma/COPD
Air hunger COPD ILD
Effort to breathe Pneumonia Cardiac ischemia/heart failure
Suffocating Cardiac ischemia Obesity/deconditioning
Heart failure Pulmonary hypertension
ILD Medications (eg, b-blockers)
‘‘Psychogenic’’ ...
while breathing against external resistors.17 The
specific prevalence of dyspnea likely depends on ILD ¼ interstitial lung disease.
the patient population. In the large Framingham
study, 6% to 27% of the adult population complex, with activation of the insular area of the
reported dyspnea. In a primary care setting, limbic system, as is evident in brain imaging
nearly 85% of dyspnea cases can be explained by studies. These same brain imaging studies reveal
seven conditions listed in Table 12. It is likely other areas associated with dyspnea, including
these have not changed in the last 20 years, but the amygdala, medial pons, and cerebellar
the causes of dyspnea among patients referred to vermis.
a pulmonologist are likely to be less obvious. There appears to be a deeply embedded
More recently, dyspnea has been shown to be a memory related to the intensity of efferent
predictor of hospitalizations and mortality in signals needed to stimulate respiration, along
COPD and is a stronger predictor of cardiac with the expected intensity of afferent neural
mortality than angina.18
input in return, via chemoreceptors, mechanore-
ceptors, and lung receptors. If this balance is
Mechanisms of Dyspnea
altered from what is familiar, dyspnea can
develop. An example of this imbalance is a
Our understanding of the mechanism of
patient with advanced COPD and hyperinflation
dyspnea remains incomplete, but recent animal
who may expend a dramatic effort to inspire,
and human studies have provided additional
owing to the flattened diaphragm, but senses
explanations.19 One contributing source of dysp-
only a small breath in return.
nea includes the chest wall mechanoreceptors,
which can be disrupted from spinal cord function Another perspective, which may help guide a
by injury, polio, or induced anesthesia, and clinical approach to dyspnea, is to classify the
appear to have an attenuating effect on dyspnea, cause of dyspnea into one of three categories:
yet the detection of both lung volume changes 1. Respiratory control center: peripheral and
and hypercarbia can be preserved. Studies of central receptors and stimuli
chemoreceptors in the aortic and carotid bodies 2. Respiratory mechanics: including neuromus-
suggest that hypercarbia appears to induce cular function and airflow, often referred to as
dyspnea in healthy subjects, and this depends the ‘‘work of breathing’’
on the level of reflex stimulation of the respira-
3. Gas exchange: with oxygen usually becoming
tory centers. Lung receptors transmit signals to
an issue before carbon dioxide
the brainstem via the vagus nerve through
several different fibers, some of which are This is by no means a comprehensive
myelinated and carry signals from rapidly taxonomy, but it may help the clinician quickly
adapting and slowly adapting receptors. How- address most conditions associated with dysp-
ever, more than 75% of signals are carried via nea. Other causes include anemia, renal failure,
unmyelinated vagal fibers, notably the pulmo- fibromyalgia, endocrine disorders, and decondi-
nary vagal C-fibers, which appear to play an tioning. At times, key elements in the description
important role in dyspnea but not cough. of dyspnea may shed light on its cause. These are
Centrally, the mechanisms appear even more outlined in Table 13.

Table 13—Dyspnea Pearls
Toxic doses of aspirin, progesterone, and pregnancy can induce dyspnea at a central level.
Multiple causes of dyspnea in a given patient are common. Beware of the patient with COPD who presents with a
different type of dyspnea, and consider pulmonary embolism and heart disease.
Patient terminology can shed light, with
* constriction and tightness associated with airflow problems
* air hunger and suffocation suggesting heart failure, and
* heavy breathing associated with deconditioning.
Orthopnea: Dyspnea encountered while in a recumbent position relieved by sitting upright.

Trepopnea: Dyspnea while in one lateral decubitus position as opposed to the other. This suggests an underlying disease
affecting one lung/pleural space more than the other; patients often prefer to lie with the less affected side dependent,
which may allow greater pulmonary blood flow through the healthier lung. One exception may be pleurisy, in which
case patients may prefer to lie with the more affected side dependent to splint excessive respiratory movement.
Platypnea: Dyspnea while upright and relieved by lying supine. This is associated with the hepatopulmonary syndrome
in which small arteriovenous dilatations have developed in the lower regions of the lungs of patients with liver failure.
These dilated vessels cause a shunt that is aggravated by the upright position, such that gravity forces greater blood flow
through the lower areas of the lung. Upon supine positioning, the gravity-dependent pulmonary blood flow is
redistributed to the posterior areas of the lungs that may be less affected by the vascular dilatations. Orthodeoxia often
accompanies this condition in which oxygen desaturation, experienced while upright, improves while supine.
Clinical Approach to Dyspnea dyspnea in 2% to 5% of patients in some case

series, although the mechanism remains un-
In a pulmonary practice, the history and known. Confidently declaring deconditioning as
physical examination provide a diagnosis about the cause most likely warrants cardiopulmonary
two-thirds of the time. Diagnostic tests should be exercise testing, which may help identify unex-
selected on the basis of individual presentation. pected pulmonary or cardiac limitations.
Those of greatest value include the following:
Treatment of Dyspnea
1. Complete pulmonary function tests, often
with bronchoprovocation Primary focus should be on treatment of the
2. Blood work: Hemoglobin, thyroid studies, underlying disease, but short-term use of opioids
brain natriuretic peptide, D-dimer, glucose, has been shown in numerous studies to relieve
blood urea nitrogen/creatinine, and electro- dyspnea in a variety of conditions including
lytes including calcium, magnesium, and COPD, cancer, interstitial lung disease, and heart
phosphorus failure. There is less evidence supporting long-
3. Six-minute walk test and/or exercise pulse term benefits of opioids, some suggesting that the
oximetry side effects may outweigh the benefits. While
4. High resolution CT scan (chest radiograph oxygen therapy has been shown to reduce
usually completed before referral) mortality in chronically hypoxemic patients,
5. Echocardiography/cardiac stress testing there are conflicting data on its ability to relieve
6. Cardiopulmonary exercise testing dyspnea. Inhaled furosemide has gained atten-
Other tests that may offer insight to the tion lately as a treatment of dyspnea, but
etiology of unexplained dyspnea might include insufficient evidence exists to support this
measurement of carboxyhemoglobin levels for modality. However, pulmonary rehabilitation
unexpected carbon monoxide exposure, bubble has been repeatedly shown to reduce dyspnea
echo studies for right to left shunts, and right on exertion in chronic lung disease. This is most
heart catheterization when pulmonary hyperten- likely due to exercise training. At this time, there
sion is suspected. Isolated defects in diffusing is insufficient evidence to recommend inspirato-
capacity should raise the suspicion of pulmonary ry muscle training, but it can be considered in
vascular disease, especially when associated with select patients with COPD.20
normal imaging findings. Gastroesophageal re- Based on smaller clinical trials, many other
flux disease has been reported as a cause of treatments of dyspnea have been proposed,

Table 14—Noncardiac Chest Pain and Their Pearls Table 15—Diseases Associated With Digital Clubbing
GERD, spasm, and gastritis (often influenced by eating, a. Respiratory

may be worse while supine) i. Malignancy
Pulmonary embolism (usually a manifestation of a 1. Bronchogenic lung cancer
pulmonary infarct) 2. Mesothelioma
Pneumothorax (common in trauma and spontaneous in ii. Suppurative infections
tall, thin, young males) 1. TB
Aortic dissection (classically located in the back and 2. Lung abscess
described as ‘‘stabbing’’) 3. Bronchiectasis (including cystic fibrosis)
Musculoskeletal (often positional) 4. Empyema
Muscle strain (often from violent cough) iii. Idiopathic pulmonary fibrosis (particularly familial)
Rib abnormalities (fracture, metastatic disease) b. Cardiac
Cartilage (trauma, relapsing polychondritis) i. Cyanotic congenital heart disease
Fibromyalgia (especially when pain is at known trigger ii. Subacute bacterial endocarditis
points) iii. Left atrial myxoma
Zoster (pain often precedes the vesicular rash) c. GI
Pleurisy (viral, idiopathic, malignant) i. Advanced liver disease (particularly primary biliary
Parapneumonic effusions cirrhosis)
ii. Inflammatory bowel disease
iii. Celiac disease
including acupuncture, cold air blown on the iv. Malabsorption
d. Other
face, nocturnal noninvasive ventilation, and i. Familial
yoga. However, widespread use cannot be ii. Thymoma
recommended. iii. Trauma
iv. Thalassemia
Chest Pain
ostitis and arthritis, it is known as hypertrophic
Cardiac causes of chest pain are usually osteoarthropathy. While the pathophysiology of
considered ahead of pulmonary causes in most clubbing remains uncertain, it is most commonly
patients because of their serious and treatable associated with pulmonary diseases, which are
nature. Because the lung parenchyma and vis- then dominated by malignancies and chronic
ceral pleura have no pain fibers, chest pain
suppurative infections (Table 15). Contrary to
associated with the respiratory system typically
popular belief, it does not appear to be caused by
involves the pleura or musculoskeletal compo-
hypoxia, and its presence in COPD warrants
nents of the chest wall. In one large outpatient
further investigation for other causes.22
series in a primary care setting, 20% of all chest
pain was musculoskeletal, with costochondritis
considered separately at 13%.
Anxiety and Depression
The type of chest pain may suggest noncar-
Growing literature demonstrates that patients
diac over cardiac causes, but insufficiently to
with underlying respiratory diseases appear to
adequately exclude an acute coronary syn-
drome.21 After an urgent electrocardiogram and be more likely to experience anxiety and depres-
chest radiograph, other diagnostic tests can be sion. This is particularly true of depression in
tailored to fit with the overall presentation. Table COPD, but higher rates of depression have also
14 outlines several common noncardiac causes of been shown in patients with obstructive sleep
chest pain and accompanying features. apnea, cystic fibrosis, and other chronic respira-
tory conditions. While a variety of therapies have
Digital Clubbing been proposed, including pharmacologic, pul-
monary rehabilitation, and counseling, strong
Clubbing is defined as swelling of the nailbed evidence supporting these treatments is currently
and results from collagen deposition, capillary lacking. However, there is widespread agreement
proliferation, and interstitial inflammation and that screening for depression in these patients is
edema. When clubbing is associated with peri- worthwhile.23

Hoarseness 4. Irwin RS, Curley FJ, French CL. Chronic cough:
the spectrum and frequency of causes, key
The number of diseases associated with voice components of the diagnostic evaluation, and
hoarseness is extensive and typically addressed outcome of specific therapy. Am Rev Respir Dis.
by primary care physicians and otolaryngolo- 1990;141(3):640–647.
gists. Common respiratory causes are dominated This prospectively evaluated diagnostic algorithm for
by upper respiratory infections. Gastroesophage- diagnosing the cause of chronic cough has stood the test
al and laryngopharyngeal reflux are also com- of time.
mon suspects, but it remains uncertain that 5. Meltzer EO, Hamilos DL, Hadley JA, et al.
therapies known to alleviate dyspepsia will also Rhinosinusitis: establishing definitions for clinical
be effective when reflux is associated with research and patient care. Otolaryngol Head Neck
dyspnea.24 More unusual causes encountered Surg. 2004;131(6 suppl):S1–S62.
by pulmonologists include recurrent laryngeal A well-written summary of a poorly defined condition
nerve damage from bronchogenic lung cancer that helps establish more uniform disease definitions.
and associated Horner syndrome, tuberculosis, 6. Hamilos DL. Chronic rhinosinusitis patterns of
granulomatosis with polyangiitis affecting the illness. Clin Allergy Immunol. 2007;20:1–13.
upper airway, use of inhaled corticosteroids, and A good review of common symptoms associated with
trauma from items such as endotracheal tubes. chronic rhinosinusitis.
7. Parikh A, Scadding GK, Darby Y, Baker RC.
Relationship Disclosed Topical corticosteroids in chronic rhinosinusitis: a
randomized, double-blind, placebo-controlled tri-
The author has disclosed the following al using fluticasone propionate aqueous nasal
relationship: Fiduciary position (of any organi- spray. Rhinology. 2001;39(2):75–79.
zation, association, society, etc, other than ACCP: One of several randomized clinical trials demonstrat-
Association of Pulm/CCM Program Directors. ing efficacy of nasal corticosteroids.
The ACCP Education Committee has reviewed 8. Johnson D, Osborn LM. Cough variant asthma: a
these relationships and resolved any potential review of the clinical literature. J Asthma. 1991;
conflict of interest. 28(2):85–90.
An older, but still relevant summary of cough-variant
Annotated References asthma.
9. Brightling CE. Chronic cough due to nonasth-
1. CDC. National Hospital Ambulatory Medical Care matic eosinophilic bronchitis: ACCP evidence-
Survey: 2008 Outpatient Department Summary Ta- based clinical practice guidelines. Chest. 2006;
bles. Bethesda, MD: US Department of Health and 129(1 suppl):116S–121S.
Human Services; 2012. A systematic review of nonasthmatic eosinophilic
2. Irwin RS, Baumann MH, Bolser DC, et al. bronchitis
Diagnosis and management of cough executive 10. Kanner RE, Connett JE, Williams DE, Buist AS.
summary: ACCP evidence-based clinical practice Effects of randomized assignment to a smoking
guidelines. Chest. 2006;129(1 suppl):1S–23S. cessation intervention and changes in smoking
This comprehensive review of cough is an excellent set habits on respiratory symptoms in smokers with
of references for both summaries and specific issues early chronic obstructive pulmonary disease: the
related to cough. Lung Health Study. Am J Med. 1999;106(4):
3. Bettiol S, Thompson MJ, Roberts NW, Perera R, 410–416.
Heneghan CJ, Harnden A. Symptomatic treat- A very large randomized clinical trial demonstrating
ment of the cough in whooping cough. Cochrane the benefits of smoking cessation programs.
Database Syst Rev. 2010;(1):CD003257. 11. Dicpinigaitis PV. Angiotensin-converting enzyme
This systematic review of whooping cough reveals the inhibitor-induced cough: ACCP evidence-based
paucity of well-designed studies addressing specific clinical practice guidelines. Chest. 2006;129(1
treatments. suppl):169S–173S.

A thorough review of ACEIs’ and angiotensin receptor 1):451–455.
blockers’ relationship to cough. A key study demonstrating that various patient
12. Dweik RA, Stoller JK. Role of bronchoscopy in descriptions of dyspnea may shed light on the
massive hemoptysis. Clin Chest Med. 1999;20(1): underlying disease.
89–105. 18. Parshall MB, Schwartzstein RM, Adams L, et al.
A good review description of the role of bronchoscopy An official American Thoracic Society statement:
in massive hemoptysis. update on the mechanisms, assessment, and
13. Chun J-Y, Morgan R, Belli A-M. Radiological management of dyspnea. Am J Respir Crit Care
management of hemoptysis: a comprehensive Med. 2012;185(4):435–452.
review of diagnostic imaging and bronchial A comprehensive review of the pathophysiology,
arterial embolization. Cardiovasc Intervent Radiol. evaluation, and management of dyspnea.
2010;33(2):240–250. 19. Burki NK, Lee L-Y. Mechanisms of dyspnea.
This is a broad, updated review of radiologic diagnosis Chest. 2010;138(5):1196–1201.
and interventional management of massive hemoptysis. An excellent, recent summary of the mechanisms of
14. Straus SE, McAlister FA, Sackett DL, Deeks JJ. The dyspnea.
accuracy of patient history, wheezing, and laryn- 20. Mahler DA, Selecky PA, Harrod CG, et al.
geal measurements in diagnosing obstructive American College of Chest Physicians consensus
airway disease, CARE-COAD1 Group: clinical statement on the management of dyspnea in
assessment of the reliability of the examina- patients with advanced lung or heart disease.
tion-chronic obstructive airways disease [erratum Chest. 2010;137(3):674–691.
in JAMA. 2000;284(2):181]. JAMA. 2000;283(14): A recent, comprehensive review of dyspnea treatment.
1853–1857. 21. Swap CJ, Nagurney JT. Value and limitations of
This prospective comparative study reveals the diffi- chest pain history in the evaluation of patients
culty in relying on symptoms and physical examina- with suspected acute coronary syndromes. JAMA.
tion to accurately diagnose various forms of obstructive 2005;294(20):2623–2629.
lung disease. This study reinforced the long-held belief that the
15. Shim CS, Williams MH Jr. Relationship of wheez- characteristics of chest pain are insufficient to safely
ing to the severity of obstruction in asthma. Arch exclude potentially life-threatening cardiac causes.
Intern Med. 1983;143(5):890–892. 22. Jamieson A. The causes of finger clubbing: a list
This is one of the original articles demonstrating poor worth learning. Am J Med. 2011;124(7):e1–e3.
correlation of wheezing intensity and asthma severity. This practical review summarizes the key features of
16. Wolkove N, Dajczman E, Colacone A, Kreisman digital clubbing.
H. The relationship between pulmonary function 23. Maurer J, Rebbapragada V, Borson S, et al.
and dyspnea in obstructive lung disease. Chest. Anxiety and depression in COPD: current under-
1989;96(6):1247–1251. standing, unanswered questions, and research
One of the early studies demonstrating poor correlation needs. Chest. 2008;134(4 suppl):43S–56S.
of dyspnea to airflow limitations and raising awareness This study helped raise awareness of these common
of directing treatment to this symptom rather than conditions and their relationship to respiratory diseases.
focusing exclusively on airflow. 24. Hopkins C, Yousaf U, Pedersen M. Acid reflux
17. Moy ML, Woodrow Weiss J, Sparrow D, Israel E, treatment for hoarseness. Cochrane Database Syst
Schwartzstein RM. Quality of dyspnea in bron- Rev. 2006;(1):CD005054.
choconstriction differs from external resistive Cochrane review of reflux-associated hoarseness
loads. Am J Respir Crit Care Med. 2000;162(2, pt treatment.

Notes

Chapter 27. Unusual and Uncommon Pulmonary
Disorders
Objectives: diagnosis at the outset and the ability to recognize

Discuss several unusual and uncommon pulmonary characteristic clinical context and imaging fea-
disorders. tures associated with these disorders. Histopa-
Describe clinical manifestations and facilitate recognition
of these disorders.
thology can be helpful but needs to be correlated
Discuss management options for these disorders. with the clinical and radiologic features in
formulating the final clinicopathologic diagnosis.
Key words: Birt-Hogg-Dubé syndrome; constrictive bron- Rational treatment and accurate assessment of
chiolitis; IgG4-related disease; pulmonary alveolar protein- prognosis depends on an accurate diagnosis.
osis; pulmonary amyloidosis; spontaneous pneumo-
mediastinum
Pulmonary Alveolar Proteinosis
Synopsis:
Rare or ‘‘orphan’’ disease is defined as a disease or condition Pulmonary alveolar proteinosis (PAP), also
affecting ,200,000 persons in the United States (Office of known as pulmonary alveolar phopholipoprotei-
Rare Diseases, National Institutes of Health). An estimated nosis, is a rare parenchymal lung disease
25 million people in the United States have one of the more
characterized by an accumulation of lipoprotei-
than 6,000 rare diseases. The failure to diagnose a rare or
unusual disease is generally due to a failure to consider the naceous material in the alveoli. Most cases (90%)
diagnosis in the initial evaluation. Thus, the diagnosis of are idiopathic; remaining cases consist of con-
unusual pulmonary disorders is facilitated by considering a genital and secondary forms of PAP.1–3 The
broad differential diagnosis at the outset and the ability to
recognize characteristic clinical context and imaging fea- congenital form is caused by mutations in the
tures that may be associated with these disorders. Histo- genes encoding surfactant proteins or the recep-
pathologic study can be helpful but more often than not tor for granulocyte-macrophage colony-stimulat-
needs to be correlated with the clinical and radiologic
findings in reaching the correct diagnosis without which
ing factor (GM-CSF). Secondary PAP occurs in
rational treatment and accurate prognostication are unlikely. association with hematologic or immunodeficien-
Herein, six uncommon to rare pulmonary diseases are cy disorders, inhalation of chemicals or inorganic
discussed—pulmonary alveolar proteinosis, pulmonary dusts (eg, silica), or certain pulmonary infections.
amyloidosis, Birt-Hogg-Dubé syndrome, IgG4-related dis-
ease, constrictive bronchiolitis, and spontaneous pneumo- PAP results from impaired surfactant metabolism
mediastinum. These disorders are associated with by macrophages due to alterations in GM-CSF
characteristic clinical and imaging features that can allow signaling. In most cases of idiopathic PAP, anti-
a diagnosis in the absence of histopathology for some of
these disorders.
GM-CSF antibodies are detectable in the serum
and BAL fluid.
The median age at the time of diagnosis of
Rare (orphan) disease is defined as a disease or idiopathic PAP is 39 years; most patients are
condition affecting ,200,000 persons in the between 20 and 60 years of age.1 Clinical features
Unites States (Office of Rare Diseases, National are nonspecific. Although the majority of patients
Institutes of Health). An estimated 25 million present with insidious onset of exertional dys-
people in the United States have one of the more pnea and cough, some patients may be asymp-
than 6,000 rare diseases. The failure to diagnose a tomatic.1,2 Less common symptoms include
rare or unusual disease is generally due to a fever, fatigue, weight loss, chest pain, and
failure to consider the diagnosis in the first place. hemoptysis. Inspiratory crackles are heard in
Diagnosis of unusual pulmonary disorders is 20% to 50% of patients; digital clubbing is
facilitated by considering a broad differential uncommon.1,2

drug-induced lung disease.4,5 Pulmonary func-
tion testing demonstrates a restrictive defect with
a reduced diffusing capacity.2,6
In an appropriate clinical setting, the diagno-
sis of PAP may be made by BAL, which typically
yields a milky effluent.1,6 Under light microscopy,
this fluid shows large amounts of PAS-positive
lipoproteinaceous material. Transbronchial biopsy
also provides the diagnosis in most cases and
demonstrates an accumulation of granular, PAS-
positive, lipoproteinaceous material within the
alveolar spaces with preserved alveolar architec-
ture, although thickening of the alveolar septa
and interstitial fibrosis may occur in some
Figure 1. HRCT scan of chest of a 39-year-old man with patients.6 In the absence of a superimposed
idiopathic (autoimmune) pulmonary alveolar proteinosis.
Bilateral ground-glass attenuation with associated septal
infection, very few inflammatory cells are seen
thickening (‘‘crazy-paving’’ pattern) is present. in the lung tissue. Surgical biopsy is now less
frequently required to confirm a PAP diagnosis.
Mildly elevated serum lactate dehydrogenase The standard treatment for PAP is whole lung
level is common. Increased levels of lung lavage during which repeated instillation and
surfactant A and D and mucinlike glycoprotein drainage of the lung with aliquots of isotonic
in the serum have also been found in patients saline (up to a volume of 20–30 L) is performed
with PAP; however, these findings are nonspe- until the run-off is clear.1,2,6 This is performed
cific and not limited to this disease.1,2 Patients with a bronchoscope passed through a double-
with PAP may have period acid-Schiff (PAS)- lumen endotracheal tube with the patient under
positive material or elevated lung surfactant A general anesthesia. Chest percussion is per-
levels in their sputum, but these are also formed during the lavage procedure to facilitate
nonspecific findings. Serologic testing for GM- removal of the lipoproteinaceous material. Main
CSF autoantibodies is not a routinely available indication for treatment is limiting exertional
assay but can be helpful in diagnosing idiopathic dyspnea associated with hypoxemia. Approxi-
(autoimmune) PAP. mately 85% of patients show improvement after
Chest radiography usually reveals bilateral, lung lavage. The median duration of clinical
patchy air-space infiltrates.4 Less common, an benefit is 15 months. Eventually, 60% to 70% of
interstitial pattern may be seen. Infiltrates are patients require repeat lavage. Lung lavage is
often more prominent in the perihilar regions, associated with improved survival.1,2 Consistent
and this ‘‘bat-wing’’ pattern may be mistaken for with its proposed role in surfactant clearance
pulmonary edema. High-resolution CT (HRCT) mechanisms, preliminary experience with GM-
scan of the chest demonstrates ground-glass CSF administration in PAP has shown favorable
and/or consolidative infiltrates in patchy or responses in 40% to 65% of patients, some
diffuse distributions. Sharp demarcation of the enjoying a complete response.6–8 GM-CSF has
infiltrates from surrounding normal lung tissue been administered subcutaneously (dose range,
is commonly observed. Reticular opacities or 5–20 lg/kg/d) or by aerosolization (dose range,
interlobular septal thickening are present within 250–500 lg twice daily every other week).2,8,9
the air-space infiltrates, creating a ‘‘crazy-paving’’ Potential therapeutic role of rituximab therapy in
pattern (Fig 1).4,5 This pattern is characteristic, PAP is being explored.
but not specific for PAP, and can be seen in The clinical course of patients with PAP is
diffuse alveolar damage superimposed on usual variable; spontaneous resolution can occur as well
interstitial pneumonia (exacerbation of idiopathic as progression to respiratory failure.1,2 Five- and
pulmonary fibrosis), acute interstitial pneumo- 10-year survival rates in PAP are 75% and 68%,
nia, ARDS, cardiogenic pulmonary edema, and respectively.1,2 Death due to PAP is uncommon
412 Chapter 27. Unusual and Uncommon Pulmonary Disorders (Ryu)

and usually related to respiratory failure or calcify. Diffuse interstitial pattern is usually seen
uncontrolled infection. Superimposed infection, with systemic AL amyloidosis. HRCT scan
especially with opportunistic pathogens such as reveals bilateral nodular and/or reticular pattern
Nocardia, may occur and disseminate. Lung trans- with septal thickening.14
plantation is an option in those individuals with Pleural effusions may occur due to pleural
progressive disease that is not adequately re- involvement or from heart failure caused by
sponding to medical therapy. Recurrent PAP after cardiac amyloidosis.15 Other pulmonary mani-
double lung transplantation has been reported.10 festations are mediastinal and/or hilar adenop-
athy, mediastinal masses, and obstructive sleep
Pulmonary Amyloidosis apnea resulting from macroglossia.11,12
Diagnosis of pulmonary amyloidosis is
Amyloidosis is a heterogeneous group of achieved by obtaining biopsy material that reveals
acquired or inherited diseases characterized by the characteristic apple-green birefringence with
deposition of amyloid in the extracellular tissue polarized microscopy after staining with Congo
space. Amyloid, a fibrillar, insoluble, proteina- red.11–13 Tracheobronchial and diffuse parenchy-
ceous material, can deposit in the tracheobron- mal forms of pulmonary amyloidosis can be
chial tree or pulmonary parenchyma in either a diagnosed by bronchoscopy, although the endos-
localized or diffuse pattern.11,12 This pulmonary copist must be prepared for potential bleeding.
involvement can occur as part of a systemic Lung nodules are diagnosed by needle aspiration
process or be isolated to the lung.11,13 biopsy or surgical resection. Diagnosis of pulmo-
Most frequent types of amyloidosis are the nary amyloidosis should lead to an evaluation to
AL (primary) and AA (secondary) types. AL identify the underlying cause or condition leading
amyloidosis can occur alone or in association to amyloid deposition, if not already known, as
with multiple myeloma or another plasma cell well as the extent of involvement.
dyscrasia. AA amyloidosis occurs with chronic Treatment of amyloidosis varies with differ-
inflammatory or infectious disorders. The fre- ent types of pulmonary involvement and the
quency of pulmonary involvement is low with underlying cause of amyloidosis.16 Treatment of
secondary and familial amyloidosis, whereas diffuse parenchymal amyloidosis associated with
pulmonary involvement by AL (primary) sys- AL (primary) amyloidosis is directed against the
temic amyloidosis is relatively common. underlying plasma cell dyscrasia. This is also
Patients with pulmonary amyloidosis may true for hilar/mediastinal adenopathy. Prognosis
come to pulmonologists for evaluation of respi- is poor for patients with primary systemic
ratory symptoms or abnormal findings on chest amyloidosis with pulmonary involvement.
imaging, with or without previously diagnosed Symptomatic tracheobronchial involvement with
amyloidosis. Laryngeal and tracheobronchial localized stenosis can be treated with broncho-
forms of pulmonary amyloidosis may be seen scopic laser or surgery. External beam therapy
as focal nodules/plaques or diffuse submucosal has been reported to be effective in the treatment
infiltration and usually occur as localized amy- of tracheobronchial amyloidosis.17 The use of
loidosis. Diffuse endobronchial involvement is bevacizumab, an antivascular endothelial growth
recognizable bronchoscopically as shiny, pale factor antibody, has been reported to be effective
plaques with scattered focal stenoses. Symptoms in managing refractory pleural effusions in
associated with airway involvement depend on patients with primary (AL) systemic amyloid-
the extent of luminal compromise and include osis.18 Treatment of AL systemic amyloidosis
dyspnea, cough, hemoptysis, wheeze, atelectasis, generally involves systemic chemotherapy and
and recurrent pneumonias. peripheral stem cell transplantation.16
Pulmonary parenchymal involvement mani-
fests as single or multiple nodules or diffuse Birt-Hogg-Dubé Syndrome
parenchymal infiltrates.11,12 The nodular form is
often detected incidentally on chest radiography. Birt-Hogg-Dubé (BHD) syndrome is a rare,
These nodules may grow slowly, cavitate, or inheritable disorder (autosomal dominant) that is

the absence of skin or kidney lesions.21 Histo-
pathologic features in the lung are nonspecific
and include intraparenchymal air-filled spaces
surrounded by normal parenchyma or a thin
fibrous wall.23
Cystic lung disease seen in BHD syndrome
(Fig 2) needs to be distinguished from other lung
diseases characterized by multifocal or diffuse
cystic changes, including lymphangioleiomyo-
matosis, pulmonary Langerhans cell histiocyto-
sis, lymphocytic interstitial pneumonitis, and
Pneumocystis pneumonia.25,26 Pulmonary lym-
phangioleiomyomatosis, whether occurring in a
sporadic form or associated with tuberous
Figure 2. HRCT scan of a 59-year-old man with Birt-Hogg-
Dubé syndrome. Cysts of varying sizes scattered bilaterally
sclerosis complex, affects women of childbearing
are seen. age almost exclusively but can be associated with
renal tumors (angiomyolipomas) and may at
associated with cystic lung disease and pneumo- times be difficult to distinguish from BHD.27
thoraces.19,20 Recent studies suggest that BHD may Lymphocytic interstitial pneumonia and Pneu-
be an underdiagnosed cause of pneumothorax. mocystis pneumonia cause parenchymal infil-
BHD was first described in 1977 and is trates aside from cysts such as ground-glass
characterized by the cutaneous triad of fibrofolli- opacities, consolidation, nodules, and reticular
culomas (hamartoma of the hair follicle), tricho- opacities.25,26 In addition, both of these disorders
discomas, and skin tags, along with a propensity are usually symptomatic and are associated with
for renal tumors. It is caused by germline specific clinical contexts. Pulmonary Langerhans
mutations in the BHD (FLCN) gene that lies on cell histiocytosis encountered in adults is usually
chromosome 17 and encodes a tumor-suppressor a smoking-related interstitial lung disease and is
protein, folliculin.21,22 Folliculin is highly ex- characterized by irregular cystic lesions and
pressed in a variety of tissues, including the nodules predominantly affecting the upper and
skin, kidney, and lung. midlung zones with relative sparing of the
Characteristic skin lesions of BHD appear as bases.28 Rarely, metastatic neoplasms such as
firm, dome-shaped papules in adulthood during adenocarcinomas and low-grade sarcomas can
the third or fourth decades of life and occur present with cystic lung lesions.25,26
predominantly on the face, scalp, neck, and The diagnosis of BHD has obvious implica-
upper chest.19 Renal tumors associated with tions on family members and the need for their
BHD syndrome include oncocytic hybrid tumor, evaluation. Patients with BHD who experience
chromophobe renal cell carcinoma, clear cell pneumothorax are at high risk of recurrence and
carcinoma, and papillary renal cell carcinoma.19 should be managed accordingly (ie, consider
Patients with BHD syndrome who present pleurodesis). These patients also need to be
with cystic lung disease or a history of pneumo- screened for renal neoplasms.20,22
thoraces tend to be middle-aged without a
previous diagnosis of the underlying genetic IgG4-Related Disease
syndrome.22,23 Approximately 90% of adult
patients with BHD will have lung cysts demon- In 2001, Hamano et al29 reported the findings
strated on CT scan.22 Approximately 25% of of high serum IgG4 concentrations and dense
patients with BHD will experience pneumotho- lymphoplasmacytic infiltrates containing IgG4-
rax that will typically occur during third to sixth positive plasma cells in the pancreas in 20
decades of life.22–24 Some germline mutations of patients with sclerosing pancreatitis (also called
the BHD gene can cause pulmonary manifesta- autoimmune pancreatitis). Subsequently, similar
tions (cystic lung disease and pneumothorax) in IgG4-related lesions were identified in many

other organs such as the bile duct, salivary gland, Serum IgG4 levels and immunostaining of
lacrimal gland, liver, kidney, retroperitoneum the biopsy specimen with anti-IgG4 antibody are
(retroperitoneal fibrosis), aorta (inflammatory useful in making the diagnosis.32,36 Although
aneurysm), as well as the lung. It is now known serum IgG4 level was initially reported to be
that IgG4-related disease (IgG4-RD) can be elevated in nearly all patients with autoimmune
localized to one or two organs or present with pancreatitis,29 the prevalence of elevated IgG4
systemic disease.30,31 level appears to be lower in patients presenting
IgG4-RD manifests similar histopathologic with various extrapancreatic lesions of IgG4-RD.
findings in different organs and is characterized In patients with intrathoracic abnormalities
by diffuse lymphoplasmacytic infiltrate consist- associated with extrathoracic inflammatory or
ing of extensive IgG4-positive plasma cells and T fibrotic lesions, particularly pancreatitis, the
lymphocytes along with fibrotic (storiform) diagnosis of IgG4-RD should be considered.
changes.32,33 Other histopathologic features may Even in the absence of extrathoracic manifesta-
include eosinophilic infiltration and obliterative tions, some unusual cases of intrathoracic lesions,
angiitis. such as mediastinal fibrosis and focal inflamma-
Quantitatively, IgG4 is the smallest subclass tory lesions, may be IgG4-related in origin.
of IgG and accounts for only 3% to 6% of total IgG4-RD responds well to corticosteroid
IgG in normal serum. The IgG subclasses exhibit therapy.31,32,34–36 Starting dose of prednisone is
differences in their effector functions. Involve- typically 30 to 60 mg/d for 1 to 2 weeks, followed
ment of immunologic mechanisms seems likely by gradual tapering of the dose during the
in IgG4-RD but exactly what role IgG4 plays in subsequent weeks to a low maintenance dose
the pathogenesis and pathophysiology of this (eg, 10 mg/d). In the absence of recurrent
disorder remains unclear.32,33 The target antigens disease, corticosteroid therapy is eventually
in this inflammatory disorder and the trigger for discontinued. The role of other immunosuppres-
the serum IgG4 elevation are also not known. sive agents, such as azathioprine and rituximab,
IgG4-RD occurs in adults, more often in men is being studied, particularly for those patients
than in women, with a median age of 60 years with recurrent or refractory IgG4-RD.
(range, 17–80 years).32,34 Manifestations of IgG4-
RD commonly include pancreatic involvement Constrictive Bronchiolitis
but extrapancreatic lesions without pancreatic
involvement can occur.32,34 Systemic symptoms Bronchioles are small airways (internal di-
including fever may also be seen. ameter, 2 mm) that do not contain cartilage in
Intrathoracic manifestations of IgG4-RD in- their walls. Membranous and terminal bronchi-
clude focal parenchymal lesions (eg, inflamma- oles are purely air-conducting and respiratory
tory pseudotumor, plasma cell granuloma), bronchioles (diameter, 0.5 mm) contain alveoli in
interstitial infiltrates (organizing pneumonia, their walls. Bronchioles can be involved in a wide
nonspecific interstitial pneumonia patterns), me- array of lung diseases. For example, some
diastinal/hilar lymphadenopathy, and mediasti- interstitial lung diseases such as hypersensitivity
nal fibrosis.31,32,35 Malignancy (eg, lung cancer) pneumonitis and large airway diseases (eg,
may be suspected on initial presentation. Radio- bronchiectasis) can commonly involve the bron-
logically, the manifestations include solitary chioles. In some lung diseases, bronchioles may
nodule or mass, round-shaped ground-glass be the main site of pathology and these disorders
opacities, bilateral interstitial infiltrates consist- have been referred to as primary bronchiolar
ing of reticular and ground-glass opacities, and disorders and are associated with characteristic
thickening of bronchovascular bundles and histopathologic features.37 Primary bronchiolar
interlobular septa. On 18F-fluorodeoxyglucose disorders include respiratory bronchiolitis, acute
(FDG) PET scanning, abnormal FDG uptake is bronchiolitis, follicular bronchiolitis, diffuse pan-
observed in pancreatic and extrapancreatic le- bronchiolitis, mineral dust airway disease, and
sions. constrictive bronchiolitis.

cough.38,40 On auscultation, lungs usually sound
clear without adventitious sounds. Wheezing may
be heard in some patients. Evidence of expiratory
slowing and hyperinflation will be observed in
more severe cases. Pulmonary function testing will
demonstrate airflow obstruction, usually without
significant reversibility.
Chest radiography typically shows hyperin-
flation in the absence of parenchymal infiltrates.
HRCT scan reveals a mosaic pattern with patchy
areas of air trapping (Fig 3).38,40–42 Scattered
changes of bronchiectasis may be seen in some
Figure 3. HRCT scan of a 41-year-old woman with patients.
constrictive bronchiolitis associated with overlap connective The treatment of constrictive bronchiolitis
tissue disease. Mosaic attenuation is present bilaterally due varies with the underling cause.38,40 Causative
to patchy air-trapping on this expiratory view.
exposure or underlying disease needs to be
controlled. In general, corticosteroids adminis-
Constrictive bronchiolitis (also called obliter-
tered systemically or by inhaled route are
ative bronchiolitis or bronchiolitis obliterans) is a
relatively ineffective in reversing the air flow
form of obstructive lung disease that results from
obstruction.38,40,43 In organ transplant recipients,
bronchiolar scarring and narrowing.38,39 Con-
administration of macrolides (eg, azithromycin)
strictive bronchiolitis can be seen in a variety of
250 mg three times per week, has demonstrated
clinical settings, most recognizably in organ
some beneficial effects.44–46
transplant recipients (ie, bronchiolitis obliterans
syndrome).38,39 In addition to organ transplant
Spontaneous Pneumomediastinum
recipients, constrictive bronchiolitis may present
as obstructive lung disease of obscure etiology Pneumomediastinum is defined as the pres-
(eg, no smoking history) or abnormal CT scan ence of free air in the mediastinum. Pneumome-
findings suggestive of small airways disease with diastinum can be classified as spontaneous,
air trapping. traumatic, and iatrogenic (surgical and endo-
Constrictive bronchiolitis can be classified by scopic procedures). Spontaneous pneumomedi-
etiology into the following groups38: astinum (SP) is defined as the presence of air in
Allograft recipients the mediastinum without preceding traumatic or
Postinfectious (viruses, mycoplasma, bacteria, procedural injury and is subclassified into
fungi) primary (no apparent lung disease) and second-
Connective tissue diseases (eg, rheumatoid ary (known lung disease) categories.
arthritis, systemic lupus erythematosus) Potential sources of air into the mediastinum in
Inhalational injury (eg, popcorn lung caused cases of SP include airways, lung, and esophagus.
The proposed pathophysiology involves the de-
by diacetyl)

velopment alveolar rupture with dissection of air
Ingested toxins (eg, Sauropus androgynus)

along the interstitium and bronchovascular tissue
Drugs (eg, penicillamine, lomustine, cocaine)

sheath after a centripetal pattern toward the hilum
Other associations including inflammatory
and the mediastinum. Rarely, pneumomediasti-
bowel diseases, microcarcinoid tumorlets or
num may be caused by a mediastinal infection
diffuse neuroendocrine hyperplasia, paraneo-
with a gas-producing organism.
plastic pemphigus, menstrual-associated
Preexisting lung diseases are identified in
Cryptogenic constrictive bronchiolitis
approximately 50% of patients with SP and include
Patients with constrictive bronchiolitis typical- asthma, COPD, and interstitial lung diseases.47,48
ly present with slowly worsening exertional Precipitating events preceding SP may include
dyspnea, sometimes accompanied by a chronic coughing, sneezing, vomiting, exercise or athletic

momediastinum and symptoms occurs during 1 to
2 weeks. Associated pneumothorax may develop
in 10% to 30% of patients, but does not require
drainage in the majority of these patients. Recur-
rence of pneumomediastinum is unusual.47–49,51,52
Nothing to Disclose

Figure 4. CT scan of chest of a 24-year-old man with
spontaneous mediastinum related to inhalational drug this chapter.
abuse. Air is present in the mediastinum without pneumo-
thorax. References
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2. Trapnell BC, Whitsett JA, Nakata K. Pulmonary
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SP is typically encountered in young men and
2527–2539.
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Notes

Chapter 28. Mediastinal and Other Neoplasms
Objectives: thoracic inlet, diaphragm, sternum, vertebral

Discuss the anatomic compartments of the mediastinum. bodies, and pleura. Several different schemes
Discuss the diagnostic approach to mediastinal lesions exist in subdividing the mediastinum into
and management options.

compartments.1 For this discussion, we will
Discuss uncommon intrathoracic neoplasms.
employ the three-compartment model: anterior,
middle, and posterior. The anterior compartment
Key words: carcinoid; germ cell tumors; hamartoma;
lymphadenopathy; lymphomas; mediastinum; mediastinal
refers to the retrosternal space anterior to the
tumors; neurogenic tumors; salivary gland type carcinoma heart and the great vessels; it includes the
thymus and lymph nodes as well as adipose
Synopsis: and connective tissue. The posterior compart-
The differential diagnosis of a mediastinal mass is ment extends from the posterior heart border
facilitated by identifying its location within the mediastinal and trachea to the posterior aspect of the
compartments (ie, anterior, middle, posterior). In addition, vertebral bodies. It includes the descending
radiologic features, clinical context, and temporal course are
important parameters to consider. Approximately 25% to
aorta, azygous veins, esophagus, autonomic
30% of mediastinal masses occurring in adults are malig- ganglia and nerves, thoracic duct, and lymph
nant, a higher portion in the anterior mediastinum and in nodes. In between is the middle compartment,
children. Overall, the most frequent mediastinal lesions are
which contains the heart, ascending aorta and
thymoma, neurogenic neoplasms, lymphomas, and foregut
cysts. CT scanning is the most important imaging procedure aortic arch, brachiocephalic vessels, main pul-
and can define the density of the mass and effect on adjacent monary arteries and veins, vena cavae, lymph
structures. A confident diagnosis sometimes can be estab- nodes, trachea, and main bronchi.
lished based on characteristic CT scan features. MRI may be
useful in patients with contraindication to the use of
iodinated IV contrast or when additional characterization Mediastinal Tumors
of musculoskeletal or neurovascular anatomy is needed.
There are many types of uncommon to rare tumors that The differential diagnosis of a mediastinal
may be encountered in the thorax. Among these, more
frequently encountered tumors include the carcinoid tumor, mass is facilitated by identifying its location
salivary gland type carcinomas, and hamartoma. Bronchial within the mediastinal compartments (Table 1).
carcinoid tumors are malignant neoplasms with neuroen- CT scanning is the most important imaging
docrine differentiation and can be associated with ectopic
hormonal syndromes. Mucoepidermoid carcinoma and
procedure in the diagnosis of mediastinal lesions.
adenoid cystic carcinoma are the most common forms of CT scans can help define the density of the mass
salivary gland-type carcinomas seen in the thorax, usually (fat, fluid, air, calcification, heterogeneous atten-
involving the trachea or major bronchi. Hamartoma is a
uation) and effect on adjacent structures (com-
benign tumor-like malformation composed of abnormal and
disorganized mixture of tissue elements. Hamartoma is the pression, infiltration). Sometimes, a confident
most common benign neoplasm to occur in the lung, diagnosis can be established based on character-
accounting for approximately 75% of all benign lung tumors istic CT scan features (eg, teratoma, mediastinal
and 4% of solitary pulmonary nodules.
goiter, pericardial cyst). MRI typically adds little
additional information beyond that provided by
CT scanning but may be useful in patients with
Mediastinum contraindication to the use of iodinated IV
contrast or when additional characterization of
The mediastinum is the intrathoracic compart- musculoskeletal or neurovascular anatomy is
ment located between the two pleural cavities. needed (eg, neurogenic tumor with intraspinal
It includes those structures bounded by the extension).2,3

In general, the diagnostic approach to medi- Table 1—Mediastinal Masses According to Compartments
astinal masses includes consideration of the
Location Disorder
following parameters:
Anterior Thymoma and other thymic tumors
1. Location
Lymphomas
2. Radiologic features Germ cell tumors
3. Clinical context: age, symptoms, concurrent Thyroid goiter and other thyroid tumors
and previous illnesses Metastases
Miscellaneous parathyroid tumors,
4. Tempo: assess from evolution of clinical mesenchymal neoplasms (eg, lipoma,
manifestations and comparison to previous leiomyoma, lymphangioma), Morgagni
imaging studies hernia, etc.
Middle Lymphomas
Approximately 25% to 30% of mediastinal Metastases
masses occurring in adults are malignant, a Nonmalignant lymphadenopathy (infections,
sarcoidosis, silicosis, Castleman disease,
higher portion in the anterior mediastinum and
etc.)
in children.3 Symptomatic patients are also more Mediastinal cysts
likely to have a malignancy (50%) compared to Vascular lesions
those without symptoms (10% to 20%).3,4 Patients Miscellaneous lymphangioma, lipomatosis,
etc.
with mediastinal masses may experience local- Posterior Neurogenic neoplasms
ized symptoms related to compression or inva- Esophageal lesions
sion of adjacent mediastinal structures, Miscellaneous lateral meningocele,
extramedullary hematopoiesis, descending
metastatic sites, constitutional symptoms, or
aortic aneurysm, Bochdalek hernia, etc.
symptoms related to paraneoplastic syndromes.
Overall, the most frequent mediastinal lesions
are thymoma, neurogenic neoplasms, lympho- cell type. Precise histologic subclassification can
mas, and foregut cysts.5–7 be difficult since histologic heterogeneity is
common within thymomas. Several schemes
Anterior Mediastinal Lesions exist for classification of thymomas.
Thymoma usually occurs in adults, particu-
Thymoma
larly during the fourth and fifth decades of
life.3,9,10 One-half to two-thirds of patients pre-
Thymoma is defined as a low-grade epithelial
sent with symptoms such as cough, chest pain,
neoplasm of the thymus and is typically located
dyspnea, dysphagia, constitutional symptoms, or
in the superior aspect of the anterior mediasti-
symptoms related to one or more of the para-
num. It is the most common mediastinal neo-
plasm in most published case series.3,5,6 thymic syndromes. These parathymic syndromes
Grossly, most thymomas are encapsulated occur in 30% to 50% of patients with thymoma
firm masses but may have necrotic, hemorrhagic, and include myasthenia gravis (most common),
or cystic components. Invasive thymomas tend to pure red blood cell aplasia, hypogammaglobu-
infiltrate the surrounding mediastinal structures. linemia (Good syndrome), and connective tissue
Microscopically, thymomas are composed of a diseases.11 The remaining cases are discovered as
mixture of neoplastic thymic epithelial cells and asymptomatic mediastinal mass on routine chest
nonneoplastic T lymphocytes.8,9 Accordingly, radiography.3,9
thymomas are subclassified as predominantly Thymoma appears on chest radiography as
epithelial, predominantly lymphocytic, or mixed rounded, well-circumscribed, anterior mediasti-
lymphoepithelial types.8,9 The predominantly nal mass (Fig 1).3 On CT scan, thymoma is
epithelial cell type category displays a higher typically a homogeneous, discrete soft-tissue
rate of recurrence and tumor-related deaths than mass but may at times exhibit heterogeneous
other subtypes. Thymomas are also subclassified attenuation related to hemorrhage, necrosis, or
based on the type of neoplastic cells present: cystic changes. The role of PET scanning is
polygonal cell type, spindle cell type, and mixed unclear.12
422 Chapter 28. Mediastinal and Other Neoplasms (Ryu)

The diagnosis of thymoma may be obtained
by ultrasound or CT scan-guided core needle
biopsy or surgical excision.3,10 Local invasive
disease may be observed in about one-third of
cases, but lymph node and hematogenous spread
are relatively rare. Anatomic staging of thymoma
is based on assessment of capsular invasion at
the time of surgery and on microscopic exami-
nation. Thymomas can be divided into three
categories for staging: encapsulated, invasive, or
metastatic. Most widely used is the Masaoka
staging system.13 Figure 1. CT scan of the chest of a 56-year-old woman with a
Optimal treatment for thymoma is complete thymoma and myasthenia gravis. A discrete 3-cm mass is
surgical excision whenever possible. 9,10,13,14 present in the anterior mediastinum, anterolateral to the
ascending aorta.
Combined chemotherapy and radiation therapy
are used for locally invasive or metastatic
disease.10,13 In patients with thymoma associated clinical and radiologic presentation as for thymic
with myasthenia gravis and less than 55 to 60 carcinoma.17,18 Approximately one-third of pa-
years of age, thymectomy yields improvement in tients experience ectopic hormone production,
the neurologic disease, although the benefit of including Cushing syndrome (most common),
thymectomy is not immediate, with remission multiple endocrine neoplasia syndrome type I,
rate gradually increasing over the following 5 to syndrome of inappropriate antidiuretic hormone
10 years.11 Thymectomy in patients with pure red secretion, and carcinoid syndrome. Surgical
cell aplasia results in 40% to 50% remission rate, resection, when feasible, is the treatment of
while those with hypogammaglobulinemia do choice.17,18
not benefit from thymic resection. The overall Thymolipoma is a rare benign neoplasm that
5-year survival rate associated with encapsulated is composed of mature thymic and adipose tissue
thymomas is 70% to 90%, whereas patients with as demonstrated on a CT scan. It usually affects
invasive thymomas have a 5-year survival rate of young adults. Treatment is surgical resection,
50%.4,9,13,14 and the prognosis is excellent.14,18
Thymic cyst is another rare mediastinal
Other Thymic Tumors lesion and appears as a unilocular or multilocular
lesion, often with calcification, on CT. It may be
Thymic carcinoma is a rare epithelial malig-
acquired or congenital.18 Surgical resection is the
nancy with malignant histologic features (high or
recommended treatment.19
low grade) and typically presents as a large,
poorly defined infiltrative anterior mediastinal
Lymphomas
mass.15,16 Thymic carcinoma typically occurs in
the fifth and sixth decades of life, with a male
Lymphomas represent 4% to 5% of the
predominance.15,16 Most patients present with
respiratory and/or systemic symptoms. Regional estimated new cases of cancer overall and 3% of
lymph node and pulmonary metastases, as well cancer deaths in the United States.20 The World
as pleural and/or pericardial effusions are Health Organization classification, updated in
frequently noted at presentation. Surgical resec- 2008, stratifies lymphomas according to their cell
tion is the preferred treatment when feasible.16 lineage and their derivation from precursor or
Response to combined cisplatin-based chemo- mature lymphoid cells.21 Lymphomas represent
therapy and radiotherapy is generally poor, with 10% to 20% of adult mediastinal malignancies,
5-year survival rates of approximately 30%.16 and the majority involve the anterior or middle
Thymic carcinoid is a rare, malignant neuro- mediastinum.3 Lymphomas involve the mediasti-
endocrine neoplasm associated with similar num usually as part of widespread disease; in less

account for 15% of anterior mediastinal tumors in
adults.3,27–29 Like primary GCTs, extragonadal
GCTs are most common in young men (usually
3rd decade of life), but mature teratomas occur
with equal frequency in men and women. Germ-
cell tumors are generally classified into the
following three groups: teratomas, seminomas,
and nonseminomatous tumors.3,4,27–29
Teratomas (benign or mature) account for
60% to 70% of mediastinal GCTs and contain
varying amounts of tissues derived from at least
two of the three primitive germ layers: ectoderm,
endoderm, and mesoderm. Teratoma typically
Figure 2. CT scan of a 16-year-old woman with a mature affects children and young adults. The majority
teratoma. A large mass of heterogeneous attenuation is
of patients with benign teratomas are asymp-
present in the anterior mediastinum along with bilateral
pleural effusions. tomatic, and the tumor is discovered inciden-
tally.3,27 Characteristic but uncommon symptoms
include expectoration of hair (trichoptysis) or
than 10% of patients, lymphoma is limited to the
sebaceous debris due to a communication be-
mediastinum.22
tween the tumor and the airways. Radiologically,
Primary mediastinal lymphomas occur typi-
mediastinal teratomas are well-circumscribed
cally in the anterior mediastinum and are more
round or lobular masses that may contain fat
common in Hodgkin’s disease than in non-
(75%), calcification (20% to 40%), or cystic
Hodgkin’s lymphoma.22,23 Patients with primary
changes (Fig 2).3,27,30 Occasionally, teeth or bone
mediastinal lymphoma are usually young adults
may be recognized and are very suggestive of the
who may or may not be symptomatic (local or
diagnosis. Malignant degeneration of this tumor
constitutional symptoms) at the time of diagnosis.
can occasionally occur. Treatment of mediastinal
Radiologic studies generally demonstrate a teratoma is surgical excision performed through
lobulated mass or bulky adenopathy in the a median sternotomy or posterolateral thoracot-
anterior mediastinum.22–25 The diagnosis of omy.4,27,29 Thoracoscopic resection has also been
lymphoma requires an adequate biopsy speci- reported.29
men obtained by surgical excision or core needle Primary mediastinal seminoma is the second
biopsy of an enlarged lymph node or extranodal most common form of mediastinal GCT but is the
mass.26 Treatment of mediastinal Hodgkin’s most common malignant germ-cell tumor in this
disease and non-Hodgkin’s lymphoma usually location.3,27 Mediastinal seminomas are typically
consists of combination radiotherapy and che- diagnosed in young males (third and fourth
motherapy. Prognosis is better for those with decades of life) who are usually symptomatic,
mediastinal Hodgkin’s disease compared with most commonly with chest pain. Increased
non-Hodgkin’s lymphoma.3,22 serum level of b-human chorionic gonadotrophin
is noted in a minority of patients and serum
Germ Cell Tumors alpha fetoprotein level is usually within normal
range. Radiologically, mediastinal seminoma
Mediastinal germ-cell tumors (GCTs) consist manifests as a large, lobular, well-circumscribed,
of a diverse group of benign and malignant homogeneous mass.30 A fine-needle aspiration
neoplasms that usually are located in the anterior biopsy specimen is often adequate to make the
mediastinum. Germ-cell tumors are uncommon diagnosis. Pure seminomas are very radiosensi-
neoplasms that most frequently present as tive, but if nonseminomatous components (eg,
testicular tumors, but about 5% of these tumors embryonal carcinoma) are present, these tumors
can arise primarily in extragonadal locations tend be more aggressive and do not readily
such as the mediastinum.27 Germ-cell tumors respond to radiation therapy. Patients with

locally advanced disease may be treated with may induce hyperthyroidism. Symptomatic goi-
chemotherapy followed by resection of residual ters are surgically excised, usually through a
tumor. At the time of diagnosis, 60% to 70% of cervical incision.32,33
patients have metastatic disease, which requires
cisplatin-based combination chemotherapy with Other Anterior Mediastinal Masses
or without radiation.3,27
Nonseminomatous GCTs include choriocar- Lesions arising from parathyroid tissue can
cinoma, embryonal carcinoma, endodermal sinus rarely produce an anterior mediastinal mass.
tumor, teratocarcinoma, and mixed germ-cell These include parathyroid cysts, carcinomas, and
neoplasms. These rare tumors are commonly adenomas. These tumors tend to be small and are
grouped together because of therapeutic and usually detected by CT scan.
prognostic similarities which include rapid Other rare causes of anterior mediastinal
growth and poor outlook. These tumors typically masses include mesenchymal tumors (eg, lipo-
occur in young men (usually third and fourth ma, leiomyoma, lymphangioma) and Morgagni
decades of life) and are commonly associated hernia. Occasionally, metastatic disease may
with symptoms that include chest pain, hemop- present as an anterior mediastinal mass without
tysis, cough, fever, weight loss, gynecomastia, or a preceding cancer diagnosis.
superior vena cava syndrome.3,29 Serum tumor
markers, serum a fetoprotein and b-human Middle Mediastinal Masses
chorionic gonadotrophin levels are elevated in
approximately 80% and 30%, respectively.27 The differential diagnosis of middle medias-
Radiologically, these tumors present as large, tinal masses is broad and includes lesions of
irregularly shaped, heterogeneous masses with many causes.
areas of necrosis, hemorrhage, or cystic changes
along with evidence invasion into adjacent Mediastinal Lymphadenopathy
structures and metastases.3,30 Treatment usually
involves cisplatin-based combination chemother- There are many neoplastic and nonneoplastic
apy, followed by surgical resection of residual diseases that can cause mediastinal and/or hilar
neoplasm.3,4,29 Serial monitoring of serum a lymphadenopathy.3,34 Metastatic mediastinal/hi-
fetoprotein and b-human chorionic gonadotro- lar lymphadenopathy may be seen with lung
phin is helpful in assessing the response to cancer, lymphomas, and cancers of extrapulmo-
therapy and detecting early recurrence. nary origin.23 Infections, particularly fungi and
mycobacteria, are also commonly associated with
Thyroid mediastinal and/or hilar lymphadenopathy.
There are many other disorders that cause
Intrathoracic goiter can present as an anterior mediastinal lymphadenopathy and include sar-
mediastinal mass and usually results from coidosis, drugs (eg, phenytoin), silicosis, amy-
extension of a cervical thyroid goiter into the loidosis, Castleman disease, and so on. 34
mediastinum. An intrathoracic goiter can cause Diagnostic approach to mediastinal lymphade-
symptoms by compressing the trachea or esoph- nopathy requires integration of the radiologic
agus, but more commonly symptoms are absent. findings, clinical context, and tempo of the
Although most intrathoracic goiters are benign, disease process.
10% to 15% may contain thyroid cancer or
lymphoma.3,31 On chest radiography, intratho- Mediastinal Cysts
racic goiter is seen as a mass associated with
tracheal narrowing or deviation or as superior Primary mediastinal cysts are benign lesions
mediastinal widening. CT scan demonstrates a usually found in the middle mediastinum and
lobular, discrete mass with heterogeneous atten- include bronchogenic cyst, enteric cyst, and
uation.4 Caution needs to be exercised in admin- pericardial cyst.3,19,35,36 Bronchogenic cyst is the
istering iodinated radiocontrast dye since iodine most common.19,37

right cardiophrenic angle), the diaphragm, and
the anterior chest wall.36 CT scan demonstrates a
unilocular lesion with characteristic water atten-
uation and a thin cystic wall (Fig 3).41 Most
pericardial cysts are congenital, but they can be
acquired lesions. These cysts are usually asymp-
tomatic but occasionally can cause cardiac
compromise.42 These lesions do not require
intervention unless symptoms or diagnostic
uncertainty exists.35
Vascular Lesions
Vascular lesions such as aneurysms and

Figure 3. CT scan of an 80-year-old man with a pericardial
cyst. A homogeneous mass of water attenuation with a thin fistulas, constitute approximately 5% to 10% of
wall is seen in the right cardiophrenic angle. all mediastinal masses and may radiologically
resemble neoplasms.43 The diagnosis is usually
Bronchogenic cysts are lined with ciliated established by contrast-enhanced CT scans, MRI,
respiratory epithelium and contain serous fluid, and/or angiography.
mucus, blood, or purulent material. Broncho-
genic cysts are typically diagnosed in adults.38,39 Other Middle Mediastinal Masses
Patients are commonly asymptomatic at presen-
tation, although symptoms can be produced from Lymphangiomas are rare congenital or ac-
airway compression or communication of the quired disorder involving the lymphatic ves-
cyst with the airway. These cysts are most sels.44 Although most commonly found in the
commonly located in the subcarinal or paratra- neck, they can also occur in the mediastinum and
cheal regions but are occasionally in the lung or appear as solitary or multilobulated cystic
pleura.37 Radiologically, bronchogenic cysts ap- masses. These lesions are considered benign in
pear as homogeneous, nonenhancing masses of nature but can slowly enlarge and infiltrate
variable attenuation, depending on the composi- adjacent structures.44,45 Total resection is optimal,
tion of the fluid.36,37 When water attenuation is if feasible.
seen, it can be highly suggestive of the diagnosis. Mediastinal lipomatosis is a benign condition
Definitive diagnosis can be obtained by CT scan- characterized by abnormal adipose tissue accu-
guided, bronchoscopic, or endoscopic aspiration mulation in the mediastinum.46 It is associated
of the cyst fluid.38,39 Most bronchogenic cysts are with endogenous and exogenous steroid excess
surgically excised, but fluid aspiration and as well as obesity. CT scan reveals diagnostic
observation are other management options.38,39 features.46,47
Enteric cysts are lined by enteric or stratified
squamous epithelium and are usually seen in the Posterior Mediastinum
middle or posterior mediastinum.38,40 The major-
ity of enteric cysts are diagnosed in childhood.40 Neurogenic Tumors
They may cause symptoms by compression of the
trachea or esophagus as well as mucosal ulcera- The most common cause of posterior medi-
tion, hemorrhage, or cyst rupture if the cyst astinal masses is neurogenic neoplasm, which
contains gastric or pancreatic mucosa.3 Surgical accounts for 75% of primary posterior mediasti-
excision is the treatment of choice.38,40 Prognosis nal neoplasms.4,48 Neurogenic tumors may arise
following complete excision is excellent.38 from the peripheral, sympathetic ganglia (auto-
Pericardial cysts are lined by mesothelial cells nomic), or paraganglionic nervous systems.
and appear as well-circumscribed lesions abut- Ninety percent of neurogenic neoplasms occur
ting the heart (most commonly in the area of the in the paravertebral gutters.48,49 The majority

(70% to 80%) of neurogenic neoplasms are Neoplasms of the sympathetic ganglia arise
benign; the occurrence of multiple lesions sug- from nerve cells and include ganglioneuroma,
gests the diagnosis of neurofibromatosis and the ganglioneuroblastoma, and neuroblastoma.
associated risk of malignant transformation.3,4,49 These tumors are more common in the pediatric
Approximately one-half of neurogenic tu- population, and the majority are malignant.3,48
mors are first detected on chest radiography in Ganglioneuroblastoma and neuroblastoma are
asymptomatic patients.3,49 CT scanning helps to aggressive malignancies and usually affect chil-
define the location, characteristics, and margins dren in the first decade of life. Treatment for
of the mediastinal mass. Approximately 10% of limited disease is surgical resection.55,56 Manage-
mediastinal neurogenic tumors extend through ment of advanced disease includes chemothera-
the neural foramen into the spinal canal, creating py and radiation. Ganglioneuromas are benign
a dumbbell shape (‘‘dumbbell tumor’’).49 In this neoplasms and occur in older children and
setting, MRI is more sensitive than CT scanning young adults. One-half of the patients are
in delineating the extension through neural symptomatic from local effects of the tumor or
foramen and spinal canal involvement.2,50 intraspinal extension. CT scan demonstrates a
Peripheral nerve sheath tumors are the most well-circumscribed paraspinal mass that may be
common type (40% to 65%) of mediastinal associated with skeletal displacement or ero-
neurogenic tumors and include schwannoma sion.49 MRI may be needed to exclude intraspinal
(also called neurilemmoma), neurofibroma, and extension.3,50 Complete surgical resection is the
malignant peripheral nerve sheath neoplasm.3,48 treatment of choice and may necessitate a
combined thoracic and neurosurgical approach.55
They are most commonly diagnosed in asymp-
Mediastinal paraganglionic tumors are very
tomatic adults in the third and fourth decades of
rare and may arise from either sympathetic or
life. The vast majority of schwannoma and
parasympathetic cells.57 They can occur in all
neurofibromas are benign and slow growing.
three compartments of the mediastinum. Para-
They usually arise from a posterior spinal nerve
vertebral paragangliomas occur in young adults
root. Radiologically, schwannomas and neurofi-
and may be functional (ie, secrete catechol-
bromas are well-circumscribed round or lobular
amines). Catecholamine-secreting paraganglio-
posterior mediastinal masses.3,49,50 Associated
mas may be associated with neurofibromatosis
abnormalities may be seen in the ribs, vertebral
1, von Hippel-Lindau disease, Carney triad, and
bodies, and neural foramina due to pressure and
multiple endocrine neoplasia type 2.58 Mediasti-
erosion caused by the enlarging mass. The
nal paragangliomas generally behave as low-
treatment of choice is surgical resection. Com-
grade, indolent neoplasms.48,57 The treatment of
bined thoracic and neurosurgical approach may choice is surgical excision.
be needed for dumbbell tumors.51,52
Malignant peripheral nerve sheath neo- Other Posterior Mediastinal Masses
plasms are rare spindle cell sarcomas (,5% of
nerve sheath tumors) and include malignant Hiatal hernias are common and may manifest
neurofibrosarcomas, malignant schwannomas, radiologically as a retrocardiac mass. Lateral
and neurogenic fibrosarcomas. Approximately thoracic meningoceles are rare and consist of
one half of these are associated with neurofibro- redundant meninges that protrude through the
matosis.48,53 Pain and enlarging mass are com- neural foramen.59 CT scan demonstrates a well-
mon presenting manifestations of this tumor, circumscribed, paraspinous cystic lesion (homo-
which appears radiologically as a sharply mar- geneous water attenuation) that is continuous
ginated, round, heterogeneous mass on CT scan. with the thecal sac.36 Symptomatic lesions are
Evidence of local invasion and/or metastases treated with surgical excision.
may also be revealed. Complete surgical resec- Extramedullary hematopoiesis refers to the
tion is the optimal treatment; in patients with proliferation of hematopoietic cells outside the
unresectable tumors, adjuvant chemotherapy bone marrow in conditions of compromised
and radiation are options.3,48,54 tissue oxygenation. Most cases are associated

Carcinoid
Bronchial carcinoid tumors are malignant

neoplasms with neuroendocrine differentiation
and account for 1% to 2% of all thoracic
tumors.66–68 There is no clear association with
smoking. Carcinoid tumors have been histolog-
ically subclassified into typical (more common)
and atypical types.63,66 Atypical tumors have
higher mitotic activity (2 to 10 mitoses per 10
high-power fields) and necrosis.69
Patients with typical bronchial carcinoids
Figure 4. CT chest of a 68-year-old man with bronchial usually present in the fifth decade of life, while
carcinoid (typical) tumor. An endobronchial lesion is those with atypical carcinoids occur in older
present at the origin of the bronchus intermedius. patients.63,66 The majority of carcinoid tumors
are central or perihilar in location.69 Patients
with hemoglobinopathies manifesting severe, often present with symptoms related to bron-
chronic anemia such as thalassemia major, chial obstruction (eg, recurrent pneumonias or
hereditary spherocytosis, hemolytic anemia, or wheezing) or vascularity of the tumor (eg,
sickle-cell anemia.60,61 Myeloproliferative disor- hemoptysis).67,68
ders and other chronic illnesses associated with Bronchial carcinoids are occasionally associ-
persistent anemia may also lead to extramedul- ated with carcinoid syndrome caused by release
lary hematopoiesis. Extramedullary hematopoie- of serotonin and other vasoactive substances into
sis can be seen in the posterior mediastinum as the systemic circulation.67,70 Rarely, biopsy or
one or multiple, inhomogeneously contrast- manipulation of a bronchial carcinoid has result-
enhancing paravertebral masses.60,61 The diag- ed in acute carcinoid syndrome (carcinoid crisis).
nosis can be confirmed with percutaneous fine- Bronchial carcinoids can also cause Cushing’s
needle aspiration or thoracoscopic biopsy if syndrome and acromegaly due to ectopic pro-
needed. Extramedullary hematopoiesis usually duction of adrenocorticotrophic hormone and
regresses with treatment of anemia and the growth hormone-releasing factor, respec-
underlying condition or radiation therapy. tively.66,67
Thoracic duct cyst is a rare lesion that can Radiologically, bronchial carcinoids may
present in the posterior mediastinum and occasion- manifest obstructive pneumonia, discrete ovoid
ally in the neck (left supraclavicular fossa). It may hilar mass, endobronchial lesion (Fig 4), or,
arise as a congenital anomaly or be related to occasionally, a peripheral nodule.68,71 CT helps
inflammatory or traumatic injuries. Symptomatic identify the location and extent of the tumor as
worsening or increase in size of the lesion after well as the presence or absence of mediastinal
meals is a diagnostic clue.62 The diagnosis can be lymphadenopathy. MRI appears to be more
established by needle aspiration of the chylous fluid sensitive than CT in detecting hepatic metastases
within the cyst or lymphangiography. (the most common metastatic site). Somatostatin
receptor scintigraphy using a radiolabeled so-
Uncommon Thoracic Tumors matostatin analog such as 111In-octreotide can
sometimes be helpful in localizing the primary
There are many types of uncommon to rare tumor and in staging.67,68 The role of PET
tumors that may be encountered in the tho- scanning remains unclear.70
rax.63–65 Among these, more frequently encoun- Carcinoids are generally attached to the
tered tumors include the carcinoid tumor, bronchus by a broad base but can be polypoid
salivary gland type carcinomas (mucoepider- and create a ball-valve effect. Caution should be
moid carcinoma and adenoid cystic carcinoma), used in biopsy of these vascular tumors (typ-
and hamartoma. ically pink to red mass) but is generally safe.70

Typical carcinoid tumors are usually indolent with cough, hemoptysis, wheezing, or obstruc-
in behavior, and hilar/mediastinal nodal metas- tive pneumonia. CT scan may identify an
tases are uncommon.66,67 However, atypical carci- endobronchial lesion or findings of obstructive
noids have an aggressive course, and metastasis to pneumonia. Surgical resection is the treatment of
mediastinal lymph nodes are seen in 20% to 60% choice, and complete resection portends an
of cases. Atypical carcinoids are associated with a excellent prognosis.
higher recurrence rate compare to typical type. Adenoid cystic carcinomas (previously called
The 5-year survival rate associated with atypical cylindroma) also arise in the trachea or a major
carcinoid is 40% to 60% compared to 85% to 100% bronchus in most cases. It occurs in adults, most
for typical carcinoid.66,72 commonly in the fifth decade of life.73,76 Dyspnea,
Surgical resection of the tumor with complete cough, wheeze, and hemoptysis are the most
mediastinal lymphadenectomy is the treatment common presenting symptoms. Surgical resection
of choice for localized bronchial carcinoid tu- is the treatment of choice; however, this tumor
mors.66,67,70 Endobronchial removal (endoscopic has a propensity to recur locally and metasta-
resection or laser photoablation) of bronchial size.73,76 Late recurrence as long as 15 to 20 years
carcinoid is not generally recommended for after initial resection has been reported. Median
definitive therapy. Surgical resection of liver survival after resection is approximately 6
metastases may be of benefit in patients with years.73,76 Radiation and palliative laser therapy
limited hepatic disease.67 Hepatic artery occlu- are employed for unresectable tumors.
sion or embolization is an option for patients
who are not candidates for hepatic resection.67 Hamartoma
Octreotide, a somatostatin analogue, and
alpha interferon are employed in the treatment Hamartoma is defined as a benign tumor-like
of metastatic carcinoid tumors.66 Cytotoxic che- malformation that is composed of abnormal and
motherapy has had a limited therapeutic ef- disorganized mixture of tissue elements. Pulmo-
fect.67,68 Radiolabeled somatostatin analogues nary hamartoma typically consists of a combina-
and biologic agents targeting vascular endothe- tion of cartilage, connective tissue, smooth
lial growth factor pathway as well as tyrosin muscle, fat, and respiratory epithelium.77 Ham-
kinase inhibitors are being investigated.66,68 artoma is the most common benign neoplasm to
occur in the lung, accounting for approximately
Salivary Gland Type Carcinomas 75% of all benign lung tumors and 4% of solitary
pulmonary nodules.77
Mucoepidermoid carcinoma and adenoid Pulmonary hamartomas occur in all patient
cystic carcinoma are the most common forms of age groups; highest incidence is in the fourth to
salivary gland type carcinomas that can occur in seventh decades of life.77,78 The majority of
the thorax and account for 0.1% to 0.2% of all pulmonary hamartomas are located in the pe-
thoracic tumors.73 Both are considered low-grade riphery of the lung and are not associated with
malignancies and lymph node spread is rare to symptoms.77,78 Radiologically, hamartoma ap-
uncommon. Neither tumor has a clear associa- pears as a solitary round or lobulated opacity
tion with smoking. with smooth margins, generally measuring 1 to 3
Mucoepidermoid carcinoma is derived from cm.79,80 Calcification is detected in approximately
minor salivary gland tissue in the proximal 25% of hamartomas, appearing as small flecks
tracheobronchial tree.74 This tumor usually ap- throughout the lesion; the classic appearance of
pears as an endobronchial mass in the trachea or ‘‘popcorn’’ calcification is infrequent.79,80 Areas
major bronchi.73–75 Histologically, mucoepider- of fat density are seen by CT scan in up to one-
moid carcinoma consists of three components: half of cases and are a reliable sign of hamartoma
mucus secreting, squamous, and intermediate in a smooth nodule measuring less than 2.5 cm in
cells.74 Pulmonary mucoepidermoid carcinoma diameter.46,79–81 Hamartomas grow slowly, if at
occurs in patients over a wide age range, from all. Diagnostic confirmation, if needed, requires
children to elderly.73 Patients usually present tissue diagnosis, which can be obtained by

transthoracic needle aspiration biopsy, bronchos- current practice among members of the European
copy, or thoracoscopy. Society of Thoracic Surgeons. J Thorac Oncol. 2011;
6(3):614–623.
Nothing to Disclose 13. Venuta F, Rendina EA, Coloni GF. Multimodality
treatment of thymic tumors. Thorac Surg Clin.
The author has disclosed that no relation- 2009;19(1):71–81.
ships exist with any companies/organizations 14. Wright CD, Kessler KA. Surgical treatment of
whose products or services may be discussed in thymic tumors. Semin Thorac Cardiovasc Surg.
this chapter. 2005;17(1):20–26.
15. Moran CA, Suster S. Thymic carcinoma: current
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Chapter 29. Lung Transplantation
Objectives: limited survival. Advances in donor and recip-

Define the indications for lung transplantation. ient selection, improved surgical techniques,
Review the guidelines for recipient selection for lung new immunosuppressive drugs, and better
transplantation.
Describe the relative and absolute contraindications to
management of infections have all contributed
lung transplantation. to improved survival. Despite these advance-
Describe outcomes following transplantation, including ments, numerous complications still exist fol-
survival and physiologic results.

lowing LT.
Review the complications following lung transplanta-
tion. According to the 2011 report from the
Provide an overview of the immunosuppressive medi- International Society of Heart Lung Transplanta-
cations used in lung transplantation. tion (ISHLT), .30,000 lung transplant procedures
have been performed worldwide; in 2009 alone,
Key words: acute rejection; cytomegalovirus; immunosup-
3,272 procedures were performed. The 1-year, 3-
pression; lung transplantation; obliterative bronchiolitis
year, 5-year, and 10-year survival rates are 79%,
Synopsis: 64%, 53%, and 30%, respectively, as reported by
the Registry of the ISHLT.1 The major rate-
Lung transplantation is now a well-accepted therapeutic
option for the treatment of end-stage lung disease. limiting factors to the long-term survival of lung
Indications for lung transplantation include idiopathic transplant patients remain chronic rejection and
pulmonary fibrosis, chronic obstructive pulmonary disease,
infection.
cystic fibrosis, and pulmonary hypertension, among others.
Following transplantation, complications can develop, Most lung transplant referrals come from
including primary graft dysfunction, infection, and rejec- pulmonary physicians from outside of tertiary
tion. Although survival rates of lung transplant recipients transplant centers. With the increase in the
have improved over the years, they still remain lower than
survival rates for other solid organ transplant recipients. number of transplant recipients, much of the
The leading factor preventing long-term survival is the subsequent follow-up care is now conducted by
development of chronic rejection. The development of the referring pulmonologist for logistical conve-
better strategies for preventing and treating rejection and
infection has allowed significant advancements in the field
nience and often is dictated by insurance
of lung transplantation. All phases of lung transplantation company mandates. This section will attempt to
including the indications; evaluation; new donor allocation concisely review the topic of LT for the pulmo-
system; outcomes; and complications including graft
nary physician.
dysfunction, acute and chronic rejection, infection, and
complications related to immunosuppression will be re-
viewed. Indications for LT
Heart-Lung Transplantation (HLT)

During the last three decades, lung transplanta-
tion (LT) has become a successful therapeutic One of the original successful lung transplant
option for patients with end-stage pulmonary procedures, which was performed primarily in
parenchymal and vascular diseases. Dr. James the late 1980s and early 1990s, was HLT.
Hardy at the University of Mississippi per- Currently, HLT is performed very infrequently
formed the first lung transplant in 1963. How- at only a few transplant centers and should be
ever, the patient survived for only 18 days. reserved for patients who cannot be treated by LT
Subsequent attempts at lung transplantation alone. The most frequent indications for HLT are
were complicated by bronchial anastomotic Eisenmenger syndrome with a surgically uncor-
dehiscence and early graft failure, resulting in rectable cardiac anomaly or severe end-stage

lung disease with concurrent severe heart dis- performed for these indications). SLT was initially
ease. thought to be a poor choice of procedure for the
treatment of COPD patients owing to concerns of
Bilateral Lung Transplantation (BLT) preferential ventilation to the compliant native
lung, but these concerns have proven to be largely
BLT is performed in patients with suppura- unfounded acutely, although hyperinflation can
tive pulmonary lung disease (ie, cystic fibrosis still pose a problem in the posttransplant period.
[CF] and bronchiectasis). In fact, 27% of all BLT Other indications for SLT include idiopathic pul-
procedures in the registry have been performed monary fibrosis (32% of all SLT procedures in the
as treatment for CF. Initially, double-lung trans- registry), familial pulmonary fibrosis, drug-in-
plantation was the procedure of choice with the duced or toxin-induced lung disease, occupational
anastomosis performed at the level of the lung disease, sarcoidosis, limited scleroderma,
trachea; however, the rate of ischemic airway lymphangioleiomyomatosis, Langerhans cell his-
complications was prohibitive. Now, BLT (essen- tiocytosis, and other disorders resulting in end-
tially, sequential single-lung transplantation stage fibrotic lung disease. SLT is also rarely
[SLT]), in which the anastomoses are performed performed for pulmonary vascular disease (,1%
at the level of the mainstem bronchi, is the of all SLT procedures in the registry), although the
preferred surgical technique. Most centers now immediate postoperative period can be difficult
also perform BLT for patients with COPD owing to the large volume of blood flow going to
(secondary to tobacco use [26% of all BLT the transplanted lung.
procedures in the registry] or a1-antitrypsin The theoretical advantages of SLT have
deficiency [7% of all BLT procedures] in the included reduced surgical morbidity, shortened
registry) owing to a longer posttransplant life hospitalization, and, often, the avoidance of
expectancy from the increased reserve provided cardiopulmonary bypass. This procedure also
during times of graft complications. In fact, in
results in the optimization of the use of donor
2009, 67% of COPD patients receiving a trans-
organs, which are in critical shortage.
plant underwent a BLT procedure.1 In addition,
most centers prefer to perform a BLT procedure
in patients with pulmonary arterial hypertension Guidelines for Recipient Selection
(PAH; 5% of all BLT procedures in the registry).
Although a single-lung allograft with normal There are consensus-based guidelines for the
pulmonary vasculature can accommodate the selection of lung transplant candidates.2 Al-
entire right ventricular output without elevation though they are consensus-based, they have
of pulmonary artery pressures, there can be taken into consideration a greater body of
hemodynamic instability postoperatively, and in evidence and transplant experience since the
times of graft compromise, such as rejection or earlier version in 1998, and have several impor-
infection, severe ventilation-perfusion abnormal- tant modifications over the original guidelines
ities can develop. Overall, BLT procedures are (Table 1).
now being performed significantly more often Any patient with end-stage pulmonary or
than SLT procedures, and account for the cardiopulmonary disease with the capacity for
increase in total number of transplants per- rehabilitation can be considered for transplanta-
formed annually. tion. The patient should have untreatable end-stage
pulmonary disease, no other significant medical
SLT illness, and a limited life expectancy. The candidate
should be ambulatory with rehabilitation potential.
SLT may be performed for the treatment of The patient must be psychologically stable, com-
obstructive nonsuppurative lung disease such as mitted to the idea of transplantation, and willing to
emphysema secondary to tobacco use or a1- comply with the rigorous medical protocols and
antitrypsin deficiency (47% and 6%, respectively, regimens required for a successful lung transplant
of all SLT procedures in the registry have been outcome.
434 Chapter 29. Lung Transplantation (Levine)

Table 1—Guidelines for Recipient Selection for Lung Transplantation
Criteria Description
General selection criteria Untreatable end-stage obstructive or restrictive pulmonary parenchymal or pulmonary
vascular disease
No other significant medical diseases
Substantial limitation of daily activity
Limited life expectancy
Ambulatory with rehabilitation potential
Satisfactory psychosocial profile and emotional support system
Age 65 y
Relative contraindications Critical or unstable medical condition
Systemic or untreated extrapulmonic disease
Colonization with resistant bacteria, fungus, or atypical mycobacteria
Symptomatic osteoporosis
Severely limited functional status
Mechanical ventilation
Ideal body weight ,70% or >130% (BMI . 30 kg/m2)
Absolute
contraindications Extrapulmonic disease (ie, renal [creatinine clearance, ,50 mg/mL/min])
HIV infection
Malignancy within prior 2 y
Hepatitis B antigen positivity
Hepatitis C biopsy-proven liver disease
Severe musculoskeletal disease
Substance addiction in prior 6 months (including tobacco use)
Absence of a reliable support system
Untreatable psychosocial problems, and medical noncompliance
Modified from Orens et al.2
Age plants for patients with systemic disease that is

not entirely limited to the lungs after a very
The 2006 international guidelines for the complete and careful evaluation (eg, a scleroder-
selection of transplant candidates2 now suggest ma patient undergoing an intensive GI evalua-
an age limit of 65 years as, generally, but not tion for reflux disease).
firmly, the upper limit regardless of procedure Patients with diabetes mellitus, hypertension,
type, although this is somewhat arbitrary, and is or peptic ulcer disease should be evaluated
very center-dependent. In fact, age limits are one carefully before being considered as candidates
of the most varied criteria used between centers, for LT, and should only be accepted if their
with many centers now increasing upper limits disease is well controlled and there is no
towards 70 years of age. Numerous patients with resulting end-organ damage.
end-stage pulmonary disease are middle-aged to Patients with active sites of infection are not
older, and there has been a trend to performing considered to be good transplant candidates.
LT in older patients. Treated TB and fungal diseases pose a particular
problem but are not contraindications for LT.
Relative Contraindications Many centers will not consider performing a
transplant in a patient who has chronic coloni-
Systemic or Multisystem Disease: Transplanta- zation with a resistant organism (eg, Burkholderia
tion is not contraindicated in patients with cenocepacia with the specific genomovar III
systemic diseases that are limited to the lungs, (contraindicated at most LT centers), methicillin-
such as scleroderma, systemic lupus erythema- resistant Staphylococcus, atypical mycobacterium,
tosus, polymyositis, and rheumatoid arthritis. or Aspergillus (contraindicated at some LT cen-
These cases should be considered on an individ- ters). Centers should try to eradicate these
ual basis. Some centers are performing trans- organisms in the pretransplant period and

consider each patient on an individual basis. prednisone 20 mg/d and may consider patients
However, if considered, these patients should be who are receiving higher doses.
candidates only for BLT procedures, since the Prior Thoracic Surgery: Prior thoracotomy or
remaining colonized lung could pose a serious pleurodesis was once considered to be a relative
threat to the new graft in the case of an SLT. contraindication to transplantation owing to
Osteoporosis: Osteoporosis has become a increased technical difficulties and increased
significant problem in the posttransplant period, bleeding. Despite this, transplantation can be
and preexisting symptomatic osteoporosis has successfully performed in these patients.
been identified as a relative contraindication to
transplantation. Bone densitometry should be Absolute Contraindications
part of the pretransplant evaluation, and treat-
ment should be initiated in those patients with The 2006 international guidelines2 identified
evidence of osteoporosis that is symptomatic or several absolute contraindications to LT, includ-
in those who are asymptomatic. ing major organ dysfunction (ie, renal creatinine
Mechanical Ventilation: A requirement for clearance of ,50 mg/mL/min), HIV infection,
invasive mechanical ventilation had been a hepatitis B antigen positivity, and hepatitis C
strong relative contraindication to transplanta- with biopsy-documented liver disease. Active
tion, although LT was been performed success- malignancy within the prior 2 years is also a
fully in small numbers of patients with CF who contraindication to transplantation. For patients
had been receiving mechanical ventilation. With with a history of breast cancer greater than stage
the advent of the new lung allocation scoring 2, colon cancer greater than Duke A stage, renal
system (to be discussed below), there are carcinoma, or melanoma greater than or equal to
increasing numbers of patients with higher level 2, the waiting period should be at least 5
scores who are receiving transplants and many years. Restaging is suggested before transplant
of these are on mechanical ventilation. Patients listing.
who are receiving noninvasive ventilatory sup- Severe Musculoskeletal Disease: Severe non-
port can be considered for transplantation.3 osteoporotic skeletal disease, such as kyphosco-
Nutritional Status: To be considered for liosis, is often an absolute contraindication to
transplantation, patients should have an ideal transplantation, primarily because of the techni-
body weight of .70% or ,130% predicted or cal difficulties encountered during surgery.
BMI .30 kg/m2. Those patients with poor Substance Abuse: Drug abuse and alcoholism
nutritional status may be too weak to withstand are considered to be contraindications to trans-
the surgical procedure; those patients who are plantation because patients with these conditions
obese make more difficult surgical candidates are at high risk for noncompliance. Patients who
and may have higher mortality rates than continue to smoke despite having end-stage
nonobese patients.4 pulmonary disease are not candidates for LT.
Corticosteroids: Initial data implicated cortico- Transplant centers require patients to abstain
steroids as a cause of tracheal bronchial dehis- from cigarette smoking, alcohol use, or narcotic
cence. At most centers, patients were required to use for 6 months to 2 years before being
have completely discontinued therapy with considered for lung transplant evaluation.
corticosteroids. This certainly eliminated a large Psychological Criteria: The patient must be
number of patients with chronic obstructive lung well motivated and emotionally stable to with-
disease and pulmonary fibrosis. Subsequently, stand the extreme stress of the pretransplant and
pretransplant low-dose therapy with corticoste- perioperative period. A history of noncompli-
roids has proved acceptable for patients who ance or significant psychiatric illness is an
cannot have therapy with corticosteroids com- absolute contraindication, although many pa-
pletely discontinued. Currently, transplant pro- tients will present with reactive depression or
grams will consider patients who can be anxiety in the terminal phase of their pulmonary
maintained in the long term on a regimen of illness.

Table 2—Disease-Specific Criteria for Lung Transplantation
Disease Criteria
COPD BODE index of 7 or at least one of the following:

FEV1 of ,20% predicted (nonreversible) and diffusing capacity ,20% or homogenous emphysema on HRCT;
Hospitalization with PaCO2 of .50 mm Hg;
Cor pulmonale or pulmonary hypertension; and O2-dependent hypercapnic patients (refer early)
BODE index of .5 (refer to lung transplant center)
IPF Diagnosis of UIP with any of the following:
Diffusing capacity, ,39% predicted;
A decrease in FVC of 10% in 6 mo of follow-up;
A decrease in pulse oximetry below 88% on a 6-min-walk test;
Honeycombing seen on HRCT;
Histologic or radiographic evidence of UIP irrespective of vital capacity (refer to lung transplant center);
CF FEV1 of ,30% predicted (refer);
Clinical deterioration with FEV1 of .30% predicted (exacerbation, hemoptysis, and pneumothorax) (refer);
PaCO2 of .50 mm Hg;
PaO2 on room air of ,55 mm Hg;
Pulmonary hypertension; and
Young, female patients (refer early)
PAH WHO class III-IV despite vasodilator treatment;
Cardiac index of ,2 L/min/m2;
Right atrial pressure of .15 mm Hg; and
Low (,350 m) or declining 6-min-walk test distance
UIP ¼ usual interstitial pneumonitis. Adapted from Orens et al.2
Disease-Specific Guidelines for LT of airway obstruction, dyspnea score, and exercise

capacity) when evaluating patients with COPD,
One of the most difficult decisions when and suggested that a BODE index score of 7
referring a patient for transplantation is defining should be among the criteria for transplantation in
the appropriate time for transplantation (also patients with COPD and that a BODE index of .5 is
called the transplant window). The potential appropriate for transplant referral. The guidelines
candidate should be sick enough to have a also suggest that patients with COPD are in the
limited life expectancy, but not so disabled that transplant window if the FEV1 is ,20% predicted
the individual will be unable to withstand the without reversibility with bronchodilator adminis-
procedure. In 2006, revised guidelines were tration, the diffusing capacity is ,20% or there is
established to define the transplant window for homogenous distribution of emphysema on a high-
specific diseases (Table 2).2 resolution CT (HRCT) scan, PaCO2 . 50 mm Hg,
In general, however, most centers agree that it and/or cor pulmonale or pulmonary hypertension
is never really ‘‘too early’’ to refer a patient for are present. Those patients who are hypercapnic
evaluation for LT. and hypoxemic and require oxygen supplementa-
tion should be given preference. If the criteria are
COPD met, rehabilitation and long-term supplemental
oxygen therapy should be initiated while the
The variability in the natural course of COPD patient is awaiting LT.
makes it especially difficult to predict when
patients should be referred for LT. Based on the Idiopathic Pulmonary Fibrosis (IPF)
available data from several large studies determin-
ing the predictors of mortality in COPD, guidelines On the basis of studies showing poor survival
have been established. The 2006 revised guidelines times in patients with IPF and the fact that most
recommend the inclusion of the BODE index (an patients have a progressive downhill course,
index derived from measurements of BMI, degree patients with pulmonary fibrosis should be

referred for transplantation early. In fact, this is complex (genomovar 3) can result in significant
the group of patients who had the highest morbidity and mortality posttransplant and
mortality rate while on the transplant list, before should be considered a strong relative contrain-
the revision in the donor allocation system. The dication to LT.8,9 In one study of 75 patients,10
2006 revised guidelines have suggested that there was a significant difference in 1-year
these patients should be referred to a transplant survival between those patients not infected
center at the time of a diagnosis of usual (92%) and those colonized with a non-B cenocepa-
interstitial pneumonitis, and should undergo cia Burkholderia strain (89%), compared to those
transplantation when diffusing capacity is colonized with B cenocepacia (29%). Similar results
,39% predicted, when there is a decrease in of variable survival rates, based on B cenocepacia
FVC of 10% in the 6 months of follow-up, when species, have been found in other studies.7,9 On
there is a decrease in pulse oximetric saturation the basis of these these data, most transplant
to ,88% on a 6-min walk test, or when centers will not transplant colonized or infected
honeycombing is seen on a HRCT scan. patients with this organism.
CF PAH
Although there has been an improvement in Based on the extrapolation of data from the
life expectancy for patients with CF, most National Heart, Blood, and Lung Transplant
patients still die from respiratory failure and Registry for PAH, selection guidelines have
cor pulmonale. The international guidelines have been established for patients with PAH. These
suggested that the following criteria be used to guidelines suggest that patients who are or
define the transplant window for CF patients: remain in World Health Organization (WHO)
FEV1 30% predicted or an FEV1 . 30% predicted class III or IV, despite receiving optimal
with progressive deterioration, such as an in- therapy, including vasodilators such as prosta-
creasing number of hospitalizations, a rapid cyclin, and those with a depressed cardiac
deterioration in FEV1, cachexia, and/or massive index (,2 L/min/m2), a right atrial pressure
hemoptysis; PaO2 , 55 mm Hg on room air; of .15 mm Hg, or low or declining 6-min walk
PaCO2 . 50 mm Hg; or pulmonary hypertension. test distances, should be considered for trans-
Female patients and patients younger than 18 plantation. Other patients should be observed
years have a more progressive course and should closely and reassessed for transplantation at 6-
be considered for LT earlier month intervals.
Patients with CF present the highest risk for
recipient-harbored infection owing to the fre- PAH Associated With Congenital Heart Disease
quent colonization and infection with multiresis- and Eisenmenger Syndrome
tant microorganisms including bacteria (gram-
negative rods and gram-positive cocci), fungi, Patients with PAH associated with congenital
and occasionally, atypical mycobacterium. Most heart disease have been found to have a
recent data suggest that patients colonized with significantly better prognosis than those patients
multidrug-resistant pseudomonas appear to with primary disease. Therefore, owing to the
have acceptable outcomes, including survival individuality of the progression of this disease,
following LT, and should not be excluded on precise criteria for transplantation have not been
that criterion alone.5,6 established. In general, patients are usually
In contrast, a former subspecies of pseudo- referred to transplant centers for evaluation
monas, now subspeciated as B cenocepacia, owing when they are in WHO class III or IV.
to its unique resistance patterns, can pose signif-
icant problems in transplant recipients. There Pretransplant Evaluation
have now been at least nine distinct genotypic
variants (genomovars) identified in the B cenoce- Once a patient is deemed to be a potential
pacia complex.7 Colonization with B cenocepacia candidate for transplantation, several studies are

usually performed for further assessment. Typi- Donor Allocation
cally, these include pulmonary function tests,
including lung volumes, spirometry, and diffus- Until the spring of 2005, as established by the
ing capacity, and a measure of exercise perfor- United Network of Organ Sharing, lungs were
mance, such as a 6-min walk test. Cardiac allocated primarily by time on the waiting list,
evaluation includes an ECG and an echocardio- and not by necessity. In the spring of 2005, the
gram, in addition to a functional cardiac study, system for donor allocation for lungs was
such as dobutamine echocardiography, and/or revised, and assigned priority for lung offers
coronary angiography, for patients older than 40 became based on a benefit or need-based lung
years or those with significant risk factors for allocation score (LAS).10 The LAS is calculated by
coronary artery disease. A CT scan is often using the following measures: (1) waitlist urgen-
obtained to look for bronchiectasis, which could cy measure (ie, the expected number of days
lived without a transplant during an additional
indicate the necessity for a bilateral procedure, or
year on the waitlist); (2) posttransplant survival
to look for focal nodules that were not apparent
measure (ie, the expected number of days lived
on plain chest radiographs. Renal and liver
during the first year post transplant); and (3) the
functions are assessed by 24-h creatinine clear-
transplant benefit measure (ie, the posttransplant
ance and liver function tests, respectively. Serol-
survival measure minus waitlist urgency mea-
ogy tests for hepatitis and HIV should also be sure). Components of the LAS include diagnosis,
obtained. Most of these investigations can be age, functional status, use of assisted ventilation,
performed at the referring center. In those height and weight, presence of diabetes, use of
patients being evaluated for SLT, a ventilation- supplemental oxygen, percentage predicted FVC,
perfusion scan with quantitation may suggest the 6-min-walk distance, serum creatinine value,
preferred side to be transplanted if there is pulmonary artery systolic pressure, mean pul-
unequal distribution of perfusion. monary artery pressure, pulmonary capillary
While awaiting transplantation, patients wedge mean, and arterial or venous PCO2.
should have close follow-up by the transplant The change in allocation system has resulted
center or their referring physician for both in several important changes, indicating that the
physiologic and emotional support. In those LAS is achieving many of its goals,11,12,13 such
patients who are in the pretransplant phase for that patients with pulmonary fibrosis have
the treatment of suppurative lung disease, moved significantly higher (ie, shorter wait time)
sputum cultures are sometimes obtained at 3- on the waiting list in comparison to their ranking
month intervals to assist in the antibiotic regimen using the prior time-accrual allocation system.
in the immediate postoperative period. Those The distribution of patients undergoing LT
changed after the institution of the LAS, with
patients who are able to should be involved in a
more IPF and CF patients undergoing a trans-
rehabilitation program before undergoing trans-
plant, and fewer COPD patients. In fact, IPF is
plantation.
now the leading indication for LT in the United
There are several studies reporting evidence
States. The mean LAS increased significantly
that strongly supports the causal role of
following the institution of the LAS, suggesting
gastroesophageal reflux (GERD)-induced aspira- that sicker people are undergoing a transplant.
tion in the development of bronchiolitis obliter- Fewer people are dying on the transplant waiting
ans syndrome (BOS). Most centers support the list, and waiting list times are shorter. Despite
evaluation for GERD before LT, especially those this, survival rates are comparable before and
patients with pulmonary fibrosis, CF, and after the implementation of the LAS. Further
especially those with collagen vascular disease refinements of the system are ongoing as we
(eg, scleroderma). This evaluation varies be- learn more of the longer-term effects. There have
tween centers but usually includes a pH probe, been concerns raised regarding the new LAS
manometry, and a gastric-emptying study. system and the scoring for PAH patients. If the

patient has a cardiac index ,1.8 L/min/m2 or a donors are now also being used at some (mostly
right atrial pressure .15 mm Hg and is not non-US) centers, but the number is increasing at
improving on therapy, the center can ask for US centers, as well, and may prove to partially
exception LAS points and these are often alleviate the shortage of donor organs.16
granted. Donors are excluded from potential lung
donation if they have evidence of active infection,
Living Donor Transplantation HIV infection, hepatitis infection, and/or malig-
nancy. Donor and recipient compatibility are
A few institutions worldwide are now per- assessed by matching by A, B, and O blood
forming living donor transplantations. The pri- types and chest wall size. At this time, human
mary indication for living donor transplantation leukocyte antigen (HLA) matching is not rou-
is CF. Generally, two blood group-compatible tinely performed in LT.
living donors each provide a lower lobe to the
recipient. Ideally, the donors should be larger Surgical Procedure
than the recipient so that the donor lobes fill the
hemithorax. This procedure is not performed at For an SLT, the recipient surgery is performed
most lung transplant centers owing to certain via a posterolateral thoracotomy incision or
technical and ethical issues involved. sternotomy. The recipient left atrium and donor
pulmonary vein undergo anastomosis first, fol-
Donor Criteria lowed by the bronchial anastomosis, and finally
the arterial anastomosis. BLT is usually per-
Donor organ shortage remains the greatest formed through a transverse thoracosternotomy
limiting factor in the numbers of LT procedures (clam shell incision or median sternotomy).
performed. Most potential lung donors are brain Cardiopulmonary bypass may be required in
dead, and, as stated above, only a small number cases of pulmonary hypertension or in cases for
of living donor-related lung transplant proce- which the recipient may not tolerate one-lung
dures are being performed. The traditional donor ventilation. Organ preservation remains a major
selection criteria include age ranging from area of research in LT. Currently, the lung can
younger than 60 years to 65 years, no history of only be preserved for a period of approximately
significant lung disease, and a limited smoking 4 to 6 h without experiencing significant ische-
history. In addition, potential donors should have mia-reperfusion injury, and goals should be to
clear lung fields on chest radiographs and keep ischemic times below 4 to 6 h. Newer
adequate gas exchange as assessed by a PaO2 of technologies, such as ex vivo lung perfusion,
.300 mm Hg on a fraction of inspired oxygen may increase this time period and permit a larger
(FIO2) equal to 1 and a positive end-expiratory area for donor allocation.16
pressure of 5 cm H2O or a PaO2/FIO2 ratio of
.300 mm Hg. A normal sputum Gram stain Management After the Postoperative
finding and/or endobronchial inspection is also Period
part of the donor evaluation examination. Mar-
ginal or extended donors (ie, those not meeting Patients are typically discharged from the
all of the above criteria) are being used more hospital within 7 to 14 days following surgery.
frequently to expand the donor pool.14,15 By Follow-up is in the outpatient clinic on a weekly,
instituting a protocol including educational and biweekly, and finally, monthly basis. Following
donor management interventions, and changing this, patients often return home for follow-up
donor classification and selection criteria, a single with the referring pulmonologist. Weekly moni-
organ procurement organization was able to toring includes measuring the levels of immuno-
increase the percentage of lungs procured per suppressive medications such as tacrolimus or
donor from 11.5% to 22.5% with an increase in cyclosporine; a CBC count to monitor leukocyte
the number of procedures performed, without levels; platelet counts because of therapy with
adverse recipient outcomes.14 Non-heart-beating mycophenolate mofetil or azathioprine; blood

chemistry measurements to follow creatinine rates, which may be in part related to the older
levels because of the use of therapy with age in this group, in general. COPD patients have
tacrolimus or cyclosporine; a chest radiograph; good 1-year survival rates (comparable to CF)
routine spirometry; and sometimes exercise and lower 10-year survival rates (comparable to
oximetry or a 6-min walk test. In addition, in IPF). Survival rates differ between procedures
some centers, patients are given home spirome- and age, as well. BLT recipients have a survival
ters and are instructed to bring in their home advantage beginning between 3 to 5 years post
spirometry measurements at each visit. transplant in comparison to SLT recipients,
Many institutions (approximately 70%) per- especially for COPD. Older patients have poorer
form surveillance bronchoscopy on a routine long-term survival rates in comparison to youn-
schedule to detect asymptomatic rejection or ger recipients.
infection, while other institutions reserve this
procedure for clinical deterioration. The chest Physiologic Results
radiograph has not been shown to be specific for
the early detection of rejection or infection. Close The degree of improvement in lung function
monitoring of pulmonary function has also been postoperatively is the product of many factors. In
studied as a way of detecting graft complications. the uncomplicated transplant recipients, one can
Pulmonary function tests have been shown to expect a gradual improvement and ultimate
have very low specificity and good sensitivity plateau of lung function by 3 to 6 months
(85%) for the detection of graft complications but, following the procedure. In patients receiving a
again, are unable to distinguish rejection from single lung, the FEV1 can be expected to improve
infection. Therefore, pulmonary function tests from 50% to 70% predicted. SLT for the treatment
remain the most sensitive test in the late of nonseptic obstructive lung disease results in
postoperative period for detecting infection or moderate residual obstructive pulmonary dys-
rejection, although they cannot differentiate function seen in spirometry findings. SLT in
between these and other possible complications. patients with underlying restrictive lung disease
can be expected to have mild residual restrictive
Outcomes physiologic status. These results likely reflect the
physiologic findings of the remaining obstructed
Survival or restricted lung. Following SLT procedures,
most of the ventilation and perfusion goes to the
Actuarial survival rates following transplan- transplanted lung. BLT procedures usually result
tation are reported at 92%, 79%, 64%, 53%, and in normal spirometry findings with an equal
30% for 1 month and for 1, 3, 5, and 10 years, division of ventilation and perfusion. Those
respectively, as reported to the ISHLT Registry,1 patients who undergo transplantation for PAH
and are significantly lower than those reported have no significant change in pulmonary func-
for other types of solid organ transplant recipi- tion, marked improvement in gas exchange, and
ents. However, survival rates have improved near-normal hemodynamics following transplan-
when examined across eras, and survival benefits tation, including a nearly complete recovery of
have been proven for LT recipients with all right ventricular function.
diagnoses.17 Early mortality (ie, at ,30 days) is Most patients who undergo either lung
most often due to primary graft failure or transplant procedure without complications are
infection, mortality between 30 days and 1 year able to carry out activities of daily living without
is most often due to infection, and late mortality compromise, although formal cardiopulmonary
(ie, at .1 year) is most often related to chronic exercise testing generally reveals a reduction in
rejection or BOS. maximum oxygen consumption to from 40% to
Survival differs by underlying diagnoses. For 60% predicted in all transplant groups. The
example, CF patients have among the highest reasons for this remain unclear and do not
survival rates at most time periods. IPF patients appear to be cardiac or pulmonary in origin.
have among the lowest one and 10-year survival The leading physiologic hypothesis is that the

immunosuppressive agents may have an effect ation of other perioperative complications such
on peripheral skeletal muscles, resulting in as volume overload, rejection, infection, and
impaired peripheral oxygen utilization.18 venous anastomotic problems. The latter can be
assessed by a transesophageal echocardiogram.
Quality of Life (QOL) Treatment includes supportive care and therapy
with diuretics. Reports have documented the
QOL issues are a relatively recent area of successful use of protective ventilatory strategies,
research in LT.19 Several studies have shown nitric oxide, and/or extracorporeal membrane
improvement in overall health-related QOL. oxygenation in these patients.23
Most patients have expressed satisfaction with Other significant postoperative complications
their transplant decision. Of interest, ,40% of include hemorrhage and phrenic nerve paralysis.
patients return to work on a part-time or full-
time basis following transplantation. Airway Complications
Complications Airway problems were significant causes of

morbidity and mortality following early attempts
Figure 1 shows some of the common post- at LT and developed in 20% to 50% of transplant
transplant complications and the approximate recipients. Airway complications24 can be divid-
time period in which they usually occur. ed into the early and late time periods. Early
airway complications usually develop during the
Primary Graft Dysfunction (PGD) first 4 to 8 weeks. They present as a partial or
complete anastomotic dehiscence and/or fungal
The most significant early postoperative anastomotic infection (usually Aspergillus or
complication following LT is the development Candida) or bacterial anastomotic infection (usu-
of PGD. It is estimated that up to 80% of patients ally Staphylococcus or Pseudomonas), and can
will experience some degree of reperfusion subsequently result in anastomotic strictures.
injury, and in 15% of patients this can be severe. Bronchomalacia can also develop.
A 2005 consensus conference20 attempted to The theoretical causes of airway complica-
standardize the grading of PGD by gas exchange tions include ischemia at the site of the anasto-
and the presence of radiographic opacities. PGD mosis, infection, poor organ preservation, and/or
is characterized clinically by the presence of new rejection. Since revascularization of the bronchial
radiographic opacities, a decrease in pulmonary circulation is generally not performed following
compliance, an increase in pulmonary vascular LT, anastomotic techniques, such as the omental
resistance, and disrupted gas exchange. Radio- wrap or pericardial fat, in which an intact portion
graphic findings include patchy alveolar consol- of the omentum or pericardial fat is wrapped
idation and/or dense perihilar haze and lower around the bronchial anastomosis, or the tele-
lobe alveolar consolidation. Pathologic findings scoping anastomotic technique, in which one
from biopsy specimens, autopsy specimens, or bronchus overlaps one to two cartilaginous rings
lung explants reveal diffuse alveolar damage. within the larger bronchus to improve blood
The typical course of PGD includes progressive flow, have been developed. These have resulted
worsening or stabilization over the subsequent in a decrease in the incidence of anastomotic
hours up to 2 to 4 days, followed by resolution. complications of 10% to 15%, with low mortality
However, PGD can persist for days following the and morbidity.
surgery. It is thought that the likely mechanism Clinically, patients with bronchial anasto-
for PGD is ischemia-reperfusion injury. Postulat- motic complications, including stenosis and
ed risk factors on the donor side include age, bronchomalacia, can present with cough, short-
female sex, African American race, and smoking ness of breath, wheezing, dyspnea on exertion,
history, and on the recipient side, diagnosis of and worsening obstruction on pulmonary func-
PAH and possibly the use of cardiopulmonary tion testing. The characteristic flow-volume loop
bypass.21,22 Management includes the differenti- demonstrates a concave appearance in both the

Figure 1. The common complications following lung transplantation and the typical time periods in which they develop.
Reprinted with permission from Melo and Levine.50
inspiratory and expiratory loops. Bronchial stric- tation and the histopathologic pattern. The types
tures or stenoses may sometimes be visualized of rejection are hyperacute, acute, or chronic, and
on chest radiographs, CT scans, and/or bron- recently, antibody-mediated rejection has been
choscopy. Partial or complete bronchial dehis- described. Hyperacute rejection is mediated by
cence can also present with mediastinal preexisting alloantibodies that immediately bind
emphysema seen on chest radiographs, or with to the donor vascular epithelium, leading to
air adjacent to the bronchial anastomosis seen on vessel thrombosis via complement activation.
CT scans. Fortunately, this is a rare complication in LT
The therapeutic options for anastomotic and will not be discussed further.
complications include balloon dilation of a
Acute Rejection25,26: Acute rejection can devel-
stricture, stent placement, laser therapy, and,
op in up to 36% of patients in the first
rarely, surgery. If anastomotic infection with
postoperative year.1 The typical time period for
fungal or bacterial organisms is suspected bron-
acute rejection is between 10 and 90 days
choscopically or is diagnosed by endobronchial
following LT. It is not uncommon for a single
washing, brushing or biopsy culture, or histolog-
ic findings, then therapy with appropriate anti- patient to experience episodes within the first
biotics should be instituted. few months following transplantation that are
either recurrent (ie, more than two episodes) or
Rejection persistent (failure to resolve with standard
therapy). Acute rejection is usually not seen as
Graft rejection is categorized clinically ac- frequently after the first year following trans-
cording to the time of onset following transplan- plantation. Risk factors for acute rejection are

poorly defined, but HLA mismatches and gas- Table 3—Pathology of Rejection in Lung Transplantation
troesophageal reflux may have a correlation.
A. Acute rejection
Clinically, patients with acute rejection pre- Grade 0- none
sent with cough, shortness of breath, malaise, Grade 1- minimal: scattered perivascular mononuclear
and fever. Occasionally, the presentation is infiltrates
asymptomatic, and most (approximately 70%) Grade 2- mild: prominent perivascular mononuclear
infiltrates
of centers advocate surveillance bronchoscopy to Grade 3- moderate: extensive perivascular mononuclear
detect this, although definitive outcome data are infiltrates extending into the interstitium
not available. Physical examination may reveal Grade 4- severe: diffuse perivascular mononuclear
infiltrates with extension into the interstitium and
rales or wheezing. The utility of the chest
alveolar space with hyaline membranes and
radiograph depends on the time after transplan- fibrinous exudate
tation. Typically, in the first month the chest B. Airway inflammation
radiograph findings can be abnormal in up to Grade 0- none
Grade 1R- low grade: scattered submucosal
75% of rejection episodes; however, in those peribronchiolar monunuclear infiltrate
episodes of rejection occurring 1 month post- Grade 2R- high grade: extensive submucosal
transplantation, only 25% of patients have peribronchiolar lymphocytic infiltrate with epithelial
abnormal radiograph findings. The most com- damage
Grade X- ungradable: no adequate tissue available for
mon radiographic patterns noted with acute grading
rejection include a perihilar flare, and alveolar, C. Chronic airway rejection- obliterative bronchiolitis
or interstitial, localized, or diffuse, opacities with 0- absent
1- present
or without associated pleural effusion.
D. Chronic vascular rejection- accelerated graft vascular
Physiologic findings during periods of acute sclerosis
rejection include hypoxemia and deterioration in Fibrointimal thickening of arteries and veins
pulmonary function. Pulmonary function abnor-
R ¼ revised. Modified from Stewart et al.25
malities are characterized by a decline in FEV1 of
at least 10% to 15% from baseline as well as a
decline in the forced expiratory flow, midexpir- with lymphocytic bronchitis or bronchiolitis can
atory phase between 25% and 75% of forced vital develop and is graded from B0, B1R (low grade),
capacity (FEF25–75%) of an expired vital capacity B2R (high grade), and BX (upgradable). As
of .10% to 15%. Once again, these changes are rejection progresses, the perivascular lymphocyt-
nonspecific and can also be seen in patients with ic infiltrates surrounding the venules and arteri-
infectious etiologies. Since clinical criteria alone oles become dense and extend into the
cannot differentiate among acute rejection, infec- perivascular and peribronchiolar alveolar septa.
tion, and less-common graft complications, In patients with severe rejection, the alveolar
transbronchial biopsy with BAL has emerged as space may be involved, and parenchymal necro-
the primary procedure for diagnosis. In addition, sis, hyaline membranes, and necrotizing vasculi-
approximately 70% of LT centers perform sur- tis have been described.
veillance bronchoscopy. A diagnosis of acute Once acute rejection has been diagnosed,
rejection by transbronchial biopsy has ranged treatment consists of the augmentation of immu-
from 61% to 94%, and specificity has ranged from nosuppression. Methylprednisolone (10 to 15
90% to 100%. A histologic grading system for mg/kg/d IV for 3 days) followed by an increase
acute pulmonary rejection was initially proposed in the maintenance prednisone regimen to 0.5 to
in 1990 and revised in 1996 and 200725 (see Table 1 mg/kg/d, with a taper over the next several
3). At least 5 alveolated pieces of lung are best for weeks, is a standard treatment regimen. Mainte-
adequate evaluation. Pathologically, acute rejec- nance immunosuppression therapy should also
tion is characterized by perivascular, mononu- be augmented. Typically, the resolution of symp-
clear, lymphocytic infiltrates, with or without toms occurs in days, and histologic follow-up in
airway inflammation, and is graded histological- 3 to 4 weeks should show resolution. Recurrent
ly from A0 to A4, by the degree of perivascular or persistent acute rejection may initiate conver-
inflammation. In addition, airway involvement sion in the baseline immunosuppression regi-

men. Lympholytic therapy, photopheresis, total Typically, chest radiographs are not helpful in
lymphoid irradiation, and/or aerosolized cyclo- the diagnosis of OB because most patients have
sporine therapy have been used with variable radiographic findings that are unchanged from
success. their baseline posttransplant radiographs. HRCT
Obliterative Bronchiolitis (OB) 27–30: Chronic scans may reveal peripheral bronchiectasis,
rejection has been equated with the histologic patchy consolidation, decreased peripheral vas-
finding of OB and remains a major cause of cular markings, air trapping, and bronchial
morbidity and mortality after LT and the leading dilation, which may aid in the diagnosis of OB.
single cause of death after the first posttransplant Air trapping on end-expiratory HRCT scans has
year. The current incidence of OB ranges from been shown to be a sensitive and accurate
35% to 50% among different centers. OB has been radiologic indicator of OB but may not be able
defined clinically by an obstructive functional to provide an early diagnosis of this disorder.
defect and histologically by the obliteration of BAL fluid neutrophilia, exhaled nitric oxide
terminal bronchioles. The mean time to diagnose levels, bronchial hyperresponsiveness, and in-
OB is 16 to 20 months following the lung creased nitrogen washout may also be surrogate
transplant procedure, but has been reported as markers of BOS.
early as 3 months after transplantation. Some Transbronchial biopsy is used to attempt to
degree of OB will develop in .50% of transplant diagnose OB. However, unlike for acute cellular
recipients by 5 years post transplant.1 rejection, transbronchial biopsy is primarily used
The etiology and risk factors for OB remain to exclude other diagnoses. The classic patholog-
unclear. Several possible causes have been ic finding is constrictive bronchiolitis. Unfortu-
proposed, including uncontrolled acute rejection; nately, the sensitivity for the diagnosis of OB by
lymphocytic bronchiolitis; cytomegalovirus transbronchial biopsy is low (range, 15% to 87%),
(CMV) pneumonitis; primary graft dysfunction; and the diagnosis of OB is often made by
CMV infection without pneumonitis; HLA-A exclusion and is graded physiologically by the
mismatches; total HLA mismatches; the absence degree of change in pulmonary function (ie,
of donor antigen-specific hyporeactivity; bacteri- FEV1) from baseline. Because of the variability in
al, fungal, and non-CMV viral infections; older obtaining bronchioles by transbronchial biopsy,
donor age; and bronchiolitis obliterans with the ISHLT has established a BOS staging sys-
organizing pneumonia. The most consistently tem.27 This staging system is based on a
identified risk factor is acute rejection, particu- reduction in FEV1 in comparison to a posttrans-
larly in those patients who experience recurrent, plant baseline FEV1, with or without the patho-
high-grade episodes of acute rejection. It is logic documentation of OB. This staging system
probable that lymphocytic bronchiolitis and includes an earlier BOS category of potential
CMV pneumonitis are also important risk factors BOS, using changes in FEV1 and/or midflows,
for OB. Other risk factors are being identified. In compared with posttransplant baseline values
the past several years, gastric aspiration and (FEV1, 81% to 90% of baseline values and/or
GERD have been recognized as an important FEF25–75% 75% of baseline values; Table 4).27
cause and/or contributing risk factor to the Once OB has been diagnosed histologically or
development of pulmonary dysfunction follow- clinically by the exclusion of alternate diagnoses,
ing LT, particularly BOS.30 treatment is begun with high-dose methylpred-
Clinically, OB can manifest as an upper nisolone therapy followed by a tapering course of
respiratory tract infection and can be mistakenly oral corticosteroids. Lympholytic agents, such as
treated as such. Other patients present without antilymphocyte globulin, or anti-IL-2 agents,
clinical symptoms but with gradual obstructive such as daclizumab, can be considered for
dysfunction seen on pulmonary function test therapy if there is no clinical response to
results. FEV1 has been the standard spirometric corticosteroid treatment. Therapy may stabilize
parameter used, but midexpiratory flow rates pulmonary function but uncommonly, results in
may be a more sensitive parameter for early significant improvement. Other common physi-
detection. ologic scenarios may be relentless deterioration

Table 4—Clinical Staging System for OB therapy for OB and may result in death.
Pseudomonas is a common offender, and aerosol-
Stagea FEV1
ized aminoglycoside antibiotics or suppressive
0 (no OB) .90% of baseline and FEF25–75% quinolone treatment may be considered. Bron-
.75% of baseline chomalacia can also develop. Survival rates after
0-p (potential OB) 81%-90% of baseline and/or FEF25–75% the diagnosis of OB have been reported at 81%,
75% of baseline
1 (mild OB) 66%-80% of baseline
67%, 60%, and 36% at 1, 3, 5 and 10 years,
2 (moderate OB) 51%-65% of baseline respectively, in one series.34 Since the condition
3 (severe OB) 50% of baseline of most patients with OB can only be stabilized,
strategies directed at prevention, early diagnosis,
Adapted from Estenne et al.27
a
Each stage is subdivided into a and b, where a is without and treatment is necessary for the preservation of
histologic documentation of OB and b is with histologic lung function. Retransplantation has been per-
documentation of OB. Adapted from the ISHLT staging formed for BOS. Survival is somewhat less than
system.
that for patients receiving de novo transplants. In
addition, the limited donor supply does not
in pulmonary function despite therapy, gradual allow for the common practice of this procedure.
steady deterioration in pulmonary function, or a Antibody-Mediated Rejection (AMR): Recently,
AMR has been described in lung transplant
series of drops in function with plateaus. One
recipients as a component of either acute or
study found that most patients had the steepest
chronic rejection.35 AMR is suggested when high
decline in FEV1% predicted within the first 6
levels of donor-specific HLA antibodies are
months after BOS diagnosis. The authors noted a
present in the serum of the recipient, and
steeper decline in the first 6 months following the
complement deposition is present in the tissue.
onset of BOS in patients with a pre-LT diagnosis
The detection, evaluation, and clinical conse-
of pulmonary fibrosis, and those of female sex.
quences of AMR are defined in the renal and
Patients with a rapid onset of BOS also had a
cardiac literature, but are not as clearly defined in
steeper decline in FEV1% predicted. Recipients of
LT. Several centers have shown evidence sug-
an SLT had a worse FEV1% predicted after
gesting that the development of HLA antibodies
diagnosis. After 24 months, the course of FEV1%
post LT is associated with increased risk for acute
predicted in BLT recipients was better than that
cellular rejection, BOS, and graft loss. Preliminary
in SLT recipients.31
studies are examining the use of plasmapheresis,
Alternate immunosuppressive agents such as rituximab, and intravenous immunoglobulins in
mycophenolate mofetil, tacrolimus, and siroli- this setting.
mus have also been associated with the stabili-
zation of pulmonary function when used as Infectious Complications
rescue treatment for BOS. Total lympholytic
radiation, aerosolized cyclosporine, photophere- Infections36 have been a major cause of early
sis, and newer immunosuppressive agents have and late morbidity and mortality following
been used for treatment in refractory cases of OB. transplantation, and remain the leading single
Inhaled corticosteroids may be added to therapy specific cause of death in the first posttransplant
in cases of lymphocytic bronchiolitis. Small year. The incidence of infection is significantly
studies have shown benefit from the use of higher than that reported in other solid organ
low-dose azithromycin (via an immunomodulat- recipients and may be related to continuous
ing mechanism) for treating patients with BOS.32 environmental exposure of the allograft. Other
A recent study also demonstrated that macro- predisposing factors include diminished cough
lides can prevent the development of BOS.33 reflex secondary to denervation, poor lymphatic
Therapy directed toward GERD (both pharma- drainage, decreased mucociliary clearance, recip-
cologic and surgical) should also be considered.30 ient-harbored infection, and, occasionally, the
Infection, including bronchiectasis, frequent- transfer of infection from the donor organ. All
ly complicates intensive immunosuppression of these contributing factors are further com-

pounded by immunosuppression. Nosocomial sterile brush sample, and/or transbronchial
infections at the site of the surgical wound, biopsy.
vascular access, and urinary tract or ventilator- Other Early Infections: Atypical pneumonias,
associated pneumonias also occur in the early such as those caused by mycobacteria and
postoperative period. In most circumstances, the Nocardia, are uncommon in LT patients but have
allograft or graft is the primary location of been reported to occur in 0.6% to 2% of
infection. recipients. The number of viral infections, such
Bacterial Infections37,38: Bacterial pneumonia is as those due to herpes simplex virus, has been
the most common life-threatening infection to significantly reduced with the common use of
develop in the early postoperative period and ganciclovir or acyclovir prophylaxis. Candidal
was reported to have an incidence as high as 10% infections may be seen in the early postoperative
to 25% in the first four postoperative weeks. period but usually do not cause invasive disease.
Common organisms include Pseudomonas aerugi- Trimethoprim-sulfamethoxazole prophylaxis
nosa and Staphylococcus species. The incidence of (usually on a three-times-per-week schedule or
perioperative bacterial pneumonia has been daily single strength) has significantly reduced
decreased to from 10% to 20% by broad-spectrum the incidence of Pneumocystis pneumonia to ,1%
antibiotic prophylaxis, usually with an antipseu- in lung transplant recipients.
domonal cephalosporin and vancomycin, and Viral Infections (CMV): In the period of 1 to 6
routine culture of the trachea of the donor and months (particularly 1–3 months) following
transplantation, CMV accounts for most of the
the recipient at the time of the surgery. Prophy-
viral infections in lung transplant recipients. The
lactic therapy with antibiotics is usually discon-
typical time period for the development of CMV
tinued at 3 to 7 days if the culture results are
infection is 30 to 150 days postoperatively, with
negative and are tailored to the cultured organ-
an incidence of illness (ie, infection and disease)
isms if the results are positive, although the
of approximately 50%. The incidence of CMV
duration of therapy varies between centers.
infection has been reported to range from 30% to
Patients with bronchiectasis who receive trans-
86% in post-LTR with a mortality of 2% to 12%.39
plants usually receive postoperative bacterial
The most important risk factor for the develop-
prophylaxis for 7 to 10 days. The prevalence of
ment of CMV infection is the donor-positive/
bacterial pneumonia remains high during the
recipient-negative (Dþ/R) serostatus of a trans-
first few months following transplantation and
plant patient, as these patients will lack immu-
decreases subsequently, although a second late nity to CMV. The lowest risk occurs in D/R
peak in incidence often occurs during the patients.40 Other important risk factors include
augmentation of immunosuppression for the type and intensity of both, induction and
treatment of chronic rejection. Bacterial infection maintenance immunosuppression, concurrent
due to Staphylococcus or, less commonly, Pseudo- infections, rejection, and host factors such as
monas, can develop at or distal to the site of the age or comorbities.40 There are data showing that
anastomosis in the early posttransplant period. CMV pneumonitis may contribute to the devel-
Of interest, the incidence of lower respiratory opment of chronic rejection.41
tract infections does not appear to be increased in CMV can cause a wide spectrum of disease,
patients who receive transplants for CF in from asymptomatic infection (ie, presence of
comparison to patients who receive transplants viral copies at low levels in the blood or shedding
for other indications. of the virus in the urine or BAL fluid) to
It is often difficult to distinguish pneumonia widespread dissemination. Various presentations
from other early graft complications such as of CMV in lung transplant patients can include
PGD, pulmonary edema, rejection, and other tissue-invasive disease such as pneumonitis and,
infectious etiologies. In addition, differentiation occasionally, gastroenteritis, hepatitis, and colitis.
between colonization and invasion may be Clinical findings of CMV pneumonitis include
difficult and often requires invasive procedures fever, cough, hypoxemia, presence of interstitial
such as bronchoscopy with BAL, quantitative or alveolar opacities, and leukopenia. The diag-

nosis of tissue-invasive disease requires cytologic negative patient group. Prophylactic treatment
or histologic changes in cell preparation or tissue. approaches vary between centers but most
Therefore, flexible bronchoscopy with transbron- centers use oral Valgancyclovir at 450 mg po
chial biopsy and BAL is often necessary and can bid. The duration of prophylaxis is center
diagnose CMV pneumonia in 60% to 90% of specific, varying from 3 months post transplant
patients. The diagnosis of CMV infection requir- to one year post transplantation, with a recent
ing treatment can also be made, given the study suggesting a prolonged benefit from one
compatible clinical picture with or without the year of prophylactic therapy.43 In the groups with
exclusion of other causes of pulmonary disease, the highest risk, CMV hyper-Ig may be added to
via bronchoscopy and the presence of CMV viral the regimen. Most centers are monitoring serial
replication (ie, copies) on blood polymerase levels of CMV blood antigenemia or PCR copies
chain reaction (PCR). The pathologic hallmark in the serum in order to preemptively treat
of CMV infection is a cytomegalic 250-nm cell patients who become positive.
containing a large central basophilic intranuclear Other viral infections that have been de-
inclusion. This inclusion is referred to as an owl’s scribed in lung transplant patients include
eye because it is separated from the nuclear herpes simplex virus (early post transplant),
membrane by a halo. These inclusions may be and the community-acquired respiratory viruses:
well seen with hematoxylin-eosin or Papanico- influenza, respiratory syncytial virus, parainflu-
laou staining. The identification of CMV cytolog- enza, human metapneumovirus, and adenovirus.
ically is very specific (98%) but lacks sensitivity Acyclovir prophylaxis for herpes infection may
(21%) for the presence of infection. Other be initiated in some programs after the discon-
pathologic findings in the lung parenchyma tinuation of therapy with ganciclovir.
include a lymphocytic and mononuclear cell Fungal Infections: Fungal infections are more
interstitial pneumonitis, and thus, CMV pneu- common in lung transplant recipients than in
monitis can sometimes be confused with acute those who have received other solid organ
rejection. transplants, and account for the most significant
Treatment for active disease includes valgan- morbidity and mortality of all infectious agents
ciclovir at a dose of 900 mg po bid, and if the following transplantation.
patient is severely ill and/or cannot tolerate po, Fungal infections have an estimated inci-
IV ganciclovir,42 which have been shown to dence of 15% to 35% and an overall mortality
reduce mortality. Some centers also use CMV- of 40% to 80%.44,45 They usually develop in the
specific hyper-Ig in the treatment of CMV first few months after transplantation.
disease. This therapy is usually continued while Aspergillus species, including A fumigatus, A
routine weekly PCR results are obtained. Both flavus, A terreus, and A niger, can be colonizing
forms of ganciclovir have the complications of organisms, or can result in infection, presenting
neutropenia. as indolent, progressive pneumonia or as an acute
Prophylaxis against CMV infections has fulminant infection that rapidly disseminates.
become a major strategy in most transplant Aspergillus exhibits the propensity to invade
centers. Initially, some centers attempted to blood vessels and may present as an infarct or
match CMV-negative recipients with CMV-nega- with hemoptysis. The radiographic findings of
tive donors when possible; however, the limited pulmonary aspergillosis include focal, lower-lobe
donor supply did not allow the continuation of opacities, patchy bronchopneumonic opacities,
this practice. The use of CMV-negative blood single or multiple nodules with or without
products is advocated. Ganciclovir prophylaxis cavitation, thin-wall cavities, and opacification
seems to be effective in delaying the onset of of the entire lung graft. A CT scan may reveal a
CMV infection. At some centers, prophylaxis is halo sign thought to be pathognomonic for
given only to the CMV-mismatched patients (ie, a invasive aspergillosis. Other forms of presenta-
CMV-negative recipient receiving an organ from tion of Aspergillus infection can include pseudo-
a CMV-positive donor). Other centers administer membranous tracheobronchitis, often at and
prophylaxis to all but the CMV-negative to-CMV- distal to the site of the anastomosis. The diagnosis

of invasive aspergillosis requires the identifica- population. Live vaccines should not be admin-
tion of organisms within tissues, although recov- istered.
ery of the organism from the BAL or sputum in
the correct clinical setting often leads to a Posttransplant Lymphoproliferative Disorders
presumptive diagnosis. These organisms can (PTLDs)
appear as septated hyphae that branch at acute
angles, and can be detected with hematoxylin- PTLDs47 are reported more frequently fol-
eosin and methenamine silver staining. The role lowing LT than following other types of solid
of galactomannan in the diagnosis of invasive organ transplantation. Lymphomas comprise
aspergillosis in the LT recipient is unclear. most PTLDs. The PTLDs are composed of a
Survival with Aspergillus infection has been heterogeneous group of lymphoid proliferations
improved with the early initiation of advanced- of variable clonality. The B-cell non-Hodgkin
generation azoles, such as itraconazole and lymphomas are the most frequent form of PTLD
voriconazole, the echinocandins, and/or rarely, and have been associated with Epstein-Barr virus
high-dose amphotericin therapy and a reduction (EBV) activity either serologically or by the
in immunosuppressive therapy. Therapy with a identification of viral DNA in tissue. There is
lipid formulation of amphotericin B could also be no clear correlation among episodes of rejection,
considered in the management of invasive fungal specific immunosuppressive drugs, and the
infections in patients who are not responding to development of PTLD. The incidence of PTLD
therapy or in whom nephrotoxicity develops. following LT has been reported to range between
Prophylaxis with azoles (voriconazole or itracon- 1.8% and 9.4%.47 Those patients who have
azole for 3 to 6 months) or aerosolized ampho- negative EBV serology results before transplan-
tericin has shown promise in decreasing the tation and receive an organ from an EBV-positive
incidence of Aspergillus infection post trans- donor, resulting in seroconversion, are at a
plant.46 significantly higher risk for the development of
Candida spp can cause a variety of syndromes a PTLD. Children are at higher risk owing to
in the lung transplant patient, including muco- their frequent EBV-negative status.
cutaneous disease, line sepsis, wound infection, The clinical features of PTLD in lung trans-
and, rarely, pulmonary involvement. Fluconazole plant recipients include development in the first
has emerged as an effective alternative for posttransplant year, involvement of the allograft,
infections caused by Candida albicans, but the and radiographic findings of solitary or multiple
echinocandins are the agents of choice for pulmonary nodules. Disseminated disease has
widespread disease. Fluconazole appears to be also been reported. Treatment includes the anti-
less active against other Candida spp, such as C CD20 monoclonal antibody rituximab, a reduc-
glabrata and C krusei. tion in immunosuppression, as well as consider-
Other rare causes of fungal infection in lung ation for adjunctive treatment with antiviral
transplant recipients have included Cryptococcus therapy, radiation, chemotherapy, surgery, and
neoformans, as well as the dimorphic fungi such adoptive immunotherapies extrapolated from the
as coccidioides, histoplasma, and blastomyces. bone marrow transplant population. Mortality
Azoles and amphotericin B remain the antifungal may be significant with high-grade PTLD. An
agents of choice for these infections, although increased incidence of other nonlymphomatous
azole agents can be used for maintenance malignancies, particularly skin cancers, has been
therapy. reported in the lung transplant population, and
Mycobacteria: Mycobacterial diseases both careful screening is recommended.
typical and atypical have been successfully
treated in the lung transplant patient. Mycobacte- Miscellaneous Complications
rium abscessus infection has been associated with
poor outcomes. The recurrence of primary disease has been
Vaccinations: Standard vaccination regimens described in patients who have received trans-
should be used in patients in the lung transplant plants for the treatment of sarcoidosis, lymphan-

Table 5—Immunosuppressive Drugs Used in Lung Transplantation
Drug Common Adverse Effects
Cyclosporine Nephrotoxicity, hypertension, neurotoxicity (tremor, seizures, and headache), hyperlipidemia,

hyperkalemia, hypomagnesemia, GI disturbance, hemolytic uremic syndrome, hirsutism,
and gingival hyperplasia
Tacrolimus Nephrotoxicity, hypertension, neurotoxicity (tremor, seizures, headache), hyperlipidemia,
hyperkalemia, hypomagnesemia, GI disturbance, hemolytic uremic syndrome,
hyperglycemia, and diabetes
Azathioprine Leukopenia, macrocytic anemia, thrombocytopenia, hepatotoxicity, and pancreatitis
Mycophenolate mofetil Diarrhea, abdominal pain, nausea, leukopenia, and anemia
Prednisone Hyperglycemia, hypertension, hyperlipidemia, osteoporosis, myopathy, insomnia, cataracts,
and weight gain
Sirolimus Anemia, thrombocytopenia, leukopenia, anastomotic dehiscence (early postoperative period),
poor wound healing, hyperlipidemia, arthralgias, interstitial pneumonitis, and lower-
extremity edema
giomyomatosis, giant cell interstitial pneumonitis, exists immediately.49 Rejection results from the
desquamative interstitial pneumonia, idiopathic activation, differentiation, and proliferation of T
pulmonary hemosiderosis, bronchioalveolar car- lymphocytes acting against donor cells that are
cinoma, Langerhans cell histiocytosis, pulmonary recognized as foreign, the major determinants of
alveolar proteinosis, and diffuse panbronchiolitis. which are cell-surface markers known as HLAs.
However, disease recurrence may be an incidental Current immunosuppressive regimens and strat-
finding in some of these patients, particularly egies are based on the inhibition of this whole-
those with sarcoidosis. cell response to foreign antigens.
Pleural effusions may develop because the Currently, most transplant centers use main-
lymphatics are not reanastomosed post trans- tenance immunosuppression regimens including
plant and/or in the setting of rejection. Pro- tacrolimus or cyclosporine, mycophenolate mo-
longed postoperative air leaks have been well fetil or azathioprine, and prednisone. In addition,
described. in the immediate posttransplant period, immu-
Gastroparesis and an increased incidence of nosuppression may be enhanced by the use of
GI emergencies have also been described in lung lympholytic agents such as antithymocyte glob-
transplant recipients. GERD, both symptomatic ulin, or human-derived IL-2 receptor antibodies
and asymptomatic, is now known to be a such as daclizumab.
significant problem following LT. This complica- All immunosuppressive drugs are wrought
tion may be more common in those patient with complications, which can pose significant
populations predisposed to the development of problems following transplantation (Table 5).
GERD, such as patients with CF. Osteoporosis Tacrolimus and cyclosporine act by inhibiting
remains a significant problem in the posttrans- IL-2 gene transcription, thus decreasing T-
plant period and is best managed with bisphos- lymphocyte activation and subsequent prolifer-
phonate agents such as alendronate or ation. Chronic nephrotoxicity is a common
pamidronate. Deep venous thrombosis and pul- complication of both agents and can develop
monary embolism were reported to have an in 25% to 75% of patients receiving these drugs,
incidence of 8.6% in one series of lung transplant and to some degree, in nearly 100% of patients
recipients.48 Hypogammaglobulinemia has also with long-term use. Acute renal toxicity is
been described. usually dose related and typically is reversible.
In addition, other potentially nephrotoxic
Immunosuppression agents, including amphotericin B, trimetho-
prim-sulfamethoxazole, nonsteroidal antiinflam-
Since transplantation of a lung graft into a matory agents, and aminoglycoside antibiotics,
recipient invokes a specific immune response, the which may compound the toxic effects of
need to suppress the recipient’s immune system tacrolimus and cyclosporine, may be used in

transplant patients. Both tacrolimus and cyclo- Corticosteroids play a main role in posttrans-
sporine are also associated with systemic hy- plant immunosuppression by binding to cyto-
pertension, which can develop in up to 25% to plasmic glucocorticoid receptors, undergoing
50% of lung transplant recipients. The occur- translocation into the nucleus, and then blocking
rence of hypercholesterolemia has also been cytokine transcription of genes and secretion
well described. The incidence of both posttrans- from phagocytes. The side effects of corticosteroid
plant hypertension and hyperlipidemia may be use are well known and include hyperglycemia,
lower with the use of tacrolimus than with hypertension, hyperlipidemia, osteoporosis,
cyclosporine. Other well-described side effects proximal myopathy, mood disturbance, cataract
of tacrolimus and cyclosporine include neuro- formation, and weight gain.
logic toxicity such as tremors, paresthesias, The lympholytic agents such as antithymocyte
headaches, confusion, depression, somnolence, globulin act by depleting CD3 lymphocytes by
seizures, white matter changes, coma, and lysis, opsonization, and phagocytosis. The admin-
death. Peripheral neurologic findings have also istration of antithymocyte globulin is associated
been described. Neurotoxicity appears to be with leukopenia, thrombocytopenia, and serum
significantly more common with tacrolimus sickness. It should not be administered to those
therapy than with cyclosporine therapy. Tacro- patients who have manifested an allergic reaction
limus use is associated with hyperglycemia and to horse serum in the past. Other induction agents
diabetes. Cyclosporine use is associated with include humanized monoclonal IL-2 receptor
hirsutism, gingival hyperplasia, and gastropare-
antagonists such as daclizumab and basiliximab,
sis. Both agents have been reported to cause a
and alemtuzumab, a CD-52 monoclonal antibody.
hemolytic uremic syndrome or thrombotic
Sirolimus is one of the newer available
thrombocytopenic purpura.
immunosuppressant agents and is being used
It is important that physicians who are caring
for cases of acute and chronic lung transplant
for transplant patients be aware of the numerous
rejection and, in small studies, as de novo
drug interactions with tacrolimus and cyclospor-
therapy following LT. Sirolimus is a macrocyclic
ine. For example, use of the azoles results in a
triene antibiotic (structurally related to tacroli-
significant increase in tacrolimus and cyclospor-
mus) with immunosuppressive, antitumor, and
ine levels at the same dose. Likewise, the
antifungal properties. Sirolimus has been dem-
discontinuation of therapy with azole agents
without increasing the dose of tacrolimus or onstrated to block the proliferative response and
cyclosporine can result in an acute and life- the activation of T cells, B cells, and other cell
threatening drop in therapeutic levels of these lines by cytokines and growth factors, thus
drugs. Interactions with macrolide antibiotics, preventing cell-cycle progression and prolifera-
calcium channel blockers, and gastric motility tion. In contrast, tacrolimus (FK-506) and cyclo-
drugs have also been reported. Levels of both sporine inhibit the production of cytokines. The
agents are decreased with the use of rifampin or use of sirolimus in the immediate posttransplant
anticonvulsant agents. period is discouraged because of the association
Mycophenolate mofetil inhibits purine synthe- with poor wound healing and bronchial anasto-
sis and blocks lymphocyte proliferation. Typical motic dehiscence. The major side effects of
side effects include GI symptoms such as diarrhea, sirolimus include cytopenias (particularly throm-
nausea, and abdominal pain. In addition, leukope- bocytopenia and leukopenia), hyperlipidemia,
nia and anemia have been described. arthralgias, and interstitial pneumonitis, which
Azathioprine also inhibits nucleic acid syn- can become a serious problem in the lung
thesis and suppresses the proliferation of lym- transplant recipient. Other side effects include
phocytes. Toxicities of this drug include those similar to the side effects described with
cytopenias such as leukopenia and thrombocyto- tacrolimus and cyclosporine, although, in gener-
penia. Macrocytic anemia can develop with long- al, the nephrotoxicity with this agent appears to
term use. Pancreatitis and cholestatic hepatitis be less than that of the other two agents, and it is
have been well described with azathioprine use. often begun for this indication. The role of

sirolimus in the lung transplant armamentarium 9. Boussaud V, Guillemain R, Grenet D, et al.
remains to be clearly established. Clinical outcome following lung transplantation
in patients with cystic fibrosis colonised with
Nothing to Disclose Burkholderia cepacia complex: results from two
French centres. Thorax. 2008;63(8):732–737.
The author has disclosed that no relation- 10. U.S. Department of Health and Human Services.
ships exist with any companies/organizations Organ Procurement and Transplantation Network.
whose products or services may be discussed in http://optn.transplant.hrsa.gov/resources/
this chapter. professionalResources.asp?index¼88. Accessed
March 10, 2012.
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Chest. 2006;129(2):412–416. Update (PCCU). 1999;13(lesson 16).

Chapter 30. Women’s Issues in Pulmonary Medicine
Objectives: airway mucosa, increased secretion production,

Describe the normal respiratory and cardiovascular and mucosal edema, particularly accentuated in
physiology of pregnancy. the third trimester. Patients can have upper
Review the management of asthma in pregnancy.

respiratory tract symptoms secondary to the
Review the management of venous thromboembolism in
pregnancy. above, including epistaxis, nasal stuffiness,
Discuss the management of TB and other respiratory hoarseness, and voice changes. Nasal polyposis
infections in pregnancy. and allergic rhinitis can begin or become exacer-
Review the causes and management of acute respiratory
failure in pregnancy. bated during pregnancy. These changes are
Discuss the statistics regarding smoking and the epide- primarily caused by estrogen production. The
miology of lung cancer in women. health-care provider should be aware of these
Review disorders unique to women—catamenial dis-
eases and lymphangioleiomyomatosis.
changes when performing procedures such as
endotracheal intubation and/or nasopharyngeal
Key words: acute respiratory failure; asthma; lung cancer;
tube placement.
pregnancy; venous thromboembolism; women The thoracic cage also undergoes anatomic
changes during pregnancy. The diaphragm be-
Synopsis: comes elevated up to an average of 4 cm above
This chapter will focus on pulmonary diseases unique to normal at full-term pregnancy. However, dia-
women, including issues surrounding pregnancy as well as phragmatic dysfunction as a result of pregnancy
diseases that may have different epidemiology and/or
is unusual because concurrent with these chang-
prognosis in women. There are numerous normal physio-
logic changes in the respiratory and cardiovascular system es, there is a widening of the lower rib cage and
during pregnancy. In addition, common pulmonary prob- alteration of the abdominal muscles, and thus
lems, such as asthma and venous thromboembolism, may diaphragmatic excursion is actually maintained
have different treatment plans in the pregnant or lactating
woman. Although fortunately rare, acute respiratory failure or increased.
can occur during pregnancy, and the causes and manage- Pulmonary Function Tests: The major change in
ment will be reviewed. The epidemiology, clinical manifes- pulmonary function testing in pregnancy is a
tations, and outcomes of tobacco-related diseases, including
COPD and lung cancer, differ in women and men and will
progressive decrease in the expiratory reserve
be discussed. Other pulmonary diseases can occur solely or volume by 8% to 40% and a decrease in residual
nearly exclusively in women, such as catamenial diseases volume by 7% to 22%, both changes caused by
and lymphangioleiomyomatosis, and will also be reviewed. the enlarging uterus and diaphragmatic eleva-
tion. Because of these changes, functional resid-
ual capacity is, in turn, decreased by 10% to 25%
Physiologic Changes in Pregnancy by the third trimester of pregnancy. Total lung
capacity may decrease slightly, inspiratory ca-
During pregnancy, the body undergoes anatomic pacity increases, and vital capacity does not
and physiologic changes affecting both the respi- change significantly during pregnancy. The de-
ratory and cardiovascular systems.1–3 It is impor- crease in residual volume with a relatively
tant that the pulmonologist be familiar with these maintained total lung capacity results in a low
normal physiologic changes (Tables 1, 2). ratio of residual volume to total lung capacity.
Closure of the small airways during normal tidal
Respiratory breathing because of the reduction in functional
residual capacity can result in changes in
The upper respiratory tract undergoes chang- ventilation/perfusion matching and gas ex-
es during pregnancy, including hyperemia of the change discussed below.

Table 1—Normal Respiratory Physiologic Changes in Table 2—Normal Cardiovascular and Fluid Physiologic
Pregnancy Changes in Pregnancy
Variables Changes Variables Change
Pulmonary Function Cardiac output Increased

Expiratory reserve Decreased Heart rate Increased
volume Stroke volume Increased
Residual volume Decreased Systemic vascular resistance Decreased
Functional residual Decreased Pulmonary vascular resistance Decreased
capacity BP Decreased
Total lung capacity Mildly decreased Blood volume Increased
Inspiratory capacity Increased RBC volume Increased, but less than
Vital capacity No change blood volume
Tidal volume Increased Hematocrit Dilutional decrease
Respiratory rate No change, mild increase Serum protein levels Decreased
Minute ventilation Increased
Peak flow No change
FEV1 No change slightly in the first trimester followed by a slight
Lung compliance No change
Total respiratory Decreased decrease later in pregnancy, likely caused by
compliance alterations in pulmonary vascular volume.
Diffusion capacity Increase followed by decrease Gas Exchange: Gas exchange in pregnancy is
Gas Exchange Values
PaCO2 Decreased to 28 to 32 mm Hg
characterized by a mild compensated respiratory
PaO2 Increase followed by decrease alkalosis secondary to an increase in minute
pH Increased to 7.40 to 7.45 ventilation out of proportion to maternal needs.
Serum bicarbonate Decreased to 18 to 21 mEq/L Thus, normal PaCO2 values are lower, 28 to 32
Alveolar-arterial gradient Mildly increased
Oxygen consumption Increased mm Hg, and serum bicarbonate values are
Carbon dioxide Increased compensatorily decreased to 18 to 21 mEq/L.
production Normal pH is slightly alkalemic at 7.40 to 7.45.
PaO2 is slightly elevated, 100 to 105 mm Hg, with
Tidal volume increases significantly during a slight decrease at term to 100 mm Hg. There is
pregnancy by 150 mL to a final value of 450 to normally a 5 to 10 mm Hg elevation in alveolar-
600 mL, or a 30% to 50% increase in the average arterial gradient above baseline, especially in the
patient. This is most likely caused by a direct supine position. Oxygen consumption increases
progesterone-mediated increase in central respi- by 20% to 30% during pregnancy, with a
ratory drive and enhancement of the hypercapnic concomitant increase in carbon dioxide produc-
ventilatory drive. There is little or no change in tion by 30% to 35%. These changes are the result
respiratory rate during pregnancy, and tachy- of increased maternal and fetal metabolic re-
pnea is an unusual finding. Because of the quirements and increases in work of breathing
increase in tidal volume, there is a significant and cardiac output. During delivery, oxygen
increase in resting minute ventilation from 6 L in consumption can increase to 40% to 100% above
the nonpregnant state to 9 L at full term (or 20%– baseline.
50% above baseline). Sleep-Disordered Breathing: Because of the
There are no significant changes in peak flow normal physiologic changes during pregnancy,
rates, FEV1, airway resistance, or maximum in particular the estrogen-related changes in
voluntary ventilation during pregnancy. Al- upper airway patency, the incidence of snoring
though lung compliance does not change signif- increases during pregnancy. Most studies also
icantly during pregnancy, there is a reduction in suggest that there is an increased incidence and
total respiratory compliance as a result of a severity of sleep-disordered breathing during
reduction in chest wall compliance because of an pregnancy, which increases as pregnancy pro-
elevated diaphragm caused by uterine enlarge- gresses.4 Obstructive sleep apnea during preg-
ment by the third trimester. Diffusion capacity of nancy may develop in patients predisposed to
the lung for carbon monoxide may increase sleep-disordered breathing, and patients with
456 Chapter 30. Women’s Issues in Pulmonary Medicine (Levine)

preexisting obstructive sleep apnea may have Dyspnea During Pregnancy
worsening severity of disease. Untreated, this
may lead to complications of maternal hyperten- Up to two-thirds of pregnant women report
sion and fetal growth retardation. Continuous dyspnea during pregnancy. Although the etiolo-
positive airway pressure has been used for gy of this normal physiologic dyspnea is not
treatment as it is used in the nonpregnant clearly defined, it is most commonly reported in
individual. the first and second trimesters, with improve-
ment toward the end of the third trimester. These
Cardiovascular findings support the fact that dyspnea is not
purely related to mechanical enlargement of the
The cardiovascular system probably under-
uterus. Marked progesterone elevations early in
goes the most significant changes during preg-
pregnancy, resulting in direct brainstem stimula-
nancy, including an increase in cardiac output,
tion and hyperventilation, and alteration in the
beginning in the first trimester and peaking at
sensitivity to carbon dioxide likely contribute to
about the 25th to 32nd week at 30% to 50% above
the sensation of dyspnea. The normal anemia of
normal. This is the result of both a change in
pregnancy may also contribute to the sensation of
heart rate as well as stroke volume and a
dyspnea.
decrease in systemic vascular resistance, partially
One must also be aware of concomitant heart
caused by shunting of blood to the low resistance
disease manifested in pregnant women. Mitral
placental bed and perhaps caused by increased
stenosis and other stenotic lesions may become
levels of vasodilator mediators. Pulmonary vas-
apparent during pregnancy, particularly in the
cular resistance also decreases. Both systolic and
third trimester when blood volume is at its
particularly diastolic pressures are reduced.
maximum, and right-to-left shunts tend to
Postural hypotension may be apparent, particu-
larly in the third trimester when the uterus can worsen.
compress the inferior vena cava (IVC), impeding
venous return to the heart. During delivery, the Treatment of Specific Pulmonary
cardiac output may be further augmented by an Diseases in the Pregnant Patient
additional 10% to 15% because of catecholamine
release. Asthma, pulmonary embolism (PE), and
Total blood and plasma volume increases infections such as TB are not uncommon in the
up to 35% to 50% of normal, peaking in the pregnant patient. It is important that the pulmo-
midthird trimester with a lesser increase in nologist be aware of the management of these
RBC volume (approximately 20%–40%). The conditions in pregnancy, including the acceptable
result is hemodilution with a relative decrease pharmacologic treatments.
in hemoglobin, hematocrit (approximately a
12% decrease), and relative RBC volume, that US Food and Drug Administration Drug
is, the anemia of pregnancy. There is also a Classification
dilutional decrease in serum protein levels,
resulting in a 5 mm Hg decrease in plasma Acceptable pharmaceutical agents in preg-
oncotic pressures, predisposing patients to nancy have been classified by the US Food and
edema formation, including pulmonary edema. Drug Administration.5 It should be noted that
There is an approximate total body fluid this classification system is expected to be revised
expansion of 6 to 8 L of water divided among in 2012. Currently, a category A drug means that
the fetus, amniotic fluid, and intracellular and well-controlled drug studies in pregnant women
extracellular spaces, and an increase in plasma have failed to demonstrate any risk to the fetus,
volume of 1 to 1.5 L. These changes in fluid and the possibility of fetal harm appears remote.
status are likely the result of increased miner- A category B drug indicates that animal drug
alocorticoid production and/or hormonally studies have shown that there was no demon-
mediated vasodilation. strated fetal risk, but controlled drug studies

have not been performed in pregnant women, or that there is nonadherence to regular asthma
animal reproduction studies have shown an therapy in up to one-third of pregnant asthmatics,
adverse effect that was not confirmed in studies resulting in worsening asthma control.
conduced in pregnant women. A category C The treatment of chronic asthma in pregnan-
agent is a drug for which studies in animals have cy is similar to that of the nongravid asthmatic.6–8
revealed adverse effects on the fetus, including In 1993, the National Asthma Education Program
teratogenicity, and there are no controlled studies sponsored by the National Heart, Lung, and
in women; or that studies in women and animals Blood Institute developed guidelines for the
are not available. These drugs can be used if the treatment of the pregnant asthmatic, which were
potential benefit of the drug outweighs the subsequently revised in 2004 and updated in
potential risk to the fetus. A category D agent is 2007.7,8 There has also been a shift to treatment
a drug for which studies have shown positive directed at a spectrum of control, from controlled
evidence of human fetal risks, but in certain to partly controlled to uncontrolled asthma. In
situations these drugs may be of benefit if the risk general, asthmatic patients well controlled on an
is outweighed by potential gain. Category X appropriate medical regimen prior to pregnancy
agents are those drugs in which animals or can remain on this regimen if control is accept-
humans have demonstrated fetal abnormalities able during pregnancy.
and/or there is evidence of fetal risks based on Short-acting selective b2-agonists are indi-
human experience and clearly the risk outweighs cated for intermittent (well-controlled) asthma
the benefit of the drug (eg, thalidomide). (albuterol has been the drug most widely
studied in pregnancy and is the preferred agent).
Asthma
These are category C agents. Low-dose inhaled
corticosteroids are the preferred agent for initi-
Of the approximate 10 to 12 million asthmatics
ating treatment for mild persistent asthma
in the United States, a significant number are of
(partly controlled) in the pregnant patient.
childbearing age. Asthma affects up to 7% to 8% of
Alternative, but not preferred, treatments in-
pregnant women.6–10 Poorly controlled asthma
clude leukotriene receptor antagonists (not zi-
can result in small but increased risks of preterm
leuton) or low-dose theophylline. Budesonide
labor and birth, preeclampsia, congenital anom-
alies, intrauterine growth retardation, and low (category B) and beclomethasone (category C)
birth weight as well as increased maternal are the best-studied inhaled corticosteroids, and
morbidity, such as placenta previa. In addition, budesonide is the preferred agent. Patients with
pregnancy affects the course of asthma. General moderate persistent asthma (partly controlled)
medical teaching states that asthma gets worse in should be placed on medium-dose inhaled
one-third of patients during pregnancy, one-third corticosteroids. A second choice alternative
improve and have fewer acute asthma exacerba- therapy could be low-dose inhaled budesonide
tions, and approximately one-third have no or beclomethasone with a long-acting b2-agonist
change in the frequency or severity of asthma. (such as salmeterol or formoterol), or a leukotri-
The best predictor of asthma severity in pregnan- ene receptor antagonist. Patients already main-
cy is the severity of asthma in the nonpregnant tained on other inhaled corticosteroids can be
state and the course of asthma in prior pregnan- continued on those agents. Other than budeso-
cies. Asthma tends to be less severe in the first and nide, all other inhaled corticosteroids are cate-
latter third trimesters and worse in the middle of gory C agents. Patients maintained on salmeterol
pregnancy (gestational weeks 25–32). Asthma or formoterol for control of moderate persistent
may improve in the last month of pregnancy asthma prior to pregnancy can remain on these
leading up to delivery, but may worsen in the agents. Salmeterol and formoterol have not been
postpartum period. Gastroesophageal reflux, si- well studied in pregnancy and are listed as
nusitis, and allergic rhinitis, leading to worsening category C. Oral theophylline or a leukotriene
asthma should be carefully evaluated in the receptor antagonist can be added if the asthma
pregnant asthmatic. In addition, it is estimated remains poorly controlled. The combination

inhalers, fluticasone/salmeterol, and budeso- could indicate fatigue and impending ventilatory
nide/formoterol are both category C agents. failure. Intubation should be considered with a
Severe persistent asthma (poorly controlled) PaCO2 of approximately 42 mm Hg consistently,
should be managed with high-dose inhaled as this relative acidosis places the fetus at risk.
corticosteroids and a long-acting b2-agonist. Heliox has been used for the treatment of status
Systemic corticosteroids (category C) can also asthmaticus. Both terbutaline and magnesium
be used for control of severe and acute exacer- have been used for control of status asthmaticus.
bations of asthma. Earlier studies raised the Epinephrine is not recommended for use during
concern of increased risk of prematurity and pregnancy because of concern for uteroplacental
low-birth-weight infants with the use of systemic vasoconstriction.
corticosteroids, but this may have been related to In the steroid-dependent asthmatic, stress-
the severity of asthma in these patients rather dose corticosteroids should be administered
than the medications used. Other studies have during labor and delivery. Prostaglandin F2a
shown a 0.3% incidence of congenital malforma- and ergonovine used for uterine atony should be
tions, an increased incidence of cleft palate, and avoided since they can cause bronchoconstric-
increased risk of preeclampsia with the use of tion. Prostaglandin E2 can be used.
systemic corticosteroids. Despite this, it is gener-
ally thought that the risks of poorly controlled Venous Thromboembolism in Pregnancy
asthma outweigh the risks of the medical
therapies used to control the disease. Patients PE is a leading cause of nonobstetric maternal
receiving systemic corticosteroids require careful mortality in developed countries. Some studies
evaluation for gestational diabetes. have suggested that PE can account for 20% to
Theophylline (category C) has been used 50% of maternal deaths, and account for 1.1 to 1.5
safely in pregnancy, although clearance in the deaths/100,000 deliveries in developed coun-
third trimester may be reduced, and there is tries.11 The spectrum of venous thromboembo-
decreased protein binding of the drug. There are lism (VTE)11–15 can affect 0.05% to 0.1% of
little data examining the use of leukotriene pregnancies, with an incidence of 0.76 to 1.72/
receptor antagonists during pregnancy, but mon- 1,000 pregnancies. PE is most common in the
telukast and zafirlukast can be used in patients postpartum period (up to 6 weeks after delivery).
demonstrating prior response to these agents. Some, but not all studies suggest an increased
Both are listed as category B agents. Zileuton incidence of DVT in the third trimester and
(category C) has been associated with teratoge- postpartum period, but the majority of subse-
nicity in animals and should be avoided. Terbu- quent studies have supported an equal distribu-
ta l i n e a n d o t h e r pare n t e r al b- a g on i s t s tion of DVT throughout the antepartum (and
administered near term can cause tocolytic equal across trimesters) and postpartum period
pulmonary edema and are often avoided, al- meaning that two-thirds develop in the antepar-
though terbutaline is a category B agent. Oma- tum period and the remainder in the postpartum
lizumab, an immunoglobulin E inhibitor, is rated period.
pregnancy Category B and can be considered for Pregnant women are at increased risk of VTE
improved control of poorly controlled asthma. during pregnancy (some reports suggest as much
Management of acute asthma (which can as five times higher) because of a combination of
develop in up to 10% of pregnant asthmatics) all three components of Virchow’s triad. There is
and status asthmaticus is the same as in the increased venous stasis, hypercoagulability, and
nonpregnant asthmatic, with short-acting b-ago- endothelial disruption of pelvic and uteroplacen-
nists and oral or parenteral corticosteroids. For tal vessels during delivery, particularly after
acute asthma, anticholinergic agents are also operative delivery. The hypercoagulability in
permissible (category B). Based on the normal pregnancy is because of alterations in levels of
compensated respiratory alkalosis of pregnancy, clotting factors (increases in fibrinogen, factors I,
when evaluating the pregnant asthmatic in the II, V, VII, VIII, IX, X, and XII), possibly decreased
midst of an acute episode, a PaCO2 of 35 mm Hg fibrinolytic activity, decreases in protein S levels,

and a progressive increase throughout pregnancy mGy fetal exposure and 1–2.5 mSv maternal
in activated protein-C resistance, resulting in exposure).13 A smaller dose of radioisotope is
increased thrombin generation and decreased recommended, and when possible, the perfusion
clot dissolution. The increase in venous stasis is scan should be performed without the ventilation
mechanical caused by reduced venous flow in scan to further minimize radiation exposure.
the lower extremity and pelvic vessels from the There are limited data evaluating the role of CT
compression of the IVC by the gravid uterus, and angiography for the diagnosis of PE in the
there is an interesting predominance of left lower pregnant patient, but it appears safe (0.03–0.66
extremity DVT (approximately 80%–90%), likely mGy fetal exposure and 4–18 mSv maternal
caused by greater compression of the left iliac exposure), and should be the next step in
vein by the right iliac artery. There is also a diagnosis if the V̇/Q̇ scan is nondiagnostic.13
predominance of iliofemoral DVT that is more Pulmonary angiography should be used when
likely to embolize. Other risk factors for VTE in indicated as the ‘‘gold standard’’ test for the
pregnancy include prolonged bed rest, cesarean diagnosis of PE (7–28 mSv maternal exposure).
delivery (as compared with vaginal delivery—a There are several important caveats to treat-
twofold increased risk), preeclampsia, advanced ing VTE during pregnancy, and this topic is
maternal age, obesity, multiparity, and prior VTE included in the 9th American College of Chest
and thrombophilia. Despite the increased risks of Physicians evidenced-based clinical practice
VTE inherent to pregnancy, an episode of guidelines on anticoagulation.14 Heparin is the
thrombosis during pregnancy should still anticoagulant agent of choice for both treatment
prompt a thrombophilic evaluation. and prophylaxis during pregnancy since it does
The most commonly used and best diagnostic not cross the placenta, and low-molecular-weight
test for determining DVT in pregnancy is heparin (LMWH) (category B) or unfractionated
Doppler ultrasound, although test results may heparin (UFH) (category C) can be safely used.
be impaired, and false-positive results can occur. However, in almost all situations, LMWH is the
In addition, problems such as difficulty in preferred agent for both treatment and prophy-
detecting iliac, pelvic, and calf thromboses exist. laxis over UFH (Grade 1B). LMWH is also the
The sensitivity and specificity of this study may preferred agent over vitamin K antagonists
be improved when performed in the left lateral (VKAs) throughout pregnancy (Grade—1A first
decubitus position. Recent evidence-based guide- trimester, 1B second and third trimesters, and 1A
lines recommend as the initial test for the at the time of delivery). For treatment of acute
diagnosis of suspected DVT in pregnancy.12 The VTE, adjusted dose LMWH is recommended
utility of the D-dimer assay in pregnancy is over adjusted-dose UFH (Grade 1B) and over
limited, as elevations may occur normally in VKAs (Grade 1A). Anticoagulation should be
pregnancy, particularly with advanced gestation- continued throughout pregnancy and 6 weeks
al age and complicated pregnancies, but is likely postpartum to complete a total of 3 months of
of some utility in the case of low clinical anticoagulation (Grade 2C). Warfarin can be used
suspicion, in earlier stages of pregnancy, when in the postpartum period. In some unique
applied in conjunction with other testing and situations, such as prophylaxis for mechanical
when a highly sensitive assay is used. In heart valves, warfarin can be used after the 13th
relatively small retrospective studies, the sensi- week of pregnancy until the midthird trimester
tivity and specificity of D-dimer for VTE in without complications. There is a paucity of data
pregnancy was 73% to 100% and 6% to 23%.13 to recommend the use of the direct thrombin
Venography is rarely used for the diagnosis of inhibitors in pregnancy.
DVT. One should be aware of the significant
The diagnostic approach to a suspected PE in complications with prolonged heparin use, in-
pregnancy differs from that in the nonpregnant cluding heparin-induced thrombocytopenia. Os-
individual. If the chest radiograph result is teoporosis can also be a complication in patients
normal, ventilation/perfusion scanning should receiving long-term therapy with heparin.
be used prior to other testing for PE (0.32–0.74 LMWH may be associated with a lower incidence

of osteoporosis and heparin-induced thrombocy- high as 12%. Specific recommendations on
topenia. Direct thrombin inhibitors can be used anticoagulation for different permutations of
in cases of heparin-induced thrombocytopenia. thrombophilia as well as for patients with
Warfarin (category X) crosses the placental mechanical valves are in the American College
barrier, particularly between 6 to 10 gestational of Chest Physicians guidelines.14 Patients requir-
weeks, and is associated with poor fetal epiph- ing long-term warfarin anticoagulation prior to
yseal cartilage formation, chondrodysplasia, and pregnancy should be converted to UFH or
fetal nasal hypoplasia. CNS abnormalities have LMWH when pregnancy is planned or as early
also been described, including malformations, in pregnancy as possible if not planned.
optic atrophy, and microhemorrhages with war-
farin use at any time during pregnancy. The use TB in Pregnancy
of warfarin is permissible during lactation.
Thrombolytic agents are relatively contrain- With increases in the rates of TB in the
dicated during pregnancy, especially near term United States, largely because of increases in
and within 2 weeks postpartum because of the HIV infection and increases in foreign-born
risk of hemorrhage. However, published case immigrants, there has been an increase in TB
reports of successful use exist. Inferior vena caval cases in childbearing adults and children. The
filter placement can be performed although actual incidence of TB in pregnancy is not
suprarenal placement is recommended because completely clear but can be in the range of 1%
the left ovarian vein empties into the left renal in poverty-stricken inner-city areas with poor
vein. access to prenatal health care. The prognosis of
The management of labor and delivery in the TB in pregnant women has been debated. At one
patient who is fully anticoagulated can be time, it was thought that TB had an increased
difficult. Epidural anesthesia should be used incidence of dissemination in the pregnant
with caution in these patients because epidural woman. Most data support that there is no
hematomas may result. Most patients receiving difference in the susceptibility to infection,
LMWH or UFH should have their anticoagula- course of disease, obstetrical outcome, progno-
tion stopped 24 h prior to elective induction sis, and incidence of TB in nonpregnant or
(Grade 1B). Patients at high risk for recurrent pregnant women unless immunosuppression
VTE should be switched to UFH at least 24 h coexists.
prior to expected induced delivery to safely Treatment of active TB in pregnancy is
discontinue anticoagulation 6 to 8 h prior to similar to that of treatment in the nonpregnant
expected delivery. individual with a few caveats.16 Drugs approved
The indications for prophylaxis for VTE in in pregnancy include isoniazid (INH), rifampin,
pregnancy have the following specific recom- and ethambutol. These drugs all cross the
mendations.14 All patients with any history of a placenta but have not been shown to have
prior VTE should receive postpartum prophy- teratogenic effects. In general, pyrazinamide,
laxis for 6 weeks with prophylactic or interme- streptomycin, and ethionamide should be avoid-
diate-dose LMWH or VKAs rather than no ed in pregnancy. There are situations in which
prophylaxis (Grade 2B). In addition, patients treatment with these other drugs may outweigh
with a single prior VTE related to a clear the potential risks of using these agents. The
transient risk factor, but not because of prior teratogenicity of streptomycin is primarily fetal
pregnancy, should be followed with clinical ototoxicity because of nerve damage, congenital
vigilance antepartum (Grade 2C), and patients auditory malformations, and/or congenital
with a history of idiopathic VTE or pregnancy- deafness. Pyrazinamide has been avoided tradi-
related VTE should undergo antepartum pro- tionally in the United States because it has not
phylaxis with prophylactic or intermediate dose been well studied in pregnancy, but it is used
LMWH (Grade 2C). This latter group is at routinely by the World Health Organization and
moderate to high risk of recurrent VTE. Preg- the International Union Against Tuberculosis
nancy-related VTE can have a recurrence rate as and Lung Disease. Thus, standard treatment for

active TB should include INH, rifampin, and in the nonpregnant individual. Pneumonia18
ethambutol for 9 months because the regimen may complicate 1.2 to 2.7 per 1,000 deliveries
does not contain pyrazinamide. These same and may be more frequent in inner cities.
drugs can be continued during lactation without Preterm labor, preterm delivery, and respiratory
compromise to the infant. If infected with a failure can result. Maternal mortality can be as
potentially drug-resistant organism, then the high as 4%.
addition of pyrazinamide should be considered Several small epidemiologic studies exam-
pending results of susceptibility testing. INH- ining the bacterial organisms responsible for
resistant cases can be treated with rifampin and community-acquired pneumonia in the preg-
ethambutol. Multidrug-resistant cases may have nant patient show the spectrum to be similar to
to consider therapeutic abortion. It is a standard that in the nonpregnant woman, and similar
recommendation that pyridoxine always be empiric therapies can be used. The cephalospo-
administered with INH during pregnancy to rins and penicillins can be safely used in
decrease the incidence of INH neurotoxicity pregnancy (all are category B). Quinolones are
(optic and peripheral neuropathy). category C agents. The macrolides are category
Chemoprophylaxis for latent TB infection B and C agents. The tetracyclines are category D
(LTBI) is somewhat more controversial.17 Because agents and should be avoided. The sulfonamide
it appears that pregnancy does not increase the drugs are category C agents and are usually
risk for active TB in patients with LTBI, many reserved for infections such as Pneumocystis
health-care workers would delay prophylactic pneumonia.
treatment until after delivery in a patient with A few specific organisms responsible for
clear chest radiograph findings and who is HIV pneumonia in pregnancy deserve mention. In
negative, not a recent converter, and not in pregnancy, cell-mediated immunity may be
another high-risk group. However, most author- altered and, thus, infections with fungal and
ities recommend 9 months of INH prophylaxis if viral organisms can be more severe and life
the patient falls in an appropriately screened high- threatening. The risk of dissemination with
risk LTBI group. Routine purified protein deriv- coccidioidomycosis, as well as mortality, is likely
ative (PPD) testing during pregnancy has fallen increased during pregnancy (20% vs 0.2% in the
out of favor at most medical centers, unless in an nonpregnant individual), although this has not
endemic TB area, or unless the patient is in a high- been borne out consistently in all studies. It is
risk group such as those with HIV infection. generally thought that dissemination is more
Children ,5 years of age with LTBI are at likely if the infection is acquired in the third
high risk of progression to disease and/or more trimester. Treatment includes amphotericin or a
severe and/or disseminated disease, and require liposomal derivative. Both agents are category B
9 months of INH prophylaxis. If a child is agents. The majority of the azoles are classified as
exposed to a mother with active TB, then the category C.
child should be separated from the mother (only Of the viral agents, varicella zoster is one of
until the mother is deemed noncontagious), the most feared during pregnancy. Although this
undergo PPD skin testing and a chest radio- illness is usually self-limited and benign in
graph, and be administered INH therapy for 8 to children, in the nonexposed adult pregnant
12 weeks even if the skin test result is negative. patient, the mortality rate associated with vari-
At that time, the PPD should be repeated. If the cella pneumonia may approach 35%. Infection is
PPD result remains negative, INH can be most severe in the third trimester. Patients
discontinued and, if positive, 9 months of INH present with fever and rash and can rapidly
prophylaxis should be completed. progress to pneumonia. A typical chest radio-
graph shows miliary and nodular infiltrates,
Pneumonia in Pregnancy usually resolving within 14 days. The end
radiographic result of such pneumonia is often
In general, the incidence of bacterial pneu- calcified, but physiologically insignificant, nod-
monia in the pregnant woman is similar to that ules. Acyclovir (category B) can be safely used

during pregnancy and should be begun with the that is, high cardiac output and low systemic
first sign of varicella infection. vascular resistance, can be confused with the
Influenza virus can also be more severe in hemodynamics of sepsis.
pregnancy, although some older data had sug-
gested that mortality associated with influenza Mechanical Ventilation
during pregnancy was similar to that in the
nonpregnant woman. However, in the 2009 The principles of mechanical ventilation in
epidemic, 5% of hospitalized pregnant women the pregnant patient are similar to those in the
with influenza died.19 Women at advanced stages nonpregnant individual. Intubation may be more
of pregnancy were at higher risk. Other risk difficult because of edema of the upper airway, a
factors for poor outcomes in these patients reduced airway caliber, and an increased risk for
included asthma, obesity, and diabetes. Since aspiration and bleeding, and smaller endotrache-
2009, it has been recommended that all women al tubes may be required. Low functional
should be immunized against influenza during residual capacity leading to low oxygen reserves
pregnancy, regardless of the trimester, with the may also make the intubation procedure more
inactivated influenza vaccine. The anti-influenza challenging. When on mechanical ventilation,
drugs are category C agents. tidal volumes may have to be reduced because of
reduced chest wall compliance from the gravid
Acute Respiratory Failure and Critical uterus, and higher peak pressures may be
Care in Pregnancy required to overcome chest wall stiffness. Gas
exchange goals should be to maintain PaCO2 in
Hemodynamics the pregnant eucapnic range of 28 to 32 mm Hg,
with a PaO2 .90 mm Hg and saturations .95% to
As pregnancy progresses, cardiac output can prevent fetal hypoxemia. A further reduction in
become positionally dependent because of the PaCO2 can lead to reduced uterine blood flow and
gravid uterus potentially obstructing the IVC and fetal hypoxemia. The fetus is very sensitive to
reducing venous return. This is particularly true hypoxemia, and attempts to compensate for
in the third trimester and is most notable in the maternal hypoxia by divergence of maternal
supine position. Severe hypotension can result. blood flow to essential tissues, a leftward shift
This effect is reduced in the full or partial left in the oxyhemoglobin dissociation curve, and
lateral decubitus position, allowing the uterus to high avidity of fetal hemoglobin for oxygen. In
be displaced from the IVC. This can be an the setting of status asthmaticus or severe ARDS,
important factor in the resuscitation of the lung protective ventilatory strategies and per-
hypotensive pregnant patient. Because of low missive hypercapnia may be required. Noninva-
colloid oncotic pressure, invasive monitoring sive mechanical ventilation has not been well
with pulmonary artery catheters, although rarely studied in pregnancy, but its utility may be
used, may have to be interpreted with caution, limited by the increased risk of aspiration and
because pulmonary edema can develop at a narrow airway caliber in this population. There
lower pulmonary artery occlusion pressure. are numerous causes of respiratory failure in
pregnancy, both those specific to pregnancy as
Sepsis well as those that could be encountered in the
nonpregnant patient.20–23
In addition to nonobstetric-related causes of
sepsis in the pregnant patient, sepsis can result Amniotic Fluid Embolism
from endometritis, pelvic thrombophlebitis, cho-
rioamnionitis, and septic abortion and from Amniotic fluid embolism (AFE)24 is a rare but
procedures such as amniocentesis, and/or infec- catastrophic complication of pregnancy. The
tion of cesarean or episiotomy incisions. It is incidence of AFE ranges between 1 in 8,000 and
important to recall that baseline hemodynamic 1 in 80,000 pregnancies, with an associated 80%
parameters in a nonseptic pregnant individual, to 90% mortality. AFE is responsible for 10% to

20% of maternal deaths in the peripartum period. oral genital sex and during gynecologic proce-
Risk factors for AFE include advanced maternal dures using air insufflation. One percent of
age, multiparity, premature rupture of mem- maternal deaths are thought to be from venous
branes, and meconium staining of amniotic fluid. air embolism. The usual sites of air entry are at
The use of uterine stimulants and tumultuous the subplacental venous sinuses, during the
labor may also be risk factors. The risk of AFE antepartum or peripartum period, followed by
extends 48 h into the immediate postpartum entry into the venous circulation. In the right
period and has also been reported to develop ventricle, air can obstruct the pulmonary blood
during abortions and placental abruption. The flow, resulting in cardiopulmonary collapse. In
pathophysiology of AFE is not completely general, it is thought that 100 mL of air can lead
known, but postulated mechanisms include true to mortality. Recruitment and activation of
mechanical obstruction of the pulmonary vascu- neutrophils, protein aggregation at the turbulent
lature with fetal squamous cells and other debris, air blood interface and obstruction of pulmonary
alveolar capillary leak caused by a release of arterial vessels by microemboli also contribute to
mediators during delivery, pulmonary edema as the pathophysiology of venous air embolism.
a result of left ventricular failure, and an Patients with venous air embolism present
anaphylactic reaction to exposure of the mother with profound hypotension, as well as nonspe-
to fetal antigens. cific signs of coughing, dizziness, tachypnea,
Amniotic fluid embolism presents cata- dyspnea, tachycardia, and diaphoresis. Respira-
strophically with the acute onset of tachypnea, tory arrest soon follows, and mortality can rise to
dyspnea, tachycardia, cyanosis, hypotension, 90%. The classic but rarely heard cardiac mill-
hypoxemia likely caused by ventilation/perfu- wheel murmur audible over the precordium is
sion abnormalities, and hemodynamic collapse. supportive of the diagnosis of venous air
Seizures can occur. Disseminated intravascular embolism. ARDS may develop. Other findings
coagulation can develop in 40% to 80% of include mental status changes, coma, seizures,
patients, and hemorrhage can be the initial stroke, myocardial infarction, and thrombocyto-
presentation. The majority (70%) of those patients penia. Bubbles may be visualized in the retinal
who survive the initial event will develop ARDS. arterioles, and subdermal air may be present. Air
This is often followed by some transient left in the heart or great vessels is occasionally seen
ventricular dysfunction as supported by older on the chest radiograph.
studies using pulmonary artery catheters. Treatment includes recognition of the syn-
The diagnoses of AFE is one of exclusion but drome, followed by placing the patient in the left
can be supported in the appropriate clinical lateral decubitus position so that the air bubble is
setting with the presence of fetal squamous cells removed from the entrance to the right ventric-
and lanugo hairs in the maternal circulation ular outflow tract. Cases of aspiration of air from
although these can also be present under normal the right heart using a pulmonary artery or
conditions and are not pathognomonic for this central venous catheter have been reported.
diagnosis. Treatment is supportive with intuba- Patients should be ventilated with 100% oxygen
tion, mechanical ventilation, vasopressors, seda- to facilitate removal of nitrogen, which comprises
tion, and sometimes neuromuscular blockade, a significant (up to 80%) of gas content in the
and rarely pulmonary artery catheter placement. embolus. The use of hyperbaric oxygen therapy
Factor replacement may be required for hemor- should be considered. There are anecdotal
rhage. The roles of corticosteroids or plasmaphe- reports of using heparin to treat microemboli
resis are unproven. and corticosteroids to decrease pulmonary ede-
ma in this syndrome.
Venous Air Embolism
Tocolytic Pulmonary Edema
Venous air embolism can occur during
normal delivery, with placenta previa, and Until recently, b-adrenergic agents were
during abortion. It has also been reported during widely used in obstetrics for inhibition of

preterm labor often administered in combination as well as by frequent examinations, a decrease in
with corticosteroids to promote fetal lung devel- gastric emptying during parturition, and being in
opment. The most common agents used were b2- the supine position. In some cases, alterations in
selective agents such as terbutaline and ritodrine, mental status because of sedation and a reduc-
and tocolytic pulmonary edema developed in as tion in vocal chord closure possibly related to
many as 4% to 5% of patients receiving these analgesia used during labor may also contribute
agents. Currently, many obstetricians use mag- to an increased risk of aspiration.
nesium for treatment of preterm labor, which has There is a correlation between the volume of
resulted in a decrease in this entity. gastric contents aspirated, the acidity of the
Usually, symptoms of tocolytic pulmonary aspirate, the presence of particulate matter, the
edema develop within 24 h but occur more bacterial load, and the host resistance on the
commonly 48 h after initiation of therapy, and progression and severity of clinical symptoms. It
can also develop within 24 h after discontinua- is thought that the low pH (,2.5) of the aspirate
tion of the drug. Those patients who receive is the major inciting pathogenic process for
prolonged tocolytic therapy with concomitant disease because of a chemical pneumonitis
infusions of crystalloid volume, those with although large volumes, particularly those con-
multiple gestations, and those with preeclampsia taining food particles, can be clinically significant
are more at risk for development of tocolytic even with higher pH levels. A small subgroup of
pulmonary edema. The mechanisms of tocolytic patients will have immediate respiratory arrest
pulmonary edema include possible fluid over- and death following aspiration caused by airway
load, direct cardiac toxicity, alterations, and obstruction by large particulate matter, progress-
reductions in colloid oncotic pressure and/or ing to asphyxia. In those cases in which small
increased pulmonary capillary permeability. volumes of gastric contents are aspirated, symp-
Tocolytic pulmonary edema presents typical- toms may be delayed until 6 to 24 h following the
ly with dyspnea, tachycardia, tachypnea, chest event. Bacterial pneumonia can develop 24 to 72
pain, crackles, and the presence of pulmonary h after the aspiration. Severe bronchospasm and
edema on chest radiograph. This syndrome ARDS can also result.
reverses quickly, usually 12 to 24 h after Treatment is supportive. As in the nonpreg-
recognition and discontinuation of the offending nant patient, there is no role for prophylactic
agent. The prognosis is excellent. Transient use of antibiotics or corticosteroids when treating this
oxygen and diuretics may be needed. aspiration syndrome. Resolution usually occurs
over the next 4 to 5 days unless secondary
Aspiration superinfection develops. Bronchoscopy may be
indicated when witnessed aspiration with large
Aspiration historically has been a significant food particles has occurred. The chances of
problem in obstetrics and is estimated to account aspiration can be reduced by the use of regional
for 2% of maternal mortality in the United States. anesthesia, restricting oral intake at the time of
The classic description was made by Mendelson delivery, and cricoid pressure if endotracheal
(in 1946) who described large volumes of gastric intubation is required.
contents entering the tracheobronchial tree in
women undergoing labor and delivery. Because ARDS
of this large volume of aspiration of low pH-
containing gastric contents, ARDS and chemical ARDS is defined similarly in the pregnant as
pneumonitis subsequently developed. Immedi- in the nonpregnant individual. In addition to the
ate asphyxia was also described. causes of ARDS discussed elsewhere in this
The obstetric patient is at risk for aspiration course, there is a long list of ARDS etiologies
for many reasons, including progesterone-in- unique to or associated with pregnancy. These
duced relaxation of lower esophageal sphincter include placental abruption, air embolism, amni-
tone, an increase in intragastric pressure because otic fluid embolism, aspiration, eclampsia, septic
of mechanical compression by the gravid uterus abortion, and the dead fetus syndrome.

Pulmonary Edema Patients with pulmonary arterial hypertension
should be counseled against pregnancy and
Pulmonary edema can accompany pre- encouraged to seek termination of pregnancy
eclampsia/eclampsia in approximately 3% of and permanent forms of birth control. Those
cases. Pulmonary edema may develop more patients wishing to continue with their pregnan-
frequently in the immediate postpartum period. cy should be managed with medications such as
Risk factors include advanced age and multi- inhaled nitric oxide and/or IV or inhaled
gravity. Mechanisms for preeclampsia-related prostacyclin during the peripartum period.
pulmonary edema include increased left ventric- Placement of a pulmonary artery catheter should
ular afterload, myocardial dysfunction, the alter- be strongly considered during delivery. Long-
ations in colloid oncotic pressure discussed term management could include epoprostenol,
earlier, as well as fluid overload. There may also (prostacyclin, a category B agent) or sildenafil
be a component of increased pulmonary capillary (category B), but the oral endothelin-receptor
permeability. Management is approached in the blocker agents, such as bosentan, are contraindi-
standard manner with oxygen, diuresis, control cated because of teratogenicity (category X).
of hypertension, and mechanical ventilation, if
required. Invasive hemodynamic monitoring Tobacco and Lung Disease in Women
may be required.
Tobacco
Peripartum Cardiomyopathy
At the end of the 19th century and beginning
Pregnancy-related cardiomyopathy can de- of the 20th century, cigarette smoking and
velop in 1 in 1,300 to 1 in 4,000 deliveries and tobacco use were limited primarily to men and
usually presents in the third trimester or up to 6 were thought to be socially unacceptable for
months postpartum. Risk factors include ad- women. However, in the early 20th century with
vanced age, multiple gestations, preeclampsia, the advent of the Suffragist movement, numer-
and African-American race. Patients typically ous ad campaigns promoted the use of tobacco
present with dyspnea, orthopnea, peripheral by women, including well-known advertise-
edema, pulmonary edema, tachycardia, and a ments with the famous slogan ‘‘You’ve come a
cardiac gallop. The chest radiograph shows long way, baby.’’ Tobacco smoking began to be
cardiomegaly and pulmonary edema, and echo- associated with the educated and/or liberated
cardiography demonstrates global hypokinesis. American woman, a concept further promoted
Prognosis is variable, and approximately 30% of by the advertising of the tobacco industry. The
these patients recover, 30% may have residual use of tobacco products by women increased
cardiac damage, and 30% may require heart dramatically following World War II and peaked
transplantation. The cause of death is often in 1965 when the prevalence of smoking among
thromboembolism from left ventricular throm- women approached 35%. In 2010, 17.3% of
bus. The recurrence of cardiomyopathy with women and 21.5% of men smoked as recorded
subsequent pregnancies is common. by the CDC.25
The initial 1964 landmark US Public Health
Pulmonary Arterial Hypertension Surgeon General’s Report on Smoking and
Health primarily addressed smoking and respi-
Patients with pulmonary hypertension, either ratory health in men. However, in 1980, the
secondary or idiopathic, are at increased risk for Surgeon General’s Report on the Health Conse-
maternal (35%–50%) and fetal mortality during quences for Smoking for Women was released.
pregnancy. The risk appears to be greatest in the This report concluded that women demonstrate
immediate peripartum period, when a large the same dose-response relationships with ciga-
amount of blood volume is ‘‘autotransfused’’ rette smoking as do men and that the risk of lung
from the uteroplacental bed back to the maternal cancer increases with the increasing number of
circulation. Acute right-heart failure can result. cigarettes smoked per day; earlier ages of

beginning cigarette smoking; longer duration of cancer. In the 2012 report, lung cancer was newly
smoking; higher tar and nicotine content of diagnosed in .109,000 women. Lung cancer
cigarettes, and inhalation of cigarette smoke. incidence rates in women began to level off from
The study predicted that mortality rates in the mid-1990s to early 2000 and are now
women from lung cancer may be comparable decreasing; however, death rates in women from
with that experienced by men, that there would lung cancer are just recently achieving the
be a rapid increase in lung cancer rates in women plateau seen in men in the 1980s and are only
similar to that seen in men 25 years previously, now decreasing.
and that lung cancer death rates in women Of the different cell types, adenocarcinoma is
would surpass those of breast cancer by the early the most common cell type of lung cancer in both
1980s. The study also found that the incidence of smoking and nonsmoking women, regardless of
other respiratory conditions such as influenza age, and is the most common cell type in young
was 20% higher in ever-smoking women than in people and in nonsmokers of both sexes. A
nonsmoking women, that there was an increase possible increase in the susceptibility of tobacco
in death rates because of COPD in smoking carcinogens in women has been a highly debated
women compared with nonsmoking women, and topic.29 Some studies have indicated that there is
that this death rate correlated with the number of an increase in the relative risk for lung cancer
cigarettes smoked. Finally, the study concluded developing in smoking women than in men;
that women smokers had worse pulmonary other studies have not been able to support this.
function than exsmokers or never-smokers and Yet other studies have shown that there is an
that the severity of decrease in pulmonary
increased odds ratio of tobacco-related lung
function was dose related to the number of
cancer in women only for some certain types of
cigarettes smoked.
lung cancer. For example, it appears that smok-
The follow-up 2001 Surgeon General Report
ing women have a higher odds ratio for small cell
on Women and Smoking26 found the following:
carcinoma developing than do men. There are
(1) in 1998, 22% of women smoked cigarettes; (2)
many postulated reasons as to why women may
lung cancer is the leading cause of cancer deaths
have an increased susceptibility to tobacco
in women, and 90% of these are related to
carcinogens, including the fact that there may
smoking; and (3) in 2000, 25% of cancer deaths
be an increased frequency of mutations in the P53
in women were caused by cancer of the lung. The
and other tumor suppressor genes in women
study also stated that the risk of lung cancer
than in men; in addition, a higher promutage-
increases with quantity, duration, and intensity
nicity DNA level (CP450), higher levels of DNA
of smoking.
adducts, and decreased capacity for DNA repair
Lung Cancer have been observed in women. Hormones
(estrogens) and hormonal replacement may play
Lung cancer27–32 has become the leading a role in the variable susceptibility to tobacco
cause of cancer deaths in both men and women carcinogens, particularly with adenocarcinoma.
in the United States, surpassing death rates in In never-smokers, age-adjusted incidence rate is
women as a result of breast cancer in 1987. More higher for women (14.4-20.8/100,000 person
than 80% to 90% of lung cancers in women are years) as compared with men (4.8-13.7/
related to tobacco use and are thus preventable. 100,000).28 Other risk factors for lung cancer in
In the 2012 Cancer report,27 26% percent of women include a family history of lung cancer;
cancer deaths in women were the result of cancer occupational exposures to compounds such as
of the lung. Although breast cancer affects a large asbestos, cadmium, beryllium, silicosis, and
number of women per year, lung cancer has a radon; and prior lung disease as are found in
significantly worse prognosis with higher mor- men. In general, women with lung cancer have a
tality rates. In the 2012 report, .72,000 women better prognosis and equal or better survival with
died of cancer of the lung and bronchus as treatment than do men, regardless of cell type
compared with 39,510 deaths caused by breast and stage.28 There is also a suggestion that

epidermal growth factor receptor positive lung Gender differences have also been reported
cancers may be more common in women. in the lung function response to smoking
cessation and smoking relapse. In intervention
COPD studies centered largely on smoking cessation,
women exhibited lower sustained smoking ab-
For COPD33–37, this is the eighth consecutive stinence rates than men, even after administra-
year in which women have exceeded men in the tion of nicotine replacement therapy, and women
number of deaths attributable to the disease exhibited greater improvements in FEV1 than
(64,000 vs 60,000), often referred to as a shift in men a year after successful quitting but recipro-
the burden of COPD to women. Particulate cally greater declines in FEV1 after relapse.
matter from cigarette smoke and air pollution, There are other interesting differences be-
including smoke from poorly ventilated wood tween women and men in regards to smoking
stoves and the burning of biomass, are related to include the following. Historically, men have
lung damage. Cigarette smoking is the major been more likely than women to receive a
cause of COPD in women, and the risk increases diagnosis of emphysema and women to receive
with the amount and duration smoked. Ninety a diagnosis of bronchitis. However, in 2008 more
percent of mortality among women in the United women reported a diagnosis of emphysema than
States is attributable to smoking. Mortality rates men; more than 2.0 million (17.3 per 1,000
attributable to COPD among men have reached a population) compared with almost 1.8 million
plateau and are decreasing, whereas COPD (16.3 per 1,000 population), respectively. The
mortality rates among women have continued degree of emphysema noted on CT for the same
to rise and are just now approaching a plateau. percent predicted FEV1 is less in women than
The prevalence of COPD in women from 2001 to men. Women also have worse quality of life,
2009 was 6.1% (7.4 million effected) and is greater increased sensation of dyspnea and higher BODE
than or equal to that in men 4.1% (4.4 million) (an index derived from measurement of BMI,
over the same time period. This may actually be degree of airway obstruction, dyspnea score, and
underestimated because several studies have exercise capacity) indices for the same degree of
suggested that COPD is less frequently diag- FEV1% predicted. Each year, more women are
nosed in women.36 This parallels the trends hospitalized with COPD than are men (approx-
previously discussed in lung cancer. imately 1.5–3.6 times).
Gender differences have been reported in lung In children who have prenatal exposure to
function response to smoking.37 A recent system- environmental tobacco smoke from a smoking
atic review of population-based cohort studies of mother, studies have shown that fetal lung
current smokers showed that females had a development is affected. These children have
significantly faster annual decline in percent more airway obstruction, increased airway hy-
predicted FEV1 with increasing age than males. perresponsiveness, and alterations in lung mat-
Because the slope of this curve is steeper than that uration and lung growth. There is a small
seen in men, it is possible that women are more decrement in birth weight and increased risk of
vulnerable to tobacco-induced COPD. Studies in intrauterine growth retardation and other obstet-
these regards have been conflicting; but most ric complications. Those children exposed to
indicate that women with exposure to tobacco environmental tobacco smoke in the postnatal
smoke have more severe COPD and more lung period have an increased incidence of cough,
function impairment with fewer pack-years of wheezes, respiratory illnesses, and infection.
tobacco use than do men. Some of the postulated Pulmonary function is decreased slightly, and
mechanisms for this increased prevalence in there is an increase in airway responsiveness.
women include: small air airway size, which alters These children tend to have an increase in
the distribution of toxins contained in tobacco, childhood asthma, earlier development of asth-
hormonal mechanisms, and variations in cyto- ma, and more severe asthma. Other studies have
chrome P450 levels. It also appears that women shown that atopy tends to develop in children
develop COPD at an earlier age than do men. exposed to environmental tobacco smoke, which

can result in worsening asthma. There have also tive with the monoclonal antibody HMB-45 (a
been correlations found between environmental melanoma-related tumor marker).
tobacco smoke and obstructive apnea in children Clinically, patients present with symptoms of
and sudden infant death syndrome in infants. dyspnea, cough, chest pain, and hemoptysis. The
physical examination may reveal decreased breath
Catamenial Pneumothorax and sounds, crackles, and sometimes ascites and/or
Hemoptysis abdominal masses. Spontaneous pneumothoraces
and/or chylothoraces may also be presenting
Catamenial complications by definition de- findings. Radiographically, LAM is characterized
velop during menstruation. Catamenial pneumo- by cyst formation and chronic interstitial infil-
thorax occurs very rarely and is usually trates. Hyperinflation develops as the disease
recurrent. Patients are usually in their late 20s progresses. Pleural effusions and pneumothoraces
to .30 years of age when they initially present. may also be present. High-resolution CTcan reveal
Symptoms develop within 24 to 48 h of the onset diffuse, homogenous cystic disease with cysts
of menstrual flow. The pneumothoraces are often ranging from a few millimeters to 1 cm in size (6-
on the right side and are often associated with cm cysts have been reported); characteristically,
pelvic endometriosis. The mechanisms of air nodularity, as seen in langerhans cell histiocytosis,
entry into the pleural space may be caused by a is absent. Pulmonary function testing most com-
defect at the site of pleural or diaphragmatic monly shows mixed obstructive and restrictive
endometriosis or may be by air gaining access to physiology with an elevated total lung capacity
the peritoneal cavity during menstruation and and residual volume and a reduced diffusion
then subsequently entering the pleural cavity capacity, but up to one-third of patients can have
through a diaphragmatic defect. The diagnosis is normal pulmonary function.
fairly straightforward when a pneumothorax Complications of LAM include recurrent
develops during the first 48 h of menstrual flow. pneumothoraces in .50% of patients, chylous
Treatment includes ovulation-suppressing drugs. effusions in approximately one-third of patients,
Patients wishing to conceive or who do not want chylous ascites, and renal angiomyolipomas in
ovulation suppressed should undergo thoracot- up to 50% of patients. These latter tumors can
omy with repair of diaphragmatic defects, if develop in the kidneys or in other solid organs
present, followed by pleurodesis. Catamenial (uterus, ovaries, liver, spleen) and are comprised
hemothorax has also been described. of blood vessels, smooth muscle, and fat.
Catamenial hemoptysis is thought to occur The diagnosis of LAM can be suspected by
because of endometriosis in the lung parenchy- the clinical presentation and characteristic radio-
ma. It is usually a cause of scant hemoptysis but graphic appearance and confirmed by lung
can, in some cases, be severe. Treatment includes biopsy with HMB-45 transbronchial, thoraco-
hormonal suppression and/or resection of lung scopic, or surgical staining. The major entities
parenchyma involved with endometriosis. in the differential diagnosis are other causes of
cystic lung disease with preserved lung volume,
Lymphangioleiomyomatosis particularly langerhans cell histiocytosis and
cystic sarcoidosis.
Lymphangioleiomyomatosis (LAM) is cov- The prognosis with LAM is variable, but
ered extensively in other portions of this syllabus median survival is often reported to be 8 to 10
but will be reviewed briefly here. LAM is a rare years. The cause of death is usually respiratory
disease (prevalence 1–2/million) affecting pre- failure.
menopausal women with a mean age of 35 Treatment for LAM has included hormonal
years.38 The disorder is characterized by prolif- manipulation with the use of antiestrogen agents
eration of atypical smooth muscle in the bron- (such as tamoxifen), progesterone agents, lutein-
chovasculature, lymphatics, and interstitium of izing hormone-releasing hormone analogs, and/
the lung as well as the abdomen and pelvis. or oophorectomy with variable results. Patients
Typically, these smooth-muscle cells stain posi- should avoid estrogens and pregnancy. Lung

transplantation has been performed for LAM, 7. National Asthma Education and Prevention Pro-
although disease recurrence has been document- gram. Report of the Working Group on Asthma and
ed. Recently, sirolimus, acting via suppression of Pregnancy: management of asthma during pregnancy.
mammalian target of rapamycin (mTOR) signal- Update 2004. Bethesda, MD: National Institutes of
ing, has been studied with a primary endpoint of Health; 2005.
decreasing angiomyolipoma volume at 12 8. National Asthma Education and Prevention Pro-
months.39 In this small study, there was a 50% gram. Expert panel report III: guidelines for the
reduction in angiomyolipoma size while on diagnosis and management of asthma. Bethesda,
therapy with sirolimus, but the tumor size MD: National Heart, Lung, and Blood Institute;
increased following discontinuation of treatment. 2007. www.nhlbi.nih.gov/guidelines/asthma/
An interesting secondary finding in the study asthgdln.htm. Accessed March 10, 2012.
was an improvement in spirometry of 5% to 10% 9. Schatz M. The efficacy and safety of asthma
in FEV1 and FVC, which was only partially medications during pregnancy. Semin Perinatol.
sustained after discontinuation of sirolimus. A 2001;25(3):145–152.
follow-up randomized, double-blind comparison 10. Murphy VE, Gibson PG, Smith R, Clifton VL.
study from the same investigators, randomized Asthma during pregnancy: mechanisms and
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followed by a 12-month observation period.40 11. Marik PE, Plante LA. Venous thromboembolic
Those patient treated with sirolimus had stabi- disease and pregnancy. N Engl J Med. 2008;359(19):
lized lung function, reduced symptoms and 2025–2033.
improved quality of life while on treatment, but 12. Bates SM, Jaeschke R, Stevens SM, et al. Diagno-
the improvements in lung function were not
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Physicians evidence-based clinical practice
Nothing to Disclose
guidelines, 9th edition. Chest. 2012(2 suppl);141:
351–418.
13. Leung AN, Bull TM, Jaeschke R, et al. An official
American Thoracic Society/Society of Thoracic
Radiology clinical practice guideline: evaluation
this chapter.
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Notes

Chapter 31. Eosinophilic Lung Diseases
Objectives: etiologies of these disorders vary from idiopathic

Review the classification of the eosinophilic lung to associations with drug exposures, infections,
diseases. neoplasm, or asthma.
Describe the structure and function of the eosinophil.
Review the clinical features of allergic bronchopulmo-
Although several classification systems exist,
nary aspergillosis. one recently used is the division between second-
Discuss the clinical features of the idiopathic acute and ary and primary disorders (Table 1).1,2 Secondary
chronic eosinophilic pneumonia. eosinophilic lung diseases are those associated
Discuss the clinical features of Churg-Strauss syndrome
and hypereosinophilic syndrome. with a specific etiology. Primary disorders are less
common and can be defined as those that are
Key words: acute eosinophilic pneumonia; allergic bron- idiopathic, either limited to the lungs or those
chopulmonary aspergillosis; chronic eosinophilic pneumo- associated with systemic disorders. An approach
nia; Churg-Strauss syndrome; eosinophil to the diagnosis of the eosinophilic lung diseases
should begin with evaluation for the secondary
Synopsis:
disorders, leaving the primary group of diseases
The eosinophilic lung diseases are a heterogeneous group of as diagnoses of exclusion. This evaluation should
disorders characterized by an increased number of eosino-
phils in one or more of the compartments of the lung and, in include a careful history for occupational or
many of these disease entities, the peripheral blood. These environmental exposures, travel, medications,
disorders may be associated with known causative factors, infectious symptoms, a history of asthma, the
may be idiopathic, or may be associated with other systemic
diseases. This chapter will review the pulmonary eosino-
presence of systemic findings, and the severity,
philic disorders thought to be due to secondary etiologies, acuity, or chronicity of symptoms. Appropriate
including allergic bronchopulmonary aspergillosis, parasit- radiographic and pulmonary function evaluation
ic-related simple pulmonary eosinophilia, tropical pulmo-
and laboratory tests for complete blood count
nary eosinophilia, and drug-induced pulmonary
eosinophilia. The chapter will also review the idiopathic with differential, and sometimes anti-nuclear
disorders, both pulmonary-limited acute eosinophilic pneu- cytoplasmic antibodies (ANCAs), other serologic
monia and chronic eosinophilic pneumonia, and those studies, and stool for ova and parasites should be
associated with systemic disease—Churg-Strauss syndrome
and hypereosinophilic syndrome. For most of these disease
obtained. As part of the evaluation, bronchoscopy
processes, the etiology; pathogenesis; clinical, laboratory, with BAL, and sometimes a bronchoscopic, or
radiographic, and pulmonary function findings; diagnostic rarely, a surgical lung biopsy, may be performed.
criteria; and treatment will be discussed.
Table 2 shows a summary of the features of many
of the disorders discussed below.
Other classification systems that have been
Overview and Classification proposed include a division of the diseases into
those classified as being primarily located in the
The eosinophilic lung diseases are a diverse airway and those located in the parenchyma/
group of diseases with the common characteris- interstitium, with two large subclassifications of
tics of eosinophils in a compartment of the lung: the latter into secondary and primary disorders.
airway, interstitium, or alveolar space. Pleural
eosinophilia will be discussed elsewhere. Radio- The Eosinophil
graphic and pulmonary function abnormalities
are also associated with many of these diseases, Eosinophils3,4 develop in the bone marrow
and in some, systemic findings are present. from CD34þ progenitor cells. After 5 days of
Laboratory examination may reveal eosinophils maturation in the bone marrow, the eosinophil is
in the peripheral blood and/or the BAL. The released into the circulation. Normal circulation

Table 1—Pulmonary Eosinophilic Disorders time in the peripheral blood stream is 18 to 24 h
until the cells enter the tissues—primarily the
Primary disorders
Lung limited
gastrointestinal tissues. Eosinophilic develop-
Acute eosinophilic pneumonia ment from hematopoietic cell progenitors is
Chronic eosinophilic pneumonia regulated by IL-5, secreted by Th2 lymphocytes,
Systemic disorders
which has a selective role in eosinophil matura-
Churg-Strauss syndrome
Hypereosinophilic syndrome tion, differentiation, recruitment, mobilization,
Secondary disorders and activation. IL-5 also regulates and inhibits
Allergic bronchopulmonary aspergillosis or mycosis eosinophil apoptosis, thus increasing eosinophil
Löffler syndrome (parasite associated)
Tropical pulmonary eosinophilia (parasite associated) survival.
Drug associated The eosinophil is 12 to 15 lm in diameter, has
Neoplastic associated a bilobed nucleus, and contains several types of
Miscellaneous
granules (that stain yellow-pink with eosin),
Collagen vascular disease
Sarcoidosis which are released upon specific cytokine stim-
Langerhans cell histiocytosis ulation. The granules contain toxic eosinophilic
Fungal pulmonary infections products including major basic protein, eosino-
Cryptogenic organizing pneumonia
Hypersensitivity pneumonitis philic cationic protein, eosinophil-derived neu-
Idiopathic pulmonary fibrosis rotoxin, and eosinophil-derived peroxidase.
Other granules contain Charcot-Leyden crystal
protein. Eosinophils normally comprise 1% to 3%
of our peripheral blood and ,2% (but never
more than 5%) of BAL. Eosinophilia emerges as a
Table 2—Comparison of the Eosinophilic Pulmonary Disorders
ABPA SPE AEP CEP CSS IHES
Associated Risk Asthma Parasites Unknown Unknown Unknown Unknown

Factors/Causes Drugs ?smoking
Asthma Yes No No Frequent Yes No
Onset Chronic: Variable Acute: days Subacute: weeks Variable: Chronic: months
months to Resp failure to months months to to years
years common years
Imaging Mucus Fleeting Diffuse Peripheral Peripheral Pulmonary
plugging, CB opacities opacities opacities patchy edema, rare
opacities/ opacities,
nodules effusions
PBS Eos Yes Often Unusual Yes Yes Yes
BAL Eos Yes Often Yes Yes Variable Variable
Laboratory Tests IgE levels Stool ANCA positive
examination in 40%
for ova and
parasites
Systemic No No No No Yes with Yes
vasculitis
Extrapulmonary No No No No Yes Yes
Findings
Treatment CS Antimicrobial, CS CS CS: some CS: variable
remove variability in response
offending response
drug
Relapses Yes No No Often Yes Yes
ABPA ¼ allergic bronchopulmonary aspergillosis; SPE ¼ simple pulmonary eosinophilia; AEP ¼ acute eosinophilic pneumonia;
CEP ¼ chronic eosinophilic pneumonia; CSS ¼ Churg-Strauss syndrome; IHES ¼ idiopathic hypereosinophilic syndrome; CS ¼
corticosteroids; Eos ¼ eosinophilia; IHES ¼ idiopathic hypereosinophilic syndrome; PBS ¼ peripheral blood stream; Resp ¼
respiratory.
474 Chapter 31. Eosinophilic Lung Diseases (Levine)

response to eosinophilic poietic cytokines includ- inciting fungi lead to airway destruction, mucus
ing IL-5, IL-3, and granulocyte macrophage plugging, and bronchiectasis.
colony-stimulating factor, which are all produced Most patients with ABPA are in their third to
by T lymphocytes, and in some diseases, IL-18, fifth decade of life, but there is no clear age
IL-6, IL-10, and platelet-activating factor. Of these predilection. Patients with CF may develop
eosinophilic poietic factors, only IL-5 is truly ABPA at a younger age. Clinically, the presen-
specific for the eosinophil and thus is a target of tation includes severe, often persistent, asthma,
potential therapeutic intervention in some dis- which is notoriously refractory to treatment other
ease states. than with systemic corticosteroids. Patients may
The role of the eosinophil in various disease have complaints of chronic cough productive of
states differs. For example, the eosinophil is an brown mucus plugs and constitutional symp-
important cell in defense from parasitic infec- toms such as fever, weight loss, and fatigue.
tions, yet in many of the eosinophilic pulmonary Rarely, hemoptysis is described.
diseases, the eosinophil is the main source of On chest imaging9 patients have recurrent
pathogenesis, and finally in others, the role of the migratory pulmonary opacities and mucus plug-
eosinophil may simply be that of an innocent ging/impaction, which may appear as a ‘‘finger
bystander. in glove’’ pattern, often with upper lobe pre-
dominance, and up to 90% have bronchiectasis.
Secondary Pulmonary Eosinophilic On CT scan imaging, radiographic findings
include nodular opacities, peribronchial thicken-
Disorders
ing, central bronchiectasis, and migratory
ground-glass opacities (GGOs). A tree-in-bud
Allergic Bronchopulmonary Aspergillosis (ABPA)
pattern may also be present.
Laboratory examination reveals eosinophilia
ABPA is a hypersensitivity immune response
and elevated IgE levels. Bronchoscopy, although
to Aspergillus antigens. The incidence is fairly
not often performed, shows elevated eosinophils
uncommon but it is estimated that 1% to 2% of
in the BAL, and mucus plugging may be
patients with asthma will develop ABPA and 2%
occasionally visualized endobronchially. Patho-
to15% of those patients with cystic fibrosis (CF)
logic findings in ABPA, although not routinely
may develop this disorder.5–8 In studies of
obtained, is characterized by eosinophils in the
patients enrolled in a specialty asthma clinic,
airways and mucus plugging with fungal hyphae
approximately 13% of asthmatic patients may without tissue invasion, eosinophilic pneumonia,
have ABPA.6 Of the several hundred species of and surrounding eosinophilic inflammation. Pul-
Aspergillus, the one most commonly associated monary function tests (PFTs) show reversible
with ABPA is Aspergillus fumigatus, although obstruction consistent with asthma, although the
other Aspergillus species and other fungi can obstruction is sometimes less reversible than that
elicit the response, and this disease is therefore in asthmatics without ABPA.
sometimes called allergic bronchopulmonary myco- There are suggested diagnostic criteria used
sis. for confirming a diagnosis of ABPA. The tradi-
The pathogenesis of ABPA is thought to be tional ones used for asthma-associated ABPA are
due to inhalation of the ubiquitous organism, those established by Ricketti et al10 and include
subsequent colonization, and in the susceptible major and minor criteria: Major criteria include
host, proliferation of the fungus in the respiratory (1) asthma, (2) immediate skin test positivity for
tract, leading to antigenic exposure. The host Aspergillus, (3) radiographic opacities, (4) in-
response is characterized by CD4þ Th2 T cell- creased Aspergillus-specific IgG and IgE, (5)
mediated eosinophilic inflammatory response increased total serum IgE level .1000 IU/mL,
from IL-4, IL-5, and IL-13 and mast cell degen- (6) positive serum precipitin results for Aspergil-
eration; IgE, IgA and IgG synthesis; and IL-8- lus, (7) central bronchiectasis, and (8) peripheral
mediated neutrophilic infiltration. The release of blood eosinophilia. This diagnostic system also
mycotoxins and proteolytic enzymes by the contains minor criteria: (1) the presence of

Aspergillus in the sputum, (2) expectoration of should be considered in corticosteroid-depen-
brown mucus plugs, and (3) a positive delayed dent patients and those with relapse. The anti-
skin test reaction to Aspergillus. A diagnosis of IgE drug omalizumab has been used successfully
ABPA is confirmed when at least six of the major in case reports of both asthma and CF-related
criteria are present. A diagnostic approach using ABPA, but no randomized controlled studies are
minimal criteria has also been suggested: ABPA- available.12
S for patients having most of the clinical and Monitoring in patients with ABPA consists of
serologic (S) criteria (1–5 major criteria above) following up the symptoms, total serum IgE
but without the central bronchiectasis (CB); and levels, blood eosinophil counts, PFTs, and imag-
ABPA-CB, which is ABPA-S with CB.6 ing. IgE levels should be monitored 6 to 8 weeks
There has also been a staging system used in after treatment and then every 8 weeks for the
ABPA, although the stages are not necessarily next year.
sequential. Stage I is the acute stage, character- The rare pathologic process sometimes asso-
ized by elevated IgE, eosinophilia, opacities, and ciated with ABPA is bronchocentric granuloma-
Aspergillus precipitins. This stage tends to re- tosis, which may develop in patients with ABPA
spond well to corticosteroid treatment. Stage II is and is associated with a more aggressive clinical
the remission stage during which IgE levels have course and pathology, often demonstrating nec-
decreased by 35% to 50% and may even return to rotizing granulomatous inflammation of the
normal. Some investigators look for sustained bronchi and bronchioles.
remission for 6 months without corticosteroids to
further define this stage. Stage III is the exacer- Simple Pulmonary Eosinophilia (SPE)
bation stage characterized by return of stage I-
type clinical findings and a doubling of the IgE. SPE, also termed Löffler syndrome, is an acute,
Stage IV is the corticosteroid-dependent stage transient, usually mild, and self-limited hyper-
during which patients require continued treat- sensitivity response to infectious organisms,
ment with corticosteroids. Stage V is the end usually parasites.13 It is characterized by migra-
stage with bronchiectasis, cavitation, and fibrosis tory pulmonary opacities and peripheral eosino-
noted on imaging. philia. A similar clinical picture can also be seen
Treatment of ABPA is with systemic cortico- in some drug reactions. The original description
steroids to suppress the immune reaction and of Löffler syndrome was associated with intesti-
inflammatory response, usually begun at a 0.5 to nal parasites, most commonly the nematodes
1 mg/kg dose of prednisone for 2 weeks, and Ascaris lumbricoides, Strongyloides stercoralis, Trich-
followed by a rapid taper to a level keeping the inella, Ancylostoma, and Necator, and is due to
disease in control, although the duration of transpulmonary passage of parasitic larvae.
therapy is not clearly defined. The importance Patients acquire the disease by ingesting eggs
of preventing irreversible damage from the from contaminated soil or food or by percutane-
disease, but minimizing the negative effects of ous larval penetration. The presentation is
prolonged corticosteroid use is unclear. IgE levels nonspecific and may include relatively mild
are useful in tracking the course of disease. Other symptoms of cough, chest pain, and constitu-
therapies that have been used include inhaled tional symptoms of fever, weight loss, and night
corticosteroids and itraconazole, and recently sweats. Wheezing and hemoptysis may also
voriconazole, which may allow one to reduce develop. Radiographs may show transient non-
the dose of systemic corticosteroids. A Cochrane segmental consolidation and GGOs, and PFTs
review on the use of itraconazole in ABPA may show obstruction. The diagnosis of some of
showed that in individual trials, the addition of these parasitic infections can be confirmed with
the azole, usually for a recommended duration of stool ova and parasite studies, but these are often
16 weeks, permitted a reduction in corticosteroid diagnostic much later in the disease course,
dose with improved clinical outcomes. 11 A usually 6 to 8 weeks after symptom onset.
reduction in IgE levels and sputum eosinophil Treatment is with antiparasitic agents such as
counts was also noted. The addition of an azole mebendazole.

Although Strongyloides is most often associ- most commonly an SPE (ie, Löffler syndrome) or
ated with SPE, rare cases of heavy helminthic a more fulminant acute or chronic eosinophilic
hematogenous seeding can be seen with dissem- pneumonia pattern. Corticosteroid and removal
inated strongyloidiasis particularly in the cell- of the offending agent are the mainstays of
mediated immunocompromised host, and is therapy. Cocaine, and less frequently heroin, via
sometimes called Strongyloides hyperinfection. an inhalational route, can also be associated
This condition can be associated with marked with significant eosinophilic pulmonary find-
peripheral eosinophilia, severe illness including ings.
ARDS, and multiorgan system failure. Cortico-
steroids administered unknowingly in this dis- Miscellaneous Known Causes
ease can be fatal. Treatment is with ivermectin,
with or without albendazole. There are other causes of pulmonary eosino-
philia that are beyond the scope of this chapter.
Tropical Pulmonary Eosinophilia Neoplastic disorders, either solid tumors includ-
ing lung cancers, or hematologic malignancies
A similar but distinct syndrome called and lymphomas, have been associated with
tropical pulmonary eosinophilia14 is specifically peripheral eosinophilia, usually as a result of
associated with the mosquito-borne filarial par- IL-3, IL-5, and granulocyte macrophage colony-
asites Wuchereria bancrofti and Brugia malayi. stimulating factor promoting differentiation and
These parasites are endemic to the tropical and survival of eosinophils. Fungal pulmonary infec-
subtropical Indian subcontinent, South East Asia, tions, connective tissue diseases, idiopathic pul-
South America, South Pacific Islands, and Africa. monary fibrosis, Langerhans cell histiocytosis,
In this syndrome, patients tend to be symptom- cryptogenic organizing pneumonia, hypersensi-
atic with fever, malaise, and weight loss, and tivity pneumonitis, and sarcoidosis have also
may have a characteristic picture of nocturnal been associated with pulmonary eosinophilia,
cough, dyspnea, and nocturnal wheezing. Labo- although usually to a lesser degree than the other
ratory features include peripheral eosinophilia entities under discussion.
and often elevated IgE levels. Chest imaging may
show interstitial and reticulonodular opacities, Primary Pulmonary Eosinophilic
but findings may be normal. Filarial serology Disorders: Lung Limited
tests are sometimes available to assist in diagno-
sis. Standard treatment is with diethylcarbama- Acute Eosinophilic Pneumonia (AEP)
zine.
Idiopathic AEP is a severe illness of acute
Drugs onset characterized by hypoxemia and respira-
tory failure. The presentation is similar to acute
Numerous drugs can cause pulmonary lung injury due to ARDS, severe community-
eosinophilia. The website at www.pneumtox. acquired pneumonia, or acute interstitial pneu-
com15 contains a complete and up-to-date list, monia. AEP is a disease affecting mostly young
and at the time of this writing more than 100 to middle-aged patients (average age, 29 years;
drugs have been implicated. Among the most range, 19–37 years) with a slight male predom-
common offending agents are the nonsteroidal inance. Forty to sixty-six percent of patients are
antiinflammatory drugs and antibiotics, specif- smokers,16,17 and often recent onset smokers,
ically nitrofurantoin and the sulfonamides, but usually for ,1 month. In fact, cigarette smoking
anticonvulsants, antidepressants, antihyperten- is the most commonly associated risk factor for
sive agents (angiotensin-converting enzyme AEP in those persons susceptible to its devel-
inhibitors and beta-blockers), and L-tryptophan opment. The patient may have recently in-
have also been described. Different drugs can creased tobacco use or resumed smoking after
have different clinical and radiographic patterns a period of discontinuation. Other associated
of eosinophilic pulmonary disorders including risk factors with the development of AEP

include heavy dust exposure, drugs, occupation- spaces, occasional acute or organizing diffuse
al exposures, and recently, both World Trade alveolar damage with hyaline membranes, and
Center dust and military exposures to sand and fibroblast proliferation. Airway involvement is
oil fields in the Middle East. A study of US rare.
personnel in Iraq found AEP in 18 patients with The revised diagnostic criteria for AEP
a frequency of 9.1 cases /100,000 person years. include (1) the acute onset of a febrile respiratory
All were smokers and 78% were of recent illness ,5 to 7 days in duration and always ,1
onset.18 Cocaine use has also been associated month, (2) bilateral diffuse opacities on chest
with AEP. An association with asthma is rare in radiograph, (3) hypoxemia with a PaO2 ,60 mm
contrast to chronic eosinophilic pneumonia Hg or an arterial saturation on room air ,90%,
(CEP), discussed below. (4) a BAL with .25% eosinophils or a lung
The pathogenesis of AEP16,17,19 is likely an biopsy showing an eosinophilic pneumonia, and
antigenic stimulus to T cells, particularly Th2 (5) the absence of other cause of pulmonary
lymphocytes, leading to IL-5 and IL- 18 produc- eosinophilia including drugs, toxins, and infec-
tion and increased eosinophils. IL-5 is likely tious pathogens.19 Additional characteristics are
important in the pathogenesis of AEP, with recent onset of tobacco use, and rapid, complete,
elevated levels noted in both the BAL and and permanent response to corticosteroids. Be-
peripheral blood of patients. IL-18 levels are also cause of the acute presentation, the frequent need
elevated in the BAL in AEP. These cytokines for critical care, and the radiographic confusion
result in accumulation of eosinophil-rich exu- with ARDS, BAL may be very helpful in the early
dates in the lung, further eosinophil activation, diagnosis and subsequent treatment of AEP.
and release of toxic eosinophilic products. Treatment is with corticosteroids at relatively
Patients present with acute onset, usually for high doses (methylprednisolone 240–1000 mg
fewer than 7 days (average 3.5 days) of dyspnea, each day in divided doses has been suggested)
fever, cough, chest pain, and myalgias, with for respiratory failure, and oral prednisone for
rapid progression to respiratory failure. Crackles, those not acutely ill, or as acute illness resolves,
both crackles and occasional wheezing, and with a rapid taper over a 2- to 4-week period.
rarely, clear breath sounds are present on Patients usually have a rapid and dramatic
examination. Acute respiratory failure is com- response usually within 1 to 3 days. In contrast
mon and two-thirds of patients will require to CEP, relapse in AEP is rare.
mechanical ventilatory support.
Radiographic presentation includes bilateral CEP
alveolar opacities mimicking ARDS in appear-
ance, GGOs, occasionally with a reticulonodular, CEP is a disease that develops in middle-
interstitial component and Kerley B lines, and aged to older (peaks in the fifth decade of life)
often mixed opacities.9 Small pleural effusions females (female to male ratio, 2.1:1), and is
can occur in up to 50% of cases. PFTs show small characterized by the indolent, subacute, chronic
airway obstruction, reduced diffusion, and re- (usually .1 month) onset of dyspnea and cough,
striction. wheezing, and constitutional findings of night
Peripheral blood eosinophilia is not a prom- sweats, fever, and weight loss.20 One-half to two-
inent feature of AEP, in contrast to CEP. thirds of patients have a history of or have active
However, BAL is characterized by a predomi- asthma, and this number may be higher during
nance of eosinophils (.25% and usually higher, the course of the disease. Fewer than 10% of
37%–54% in some studies) and biopsy is rarely patients are smokers, in contrast to AEP.19 The
needed. Elevated lymphocytes and neutrophils etiology of CEP is unknown. Table 2 summarizes
may accompany the increased eosinophils in the some of the major differences between AEP and
BAL in AEP. Pleural effusions tend to be CEP.
eosinophilic exudates. If biopsy is performed, The pathogenesis of CEP is thought to be due
histologic findings include marked eosinophilic to an unknown trigger, resulting in selective
infiltration in the interstitium and alveolar migration of Th2 cells to the lungs, likely

mediated by a thymus and activation-regulated Primary Pulmonary Eosinophilic
chemokine and RANTES. In the alveolar space, Disorders: Systemic
there is chronic release of IL-5 and related
cytokines from Th2 cells and eotaxin, resulting Churg-Strauss Syndrome (CSS)
in eosinophilic accumulation in the lungs, and
subsequent release of toxic eosinophilic prod- CSS, also known as allergic granulomatosis and
ucts.20 angiitis, is a rare vasculitis associated with
Radiographic changes in CEP include migra- eosinophilic granulomatous inflammation of the
tory, bilateral, pleural-based, alveolar, and inter- respiratory tract, necrotizing vasculitis of small to
stitial opacities and GGOs, which have been medium-sized vessels, asthma, and peripheral
described as the ‘‘photonegative of pulmonary eosinophilia. The incidence is thought to be 0.11
edema.’’ It should be noted that this classic to 2.66 new cases/million/year,21 with mean age
pattern is present in ,25% to 30% of cases. Other of development from 38 to 52 years (range, 7–74
findings include atelectasis, consolidation, septal years) and no clear gender predilection. CSS is
thickening, and small adenopathy and rarely, classified as one of the ANCA-associated vascu-
small pleural effusions.9 PFTs show mixed litides, although only 40% of patients have a
restriction and obstruction and findings may be positive ANCA finding.21–23
normal in some patients. Clinically, patients present with asthma;
The peripheral blood in patients with CEP atopy; and constitutional symptoms of fever,
nearly always reveals significant eosinophilia malaise, and weight loss; arthralgias; and
(.30%) and is present in 90% of those with the myalgias. Various other systems may be in-
disease; BAL shows high eosinophil counts, volved including the upper airway with sinus-
usually .50% or 60%. Of interest, the differential itis (62%–77%), rhinitis (47%–93%), and nasal
of the remainder of the cells in the BAL fall into polyps; skin changes (53%–68%) with purpura,
the usual cell distribution. IL-5 levels are in- nodules, urticaria; neurologic findings with
creased in the BAL. Serum IgE levels are often peripheral neuropathy (75%–81%), particularly
elevated in 50% of cases. Pathologically, lung mononeuritis multiplex in 77% of cases (possi-
tissue reveals interstitial and alveolar infiltrates bly presenting as foot drop), with rare central
with eosinophils and areas of organizing pneu- nervous system involvement; abdominal symp-
monia, without tissue destruction or diffuse toms (up to 33%) including pain due to
alveolar damage. obstruction or vasculitis leading to ischemia;
Although established diagnostic criteria for cardiac findings (50%) including heart failure,
CEP are not as clearly defined as those estab- pericarditis, myocarditis, cardiomyopathy, and
lished for AEP, suggested criteria19 include (1) arrhythmias; and renal findings (in ,25%) of
symptoms of subacute onset of cough, dyspnea, focal segmental glomerulonephritis and/or he-
constitutional symptoms for .2 weeks; (2) BAL maturia. Although asthma is a near-universal
eosinophilia .25%, and often .40%, or periph- finding in CSS (96%–100%), other pulmonary
eral eosinophilia .1,000/mm3; (3) the presence manifestations develop in approximately 40%
of peripheral opacities; and (4) the absence of of patients with CSS (range, 37%–77%). Unlike
other causes of pulmonary eosinophilia. the other vasculitides, alveolar hemorrhage is
Treatment is with corticosteroids at a sug- rare.
gested 1 mg/kg/d dose of prednisone or The usual radiographic manifestations9 in-
equivalent and is usually tapered slowly over a clude patchy and transient alveolar opacities,
6- to12-month period. Relapse is common (close consolidation, nodules (with rare cavitation), and
to 50%; range, 47%-83% in some series),20 in occasional (in approximately 10%) small pleural
contrast to AEP. Inhaled corticosteroids have effusions. CT scan findings include GGOs,
been used successfully in the remission phase, peribronchiolar thickening, interlobular septal
particularly in those patients with concomitant thickening, and rarely, adenopathy. The opacities
asthma. may have a peripheral predominance and can

resemble those of CEP. PFTs usually demonstrate with eosinophilic infiltration. The third stage is
obstructive dysfunction. the true vasculitic stage involving nerves, skin,
Typical laboratory findings include a leuko- and kidney, and is the phase most often
cytosis with eosinophilia sometimes .80%, an associated with poor outcomes and death.
elevated IgE level, and BAL with eosinophils Untreated, mortality with CSS is high, ap-
usually comprising .25% of the cell count. The proaching 50%. With treatment, survival is
ANCA finding is positive in approximately 40% significantly improved, with morality ,5%, and
of cases of CSS, and myeloperoxidase p-ANCA is in general is better than that for the other
more common than c-ANCA, and may have vasculitides. Remission is achieved in 80% of
some correlation with disease activity and patients, although relapse may occur in 20% to
specific organ involvement. ANCA positivity 30%. Initial treatment is with corticosteroids at a
may portend a more vasculitic phase of the suggested dose of 1 mg/kg/d of prednisone or
disease, including renal, neurologic, and cutane- equivalent, and many patients can be treated
ous manifestations, and ANCA negativity may with corticosteroids alone, but prolonged therapy
be associated with more eosinophilic infiltration may be required. Others will need the addition of
and have more cardiac and pulmonary involve- a cytotoxic agent, such as cyclophosphamide, if
ment, as well as fever.22 The effusions have there is evidence of end-organ involvement such
eosinophils and are usually exudates. Although as cardiac, renal, or neurologic disease, or rare
lung biopsy is rarely performed, histopathologic alveolar hemorrhage. Other agents have been
findings include an eosinophilic necrotizing used in severe, refractory, or relapsed disease or
vasculitis of the pulmonary arteries and veins, may help in maintaining remission, such as
extravascular and perivascular necrotizing gran- methotrexate, mycophenolate mofetil, azathio-
ulomas in the parenchyma and bronchioles, and prine, or cyclosporine. Reports of use of plasma
eosinophilic pneumonia. exchange, intravenous immunoglobulin, interfer-
Several diagnostic classification systems for on-alpha, tumor necrosis factor inhibitors, and
CSS exist, and none are perfect. According to the omalizumab have also been described for refrac-
American College of Rheumatology, if four of the tory disease. Most recently, the anti-CD20 agent
following criteria are present, the diagnosis of rituximab has been used in this and other
CSS is made with a sensitivity of 85% and vasculitides. The most common cause of death
specificity of 99.7%21: (1) asthma, (2) eosinophilia in CSS, as in some other eosinophilic diseases, is
.10%, (3) mononeuritis or polyneuropathy, (4) myocardial involvement.
transient radiographic opacities, (5) bilateral The association with CSS and the leukotriene
maxillary sinus abnormalities, and (6) extravas- agents, as well as recently with omaluzimab, has
cular eosinophilic vasculitis. The Chapel Hill been described. However, as more data become
consensus definition is the presence of eosino- available, they will most likely show that as these
philic granulomatous inflammation involving the corticosteroid-sparing agents were added to an
respiratory tract, necrotizing vascultis of small to asthmatic patient’s regimen, the withdrawal of
medium-sized vessels, asthma, and eosinophilia. corticosteroids resulted in a flare of CSS, in
CSS is thought to have three distinct clinical essence, unmasking the clinical findings of
phases but recent data suggest that there may be CSS.23–25
more overlap between the stages than was
initially thought, and that the order of the three Hypereosinophilic Syndrome (HES)
phases may vary or be concurrent. The first
phase is the prodromal phase that consists of HES is a rare disease of unknown etiology,
asthma, allergic rhinitis, and nasal polyposis and defined by the presence of a persistently elevated
may be present for years (an average of 7 years) eosinophil count in the peripheral blood of .1.5
before advancing to the next stage. Stage 2 is 3 109/L for greater than 6 months, with evidence
associated with marked peripheral blood eosin- of eosinophilic infiltrative end-organ damage, in
ophilia, and pulmonary and other tissue (often the absence of other known causes of eosinophil-
gastrointestinal and myocardium) involvement ia.26 Recently, the 6-month time period has been

modified to include those patients requiring placebo group.28 Another agent, alemtuzamab,
treatment for the eosinophilia earlier than the 6- targets the CD52 antigen, which is expressed by
month time point. There is no vasculitis seen in eosinophils. Outcomes have been beneficial, with
HES, and the presence of associated asthma is a reduction in the number of eosinophils,
seen in only a minority of patients. In addition to decreasing symptoms, and improvement in
the idiopathic form of HES, there are myelopro- quality of life. As a last resort, bone marrow
liferative forms of the disease associated with transplant has been considered. The manage-
Fip1-like 1-platelet-derived growth receptor al- ment of asymptomatic patients with HES re-
pha fusion genes (FIP1L1-PDGFRA), and clonal mains unclear. Most authorities recommend
lymphocytic variants of the disease. instituting routine monitoring including echocar-
Clinically, patients may be asymptomatic or diograms every 6 to 12 months, and sometime
may show single- or multiple-organ involvement monitoring of troponin levels, or cardiac MRI
ranging from mild to severe. The organs most screening.
often affected include the heart, the nervous
system, the skin, the gastrointestinal system, and Nothing to Disclose
the lungs in 25% to 40% of cases.27 Patients
present with dyspnea, cough, and constitutional The author has disclosed that no relation-
symptoms of weight loss, fatigue, malaise, fevers, ships exist with any companies/organizations
and sweats. Rarely, wheezing may be present. whose products or services may be discussed in
The heart, although not the most common organ this chapter.
involved, can be the most severely affected with
findings including endomyocardial fibrosis, val- References
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Chapter 32. Tuberculosis and Other Mycobacterial
Diseases
David Ashkin, MD
Objectives: immigration of foreign-born persons from high-

Become familiar with the epidemiology of TB. incidence areas, an increased number of medi-
Review the pathogenesis and clinical presentation of TB. cally underserved persons (eg, homeless persons
Address issues concerning the prevention of TB, includ-
and drug abusers), and, probably most impor-
ing the diagnosis and treatment of TB infection.
Review issues concerning the diagnosis and treatment of tantly, the deterioration of the public health
TB disease. infrastructure for the control of TB. Associated
Outline pertinent topics concerning mycobacteria other with the increased incidence was an increase in
than TB (eg, Mycobacterium avium complex and Mycobac-
terium kansasii).
the number of cases of drug-resistant TB.
With improvements in TB control, the overall
number of cases in the United States has
Key words: multidrug-resistant tuberculosis; nontubercu-
lous mycobacteria; tuberculosis decreased over the last 18 years, but because of
the large number of TB cases worldwide and the
Synopsis: large number of international individuals arriv-
TB is still a leading cause of death worldwide despite the ing in the United States every year, TB remains a
availability of an effective medical cure. Fueled by the significant national public health problem. In
worldwide HIV epidemic and the development of drug- 2010, there were a total of 11,182 cases of TB in
resistant strains, the control of TB is still a major public
health issue. This chapter will review the epidemiology of
the nation, with a rate of 3.6 per 100,000
TB in the United States as well as the world. Guidelines for population (the lowest rate and total number of
the diagnosis of latent TB infection, including new tools TB cases ever documented since national report-
such as interferon release assays interferon release assays, ing began in the United States). The highest
will be reviewed, as well as the currently recommended
treatment options. Guidelines for the diagnosis of active TB numbers of cases have been reported in Califor-
disease, including molecular diagnostics, and treatment nia, Texas, New York, and Florida, which
options for active TB disease, including for individuals with collectively account for approximately 50% of
drug-resistant strains, will also be addressed. Infection
TB cases nationally. It is estimated that approx-
control issues concerning TB will also be discussed. The
epidemiology, diagnosis, and treatment of patients with imately 15 million people are infected with TB in
disease caused by nontuberculous mycobacteria, which is the United States, making for a large potential
more prevalent in the United States than TB, will also be reservoir of disease in the population. The
reviewed.
infection rate among foreign-born individuals in
the United States is approximately seven times
higher than that for the US-born population.
Tuberculosis Although the number of cases in the United
States has been decreasing, the proportion of
Epidemiology cases in the foreign-born population has in-
creased from 27% in 1992 to 60% in 2010. In
At the turn of the 20th century, TB was one of addition, 82% of the reported multidrug-resistant
the leading causes of death in the United States. cases in the United States occurred in foreign-
After the discovery of effective chemotherapy, born individuals.
the rate of TB significantly declined an average of Worldwide, TB has not declined to the extent
8% per year between 1953 and 1983. From 1985 to that it has in the United States. According to the
1992, however, TB unexpectedly increased by most recent statistics from the World Health
approximately 20%. Factors associated with the Organization, the number of new cases of TB in
resurgence included the HIV epidemic, increased 2010 was approximately 8.8 million worldwide,

with a total prevalence estimated at 12 million complex organisms. MTB enters the air when
cases of TB disease. Eighty-five percent of TB patients with active pulmonary TB cough, speak,
cases occur in developing countries in Africa and sneeze, or sing, although coughing remains the
Asia where HIV infection is common, and most effective method of aerosolization. Droplet
resources are scarce or unavailable to ensure nuclei may also be produced by aerosol treat-
proper TB treatment. It is estimated that 1.4 ments, sputum induction, aerosolization during
million people died of the disease, with a fatality bronchoscopy, manipulation of lesions, or pro-
rate as high as 50% in some countries with high cessing of tissue or secretions in the hospital or
rates of HIV coinfection. In addition, approxi- laboratory. These droplet nuclei are so small that
mately one-third of people in the world, or 1.86 air currents normally present in an indoor
billion people, are infected with Mycobacterium environment can keep them airborne for long
tuberculosis (MTB). To make matters worse, the periods. Individuals who are in prolonged, close
incidence of drug-resistant TB worldwide is contact with patients with active TB, especially in
increasing, with new strains with more extensive environments with poor ventilation, are most
forms of resistance (eg, extensively resistant TB likely to inhale the organism and become
[XDR-TB]) being more commonly recognized. infected (especially in congregate settings such
During the 1990s, an estimated 30 million people as jails, prisons, shelters, or hospitals); however,
died as a result of TB, making a strong argument only approximately one-third of these exposed
for its being the most important pathogen in the individuals become infected. In countries where
world today. TB is endemic, exposure to a person with active
TB is more likely, thus increasing the chances for
Causative Agent of TB transmission.
When a person inhales a droplet nucleus,
TB is caused by a group of closely related which may contain between one and 400 organ-
mycobacteria (MTB, Mycobacterium bovis, M bovis isms, it usually is trapped in the upper respira-
bacillus Calmette-Guerin [BCG], Mycobacterium tory tract and cleared. Organisms deposited on
africanum, Mycobacterium caprae, Mycobacterium intact mucosa or skin do not invade the tissue.
microti, Mycobacterium pinnipedii, and Mycobacte- The smallest droplets, those measuring ,5 lm,
rium canetti), which form the MTB complex. The make it to the alveoli.
MTB organism is responsible for the vast The chances of the transmission of MTB are
majority of cases of TB in the United States. influenced by the following four factors: (1) the
number of organisms entering the air; (2) the
Transmission of MTB concentration of organisms in the air, determined
by the size of the space and the adequacy of
The risk factors for acquiring TB infection, a ventilation; (3) the length of time an exposed
prerequisite for the development of disease, are person breathes the contaminated air; and (4)
related to having contact with a source case. In possibly the immune status of the exposed
the United States, important risk factors for individual. Some believe that HIV-infected per-
infection are as follows: close contact with a sons and others with impaired cell-mediated
person with TB; immigration from an endemic immunity may be more likely to become infected
area (eg, Africa, Asia, or Latin America); expo- with MTB after exposure than persons with
sure to untreated TB cases in congregate living normal immunity; however, disease is more
facilities (eg, homeless shelters, correctional likely to develop in those persons with impaired
facilities, nursing homes, or other health-care cell-mediated immunity if they are infected.
facilities); age; and residence in high-incidence
locations (eg, inner cities and travel to foreign Pathogenesis
endemic areas).
TB is usually spread human to human, After inhalation, the droplet nucleus is
through the air by droplet nuclei, which are carried down the bronchial tree to a respiratory
particles 1 to 5 lm in diameter containing MTB- bronchiole or alveolus, where it is phagocytized
484 Chapter 32. Tuberculosis and Other Mycobacterial Diseases (Ashkin)

by resident alveolar macrophages. The nuclei are Some individuals appear to be more suscep-
able to survive at this primary site of infection; tible than others to progression to TB disease.
bacilli multiply initially within the macrophage This is particularly apparent among individuals
and within 2 weeks are transported through the with certain medical conditions associated with
lymphatics to establish secondary sites. The varying degrees of immunosuppression (ie,
development of an immune response, heralded HIV, diabetes mellitus, certain cancers, chemo-
by the development of delayed type hypersensi- therapy or immunosuppressive therapy [includ-
tivity over the next 4 weeks, leads to granuloma ing tumor necrosis factor (TNF)-a inhibitors],
formation with a subsequent decrease in bacilla- silicosis, gastrectomy, old age, malnutrition, IV
ry numbers. This stage of disease is called latent drug use, and renal insufficiency) and in
TB infection (LTBI) and is most commonly children ,4 years old. Most of these individuals
detected by a reaction to the tuberculin skin test have conditions that are felt to impair their
(TST). Patients with LTBI are asymptomatic, but cellular immunity. In fact, patients who have
they have the potential to progress to active been infected with HIV, with their severe defect
disease later. For most individuals with normal in cellular immunity, are significantly more
immune function, the proliferation of MTB is likely to have TB progress from infection to
arrested once cell-mediated immunity develops, disease (relative risk increased 80-fold to 170-
though small numbers of viable bacilli may fold compared with individuals not infected
remain within the granuloma. Although a pri- with HIV). Unlike immunocompetent individu-
als, who have a 5% to 10% chance of progress-
mary complex can sometimes be seen on chest
ing from infection to disease during their
radiograph, the majority of pulmonary TB
lifetimes, HIV-infected individuals coinfected
infections are clinically and radiographically
with TB have a rate that may be as high as 8%
inapparent. Most commonly, a positive TST result
per year. The risk of TB among HIV-infected
is the only indication that infection has taken
patients who are anergic may be elevated.
place. Individuals with LTBI but not active
The ‘‘partnership’’ between HIV and TB has
disease are not infectious and thus cannot
augmented the deadly potentials of each dis-
transmit the organism.
ease. By destroying the CD4 cells of the host’s
After TB infection, active disease develops in
immune system, HIV allows dormant TB to
3% to 5% of immunocompetent individuals
activate and rapidly cause disease. In response
within 2 years (defined as progressive primary
to the reactivation of TB, CD4 cells become
TB, which is seen more commonly in patients stimulated and begin to replicate. This activa-
with a large inoculation or immunosuppression), tion further renders the CD4 cells that are
and an additional 3% to 5% of infected persons vulnerable to invasion by the HIV and allows
develop active TB disease during the remainder the virus to further replicate within these cells.
of their lifetime. Most infected individuals are This leads to a vicious cycle of increasing viral
able to mount an effective immune response that load, which causes a further deterioration of the
encapsulates these organisms, usually for the rest host’s immune system. Studies have shown that
of the host’s life, thus preventing the progression the 1-year mortality rate for treated, HIV-related
from infection to disease. Years after the initial TB ranges from 20% to 35% and shows little
infection and in a small proportion of patients variation between cohorts from industrialized
(approximately 5%), the immune system may not and developing countries.
be able to contain these latent organisms, so In a person with intact cell-mediated immu-
reactivation of TB disease develops. Most cases of nity who has previously been infected with MTB,
TB were thought to be due to reactivation from some protection against reinfection usually is
remote infection (about 90% of cases), but studies present if MTB exposure recurs. In an otherwise
utilizing DNA fingerprinting indicate that recent healthy, previously infected person, any organ-
transmission (especially among HIV-positive isms that are deposited in the alveoli after
individuals) probably accounts for as much as reexposure are likely to be killed by the cell-
40% of cases of TB. mediated immune response. Exceptions may

Table 1—Classification of TB iar with these categories because they may be
asked to assist in the evaluation of such
Classification Description
individuals.
0 No TB exposure, not infected
1 TB exposure, no evidence of infection Diagnosis and Treatment of LTBI
2 TB infection, no disease
3 TB, clinically active The TST is the most common method for
4 TB, not clinically active
5 TB suspected (diagnosis pending) identifying MTB infection in persons who do not
have TB disease. Although the available TST
Reprinted with permission from ACCP Pulmonary Medicine antigens are substantially ,100% sensitive and
Chest Physicians; 2009. specific for the detection of infection with MTB,
no better diagnostic methods have yet been
proven to be more effective. Blood tests approved
occur, but in immunocompetent individuals, by the US Food and Drug Administration
clinical and laboratory evidence indicates that (QuantiFERON-Gold In Tube; Cellestis Limited;
disease produced by the inhalation of a second and T-Spot.TB; Oxford Immunotec) based on the
infecting strain is uncommon. However, reinfec- quantification of interferon-c released from sen-
tion has been documented both in persons sitized lymphocytes in whole blood incubated
without recognized immune compromise and in with antigens that are specific for MTB and
those with advanced HIV infection. control antigens hold the promise for the more
specific diagnosis of LTBI.
Classification of TB These tests have been reported to be more
specific than the TST and may be able to
Table 1 outlines a classification system that is differentiate those individuals who may have
used mainly as an operational framework for traditionally had false reactions on a TST because
public health programs, which may be helpful of previous exposure to nontuberculous myco-
for practicing clinicians in categorizing their bacterium (NTM) and/or BCG from those
patients. This classification is based on the broad persons who are truly infected with MTB. In
host-parasite relationships as described by ex- fact, guidelines from the CDC recommend that
posure history, infection, and disease. Table 2 the use of such interferon-c release assays for
reviews the US Citizenship and Immigration MTB (IGRA) may be used in all circumstances in
Services TB Classification for immigrants and which the TST is currently used, including
refugees developed by the Centers for Disease contact investigations, the evaluation of recent
Control and Prevention (CDC). The purpose of immigrants, and sequential testing surveillance
this classification is to identify new arrivals that programs for infection control (eg, those for
are at high risk for TB and evaluate them to try health-care workers). In addition, the need for
to decrease the risk of active TB. It may be only one visit to draw the specimen (as opposed
important for practicing physicians to be famil- to two visits needed, one for conducting the TST
Table 2—United States Immigration/Refugee TB Classification
Class Chest Radiograph AFB Smear Restriction
A—TB, infectious Active TB Positive No entry to United States until treated and smears are
negative
B1—TB, clinically active, Active TB Negative Report to local health department for further medical
not infectious evaluation within 30 days of arrival in United States
B2—TB, not clinically active Inactive TB Not required unless Same as above
symptomatic
No class (normal) Normal Not required None
Physicians; 2009.

and a second for reading the reaction) and a more TNF-a inhibitors for conditions such as rheuma-
reproducible result are also proposed advantages toid arthritis or inflammatory bowel disease. As
of the IGRA. However, the need for better such, it is generally recommended that patients
definition of its performance in certain popula- who are prescribed these agents first be tested for
tions (eg, young children and immunosup- LTBI and treated if found to have a reaction
pressed persons) and the need to get the induration of .5 mm.
specimen to a laboratory within 12 to 16 h of Indurations measuring 10 mm are considered
drawing the specimen are significant current to be a positive result for individuals with a
drawbacks of the IGRA. moderate-to-high probability of TB infection (eg,
The TST is based on the fact that infection recent arrivals [,5 years] from endemic areas,
with MTB produces a delayed-type hypersensi- residents and employees of high-risk congregate
tivity reaction to certain antigens that are derived settings, or mycobacterial laboratory personnel)
in extracts of a culture filtrate called tuberculin; or medical conditions that increase the likelihood
the preparation used for testing is called tuber- of disease progression (Table 3).
culin purified protein derivative (PPD). The
Patients who do not fall into these categories
diagnosis of TB infection relies on determining
should be judged to have a positive reaction with
the size of the delayed-type hypersensitivity
indurations of 15 mm. In general, these individ-
reaction to an intradermal injection of 0.1 mL of
uals should not undergo testing for LTBI unless
5 tuberculin units of PPD (ie, the Mantoux
otherwise indicated. Persons with HIV infection
method). Tests should be read between 48 and
may have a compromised ability to react to TSTs
72 h after injection when the induration is at its
because of cutaneous anergy associated with
maximum, although induration may last for up
progressive HIV immunosuppression. However,
to 7 days (erythema should not be read). The
diameter of the induration (measured transverse- the usefulness of anergy testing to determine any
ly to the long axis of the arm) should be lack of delayed-type hypersensitivity response in
measured using a ballpoint pen. Results should persons with HIV infection has not been shown
be recorded as millimeters of induration. Multi- to be correlated and is not recommended.
ple puncture tests (eg, the tine test) are not Confusion often arises when trying to apply
recommended because of their lower reliability. TST guidelines for LTBI in patients who have a
Because of the lower specificity of the TST in history of vaccination with BCG. It has been
populations with a low risk of TB infection shown that when a positive reaction occurs
(especially in areas with an increased prevalence secondary to BCG vaccination, this reaction
of NTMs), specific cut points have been devel- remains for at most 7 to 10 years after inocula-
oped to improve the specificity according to the
individual’s risk of true TB infection and the risk Table 3—Medical Conditions (Other Than HIV) That
of the development of active disease if infected. Increase Risk of Progression of TB Infection
An induration measurement of 5 mm is
Injection drug use
considered to be indicative of TB infection in Silicosis
patients with a high probability of infection or a Diabetes mellitus
high risk of disease when infection is present (eg, Chronic renal failure
Lymphomas, leukemias
recent close contacts with TB patients, individu-
Cancers of the head, neck, and lung
als with radiographic evidence of old TB, Malnutrition (weight loss ,10% below ideal body weight)
individuals with HIV infection, patients with Gastrectomy or jejunoileal bypass
organ transplants, patients to whom TNF-a Children younger than 4 y who are exposed to persons at
high risk for TB
inhibitors have been prescribed, and other Patients who receive immunosuppressive agents (including
immunosuppressed patients receiving the equiv- prednisone ,15 mg/d for ,1 mo and TNF-blocking
alent of 15 mg of prednisone each day for .1 agents)
month). Many reports suggesting an increased
risk of progression of TB infection to active TB Board Review. 25th ed. Northbrook, IL: American College of
disease have been described in patients receiving Chest Physicians; 2009.

tion. Because most countries that utilize BCG of active TB should be offered treatment for LTBI
vaccinate infants, by the time most practitioners irrespective of age.
see adults who have been vaccinated, the The use of the terms preventive therapy and
reaction should have waned. The CDC recom- chemoprophylaxis has been confusing at times.
mends ignoring the history of BCG vaccination To describe the intended intervention more
and applying the same principles and guidelines accurately, the current guidelines recommend
concerning LTBI that would be used for individ- substituting the term treatment of LTBI. It is
uals who have never been vaccinated. hoped that the change in nomenclature will
Persons with negative TST reactions who are promote a greater understanding of the concept,
to undergo repeat annual or semiannual skin resulting in more widespread implementation of
testing (eg, health-care workers or residents of this important TB control strategy.
long-term care facilities) should receive an initial The current guideline recommends isoniazid
two-step test. This test will help distinguish therapy for 9 months (either 5 mg/kg/d to a
whether the development of a subsequent posi- maximum of 300 g, or 15 g/kg biweekly to a
tive TST reaction was caused by an unrecognized maximum of 900 g) for all individuals. This
booster reaction as opposed to a reaction caused recommendation is based on studies that re-
by a true conversion from a recent TB exposure vealed 9 months of therapy to be superior to 6
and subsequent infection. Those patients with an months, but as effective as 12 months of therapy,
initial two-step test negative reaction who are in preventing the development of active disease
in those persons infected with TB. If 9 months of
found on subsequent TSTs to have an increase in
isoniazid therapy cannot be accomplished, 6
the size of the reaction induration of 10 mm
months of isoniazid therapy is a less efficacious
should be considered to have TST conversion
alternative. Nine months of isoniazid therapy is
indicative of recent infection with MTB. Two-step
also recommended for children. Following con-
testing is not necessary when IGRA is used.
cerns about decreased rates of completion of
The identification of persons with LTBI has
preventive therapy, studies have shown that
previously been accomplished by screening
rifampin (10 mg/kg to a maximum of 600 mg)
individuals or groups at variable risk for TB (ie,
for 4 months to be an effective alternative to
widespread TST programs). In many situations,
isoniazid.
this screening was performed with limited
Before beginning therapy in patients with
consideration of the risk of TB in the population LTBI, active disease should be ruled out. Baseline
being tested. The emphasis is now on testing laboratory testing is not routinely indicated for
only those individuals who are at high risk and all patients at the start of or during isoniazid
would benefit from treatment. To focus on therapy. It is recommended that all patients being
groups with the highest risk of TB, the term treated for LTBI with isoniazid should receive an
targeted tuberculin testing is now being used. The initial clinical evaluation and, at the least,
dictum now is, ‘‘The decision to tuberculin test is monthly follow-up evaluations. HIV-infected
the decision to treat (and complete).’’ TSTs, for persons, pregnant women and those in the
the most part, should not be performed in immediate postpartum period (within 3 months
individuals for whom treatment is not contem- of delivery), persons with a history of chronic
plated. A risk of TB that is substantially greater liver disease, those persons who use alcohol
than that in the general United States population regularly, and those persons who are at risk of
is found in persons recently infected with MTB, liver disease (eg, individuals receiving other
and in those with clinical conditions associated medications that affect liver function) should
with an increased risk of progression of LTBI to receive baseline laboratory testing. Those persons
active TB (Table 3). Targeted tuberculin testing with abnormal baseline liver study findings may
should be offered only to those groups at risk and require continued monitoring. All patients
should be discouraged in those individuals at should be educated about the symptoms of
low risk. Persons infected with TB who are hepatitis and should be instructed to immediate-
considered to be at high risk for the development ly notify the health-care provider if symptoms

occur, at which time therapy should be stopped Table 4—General Indications for a Chest Radiograph to
Detect TB
immediately and specimens for transaminase
studies should be drawn. If the results are Unexplained cough (for .3 wk)
increased fivefold above the upper limit of Unexplained cough with fever (.3 d)
normal, or threefold above the upper limit of Unexplained pleuritic chest pain, hemoptysis, and/or
normal with symptoms present, treatment for dyspnea
Unexplained fever, night sweats, and weight loss
LTBI should be withheld.
Clinical Manifestations, Diagnosis, and Board Review. 25th ed. Northbrook, IL: American College of
Treatment of Active TB Disease
Patients with prolonged symptoms, especial-
Active TB remains primarily a disease of the
ly those who are at high risk for TB, should have
pulmonary system; however, in individuals with
a chest radiograph immediately (Table 4). Pul-
HIV infection, up to 60% of patients with TB will
monary TB in immunocompetent hosts nearly
have extrapulmonary involvement either alone
always causes abnormalities on the chest radio-
(approximately 30%) or in addition to pulmonary
graph, although an endobronchial lesion may not
disease (about 33%), as opposed to 15% in
be associated with a radiographic finding. In
individuals who are without HIV infection. TB
patients with primary TB occurring as a result of
can occur in almost any organ, but the most
recent infection, the process is generally seen as a
common sites of extrapulmonary involvement
middle lung or lower lung zone infiltrate, often
include the pleura, lymph nodes (particularly
associated with ipsilateral hilar adenopathy
cervical and hilar), CNS (as meningitis or
(Ghon complex). In patients with primary pul-
tuberculoma), genitourinary system, blood, and
monary pleuritis, a unilateral pleural effusion
bone marrow. may be present. The TST result initially may be
The key element in the diagnosis of TB is to negative in these patients. Pleural fluid test
have a high degree of suspicion, especially in findings are usually predominated by lympho-
those groups of persons who are at high risk. cytes, are negative for acid-fast bacilli (AFB), and
Early recognition of the disease is essential to are positive on culture in only 50% to 60% of
stop further transmission; however, no single cases. The addition of pleural biopsy for histo-
clinical, radiographic, or laboratory tool is sensi- logic studies and culture increases the yield to
tive or specific enough to be diagnostic, and approximately 80%.
astute clinical assessment is required. Pulmonary TB that develops as a result of the
A careful history to elicit the most common endogenous reactivation of LTBI in immunocom-
symptoms of pulmonary TB (ie, fever, productive petent hosts usually causes abnormalities in the
cough, weight loss, wasting, night sweats, short- upper lobes of one or both lungs. Cavitation is
ness of breath, and occasionally hemoptysis) common in this form of TB. The most frequent
should be obtained. The systemic nature of many sites are the apical and posterior segments of the
of these symptoms is due to the cytokine release lung, with the right lung affected slightly more
associated with the inflammatory response by often than the left. Healing of the tuberculous
the host to the organism. These symptoms are lesions usually results in a scar, with the loss of
usually present for a prolonged period, charac- lung parenchymal volume and, often, calcifica-
teristically weeks to months. A history of tion. In the immunocompetent adult with TB,
possible TB exposure risk (eg, previous exposure, intrathoracic adenopathy is uncommon but may
history of homelessness or prolonged stay in a occur, especially with primary infection. As TB
correctional or other congregate setting, history progresses, infected material may be spread via
of drug abuse, migration from an endemic area, the airways into other parts of the lungs, causing
prior PPD test) should also be elicited. Physical a patchy bronchopneumonia. The erosion of a
examination generally is not helpful in establish- parenchymal focus of TB into a blood or lymph
ing the diagnosis. vessel may lead to dissemination of the organism

and a miliary pattern (evenly distributed small specimen. In addition, the smear is not specific
nodules) on the chest radiograph. because other mycobacteria may have a similar
Nodules and fibrotic scars are seen most appearance. Patients with smear-positive sputa
commonly in old, healed TB and may contain are more likely to transmit infection to contacts
slowly multiplying tubercle bacilli with the compared with those with smear-negative stud-
potential for future progression to active TB. ies, although this latter group has clearly been
The risk of progression is significant, and persons shown to transmit infection.
who have nodular or fibrotic lesions consistent Culture findings are positive in approxi-
with findings of previous disease seen on a chest mately 80% of cases, but unfortunately organ-
radiograph, and who have a positive TST isms take a prolonged time to grow, up to 8
reaction, should be considered high-priority weeks for solid media and 1 to 3 weeks for liquid
candidates for the treatment of LTBI, regardless media. At least 500 organisms/mL need to be
of age. present in the specimen in order to obtain a
In patients with HIV infection, the nature of positive culture result. Susceptibility testing
the radiographic findings depends to a certain (which should be performed on all initial
extent on the degree of immunosuppression. TB isolates) may take another 1 to 3 weeks, although
that occurs in persons with HIV infection and tests that use molecular technology are now
with preserved or restored immune function becoming more available that could shorten the
tends to have the typical radiographic findings turn around time for susceptibility studies to a
that were described in the proceeding two matter of hours.
paragraphs. In more advanced HIV disease with Fifteen to twenty percent of diagnosed cases
associated immunosuppression, the radiographic cannot be confirmed microbiologically and are
findings become more atypical; cavitation is considered to be culture-negative or clinical TB. In
uncommon, and lower lung zone or diffuse these patients, the diagnosis is based on the
infiltrates and intrathoracic adenopathy are presence of symptoms, positive TST results, a
frequent. Clear lung fields may be present in up radiographic appearance compatible with TB, and
to 35% of patients with active TB and AIDS. an improvement in clinical status after treatment
Patients with symptoms or chest radiograph with antituberculous therapy, despite negative
findings that are suspicious for TB disease should microbiological studies and no other etiology
be immediately isolated if they are admitted to a accounting for the illness. This is found more often
health-care facility or congregate setting. in children and individuals from whom quality
The foundation of a rapid, accurate microbi- specimens are difficult to obtain. Bronchoscopic
ological diagnosis of TB is proper specimen studies using BAL and transbronchial biopsy,
collection and rapid transport to the laboratory. which are performed with appropriate infection
At least three sputum specimens should be control precautions, may help to establish the
obtained for AFB smear and culture; recent diagnosis and rule out other etiologies when the
recommendations include at least one specimen diagnosis is in question. When TB is strongly
to be sent for nucleic acid amplification to suspected, the initiation of presumptive antituber-
attempt to establish the diagnosis microbiologi- culous therapy is appropriate while awaiting
cally. A quality sputum specimen should contain microbiological confirmation.
a volume of 5 to 10 mL. If the patient is unable to Nucleic acid amplification techniques hold
produce an adequate specimen, sputum induc- the promise of being able to detect a few strands
tion and/or bronchoscopy should be considered of nucleic acid in a sample, amplify it, and
(with proper infection control precautions used). identify the presence of TB within a matter of
Sputum smears, the time-honored test for the hours. The test is .90% sensitive and 99%
diagnosis of TB, only yield a positive result for specific when used in smear-positive cases.
TB in approximately 50% of active cases. The Unfortunately, in smear-negative cases, the sen-
advantage of the smear is that it is both rapid and sitivity may only be 60% to 80%. The test has
cheap. The reason for its low sensitivity is the been approved by the US Food and Drug
need for 10,000 to 100,000 organisms in 1 mL of Administration for use on respiratory specimens

(not approved for nonrespiratory specimens) patients with most forms of extrapulmonary
from untreated cases. The most recent recom- disease (see below). However, for individuals
mendations from the CDC recommend obtaining with HIV infection with a CD4 count ,100 cells/
at least one (and many authorities recommend lL, daily or intermittent therapy three times a
the use of multiple) specimens to improve the week is recommended instead of biweekly
test sensitivity on patients suspected of having therapy as the result of reports of the develop-
active TB disease; however, the clinician must be ment of relapse with rifampin-monoresistant
aware that a negative test result does not rule out disease. In addition, children with miliary TB
the possibility of TB and that a positive test result and patients with bone/joint TB or tuberculous
might not guarantee a diagnosis of TB. meningitis, should receive a minimum of 9 to 12
Since the advent and utilization of effective months of therapy.
chemotherapy against TB in the 1950s, 95% of all If pyrazinamide cannot be administered for
individuals with pansusceptible TB who com- the first 2 months, a reasonable alternative is
plete therapy are now cured. In those individuals isoniazid and rifampin administered for 9
with multidrug-resistant strains (resistant to at months. A 4-month regimen of isoniazid and
least isoniazid and rifampin) and XDR-TB rifampin is acceptable therapy for adults who
(resistance to isoniazid, rifampin, a quinolone, have active TB and negative results of smears
and either capreomycin, kanamycin, or amika- and cultures (ie, culture-negative or clinical TB).
cin), traditional chemotherapy may be ineffective It is essential to treat pregnant women who
in .40% of patients. have active TB. Isoniazid and rifampin have been
The American Thoracic Society (ATS) and the shown to be safe for use in pregnant women and
CDC recommended that four-drug therapy with should be administered. Pyrazinamide, although
isoniazid, rifampin, pyrazinamide, and either recommended by many authorities, has not been
ethambutol or streptomycin be started initially thoroughly studied in pregnant women and should
in patients from areas where isoniazid resistance be used at the discretion of the treating clinician.
exceeds 4%, until susceptibility test results are Streptomycin has been shown to be harmful to the
available. In areas with ,4% isoniazid resistance, developing fetus and should not be used.
the fourth drug may be omitted from the initial Corticosteroids have been shown to be of
regimen. Once the results reveal susceptibility to benefit in preventing cardiac constriction from
isoniazid, rifampin, and pyrazinamide, therapy TB pericarditis and in decreasing neurologic
with ethambutol or streptomycin should be sequelae resulting from TB meningitis. They
discontinued. After 2 months of therapy, pyra- may have a role in preventing bronchial stenosis
zinamide is stopped, and isoniazid and rifampin in cases of diffuse endobronchial TB.
are continued for an additional 4 months for a The need to treat with multiple drugs for a
total of 6 months of treatment (completion is also prolonged period leads to the major obstacle
defined by the number of doses administered) facing the control of TB, adherence to therapy. If
(Table 5). It is important to obtain sputum patients do not take their medications as pre-
cultures at the time of the completion of 2 scribed for the entire period, treatment failure
months of therapy (called the initial phase of and resistance has been shown to develop. Once
treatment) to identify patients who are at medications are begun, adherence needs to be
increased risk of relapse. If culture findings are assured. The decline of TB in the United States
not negative after 2 months of therapy and has been attributed in large part to the imple-
cavities are present on chest radiographs, then mentation and utilization of DOT, which has
treatment should be extended to 9 months of been shown to significantly improve the comple-
total therapy and for at least 4 months after tion rates of TB therapy, as well as to impede the
negative culture results are achieved. This regi- development of resistant strains. The responsi-
men can be administered effectively either daily bility for successful treatment has clearly been
or intermittently, utilizing directly observed assigned by current guidelines to the public
therapy (DOT) (Table 5). It may also be used for health program or private provider, not to the
those individuals infected with HIV as well as patient. Furthermore, it is strongly recommended

Table 5—TB Treatment Options for Adults and Children With Culture-Positive Pulmonary TB Caused by Drug-Susceptible
Organisms
Continuation Phase
Initial Phase Ratinga
Interval and Range of (Evidence)b
Interval and Dosesc Dosescd Total Doses
Regimen Drugs (Minimal Duration) Regimen Drugs (Minimal Duration) (Minimal Duration) HIV HIVþ
1 INH 7 d/wk for 56 1a INH/RIF 7 d/wk for 126 182–130 (26 wk) A (I) A (II)
doses doses
RIF (8 wk) or 5 d/wk (18 wk) or 5 d/wk
for
PZA for 40 doses 90 doses (18 wk)
EMB (8wk)
1b INH/RIF Twice weekly for 92–76 (26 wk) A (I) A (II)f
36 doses (18 wk)
1cg INH/RPT Once weekly for 18 74–58 (26 wk) B (I) E (I)
doses
(18 wk)
2 INH 7 d/wk for 14 2a INH/RIF Twice weekly for 62-58 (26 wk) A B
doses
RIF (2 wk), then twice 36 doses (18 wk) (II) (II)c
PZA weekly for 12 2bg INH/RPT Once weekly for 18 44-40 (26 wk) B(I) E(I)
doses doses
EMB (6 wk) or 5 d/wk (18 wk)
for 10 doses (2
wk),e
then twice weekly
for 12 doses (6 wk)
3 INH Tjree times per wk 3a INH/RIF Three times weekly 78 (26 wk) B (I) B (II)
for
RIF for 24 doses (8 wk) 54 doses (18 wk)
PZA
EMB
4 INH 7 d/wk for 56 4a INH/RIF 7 d/wk for 217 273–195 (39 wk) C (I) C (II)
doses doses
RIF (8 wk) or 5 d/wk (31 wk) or 5 d/wk
for
EMB ror 40 doses (8 155 doses (31 wk)f
wk)f
4b INH/RIF Twice weekly for 118–102 (39 wk) C (I) C (II)
62 doses (31 wk)
Reprinted with permission from the CDC from MMWR Morb Mortal Wkly Rep 2003:52;1–77. Abbreviations: EMB, ethambutol;
RIF, rifampin; RPT, rifapentine; , negative; þ, positive.
a
Ratings: A, preferred; B, acceptable alternative; C, offer when A and B cannot be given; E, should never be given.
b
Evidence: I, randomized clinical trial; II, data from clinical trials that were not randomized or were conducted in other
populations; III, expert opinion.
c
When DOT is used, drugs may be administered 5 d/wk and the necessary number of doses adjusted accordingly. Although
there are no studies that have compared five daily doses with seven daily doses, extensive experience indicates this would be
an effective practice.
d
Patients with cavitation seen on an initial chest radiograph and positive culture findings at the completion of 2 mo of therapy
should receive therapy with a 7-mo continuation phase (31-wk; either 217 doses [daily] or 62 doses [twice weekly]).
e
Five-day-a-week administration is always given by DOT. Rating for 5 d/wk regimens is AIII.
f
Not recommended for HIV-infected patients with CD4þ cell counts of ,100 cells/lL.
g
Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion
of 2 mo of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen
and found to have a positive culture from the 2-mo specimen, treatment should be extended an extra 3 mo.

that the initial treatment strategy use patient- mended for anyone with baseline abnormalities
centered case management with an adherence or concomitant liver disease. Clinical monitoring,
plan that emphasizes DOT. through regular inquiry of the patient as to the
Through DOT, representatives of health-care development of symptoms of toxicity, is recom-
facilities (usually from the public health system) mended for all other patients. If transaminase
go into the community to observe and ensure levels become elevated and symptoms of hepa-
that patients take their medications. Numerous titis occur, therapy with all medications should
studies have demonstrated that there is no be discontinued. Once signs and symptoms
reliable way to predict which patient will be resolve or improve, medications should be
adherent to therapy; therefore, all patients with reintroduced sequentially and the patient should
active TB disease should be considered for DOT. be monitored for the recurrence of hepatitis.
Those who are not started on DOT should be Pyrazinamide can also cause hepatotoxicity as
given combination pills (ie, pills containing well as high uric acid levels, resulting in goutlike
isoniazid, rifampin, and pyrazinamide together) symptoms. Ethambutol is associated with optic
to avoid monotherapy and the subsequent neuritis, especially in doses of .20 mg/kg/d and
development of resistance. in patients with renal insufficiency. The monthly
Patients must be monitored for the effective- assessment of visual acuity and color discrimi-
ness of treatment and toxicity. Soon after begin- nation is recommended to identify patients who
ning therapy, patients should have an may be experiencing this toxicity.
improvement in symptoms (eg, cough, fevers, Drug resistance has been increasingly recog-
night sweats, and weight gain). Those who do nized in the United States as well as worldwide.
not experience a symptomatic improvement or The most common reasons for the development
whose culture results fail to convert to negative of drug resistance are patient nonadherence to
within 2 months of treatment initiation should be therapy and/or physician mistakes (eg, adding a
evaluated for treatment failure. More than 80% of single drug to a failing regimen). Multidrug-
patients receiving appropriate therapy are cul- resistant TB is defined as strains that are resistant
ture negative after 2 months of treatment. to at least isoniazid and rifampin. XDR-TB is
The potential reasons for treatment failure defined as resistance to at least isoniazid,
include the following: (1) resistance to prescribed rifampin, a quinolone, and either capreomycin,
medications or the use of an inadequate combi- kanamycin, or amikacin. Outbreaks of such
nation of drugs, resulting in increased drug strains have been well documented, resulting in
resistance; (2) inadequate medication levels significant morbidity and mortality, especially
caused by malabsorption, food or drug interac- among populations with HIV infection. The
tions, or concurrent medical conditions; and (3) control and prevention of such outbreaks have
noncompliance with prescribed treatment regi- required the expenditure of significant efforts
mens. Of these, the latter is by far the most and resources by hospital and TB control
common cause of treatment failure. It is impor- programs.
tant to seek the advice of a TB expert when The treatment of multidrug-resistant TB is
patients have resistant disease, complicating frequently unsuccessful, requiring the use of
concurrent medical conditions, or a lack of more toxic, expensive drugs, in addition to
expected response to therapy. possible surgery; thus, emphasis is on preven-
Adverse reactions are not uncommon in the tion. In patients with confirmed multidrug-
treatment of TB. Isoniazid, which is best known resistant disease, therapy with at least two drugs
for its hepatotoxicity, also causes peripheral to which the isolate is susceptible is recommend-
neuropathy, for which vitamin B6 (pyridoxine) ed for at least 12 months after documented
is prescribed as prophylaxis. Rifampin may cause conversion of the cultures to negative results.
hepatotoxicity in addition to muscle and joint Most experts recommend 18 to 24 months of total
stiffness and pain. Baseline liver function tests therapy. Patients with isoniazid-resistant TB can
should be performed for all patients beginning be treated with rifampin, pyrazinamide, and
treatment, and monthly monitoring is recom- ethambutol for 6 to 9 months. Patients with

rifampin-resistant TB should be treated with and/or clinical worsening. If no other etiology
isoniazid, pyrazinamide, and ethambutol for at can be found, continued treatment for HIV and
least 12 months after culture results convert to TB usually results in an improvement without
negative. Consultation with a TB expert is further intervention. In selected cases, the use of
recommended for the management of drug- immunomodulators (eg, steroids) may be indi-
resistant TB. cated to slow the progression of this response.
Patients with HIV have a response to therapy
similar to that of individuals without HIV Infection Control
infection; however, the treatment of HIV has
altered TB therapy. Protease inhibitors (PIs), Given the increased number of immunosup-
nonnucleoside reverse transcriptase inhibitors, pressed individuals in health-care facilities,
and chemokine (CC motif) 5 receptor antago- infection control efforts to stem nosocomial
nists, three of the most potent agents available to outbreaks of TB among patients and staff are
control HIV, interfere with rifampin, which is the essential. All patients who are suspected of
most important drug available in TB treatment. having active TB should be immediately isolated
Rifampin is a potent inducer of the hepatic p450 and remain so until they are no longer infectious
system. For example, this induction enhances the or until TB has been ruled out.
metabolism of many of the PIs, causing reduced Airborne infection isolation rooms should
serum levels and leading to ineffective viral have negative air pressure to prevent infected
suppression, as well as the development of air from entering hallways and should use at
resistance. Conversely, many of the PIs may least six air exchanges per hour. Health-care
interfere with the metabolism of the rifamycins, workers who are caring for these individuals
causing high serum levels and potential toxicity. should wear N95 masks to avoid inhaling
On the basis of more current experience, infectious particles while working in the enclosed
rifabutin, which is a rifamycin derivative with room. The observance of these guidelines is
less effect on the hepatic p450 system but especially important in rooms where cough-
equivalent efficacy against TB, may be used safely inducing procedures are performed. Patients in
and effectively with the PIs. A resource familiar health-care facilities can be removed from isola-
with the potential pharmacokinetic interactions of tion once they have received medications for 10
these medications should be consulted to deter- to 14 days, they are responding clinically, and
mine the best combinations and dosages for the their AFB smear results are negative. Patients
particular patient (recent recommendations can be may be discharged from the hospital before they
found at http://www.cdc.gov/tb/publications/ are removed from respiratory isolation if the
guidelines/TB_HIV_Drugs/default.htm) following conditions are met: (1) they are
With the use of antiretroviral therapy and the returning to their previous residence (in non-
subsequent improvement in the host’s immune congregate settings) and the health department
response, patients with TB disease may actually has assessed that no vulnerable individuals (ie,
exhibit a paradoxical worsening of their clinical immunocompromised persons and children ,2
condition, which is thought to be due to an years of age) are present; and (2) others who have
inflammatory response from the immune reacti- been exposed have been evaluated for LTBI
vation (called the immune reconstitution inflamma- therapy.
tory syndrome). These patients may experience the
development of new lesions and/or symptoms Vaccination
(eg, new ascites, lymphadenopathy, fever, pleural
effusions, or cerebral lesions). These may be life- BCG, which is an attenuated strain of M bovis,
threatening conditions, depending on the site was first used as a vaccine in humans in the early
and size of the lesion. Clinicians treating TB 1920s. It has since become the most widely used
patients who have HIV must be aware of this vaccine preparation in the world, despite ques-
phenomenon and rule out other etiologies that tions regarding its 0% to 80% efficacy in
maybe responsible for development of the lesions preventing pulmonary TB in adults. Although

the data are less than ideal, numerous studies tissue infections. It is not known whether NTM
have consistently shown the effectiveness of the disease develops soon after infection or, like TB,
BCG vaccine in reducing the incidence of TB in develops after a period of latency.
infants and young children, particularly against
potentially fatal disseminated TB. For this reason, Clinical Manifestations
BCG remains an important part of vaccination
Early reports concerning patients with pul-
programs in most of the world because of the
monary disease caused by NTMs involved older
effectiveness in reducing pediatric mortality rates
white men with a history of underlying lung
for disseminated TB. Its inferior efficacy in
disease. The diseases appeared to be regional,
preventing TB, compared with isoniazid treat-
with most patients from the rural southeastern
ment for LTBI, and its interference with TST has
United States having disease caused by M avium,
limited its use in the United States.
whereas most from the central states had disease
caused by M kansasii. NTM disease is not
Diagnosis and Treatment of reportable in the United States and an accurate
Pulmonary Disease Caused by NTMs incidence of the disease is limited. Severely
immunosuppressed (CD4 counts of ,100 cells/
Epidemiology, Transmission, and Pathogenesis
lL) individuals with HIV infection are particu-
larly susceptible to disseminated disease caused
Although not as important worldwide as TB,
by M avium. Before the widespread use of
diseases due to other mycobacteria appear to be
highly active antiretroviral therapy, dissemi-
more common than TB in the United States. The
nated M avium disease developed in individuals
recognition of these organisms as pathogens is
with HIV infection who had CD4 counts of
relatively recent. These organisms, characterized
,100 cells/lL at a rate of 20% annually.
as the NTMs, share a number of features. Unlike
Localized pulmonary disease due to M avium
MTB, the NTMs are normal inhabitants of the
occurs in ,5% of cases in hosts with HIV
environment (usually soil and water). Also,
infection. With the effective use of highly active
unlike TB, pulmonary disease and other infec-
antiretroviral therapy, however, the incidence of
tions caused by the NTMs are not contagious,
M avium disease seems to be decreasing.
and patients with these diseases are generally not
Chronic pulmonary disease is the most
isolated. Many clinicians believe that these
common localized manifestation of NTMs; it
organisms are opportunistic rather than virulent
usually appears in older individuals, but not all
pathogens, because some local or systemic
patients have a history of underlying lung
immune impairment is required for them to
disease. M avium complex (MAC, consisting of
cause disease.
M avium and the less common but difficult-to-
Much remains to be understood about the
distinguish Mycobacterium intracellulare) and M
pathogenesis of NTM infection and disease. It is
kansasii, are the most frequent NTM pathogens
assumed that most persons have exposure to
causing lung disease in the United States. Other
these organisms through the environment. The
less common NTM pathogens include Mycobac-
aerosolization of environmental NTMs may play
terium abscessus, Mycobacterium fortuitum, Myco-
a role in respiratory disease, whereas ingestion
bacterium chelonae, Mycobacterium szulgai,
may be the source of infection for children with
Mycobacterium simiae, Mycobacterium xenopi, My-
NTM lymphadenitis and for most patients with
cobacterium malmoense, Mycobacterium celatum,
AIDS, whose disseminated Mycobacterium avium
and Mycobacterium asiaticum.
or Mycobacterium genavense begins as a GI
Pulmonary disease caused by MAC generally
colonization. Bacteremic spread of the organism
is classified into the following three syndromes:
in patients with AIDS then involves multiple
organ systems, including bone marrow, lymph 1. Upper lobe disease that mimics reactivated TB
nodes, liver, and spleen. Direct inoculation with clinically and radiographically. This syndrome
NTM organisms from water or other material is is the best-known one. Patients are generally
the likely source of infection in patients with soft older men with a history of COPD.

2. MAC that develops as a complication of scan studies have shown that up to 90% of
previous bronchiectasis. This condition is patients with mid and lower lung field non-
usually seen in patients with a history of TB cavitary disease with MAC have associated
or M kansasii infection who present with a multifocal bronchiectasis, with many patients
recurrence of symptoms and a new infiltrate having clusters of small (,5 mm) nodules in
in an area of old disease. These patients also associated areas of the lung (ie, the ‘‘tree-in-bud’’
tend to be older, but there is no gender pattern).
predilection and no relationship to smoking-
related disease. This syndrome also may occur Diagnosis
in patients with bronchiectasis due to prior
virus-related or bacteria-related damage or In the absence of specific diagnostic features
cystic fibrosis. in the history, physical examination, and chest
3. MAC with no underlying disease. These radiograph findings, culture isolation of the
patients are predominantly women, are non- NTM is essential; however, because these organ-
smokers, and have interstitial rather than isms are commonly found in nature, the contam-
cavitary radiographic changes, which usually ination of culture material or transient infection
are confined to the lingula and right middle does occur. Thus, a single positive sputum
lobes (referred to as Lady Windermere syn- culture finding, especially with a small numbers
drome). Some investigators have noted a of organisms, is not always sufficient to diagnose
progression to respiratory failure in some NTM disease. The previous notion that individ-
individuals. The finding of MAC in these uals had true colonization with NTMs (ie, no
patients was thought to be colonization, but tissue invasion) is now thought to probably be
studies utilizing high-resolution CT scanning rare. Given the changing understanding of the
have suggested that the development of disease caused by NTMs, the ATS published an
bronchiectasis in these patients is attributable official statement concerning the diagnostic
to pathologic disease caused by MAC. criteria of NTM lung disease in HIV-seropositive
and HIV-seronegative hosts. These criteria fit best
Signs and symptoms of NTM pulmonary
with MAC, M abscessus, and M kansasii, because
disease are variable and nonspecific. They
too little is known about other NTMs to be
include chronic cough, sputum production, and
certain how applicable these criteria would be.
fatigue. Less commonly, malaise, dyspnea, fever
The following criteria should be used to
hemoptysis, and weight loss can occur, usually
establish a diagnosis of pulmonary disease
with advanced NTM disease. Evaluation is often
caused by NTMs. The criteria apply to symp-
complicated by the symptoms caused by coex-
tomatic patients with infiltrate, nodular, or
isting lung diseases, including COPD associated
cavitary disease, or high-resolution CT scans that
with smoking, bronchiectasis, previous mycobac-
show multifocal bronchiectasis or multiple small
terial diseases, cystic fibrosis, and pneumoconi-
nodules. Other etiologies for the clinical and
osis.
radiologic findings should be excluded. At least
There are some differences in the radiograph-
three respiratory samples from each patient
ic features of NTM lung disease compared with
should be evaluated. Those having one of the
those produced by MTB. NTMs tend to cause
following should be considered to have disease
thin-walled cavities with less surrounding pa-
caused by NTMs:
renchymal infiltrate, have less bronchogenic but
more contiguous spread of disease, and produce 1. Positive culture results from at least two
more marked involvement of the pleura over the separate expectorated sputum samples (if the
involved areas of the lungs. Occasionally, they results from the initial sputum samples are
may produce dense pneumonic disease or a nondiagnostic, consider repeat sputum AFB
solitary pulmonary nodule without cavitation. smears and cultures); or
Basal pleural disease is not often found, and 2. Positive culture results from at least one
pleural effusions are rare. High-resolution CT bronchial wash or BAL; or

3. Transbronchial or other lung biopsy speci- treated (defined as high rates of sputum conver-
mens with mycobacterial histopathologic fea- sion with long-term negative results on culture)
tures (eg, granulomatous inflammation or with medications alone. Treatment consists of a
AFB) and positive culture findings for NTMs regimen of daily clarithromycin (500 mg bid) or
or biopsy specimens showing mycobacterial azithromycin (250 mg), rifampin (600 mg) or
histopathologic features (eg, granulomatous rifabutin (300 mg), and ethambutol (25 mg/kg
inflammation or AFB) and one or more for 2 months, then 15 mg/kg) in adults without
sputum or bronchial washings that are culture HIV infection. Therapy with streptomycin two to
positive for NTMs; or three times weekly should be considered for the
4. Patients who are suspected of having NTM first 8 weeks as tolerated. Patients should be
lung disease but who do not meet the treated until culture findings are negative for 1
diagnostic criteria should be followed up year.
until the diagnosis is firmly established or Disseminated MAC Disease in HIV-Infected
excluded. Patients: Therapy in adults should include cla-
rithromycin (500 mg bid) or azithromycin (250 to
Expert consultation should be obtained when
500 mg), plus ethambutol, 15 mg/kg/d. Consid-
NTMs are recovered that either are infrequently
eration should be given to the addition of a third
encountered or usually represent environmental
drug (preferably rifabutin at a dose of 300 mg/d).
contamination. Routine susceptibility testing of
Therapy should be continued for life until more
all NTMs is discouraged, but such testing is
data become available. Prophylaxis should be
warranted to obtain baseline data for unrespon-
given to adults with AIDS with CD4 counts of
sive disease, or when relapses occur.
,50 cells/lL, especially in the presence of a
history of prior opportunistic infections, consist-
Treatment
ing of rifabutin (300 mg/d), clarithromycin (500
mg bid), azithromycin (1,200 mg once weekly), or
Note that making the diagnosis of NTM lung
azithromycin (1,200 mg once weekly) plus
disease does not, per se, necessitate the institu-
rifabutin, 300 mg daily.
tion of therapy, which is a decision based on the
potential risks and benefits of therapy for
Nothing to Disclose
individual patients.
M kansasii: Treatment for pulmonary disease
caused by this organism was disappointing
before the advent of rifampin therapy. With the
introduction of rifamycins, the rate of treatment
this chapter.
failures has decreased. The recommended treat-
ment for adults consists of a regimen of daily
isoniazid (300 mg), rifampin (600 mg), and
ethambutol (25 mg/kg for 2 months, then 15
American Thoracic Society, Centers for Disease
mg/kg for 18 months), with a minimum of 12
Control and Prevention, Infectious Diseases Society
months of treatment after culture results become
of America. Treatment of TB. Am J Respir Crit Care
negative. Clarithromycin or rifabutin must be
Med. 2003;167(4):603–662.
substituted for rifampin in HIV-positive patients
who receive PIs. American Thoracic Society, Centers for Disease
M avium: The medical treatment of pulmo- Control and Prevention. Targeted tuberculin testing
nary disease caused by MAC in HIV-negative and treatment of latent tuberculosis infection. Am J
patients historically has been frustrating and Respir Crit Care Med. 2000;161(suppl 3):S221-S247.
disappointing. However, significant advances in American Thoracic Society, Centers for Disease
the drugs available (eg, macrolides) have been Control and Prevention. Diagnostic standards and
made, and there is now greater expectation that classification of tuberculosis in adults and children.
pulmonary MAC disease can be effectively Am J Respir Crit Care Med. 2000;161(4):1376–1395.

American Thoracic Society, Centers for Disease treatment of HIV-related tuberculosis. Available at:
Control and Prevention, Infectious Disease Society of http://www.cdc.gov/tb/publications/guidelines/
America. Controlling tuberculosis in the United TB_HIV_Drugs/default.htm. Accessed March 16,
States. MMWR. 2005;54(9):1–81. 2012.
The four official statements from the CDC and ATS that set Recent recommendations concerning the concomitant
the standards for diagnosis and treatment of TB disease and administration of HIV antiretroviral agents and rifamy-
infection. They also make recommendations for public cins.
health department programs for control of the illness. Each
Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of
is comprehensive and reviews the science behind the
BCG vaccine in the prevention of tuberculosis:
recommendations.
metaanalysis of the published literature. JAMA.
American Thoracic Society, Infectious Diseases Soci- 1994;271(9):698–702.
ety of America. Diagnosis, treatment and prevention A meta-analysis showing that BCG therapy was about 50%
of nontuberculous mycobacterial diseases. Am J Respir effective at preventing TB.
Crit Care Med. 2007;175(4):367–416.
Mahmoudi A, Iseman MD. Pitfalls in the care of
An official statement from the ATS/Infectious Diseases
patients with tuberculosis: common errors and their
Society of America. A very good and thorough review on
acquisitions of drug resistance. JAMA. 1993;270(1):65–
NTM diagnosis and treatment.
68.
Behr MA, Warren SA, Salamon H, et al. Transmission This classic article revealed that physicians caring for TB
of Mycobacterium tuberculosis from patients smear patients made on average 3.93 errors that subsequently
negative for acid-fast bacilli. Lancet. 1999;353(9151): contributed to the acquisition of drug resistance. The most
444–449. common errors were as follows: (1) adding a single drug to
A study utilizing DNA fingerprinting, which revealed that a failing regimen; (2) failure to identify preexisting or
as many as 17% of TB cases may be the result of acquired drug resistance; (3) initiation of an inadequate
transmission from smear-negative, culture-positive pa- primary regimen; (4) failure to address nonadherence to
tients. therapy; and (5) inappropriate isoniazid prophylaxis. The
Burman WJ. Issues in the management of HIV-related average cost of treatment per patient was $180,000.
tuberculosis. Clin Chest Med. 2005;26(2):283–294. Narita M, Ashkin D, Hollender ES, Pitchenik AE.
Good review of the treatment of HIV-infected patients with Paradoxical worsening of tuberculosis following
TB, including necessary regimen adjustments when using antiretroviral therapy in patients with AIDS. Am J
HIV and TB medications concomitantly. Respir Crit Care Med. 1998;158(1):157–161.
Centers for Disease Control and Prevention, National Case series description of ‘‘paradoxical response’’ or
Institutes of Health, and the HIV Medicine Associa- ‘‘immune reactivation with inflammatory response’’ in
tion of the Infectious Diseases Society of America. patients coinfected with TB and HIV who were treated with
Guidelines for prevention and treatment of opportu- antiretroviral therapy.
nistic infections in HIV-infected adults and adoles- Prince DS, Peterson DD, Steinger RM, et al. Infection
cents. MMWR. 2009;58(4):1–198. with Mycobacterium avium complex in patients with-
Most current recommendations from the CDC for the out predisposing conditions. N Engl J Med. 1989;
prevention and treatment of TB MAC among HIV-infected 321(13):863–868.
individuals. Description of a group of patients who did not meet the
Centers for Disease Control and Prevention. Updated previously recognized demographics for pulmonary disease
guidelines for using interferon gamma release assays caused by MAC.
to detect Mycobacterium tuberculosis infection, United Wallace RJ. Nontuberculous mycobacterial infections
States 2010. MMWR. 2010;59(RR05):1–25. in the HIV-negative host. In: Rom WN, Garay S, eds.
Recent recommendations concerning the use of this test for Tuberculosis. Boston, MA: Little, Brown and Company;
the diagnosis of LTBI. 2004:651–662.
Centers for Disease Control and Prevention. Updated Well-written chapter by one of the nation’s leading experts
guidelines on managing drug interactions in the reviewing NTM in HIV-negative hosts.

Chapter 33. Idiopathic Pulmonary Fibrosis, Nonspecific
Interstitial Pneumonia/Fibrosis, and Sarcoidosis
Objectives: 30% of patients, resulting in permanent damage and fibrosis

of affected organs. Fatality rates range from 0.5% to 4%.
Describe the salient epidemiologic, clinical, physiologic, Corticosteroids are the mainstay of therapy, and may
and radiographic features of idiopathic pulmonary produce dramatic remissions in patients with severe or
fibrosis, nonspecific interstitial pneumonia/fibrosis, and progressive sarcoidosis. Immunosuppressive agents may
sarcoidosis. have a role in patients failing or experiencing adverse effects
Discuss the salient features seen on high-resolution CT from corticosteroids. Lung transplantation is a therapeutic
scans and their impact on prognosis. option for patients with severe pulmonary sarcoidosis
Review the characteristic histopathologic features of each refractory to medical therapy.
of these disorders and the role of transbronchial or
surgical (open or thoracoscopic) lung biopsies.
Discuss the clinical role (if any) of ancillary studies such
as radionuclide scanning or BAL to stage or follow up
these disorders. Idiopathic Pulmonary Fibrosis
Review therapeutic strategies.
Idiopathic pulmonary fibrosis (IPF), also known
Key words: cryptogenic fibrosing alveolitis; idiopathic as cryptogenic fibrosing alveolitis, is a specific
pulmonary fibrosis; nonspecific interstitial pneumonia;
form of chronic interstitial lung pneumonia
sarcoidosis; usual interstitial pneumonia
associated with the histologic pattern of usual
Synopsis: interstitial pneumonia (UIP).1–5 Although UIP is
a distinct histologic lesion,4 this histologic pat-
Idiopathic pulmonary fibrosis (IPF) is a specific form of
chronic interstitial pneumonia associated with the histolog- tern is not specific for IPF and can also be found
ic. Clinical features of IPF include progressive cough, in other diseases (eg, connective tissue diseases
dyspnea, restrictive ventilatory defect, and progressive [CTDs], asbestosis, and diverse occupational,
fibrosis and destruction of the lung parenchyma. IPF is rare
(prevalence 13–42 cases/100,000), and primarily affects
environmental, or drug exposures).1–3,6 A diag-
older adults (age .50 years). The diagnosis of IPF often nosis of IPF can be established only when these
requires surgical lung biopsy (SLB), but the diagnosis can be and other alternative etiologies have been ex-
affirmed with confidence in some patients provided CT cluded.2,3,5 Cardinal features of IPF include
imaging and clinical features are consistent. The clinical
course is variable, but inexorable progression (typically over progressive cough, dyspnea, bilateral interstitial
months to years) is typical. Mean survival from the onset of infiltrates on chest radiographs, a restrictive
symptoms approximates 3 to 5 years. Medical treatment is ventilatory defect on pulmonary function tests
largely ineffective. Lung transplantation is the best thera-
(PFTs), and progressive fibrosis and destruction
peutic option. Another rare interstitial lung disease, termed
nonspecific interstitial pneumonia (NSIP), shares clinical of the lung parenchyma.1,2,5,7 The features are
features in common with IPF, but has distinct differences in nonspecific and may be observed with myriad
histologic findings and prognosis. SLB is necessary to other interstitial lung diseases (ILDs).2,3 The term
substantiate the diagnosis of NSIP. Corticosteroids or
immunosuppressive agents may be efficacious in NSIP,
IPF should be restricted to patients with the
but are ineffective in IPF. The relationship between NSIP appropriate clinical features and the histologic
and usual interstitial pneumonia remains uncertain. Sar- pattern of UIP.2,3,5 Other histologic patterns (eg,
coidosis is a granulomatous disease of uncertain etiology desquamative interstitial pneumonia [DIP],8 re-
that involves the lungs or intrathoracic lymph nodes in
.90% of patients. However, virtually any organ can be spiratory bronchiolitis ILD [RBILD],8 nonspecific
involved. Sarcoidosis is worldwide in distribution, but the interstitial pneumonia [NSIP],9,10 acute intersti-
prevalence varies according to racial and geographic factors. tial pneumonia [AIP],11 lymphoid interstitial
More than two-thirds of patients present between the ages
pneumonia [LIP],12 cryptogenic organizing pneu-
of 20 and 40 years. The natural history of sarcoidosis is
usually favorable (spontaneous remissions occur in .50% of monia [COP],13 and chronic hypersensitivity
cases), but the disease is chronic and progressive in 15% to pneumonia14) are distinct entities with differing

clinical expression and prognoses. A definitive cancer, multiple myeloma, and acute myeloge-
diagnosis of UIP requires surgical lung biopsy nous leukemia.27
(SLB), but the diagnosis of UIP can be affirmed
with confidence by high-resolution CT (HRCT) Risk Factors for IPF
scans in some patients.5,15,16 IPF is one of the
most frustrating disorders to manage, because The cause of idiopathic UIP is unknown, but
treatment is largely ineffective.1,5,17–19 environmental and occupational exposures likely
play etiologic roles.31–33 IPF is more common in
Epidemiology current or former smokers.5,17,28,33–36 The degree
of exposure (quantified as pack years of smok-
IPF is rare, but precise data regarding ing) is directly correlated with the occurrence of
incidence and prevalence are lacking.5,20–22 Most IPF.34,37 Importantly, ever smoking remains a risk
population-based epidemiologic surveys are factor for the development of IPF, even after
based on clinical diagnosis, death certificates, or smoking cessation.34 In familial IPF, smoking was
diagnostic coding, and lack histologic confirma- the strongest associated risk factor, with an odds
tion; such studies include a mixture of ILDs, ratio (OR) of 3.6.38 Risk factors for IPF cited in
including disorders other than UIP.20,23–25 Stud- some studies included exposure to metal and
ies from Europe22–24 and Japan25 cite prevalence wood dusts25,31,35,39 or organic solvents25 and
rates of IPF ranging from three to eight cases per residence in agricultural or polluted urban
100,000 population. In the United States, preva- areas.25,29,35 However, a study from the British
Isles found no increased risk of IPF among
lence rates range from 13 to 42 cases per
individuals exposed to wood or metal dusts.24
100,000.20,21 The incidence of IPF appears to be
In that study, excess mortality due to IPF was
increasing. The incidence of IPF increased
noted in electricians, electrical engineers, fire-
progressively in the United Kingdom between
men, and cleaners (occupations associated with
1991 and 2003.22 Another study cited a sixfold
exposure to potentially toxic fumes or chemi-
increased incidence of IPF in the United King-
cals).24 A meta-analysis of six case-control stud-
dom between 1978 and 2008.26 Similarly, in the
ies found six exposures associated with IPF: ever
United States, deaths attributed to pulmonary
smoking, agriculture farming, livestock, wood
fibrosis increased significantly from 1992 to 2003
dust, metal dust, and stone/sand.33 ILD is an
(.28% increase).27 The incidence of IPF is much
occupational disease in coal miners, sandblasters,
higher in men and in the elderly (peak onset and workers exposed to asbestos, tungsten
after the sixth decade of life).19–22,25–29 In the carbide, beryllium, and other metals,32 suggest-
United States, mortality rates from IPF are ing that at least some cases of ‘‘idiopathic’’ UIP
climbing more rapidly in women than men,27 represent pneumoconioses. The considerable
possibly reflecting the impact of cigarette smok- variability that exists in the development of
ing. In one study in the United States, the pulmonary fibrosis among workers exposed to
prevalence of IPF in adults between 35 to 44 similar concentrations of fibrogenic/organic
years old was 2.7 per 100,000.20 By contrast, the dusts implies that genetic factors are likely
prevalence exceeded 175 per 100,000 in adults important in modulating the lung injury.33 In a
older than 75 years.20 Mortality rates from IPF recent study, risk factors for IPF included former
are markedly increased in the elderly. In the or current cigarette smokers; exposure to dusts,
United States, projected deaths (per million) in smoke, gases, or chemicals; and having a parent
2008 were as follows: 18 (age 45–54); 71 (age 55– or sibling with IPF.36
64); 306 (age 65–74); 827 (age 75–84); and 1,380 Chronic aspiration secondary to gastroesoph-
(age .85).27 Idiopathic UIP is rare in children.30 ageal reflux (GER) is a possible cause (or
Despite its rarity, IPF accounts for more than contributory factor) in the pathogenesis of
16,000 deaths annually in the United States27; IPF.40–44 Pulmonary fibrosis is a common com-
this mortality rate is higher than that for a plication of systemic sclerosis (scleroderma), a
number of malignancies, including bladder disorder with an extremely high prevalence of
500 Chapter 33. Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia/Fibrosis, and Sarcoidosis (Lynch)
esophageal dysmotility.45 Aspiration of stomach tant protein, A2 (SFTPA2), have been associated
contents (acid or not) leads to lung injury and with familial pulmonary fibrosis and lung
fibrosis.32,46 Esophageal reflux has been noted in cancer.63 Interestingly, multiple types of intersti-
more than two-thirds of patients with IPF tial pneumonias have been noted in FIP (eg, UIP,
awaiting lung transplantation (LT).40–42,47 Impor- NSIP, DIP, COP).38,64 In one study of 78 patients
tantly, 30% to 50% of IPF patients with GER have with histologically confirmed FIP, histologic
no symptoms of reflux.40,41,47 Further, severity of patterns included UIP (86%), NSIP (10%), COP
IPF does not correlate with severity of GER.40,41 (2.5%), and unclassified (1.3%).38 Forty-five per-
Among LT recipients (with or without IPF), GER cent of pedigrees exhibited more than one
can cause allograft injury46,48 and appears to be a histologic pattern among affected family mem-
risk factor for bronchiolitis obliterans syn- bers.38 In familial IPF, asymptomatic ILD may
drome.48,49 In light of these findings, aggressive progress to symptomatic IPF over a period of
treatment of GER is recommended to reduce the decades.64 Interestingly, gene expression profiles
chance for repetitive lung injury, which may elicit of lung tissues from patients with familial IP
fibrosis. In a small series of patients with early (either UIP or NSIP) exhibit striking similarities,
IPF, aggressive treatment of GER was associated but differ from gene expression profiles in
with stabilization or improvement of lung func- sporadic IPF.65,66 Mutations in genes encoding
tion.40 In a recent retrospective study of 204 IPF proteins involved in chronic inflammation (ie,
patients from two academic medical centers, chemokines, complement, and immunoglobu-
treatment of GER was independently associated lins), smooth muscle markers (ie, smooth muscle
with longer survival and lower radiological cells and myofibroblasts) and/or matrix mobili-
fibrosis scores.44 Additional studies are required zation and resolution65,66 may be important in
to assess the role of GER or aspiration in the the pathogenesis of IPF. Dysregulation of gel-
pathogenesis or progression of IPF and thera- forming mucin genes (eg, MUC5B) may play a
peutic strategies to prevent or reduce GER. role in the pathogenesis of IPF. Compared with
unaffected control subjects, a polymorphism in
Genetic Factors the MUC5B promoter regions was more common
in familial IP and IPF, and MUC5B expression
Several lines of evidence suggest that genetic was 14.1 times higher in lung tissue from subjects
factors are important in the pathogenesis of IPF. with IPF.67 Genetic polymorphisms for IL-1
Clusters of interstitial pneumonias/fibrosis in receptor antagonist or tumor necrosis factor-a
families (familial interstitial pneumonia [FIP]) (TNF-a),68 complement receptor 1,69 or trans-
have been noted in 0.5% to 3.7% of patients with forming growth factor-b (TGF-b)70 may influence
IPF30,38,50–52; a higher rate (10%) was cited in a risk of IPF or disease progression. Interestingly,
cohort of Dutch IPF patients.53 In a multivariate polymorphism of the angiotensinogen gene was
analysis of risk factors for IPF, having a parent or associated with IPF progression but not with
sibling with IPF was the strongest risk factor (OR disease predisposition.71 Germ line mutations in
6.1); other factors (eg, GER, former cigarette the genes hTERT and hTR, encoding telomerase
smoking, occupational exposures) increased risk reverse transcriptase and telomerase RNA, were
but the effects were not as strong (OR 2.5–2.8).36 implicated in dyskeratosis congenita, a rare
The mode of transmission of FIP is not hereditary disorder associated with pulmonary
known, but is believed to be autosomal dominant fibrosis and aplastic anemia.72 These mutations
with variable/reduced penetrance.38,50,52 Link- result in telomere shortening, which limits the
age with chromosome 14 has been suggested.5 replicative capacity of tissues and has been
Familial IP is indistinguishable from nonfamilial implicated in age-related disease. Interestingly,
(sporadic) IPF, but patients tend to be younger older age and smoking also cause telomere
with the familial variant.51,54 Mutations in the gene shortening.72,73 Short telomeres were more com-
for surfactant protein C may cause FIP,53,55–59 mon in FIP and sporadic IPF compared with
but appear to be rare in sporadic IPF.5,60–62 control subjects, even when mutations in hTERT
Mutations in the gene encoding another surfac- and hTR were lacking.74,75 hTERT mutations

shorten life expectancy; further, family members GER,41,90 are more common in patients with
within IPF kindreds who do not inherit the TERT IPF. The onset of the disease is usually indolent,
mutation have shorter telomere lengths than but IPF progresses inexorably over months to
control subjects.73 Pulmonary fibrosis may also years.1,2,7,18,19,28 The course is highly variable,
complicate diverse genetic disorders such as with some patients maintaining stability for
Hermansky-Pudlak syndrome,76 familial hypo- years,1,7,92 whereas in others, the course is rapid,
calciuric hypercalcemia,77 neurofibromatosis,78 with fatal respiratory failure evolving over a few
etc. A kindred with IPF, hepatic nodular regen- months.81,93 Additionally, some patients have
erative hyperplasia, and bone marrow hypopla- gradual progression over years, followed by
sia was described.79 IPF occurs in Caucasians and acute exacerbations (AEs), associated with
in nonwhites; prevalence among different ethnic abrupt and often fatal hypoxemic respiratory
groups has not been studied.2,5 However, in the failure.7,92,94 Differences in gene expression pro-
United States, mortality rates due to IPF were files may differ between those with more rapid
higher in non-Hispanic whites compared with progression compared with those with indolent
Hispanics or blacks.27 A retrospective study of disease.81,82 Spontaneous remissions do not
IPF in New Zealand cited a lower incidence in occur.1,2 Mean survival from the onset of symp-
those of Maori or Polynesian descent than in toms approximates 3 to 5 years.19,28,95 Fewer than
those of European descent.80 15% of patients survive 10 years from the onset of
Differences in susceptibility to fibrogenic symptoms.18,19,28
agents may reflect genetic polymorphisms.50,51 The major cause of death in IPF patients is
Animal models involving different inbred strains respiratory failure. 7,96,97 Surveys of deaths
of rodents demonstrate dramatic variability in among IPF patients in the United Kingdom and
the lung inflammatory/fibrotic response to inju- United States noted that progression of lung
rious agents. In humans with IPF, differences in disease accounted for 72%97 and 60%27 of deaths,
gene expression have been noted among subjects respectively. Other causes include pulmonary
with rapidly progressive IPF compared with embolism,96 lung cancer,96,98 cardiac failure, and
those with slowly progressive IPF.81,82 Recently, cerebrovascular accidents.99 Acute respiratory
differences in microRNA expression were noted failure requiring mechanical ventilation may
in IPF subjects exhibiting a rapid course com- complicate IPF, either from infection or from an
pared with slowly progressive IPF or normals.83 AE of the underlying disease process.94,100–103 In
The above studies suggest that IPF is a hetero- this context, mortality is high (.90%). For this
geneous disorder caused by a number of envi- reason, mechanical ventilation is usually ill
ronmental/occupational exposures in advised in patients with severe IPF. Unfortunate-
combination with genetic predispositions. ly, medical therapy has not been shown to alter
the course of the disease (discussed in detail
Clinical Features of IPF later).
Numerous clinical variables may predict
Initial symptoms of IPF are cough (typically prognosis in IPF.7 Older age,7,18,19,95 more severe
nonproductive) and dyspnea.1 Over time, the impairments in pulmonary function or HRCT
cough may become paroxysmal and debilitating scans,18,19,95,104 and presence of pulmonary arte-
and dyspnea and exercise limitation worsen. rial hypertension (PAH)105–107 have been associ-
Physical examination reveals end-inspiratory ated with a worse prognosis. Several studies
rales (often with a ‘‘Velcro’’ quality) in .85% of cited higher mortality in men.7,18,19,81,108 The
patients with IPF.1,19 Clubbing is noted in .25% effect of cigarette smoking on prognosis has been
of patients.1,2,19 Extrapulmonary involvement variable.7 One early study cited a survival
does not occur,1 and should suggest other advantage in current smokers compared with
disorders (particularly CTD-associated pulmo- former and never smokers.19 A subsequent study
nary fibrosis).84 However, certain diseases, such also found a survival advantage in current
as ischemia cardiac disease,85–87 deep venous smokers compared with former smokers, but
thrombosis,85,88,89 diabetes mellitus,90,91 and after adjusting for disease severity, this effect was
no longer significant, suggesting a ‘‘healthy were found in four; another 12 had torque teno
smoker effect.’’28 Interestingly, recent studies virus, the significance of which is unclear.124 In
cited longer survival among IPF patients with one study, risk factors for AE by multivariate
concomitant compared with no emphyse- analysis included BMI, extent of disease, and
ma.109,110 In one study, higher BMI correlated .10% decline in FVC at 6 months.121 Lung
positively with survival.111 surgery (eg, lung biopsy, resections) has been
cited as a possible risk factor for AE.93,117,125,126
Lung Cancer Complicating UIP This syndrome is usually fatal (in-hospital
mortality .50%).93,94,123 Optimal treatment is
Lung cancer occurs in 4% to 13% of patients unknown.93 High-dose IV pulse methylprednis-
with IPF.98,112–114 The risk is higher in smok- olone has been associated with anecdotal re-
ers,113,114 but the heightened risk of lung cancer is sponses in some cases of AE94,118,119,123 and is
not solely due to the effects of cigarette smok- recommended by most experts.5 However, ste-
ing.98 Surgical resection may be curative in IPF roids were ineffective in one large study.93
patients with non-small cell lung cancer, but
postoperative morbidity and mortality is in- Laboratory Tests
creased.115–117
Laboratory test results in IPF are nonspecific.
AEs of UIP The erythrocyte sedimentation rate is elevated in
60% to 94% of patients; circulating antinuclear
AEs of IPF, characterized by an accelerated antibodies or rheumatoid factor have been found
course, severe hypoxemia, dyspnea, and pulmo- in 10% to 26% of patients with IPF.1,2 These
nary infiltrates on chest x-rays or CT scan, serologic studies do not correlate with the extent
develop in at least 10% to 25% of IPF pa- or activity of the disease, and do not predict
tients.93,94,118–120 In a cohort of 461 Korean therapeutic responsiveness.1,2 However, for new
patients with IPF, incidence rates of AE were cases of suspected IPF, we obtain serologies for
14.2% at 1 year and 20.7% at 2 years.93 A CTD (eg, antinuclear antibody and antibodies to
retrospective study of 74 Japanese patients with SSA, SSB, centromere, Scl-70 [scleroderma], Sm,
IPF cited incidence rates of AE at 1, 2, and 3 years RNP, Jo-1, and double-stranded DNA) and
of 8.7%, 12.6%, and 23.0%, respectively.121 The hypersensitivity pneumonitis (HP) to rule out
cardinal histologic feature on lung biopsy or those disorders. Circulating antibodies for AN-
necropsy is diffuse alveolar damage þ/ orga- CA have been noted in patients with otherwise
nizing pneumonia superimposed on a back- typical IPF.127,128–130 However, in this context,
ground of UIP.101,118 Lungs from patients with renal involvement (particularly microscopic poly-
AE demonstrate enhanced alveolar epithelial cell angiitis) and vasculitis may be observed.127,130
(AEC) injury, apoptosis, and proliferation and Elevations of the glycoprotein KL-6131 and lung
upregulation of certain genes.122 Idiopathic AIP11 surfactant proteins A and D131,132 have been
exhibits similar clinical and histological features noted in serum and BAL fluid in patients with
as AEs of IPF, but lacks the requisite features of IPF, and may have prognostic value. These
UIP. The factors responsible for this accelerated assays are available in only a few research
phase of IPF are unknown, but viral infections, laboratories, and additional studies are required
high concentrations of oxygen, or drug reactions to assess their specificity and clinical role.
are plausible etiologic factors.94 In a study of 27
patients with 37 AEs of IPF, 76% of exacerbations Chest Radiographs
occurred between December and May, suggest-
ing an infectious etiology; however, no organisms Chest radiographs in IPF typically reveal
were identified.123 Wootton et al124 performed bilateral interstitial (reticular) infiltrates, with a
highly sensitive panviral PCR and microarrays in predilection for the basilar and peripheral (sub-
serum and BAL fluid from 43 patients with AE of pleural) regions of the lung,1,2 (Fig 1). With
IPF. Community-acquired respiratory viruses disease progression, all lung fields are affected

Figure 2. UIP. HRCT scan demonstrates foci of GGOs in the
subpleural regions of the lower lobes (arrows). A few small
honeycomb cysts are also present. The central portions of
the lung are relatively spared. Reprinted with permission
from ACCP Pulmonary Medicine Board Review. 25th ed.
Figure 1. IPF/UIP. Posteroanterior chest radiograph from a Northbrook, IL: American College of Chest Physicians; 2009.
61-year-old man with IPF/UIP demonstrates extensive
reticulonodular infiltrates with a bibasilar predominance. change [HC]); coarse reticular or linear opacities
A mixed alveolar and interstitial pattern is evident in the
lower lobes. Reprinted with permission from ACCP Pulmo-
(intralobular and interlobular septal lines); rag-
nary Medicine Board Review. 25th ed. Northbrook, IL: ged pleural surfaces; and bronchiectasis and
American College of Chest Physicians; 2009. bronchioloectasis (Figs 2–6).15,134 Air broncho-
grams (1–2 mm in diameter) reflect dilated
peripheral airways surrounded by fibrotic lung
and lung volumes decline. Similar radiographic
tissue. Bronchovascular thickening, a cardinal
features may be observed in asbestosis and CTD-
feature of sarcoidosis, is minimal or absent in
associated pulmonary fibrosis.133 Pulmonary
UIP.134 Focal ground-glass opacities (GGOs)—
hypertension and cor pulmonale may be seen
hazy zones of increased alveolar attenuation—
in far-advanced cases.134 Intrathoracic lymph-
may be present in IPF/UIP,140 but are not a
adenopathy and pleural thickening are not
features seen on plain chest radiographs, but
may be noted on CT scan.135 Chest radiographs
have limited prognostic value, but serial radio-
graphs (including old films) may gauge the pace
and evolution of the disease.1
Thin-Section HRCT Scans
HRCT Scan Features and Value in the Differen-

tial Diagnosis: HRCT scans, using thin (1–2-mm)
sections without the use of contrast, are far more
accurate than conventional chest radiographs in
assessing the extent and nature of the dis-
ease.15,134 HRCT scans have diagnostic136,137 and
Figure 3. HRCT scan from a 53-year-old man with UIP
prognostic108,138–141 value, and should be part of confirmed on open-lung biopsy specimen. Note extensive
the initial evaluation of suspected ILD. The areas of GGOs with air bronchograms in the lower lobes.
HRCT features of IPF/UIP are stereotypic and Despite extensive involvement of the posterior regions of
predictable and include a patchy, heterogeneous both lower lobes, the anterior portion of the left lower lobe is
relatively normal, emphasizing the patchy nature of the
distribution with a predilection for the peripheral disease. Reprinted with permission from ACCP Pulmonary
(subpleural) and basilar regions of the lungs; Medicine Board Review. 25th ed. Northbrook, IL: American
small cystic radiolucencies (ie, honeycomb College of Chest Physicians; 2009.
Figure 6. HRCT scan from a 48-year-old woman with UIP,
with extensive cystic radiolucencies (honeycomb cysts)
scattered throughout the lung parenchyma. Despite treat-
Figure 4. HRCT scan from a 63-year-old woman with UIP ment with CSs, AZA, and CP, she died of progressive
confirmed on open-lung biopsy specimen. HC is evident, respiratory failure. Reprinted with permission from ACCP
particularly in the peripheral (subpleural) regions. Dilated Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
bronchi, indicating traction bronchiectasis, are also present. American College of Chest Physicians; 2009.
There are no GGOs. Reprinted with permission from ACCP
American College of Chest Physicians; 2009. anatomic distortion, and dilated pulmonary
arteries are observed. Zones of emphysema
dominant feature.15 HC is highly characteristic of (particularly in the upper lobes) may be present
IPF/UIP, but may be absent in mild cases.16,140 concomitantly in smokers.143,144 Mediastinal
The process is usually relatively symmetrical, but lymph node enlargement (LNE) has been noted
asymmetry may occur, often with predominant in 53% to 93% of patients with IPF135,136,145 but is
involvement of the right lung; it has been nonspecific.146 LNE in IPF usually involves only
hypothesized that this may reflect GER dis- one or two nodal stations, and the nodes usually
ease.142 In severe cases, severe volume loss, measure less than 15 mm.145 The presence of
LNE correlated with the extent of disease in
some,145 but not all, studies.135 One study noted
that increase in LNE over time was associated
with progression of fibrosis in UIP or NSIP.145
Differential Diagnosis by HRCT Scan: Focal
GGOs may be observed in UIP, but predominant
or extensive GGOs suggest an alternative diag-
nosis such as DIP,147 HP,148 cellular NSIP,9 COP,13
chronic eosinophilic pneumonia,149 or pulmo-
nary alveolar proteinosis.150 HC is a cardinal
feature of UIP,134 but is absent in AIP11 and
DIP.147 Honeycombing is not a prominent feature
in NSIP, but focal HC may be seen in fibrotic
variants of NSIP.16,151 Cystic radiolucencies may
be observed in other disorders (eg, Langerhans
Figure 5. HRCT scan from a 44-year-old man with severe
cell histiocytosis,152 sarcoidosis,153 lymphangio-
UIP on open-lung biopsy specimen. Note the marked cystic
radiolucencies (some cysts are .3 cm in diameter) and leiomyomatosis,154 chronic HP,155 LIP,156 pneu-
honeycombing involving both lungs. Although most of the moconiosis) but the distribution of lesions and
lung parenchyma has been destroyed, note the accentuation presence of concomitant abnormalities differen-
of the cystic disease process in the peripheral (subpleural)
tiates these disorders from UIP.157
regions. Reprinted with permission from ACCP Pulmonary
Medicine Board Review. 25th ed. Northbrook, IL: American Can HRCT Scans Obviate the Need for SLB in
College of Chest Physicians; 2009. IPF?: HRCT scans may obviate the need for SLB,

provided the CT features are classical for UIP sive GGO had histologic patterns distinct from
(including presence of honeycombing),5,16,108 The UIP such as DIP,147 NSIP,151,162 or HP.148 Combi-
accuracy of a ‘‘confident diagnosis’’ of UIP by a nations of patterns (eg, GGO, reticular, HC) may
trained observer is .95%.5,16,108,136 However, be present in individual patients.1,134 In some
classical features of UIP (‘‘confident diagnosis’’ patients, GGOs evolve to HC or reticular
by CT scan) are present in only 34% to 67% of lines.160,161 Reticular patterns or HC do not
patients with histologically confirmed UIP.1,136,140 regress and may worsen over time.15,143,161,163
Interobserver and intraobserver variability may Severe HC on CT scans is a strong predictor of
be problematic140; consensus is usually reached mortality (.80% mortality within 2 years).108,164
when extensive HC and subpleural predomi- In a cohort of 106 patients with UIP,108 CT-fib was
nance are present.16 CT patterns overlap between a significant predictor of mortality. A mean CT-
UIP and fibrotic NSIP.151 Subpleural predomi- fib score 2.0 in any lobe was associated with
nance, reticulation, and HC may be found in increased mortality (risk ratio 3.35) compared
fibrotic NSIP, and focal GGOs may be observed with patients with a CT-fib score ,2 in all lobes.
in UIP.140,151 Predominant GGOs make UIP A similar finding was noted when patients were
unlikely.151 When CT features are typical for segregated by mean CT-fib 2 for all lobes (risk
UIP, specificity approaches 100%.16,136 In one ratio 2.5; P ¼ .002). However, when the histologic
study, two radiologists independently assessed diagnosis was incorporated into the model, the
CT scans from a cohort of patients with either diagnosis of UIP was the most powerful predic-
idiopathic UIP (n ¼ 73) or NSIP (n ¼ 23).16 CT
tor of mortality, and overshadowed the predic-
scans were categorized as definite UIP, probable
tive ability of the CT-fib score.108 In a multicenter
UIP, indeterminate, probable NSIP, or definite
prospective study of 315 IPF patients, higher CT-
NSIP. CT features were typical (definite or
fib scores and lower diffusing capacity of lung for
probable) of UIP in 27 of 73 patients (37%) with
carbon monoxide (DLCO) correlated with in-
histologic UIP on SLB. Importantly, all 27
creased mortality risk (by multivariate analy-
patients with a CT pattern of ‘‘probable’’ or
sis).15 CT patterns ‘‘typical’’ of IPF/UIP have
‘‘definite’’ UIP had histologic UIP on SLB. In
been associated with a higher mortality com-
contrast, only 18 of 44 (41%) with ‘‘probable’’ or
pared with ‘‘atypical’’ CT scans,140,158,162 suggest-
‘‘definite’’ NSIP on CT scans had histologic NSIP
ing that CT features typical of IPF reflect
on SLB (59% had UIP).16 These data suggest that
advanced disease. Sumikawa et al140 retrospec-
CT features of UIP are associated with advanced,
late-stage disease. Among patients with earlier tively reviewed 98 patients with a histologic
phases of UIP, CT features may be ‘‘atypical’’158 diagnosis of UIP who had CT scans. Patterns of
or ‘‘indeterminate.’’16 When HRCT features are CT scans were categorized as (1) definite UIP, (2)
classical for UIP (including HC), SLB is not probable UIP, or (3) suggestive of alternative
necessary.5 However, SLB should be performed diagnosis. Mean survival rates were 45.7, 57.9,
when CT scans are nondiagnostic or atypical and 76.9 months respectively. Median survival
(unless specific contraindications exist).5,108 rates were 34.8, 43.4, and 112 months, respective-
Prognostic Value of HRCT in IPF: The progno- ly. Although these differences between groups
sis of IPF can be inferred from the extent and did not achieve statistical significance, these data
nature (ie, predominant pattern) of HRCT abnor- suggest that CT scans interpreted as definite UIP
malities.138–141 Increasing extent of fibrosis on CT have a worse prognosis. By multivariate analysis,
(CT-fib) (ie, reticulation, HC) correlates with increasing extent of traction bronchiectasis and
higher mortality.138–141 Early reports noted that fibrosis scores were associated with worse
a ‘‘predominant GGO pattern’’ in patients with prognosis. In summary, extensive HC or reticu-
IPF correlated with higher rates of response to lation on CT scans and no or minimal GGO
corticosteroid (CS) therapy (improvement in 33% suggests a low likelihood of response to medical
to 44% of cases) and higher survival compared therapy and high mortality.108,164 Unless contra-
with reticular or HC patterns.159–161 However, it indications exist, these patients should be listed
is likely that CS-responsive patients with exten- for LT.165
Several studies assessed evolution of CT ence (PAO2 PaO2); reduced oxygen consump-
scans over time.139,143,162,163 Pulmonary function- tion; increased dead space; increased minute
al parameters improved only when GGO re- ventilation for the level of oxygen consumption;
gressed on HRCT scans.143,163 Serial PFTs are high-frequency, low-tidal volume breathing pat-
more useful than serial CT scans to assess tern; and low O2 pulse.19,166,169
prognosis. In one study of 60 patients with IPF,
increasing extent of GGO on CT scans (.10% Impact of Physiologic Tests on Survival
increase from baseline) at 6-month follow-up was
associated with higher mortality whereas DCT- Not surprisingly, severe derangements in
fib score did not predict long-term survival.162 By PFTs or oxygenation predict a worse prognosis
multivariate analysis, decreases in FVC at 6 and lower survival rates.1,138,166,170–172 Survival is
months and UIP diagnosis were associated with worse in patients with severe impairments in
worse survival compared with patients who had vital capacity (VC) or DLCO. The 3-year mortality
stable or improved FVC or a histologic diagnosis rate exceeds 50% when VC falls below 60% of
of NSIP.162 Changes in CT-alveolar or CT-fib predicted or DLCO falls below 45% of pre-
scores did not contribute further information dicted.1,166 Changes in TLC are less predictive
once these factors were included in the multi- of survival.1,166 However, the prognostic value of
variate model. Given the potential for fibrosis to physiologic parameters at a single time point is
evolve over time, the value of CT scans in limited.92 Changes in pulmonary functional
predicting long-term prognosis is modest.16 parameters at 6 or 12 months have greater
prognostic value than baseline data.170,173–176
Physiology Deterioration in VC or DLCO at 6 or 12 months
predicts a higher mortality.170,173–176 Although
Characteristic physiologic aberrations in IPF optimal parameters to assess evolution of the
include reduced lung volumes (FVC and total disease have not been validated,177 the American
lung capacity [TLC]) consistent with a restrictive Thoracic Society (ATS) suggested changes in the
defect, normal or increased expiratory flow rates, following parameters could be considered sig-
impaired oxygenation, and impaired gas ex- nificant: 10% DFVC or TLC; 15% DDLCO; or
change.166 The DLCO is reduced, often dispropor- 4% DO2 saturation (SO2) or 4 mm in PaO2
tionately to other aberrations.166 The DLCO is an during exercise.2 In a retrospective study, serial
indirect reflection of the pulmonary vasculature; PFTs were performed in 80 patients with UIP and
reductions reflect destruction or loss of alveolar 29 patients with NSIP.162 Multivariate analysis
walls or capillaries. In nonsmokers with IPF, among IPF patients found that 10% decrease in
expiratory flow rates are preserved and the ratio FVC at 6 months was an independent risk factor
of FEV1 to FVC is increased. When emphysema for mortality (hazard ratio, 2.47; P ¼ .006).162
coexists, lung volumes (ie, FVC and TLC) are Change in DLCO or TLC at 6 months did not
preserved, and DLCO is disproportionately re- add independent prognostic value. Baseline
duced.144,167 The DLCO is more variable even alveolar-arterial gradient (PAO2 PaO2) was not
among individual patients. Normalizing the a predictor of survival. In a cohort of 81 patients
DLCO by the lung volume, yielding the DLCO/ with IPF,176 survival correlated with baseline
lung volume ratio, does not improve the predic- dyspnea scores and pulmonary functional pa-
tive value of DLCO and is not necessary.166 rameters (FVC percentage predicted,
Impaired oxygenation, which is accentuated with PAO2 PaO2), as well as changes in these param-
exercise, is a cardinal feature of IPF.19,166,168 Early eters at 6 or 12 months. Not surprisingly, survival
in the course of the disease, arterial PaO2 may be was worse among patients with deteriorating
preserved at rest, but invariably worsens with dyspnea scores or PFTs at 6 or 12 months.176
exercise. As the disease advances, hypoxemia at British investigators retrospectively reviewed the
rest is a nearly universal feature. Cardiopulmo- prognostic significance of histopathologic diag-
nary exercise tests (CPETs) reveal hypoxemia or noses, baseline PFTs, and serial trends in PFTs
widened alveolar-arterial oxygen pressure differ- (eg, FVC, FEV1, DLCO) at 6 and 12 months in 104

patients (UIP, n ¼ 63; fibrotic NSIP, n ¼ 37).173 Hypoxemia (at rest or exercise) is an inde-
Survival was better in fibrotic NSIP compared pendent predictor of mortality in IPF or fibrotic
with UIP (P ¼ .001) but not in patients with NSIP.19,168,173,180–182 The 6-min walk test (6MWT)
severe functional impairment. Mortality during with oximetry is a noninvasive and relatively
the first 2 years was linked solely to the severity inexpensive way to ascertain prognosis and need
of functional impairment at presentation (ie, for supplemental oxygen therapy and follow the
lower DLCO and FVC levels). The composite course of IPF.183 We performed 6MWT in 83
physiologic index (CPI) score (discussed later) patients with UIP and 22 patients with NSIP;
was the strongest determinant of outcome desaturation to 88% strongly correlated with
(P , .001).173 At 6 months, serial PFTs and mortality.168 Among patients with UIP, desatura-
histopathologic diagnosis were prognostically tion was associated with increased risk of death
equivalent.173 However, at 12 months, serial (hazard ratio, 4.2; P ¼ .01) after adjusting for age,
PFT trends (DLCO, FVC, FEV1, CPI) predicted sex, smoking, baseline DLCO, FVC, and resting
mortality better than any other covariates, in- SO2.168 Further, 6-min walk distance (6MWD)
cluding histologic pattern (all P , .0005). In this correlates with DLCO percentage predicted164,180
context, DDLCO provided the best prognostic and has prognostic value. In one study of IPF
information (2-year survival); histologic pattern patients awaiting LT, survival time was shorter
provided no additional prognostic value. How- among patients with 6MWD ,350 m.184 A
ever, for late deaths (beyond 3 years), mortality retrospective study in a cohort of 454 IPF patients
awaiting LT found that lower 6MWD was
was higher with UIP than with fibrotic NSIP.
associated with increased mortality (assessed at
Clinically significant changes in FVC and DLCO
6 months), and was superior to FVC percentage
have typically been considered as .10% and
as a predictor of mortality.180 Patients with
.15% from baseline, respectively.7 However, in
6MWD ,207 m had a more than fourfold greater
one cohort of IPF patients, even marginal
mortality than those with 6MWD 207 m, even
declines in FVC (5%–10%) at 6 months were
after adjustment for demographics, FVC percent-
associated with increased mortality.170 Compared
age predicted, pulmonary hypertension, and
with IPF patients with stable PFTs at 6 months,
medical comorbidities.180 Flaherty et al174 as-
mortality was higher in IPF patients experiencing
sessed the prognostic value of 6MWD and extent
a significant decline in FVC (.10%) (hazard ratio
of desaturation on 6MWT in a cohort of 197
[HR] 2.80, P , .001) as well as patients experi-
patients with IPF. By multivariate analysis,
encing marginal declines in FVC (5%–10%) (HR 6MWD was not a reliable predictor of mortality
2.31, P ¼ .01). By contrast, marginal declines in but the degree of desaturation during 6MWT had
DLCO (7.5%–15%) at 6 months did not provide greater prognostic value. Patients with arterial O2
useful prognostic information. What quantitative saturation (SaO2) 88% during their initial
changes in FVC or DLCO should be considered 6MWT had a median survival of 3.2 years
significant has not been tested in IPF.178 Howev- compared with 6.8 years for those with baseline
er, a review of 1,156 randomized IPF patients in SaO2 .88% (P ¼ .006).174 A study of 123 patients
two clinical trials noted that absolute change in with moderate IPF and baseline 6MWD between
percentage predicted FVC at 24 weeks was a 150 and 499 m noted that 6MWD remained
robust and reliable predictor of mortality.179 Risk relatively stable at 6 or 12 months compared with
of death at 1 year was nearly fivefold higher (HR baseline values.177 Abnormal heart rate recovery
4.78, P , .001) for patients with 10% decline in after 1 min of rest after the 6MWT may be a
percentage predicted FVC and more than two- powerful predictor of mortality.185 du Bois et
fold higher (HR 2.13, P , .001) in patients with al183 assessed the prognostic value of 6MWD in a
declines in percentage predicted FVC between cohort of 822 IPF subjects enrolled in the gamma-
5% and 10%.179 In fact, declines in percentage interferon (c-IFN) trial. A decline in 6MWD by
predicted FVC as low as 2% to 6% from baseline 50 m at 24 weeks was associated with a greater
were considered clinically important (ie, minimal than fourfold mortality risk at 1 year (HR 4.27).
clinically important difference). Although the prognostic value of 6MWT and
optimal parameters to follow have not been that study, it is likely that incorporating HRCT
clarified,5 du Bois et al183 suggested that in IPF scan data in place of chest radiographs would
patients, D6MWD of 24 to 45 m may be enhance the predictive value of such systems.
considered as minimal clinical important differ- Further, it can be argued that other parameters
ence. Formal CPET provides additional data (eg, FVC or DLCO) could be substituted in place of
including measurement of maximal oxygen TLC. British investigators developed a CPI
uptake (V̇O2), an integrated measure of respira- incorporating CT scans and physiologic param-
tory, cardiovascular, and neuromuscular func- eters.188 The CPI score evaluated disease extent
tion.186 Fell et al169 evaluated V̇O2 as a predictor observed by CT scans and selected functional
of survival in a cohort of 117 patients with IPF. variables (eg, percentage predicted FVC, DLCO,
Patients with baseline V̇O2 ,8.3 mL/kg/min had and FEV1). Exercise components were not in-
an increased risk of death after adjusting for age, cluded in this index. The CPI accounts for
smoking status, FVC, and DLCO. V̇O2 was a coexisting emphysema, which may confound
stronger predictor than desaturation ,88% of pulmonary functional indices. CPI predicted
6MWT. However, V̇O2 did not predict survival mortality better than PFTs or CT parameters in
when examined as a continuous variable. Fur- isolation. Further, the CPI was compared with
ther, CPET with arterial cannulation is invasive, the original187 or modified19 CRP scoring systems
is logistically difficult, is difficult to perform for in 30 patients with UIP who underwent exercise
some patients, and lacks practical value. testing. The CPI was a superior predictor of
outcome compared with the physiologic compo-
Clinical-Radiographic-Physiologic (CRP) Scoring nent of the original CRP score (P ¼ .02) and the
Systems physiologic component of the modified CRP
score (P ¼ .009). The CPI score is promising, but
Watters et al187 developed the CRP scoring may not be easily adapted into clinical practice
system, a composite score incorporating clinical settings. Additional studies using these or similar
(dyspnea), radiographic (chest radiographs), and CRP scoring systems would be of interest.
physiologic parameters to more objectively mon- Recently, a model predicting mortality was
itor the course of IPF. A modification of the CRP derived from a cohort of 1,099 IPF patients
score (arbitrary total of 100 points) was devel- enrolled in two clinical trials.172 Four predictors
oped; it predicted survival better than physio- (age, respiratory hospitalization, percentage pre-
logic or radiographic features alone.19 In one dicted FVC, and 24-week change in FVC) were
prospective study of 238 patients with UIP, a utilized to predict 1-year mortality. This scoring
comprehensive CRP score (obtained at the time system predicted 1-year mortality risk of 9.9% (vs
of initial visit) was used to predict survival.19 9.7% observed). These data have not been
Parameters included age; finger clubbing; smok- prospectively validated, but suggest that four
ing history; the extent of profusion of interstitial readily ascertainable predictors may be prognos-
opacities and pulmonary hypertension on chest tically useful.
radiographs; percentage predicted TLC; and PaO2
during maximal exercise. In addition, an abbre- What Is the Role of Sequential Physiologic
viated CRP score, excluding PaO2 during maxi- Studies To Follow UIP?
mal exercise, was applied. The comprehensive
CRP score was superior to the abbreviated CRP Sequential physiologic studies are critical to
score, but both scoring systems had excellent assess the evolution of the disease. I obtain serial
prognostic value. The modified CRP score measurements of FVC, DLCO, and 6MWT at 3- to
predicted 5-year survival with remarkable accu- 4-month intervals to follow the course of the
racy.19 Five-year survival rates at CRP scores of disease.1 The FVC is logistically easy to perform,
20, 40, 60, and 80 points were 89%, 53%, 4%, and relatively inexpensive, and less variable than
,1%, respectively. The abbreviated CRP was less TLC or DLCO. Thus, FVC is an ideal parameter to
accurate, but more adaptable to clinical practice. follow in individual patients. Because of inherent
Although HRCT scan data were not included in variability, serial changes in DLCO are less

reliable. Formal CPETs with arterial cannulation tive study evaluated 61 patients with IPF who
are inconvenient, are expensive, and lack practi- had RHC.192 Five-year survival was 83% among
cal value.1 Serial 6MWTs with oximetry are more patients with normal PAP and preserved DLCO
convenient and cost-effective for monitoring the (40% predicted) compared with only 16%
course of the disease and assessing the need for among patients with high PAP, low DLCO, or
supplemental oxygen. both (P , .001).192 Several investigators found
that the DLCO correlates with PAH, whereas FVC
PAH Complicating IPF or lung volumes do not.107,189,193–195
Screening for PAH among patients with IPF is
PAH and right ventricular (RV) dysfunction reasonable because it has prognostic value and
are common in IPF.106,189,190 The pathogenesis of may influence therapy. TTE is invaluable to
PAH in IPF is complex, and does not correlate assess RV size and function and estimate sPAP
with lung volumes or extent of pulmonary and is superior to chest CT scans as a predictor of
dysfunction.107,189,191–193 Pulmonary artery re- PAH.195 Severe RV hypertrophy, reduced RV
modeling and proangiogenic cytokines are likely function, and abnormal bowing of the interven-
central to developing PAH in IPF,189,191 but tricular septum on TTE reflect RV dysfunction.
ablation of pulmonary vessels and vasoconstric- TTE may allow estimation of sPAP, which has
tion may play contributory roles.189 In patients prognostic value. However, TTE has only modest
with advanced IPF, PAH was noted in 20% to predictive value for PAH.195,198,199 In one study
84% of patients.105–107,144,194,195 However, one of 106 patients with ILD, estimates of sPAP by
prospective study of IPF patients (all stages) TTE and RHC were discordant by .10 mm Hg in
noted PAH (mean pulmonary artery pressure 63% of patients.198 Accuracy improved when
[mPAP] .25 mm Hg by right heart catheteriza- sPAP was less than 45 mm Hg.198 We performed
tion [RHC]) in only 8.1%.192 One study of 44 TTE and RHC in 61 IPF patients; estimation of
patients with IPF awaiting LT found that mPAP RV systolic pressure (RVSP) was possible in 33
increased progressively over time (rate of change patients (54%).195 Using RVSP .40 mm by RHC
3.8 mm Hg/month in the entire cohort).190 as a cutoff, sensitivity and specificities for PAH
Baseline lung function, oxygen requirements, or were 76% and 38%, respectively. Exercise-in-
mPAP did not predict the rate of change in mPAP duced desaturation, reduced DLCO (,40% pre-
or which patients progressed to New York Heart dicted), or need for supplemental oxygen are
Association (class IV). surrogate markers for PAH in IPF.105,195 The
The presence of PAH is associated with FVC/DLCO ratio and O2 saturation (SO2) may be
markedly worse survival.105,107,144,192,196,197 In markers for PAH.105,195 In a cohort of IPF
one study, 88 patients with IPF had estimates of patients, a model incorporating FVC/DLCO ratio
systolic pulmonary artery pressure (sPAP) by and SO2 was superior to TTE (improved specific-
transthoracic echocardiography (TTE).105 sPAP ity and negative predictive value) in assessing
was elevated in 84% of patients and exceeded 50 PAH.195 DLCO did not contribute to mPAP
mm in 27 patients (31%). Median survival was prediction above and beyond SO2, whereas
significantly worse among patients with sPAP FVC/DLCO ratio did. In a cohort of 37 IPF
.50 mm Hg (0.7 years) compared with patients patients, Ghanem et al200 affirmed that the
with sPAP 35 mm Hg (4.8 years) or sPAP prediction model espoused by Zisman et al195
between 36 and 50 mm Hg (4.1 years). Other was highly predictive of estimated RSVP. RHC is
parameters associated with worse survival by the gold standard to diagnose PAH,199 but RHC
univariate analysis included male gender, lower is invasive and its role in patients with IPF is
DLCO, use of oxygen, coronary artery disease, and controversial. RHC is not necessary in IPF
worse New York Heart Association class.105 In patients when TTE is normal, but should be
another cohort of 79 IPF patients, 1-year mortal- considered when TTE suggests RV dysfunction
ity rates were 28% in those with PAH (defined as or PAH.
mean PAP .25 mm Hg by RHC) compared with Reduced 6MWT distance and elevated plas-
5.5% in those without PAH.107 Another prospec- ma brain natriuretic peptide (BNP) are surrogate
Table 1—Classification of IIPs
Histologic Pattern Clinical-Radiologic-Pathologic Diagnosis
Usual interstitial pneumonia Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis

Nonspecific interstitial pneumonia Nonspecific interstitial pneumonia (provisional)
Organizing pneumonia Cryptogenic organizing pneumonia
Diffuse alveolar damage Acute interstitial pneumonia
Respiratory bronchiolitis Respiratory bronchiolitis interstitial lung disease
Desquamative interstitial pneumonia Desquamative interstitial pneumonia
Lymphoid interstitial pneumonia Lymphoid interstitial pneumonia
Adapted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of Chest
Physicians; 2009.
markers of PAH and mortality in patients with thelin-1 (ET-1) receptor antagonists have been
pulmonary fibrosis or diverse ILDs.193,196,201 In used in small series and nonrandomized trials in
one study, 39 patients with pulmonary fibrosis IPF patients with PAH, but impact on long-term
and severe restrictive lung disease (FVC ,55% outcome has not been established.202 Trials
predicted) (including 28 with UIP) underwent assessing PAH-specific therapies in IPF with
RHC, measurement of BNP levels, and 6MWT.193 associated PAH are required to assess benefit.
Among 28 patients with IPF, elevated BNP
concentrations correlated with increased PAP
and pulmonary vascular resistance and correlat-
ed inversely with 6MWT distance. Importantly,
PFTs did not differentiate between patients with
normal and elevated PAP. Korean investigators
retrospectively analyzed 131 IPF patients who
had both TTE and plasma BNP measurements;
sPAP .40 cm H20 was used as the threshold for
PAH.196 Both PAH and elevated BNP were
independent predictors of mortality. One-year
mortality and mean survival rates were worse
among patients with PAH (61% and 10.8 months)
compared with 20% and 23.7 months among
patients without PAH. Prognosis was much
worse among patients with elevated BNP levels
compared with those with normal BNP levels (1-
year mortality 70.5% vs 23.7%, mean survival
11.0 months vs 22.5 months, respectively). The
combination of both PAH and BNP was a more
robust marker of mortality than either value
alone. In a cohort of 90 patients with diverse
ILDs, elevated BNP correlated with RVSP (on
echocardiography) and was associated with Figure 7. Top, UIP in open-lung biopsy specimen. Patchy
increased mortality (independent of age, sex, or subpleural fibrosis with dense scarring cause remodeling of
lung architecture. Note the marked heterogeneity (hema-
pulmonary function).201 These data193,196,201 sug- toxylin-eosin). Bottom, UIP in an open-lung biopsy speci-
gest that plasma BNP concentration may be a men. Fibrosis shows heterogeneity with dense eosinophilic
useful a noninvasive marker to screen for PAH. collagen and a loose FF. The adjacent lung is relatively
unaffected. These findings are consistent with UIP (hema-
The impact of treating PAH in patients with
toxylin-eosin). Reprinted with permission from ACCP
IPF has not been elucidated. Sildenafil (a phos- Pulmonary Medicine Board Review. 25th ed. Northbrook,
phodiesterase inhibitor), prostanoids, or endo- IL: American College of Chest Physicians; 2009.

Figure 8. IPF: open-lung biopsy specimen reveals end-stage
honeycomb lung. The large cystic airspaces represent
destroyed and coalescent alveolar septa. Minimal inflam-
matory cells are present at this late phase. Reprinted with
permission from ACCP Pulmonary Medicine Board Review.
25th ed. Northbrook, IL: American College of Chest
Physicians; 2009.
Histologic Features
The histologic pattern of UIP observed in

2,4
IPF can be found in other etiologies (eg, CTD,
asbestosis, and diverse occupational, environ-
mental, or drug exposures).2,5 Current recom-
mendations restrict the term IPF to patients with
idiopathic UIP.2,5 In 2002, the American Thoracic
Society (ATS) and the European Respiratory
Society (ERS) published a classification schema
recognizing seven idiopathic interstitial pneumo-
nias (IIPs): UIP, NSIP, organizing pneumonia,
AIP, RBILD, DIP, and LIP3 (Table 1). UIP is the
most common of the IIPs, comprising 47% to 71%
of cases; NSIP accounts for 13% to 48% of Figure 9. Top, DIP: open-lung biopsy specimen demon-
cases.2,10,95,108,203 Clinical, physiologic, and radio- strates extensive and diffuse filling of the alveolar spaces
graphic features of UIP and NSIP overlap; with alveolar macrophages. A single lymphoid aggregate is
present. The alveolar architecture is preserved. Center, DIP
further, fibrotic NSIP and UIP may be difficult showing dense aggregates of alveolar macrophages filling
to distinguish even by experienced patholo- the alveolar spaces. The alveolar walls are thickened, but the
gists.162,173,204,205 The remaining IIPs are less alveolar architecture is preserved. Fibrosis and honeycomb
cysts are absent. Bottom, DIP: dense aggregates of alveolar
common, and exhibit clinical features that are macrophages fill alveolar spaces (hematoxylin-eosin). Re-
in sharp contrast to UIP. Salient features of these printed with permission from ACCP Pulmonary Medicine
other IIPs are reviewed elsewhere (eg, DIP,8 Board Review. 25th ed. Northbrook, IL: American College of
RBILD,206 NSIP,10,207 AIP,208 COP,13 and LIP12).
The literature is confusing, however, as these
variants are often included in series of IPF, even UIP: The histologic diagnosis of UIP requires
though clinical, radiographic, and prognostic an SLB, preferably with wedge biopsies from two
features are disparate. Several of these entities or three sites.6,209 Care should be taken to avoid
are briefly discussed below. COP is discussed the worst areas (ie, advanced HC).6,209 Cardinal
elsewhere in this book. features of UIP that distinguish this entity from
other IIPs are temporal heterogeneity, profusion DIP: DIP is a histologic syndrome character-
of fibroblastic foci (FF), and HC.2,4 UIP exhibits ized by dense collections of alveolar macrophag-
both geographic and temporal heterogeneity. The es within airspaces (Fig 9), a homogeneous
lesions are bilateral but patchy, and exhibit a pattern, preserved alveolar architecture, and
striking predilection for the basilar and periph- minimal or absent fibrosis or honeycombing.8,212
eral (subpleural) regions of the lung. This A significant interstitial component is lacking
nonuniform distribution can be appreciated at and is overshadowed by the intra-alveolar
low-power magnification (Fig 7, top). In addition component. The striking heterogeneity and pe-
to geographic heterogeneity, the lesions also ripheral distribution characteristic of UIP are
exhibit temporal nonuniformity. Areas of active lacking in DIP. The uniformity of the lung lesion
injury, inflammation, and fibroblastic prolifera- in DIP suggests a reaction to an inhaled stimulus,
tion coexist with areas of dense (old) fibrosis. rather than persistent alveolar injury character-
Even within the same lobe, alternating zones of istic of UIP. More than 90% of patients with DIP
interstitial inflammation, fibrosis, HC, and nor- are smokers, suggesting that constituents of
mal lung can be observed. Alveolar walls are tobacco play a pathogenic role.8,212 Chest radio-
thickened by excessive collagen, extracellular graphs typically demonstrate reduced lung vol-
matrix, patchy mononuclear cell infiltrates (eg, umes and nonspecific linear or reticulonodular
lymphocytes, plasma cells), and fibroblasts interstitial infiltrates; in one-quarter of patients,
(FBs).2,4 Intra-alveolar macrophages may be bibasilar, hazy GGOs are present.8 HRCT scans
observed, but are not conspicuous. Scattered demonstrate diffuse GGO, often with bibasilar or
neutrophils or eosinophils may be present. These subpleural predominance; HC is absent.8 The
inflammatory changes are not prominent, and are average age of onset of symptoms for patients
usually confined to areas of collagen deposition with DIP is approximately 40 years.8,212 PFTs
or HC.4 The variability of UIP is also evident demonstrate a restrictive defect, with reduced
when the nature of the fibrosis is examined. DLCO.8,212 Prognosis is generally good, with long-
Zones of ‘‘old,’’ relatively acellular collagen term survival exceeding 90% at 5 years.8,212
bundles are interspersed with aggregates of Although most patients are treated with CSs,
actively proliferating myofibroblasts and FBs. spontaneous improvement may occur.8,212 Ces-
These aggregates, termed FF, develop in areas sation of cigarette smoking is mandatory. Most
of prior lung injury and are associated with patients improve or stabilize with CSs,8,212 but
active collagen synthesis. FF are not pathogno- progressive, even fatal, respiratory failure can
monic, but are necessary for the diagnosis of UIP ensue. The role of cytotoxic and other immuno-
(Fig 7, bottom).4 Small cystic radiolucencies suppressive agents has not been studied.
(termed honeycomb cysts) within the subpleural RBILD: RBILD, grouped with the IIPs, is
regions reflect irreversible scarring and architec- characterized by dense collections of pigmented
tural remodeling.4,210 HC is an essential and alveolar macrophages within respiratory bron-
often prominent feature of UIP, but is not specific, chioles but sparing the distal lung parenchy-
as HC may be a sequela of severe lung injury due ma.212,213 Honeycombing and severe fibrosis are
to diverse causes.3 In late phases of UIP, the lung not found. The pathologic lesion respiratory
architecture is destroyed and replaced by large bronchiolitis was originally described in an
cystic airspaces (remnants of previous alveoli) autopsy series of young cigarette smokers who
and dense scar. Such cases are termed end-stage died of nonpulmonary causes. The lesions were
fibrosis or honeycomb lung4 (Fig 8). Secondary subsequently termed small airways disease or
features include pulmonary hypertensive chang- smoker’s bronchiolitis. Histologic features over-
es, smooth-muscle hypertrophy and hyperplasia, lap with DIP, but DIP is more uniform and
type II pneumocyte proliferation and hyperpla- extensive than RBILD and exhibits a striking
sia, bronchioloectasis, and traction bronchiecta- intra-alveolar component.212 DIP and RBILD
sis. Subpleural fat and metaplastic bone reflect share common histologic features and occur
severe disease.211 Focal emphysematous blebs almost exclusively in smokers,213,214 suggesting
may be present in smokers. a common pathogenesis. Patients with RBILD are

ous 2- to 3-mm irregular peribronchiolar nod-
ules; GGOs or emphysema may also be
present.213 PFTs reveal reduced DLCO and mild
airflow obstruction; lung volumes are variable.212
The course of RBILD is indolent or stable, and
prognosis is generally excellent. However, data
are limited. Cessation of cigarette smoking is
essential.212 Improvement and even complete
resolution often occurs following cessation of
cigarette smoking.212 CSs are required in a
minority of patients. Late fibrosis or fatalities
are rare. However, British investigators identified
10 patients with RBILD from 1980 to 1998, seven
of whom were treated with prednisolone (com-
bined with azathioprine [AZA] or cyclophospha-
mide [CYC] in six).215 Despite cessation of
smoking and aggressive therapy, three deterio-
rated.
AIP: AIP (originally described by Hamman
and Rich in 1944) is a syndrome characterized by
rapidly progressive respiratory failure (often
within a few days) and histologic features of
diffuse alveolar damage on lung biopsy.11,208
Although this entity is distinct from IPF, some
patients with IPF develop an accelerated phase
and histologic features consistent with AIP.94
Clinical features of AIP include bilateral alveolar
infiltrates, an acute and rapid course, hypoxemic
respiratory failure requiring mechanical ventila-
tory support, extensive GGOs on HRCT scans, a
high mortality rate (.50%), and potential re-
sponsiveness to high-dose CSs.11,208 An acute
virallike prodrome often precedes the onset of
Figure 10. Top, NSIP: open-lung biopsy specimen shows AIP; fever is present in up to 50% of patients.11,208
patchy interstitial fibrosis that lacks the subpleural distri- Histologic features include hyaline membranes,
bution and temporal heterogeneity of UIP. Center, NSIP: fibrinous exudate, epithelial cell necrosis, and
open-lung biopsy specimen. The alveolar septa are thick- interstitial and intra-alveolar edema.94,208 As the
ened by fibrosis and interstitial chronic inflammation
(hematoxylin-eosin). Bottom, NSIP: open-lung biopsy spec- process organizes and undergoes repair, type II
imen. Prominent interstitial inflammation without dense cells proliferate along alveolar walls, hyaline
scarring is evident. Some pneumocytes are hyperplastic. membranes and airspace exudates resorb, and
These inflammatory features are consistent with the cellular
FBs proliferate within the alveolar interstitium
form of NSIP. Reprinted with permission from ACCP
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: and spaces. The histologic features of AIP are
American College of Chest Physicians; 2009. nonspecific, and are found with myriad disor-
ders including ARDS, inhalation or drug-in-
generally young (age ,45 years) and present duced injury, collagen vascular diseases, or
with mild symptoms of cough, dyspnea, or infections.94,208 Mortality rates with idiopathic
sputum production.213 Chest radiographs dem- AIP range from 50% to 88%.11,208 Although data
onstrate small irregular opacities or reticular or are limited, sustained and complete remissions
reticulonodular infiltrates, but are normal in up have been achieved with high-dose CSs.11,94,208
to 28% of patients.212 HRCT scans reveal numer- Patients surviving the initial episode may heal
with no sequelae or with variable degrees of Clinical Manifestations of NSIP
fibrosis.11,208 Recurrent, even fatal, episodes of
AIP may occur months or years after the initial Clinical manifestations of NSIP are similar to
episode.11 Although data are limited, and efficacy those of IPF, with bibasilar crackles, cough,
remains controversial,5 aggressive treatment dyspnea, interstitial infiltrates, reduced DLCO,
with high-dose IV pulse methylprednisolone is and a restrictive defect on PFTs.9,10,218 Because
reasonable for patients with AIP. clinical and radiographic features overlap with
NSIP/Fibrosis: In 1994, Katzenstein and Fior- IPF, it is highly likely that examples of NSIP were
elli216 proposed the term NSIP/fibrosis to de- included in historical series of IPF. However,
scribe lung biopsies from immunocompetent NSIP and IPF differ in several important respects.
patients with clinical syndromes resembling IPF The onset of NSIP may be subacute (evolving
but with histologic features distinct from UIP, over a few weeks), whereas IPF evolves over
DIP, RBILD, AIP, or LIP.4 An inciting cause was years).9 Fever, noted in one-third of patients with
not identified in most patients, but some had NSIP, is not found in IPF. Clubbing is found in
underlying CTD, drug reactions, or HP.216 In the 10% to 40% of patients with NSIP, but in 66% to
sentinel report,216 the prognosis of NSIP was 93% of patients with IPF.1,218 Compared with
distinctly better than IPF. An international ATS/ patients with IPF, patients with NSIP are youn-
ERS consensus statement on the classification of ger, and there is a slight female predominance in
IIPs published in 2002 recognized NSIP as a NSIP.10,207 BAL lymphocytosis is common in
NSIP,175 but rare with IPF. However, significant
distinct histopathological pattern found in re-
overlap exists between NSIP and IPF.219 HRCT
sponse to occupational exposures or CTD or as
features of NSIP and IPF/UIP differ.220 Bilateral
an idiopathic form.3 NSIP likely represents a
GGOs are characteristic in NSIP, but rare in IPF/
stereotypic response to diverse injuries or toxins.
UIP.221 HC, a cardinal feature of UIP, is absent or
The relationship between NSIP and UIP remains
sparse in NSIP.14 Most importantly, the prognosis
uncertain.4,10
of NSIP is much better than that of IPF/UIP.10
Some patients with NSIP improve either sponta-
Histopathology of NSIP
neously or in response to CS or immunosuppres-
sive therapy. In striking contrast, improvement is
Salient histologic features of idiopathic NSIP
rare in IPF (,10%), even with aggressive
included varying degrees of inflammation and
therapy.1,9,18,222 In several early studies, 5-year
fibrosis that are temporally uniform, that is,
survival with NSIP exceeded 70%, compared
occurring over a single time span (Fig 10).216
with ,30% with IPF.95,108,211 It is likely that many
The temporal uniformity in NSIP suggests a patients in earlier publications labeled as IPF but
response to a single insult. Scattered foci of manifesting GGO on HRCT scans, BAL lympho-
organizing pneumonia are noted in nearly 50% of cytosis, or ‘‘steroid responsiveness’’ in fact
patients; prominent accumulation of intra-alveo- represented cases of NSIP.223–225 Subsequent
lar macrophages (mimicking DIP), is observed in studies suggest that the designation NSIP is
one-third of cases.216 The key histologic feature excessively broad.9,10 Segregation by histologic
distinguishing NSIP from UIP is its temporal features into cellular interstitial pneumonia (cel-
uniformity.10,217 In NSIP, the lesions appear to be lular NSIP) or fibrotic forms of NSIP identifies
of similar age, whereas in UIP, both recent and patient subsets with differing prognoses.10 Pa-
old lesions are present concomitantly.4 Varying tients with the cellular form have more GGOs
degrees of fibrosis and inflammation are ob- and less honeycombing on HRCT scans, a higher
served in NSIP and UIP, but honeycombing, a rate of CS responsiveness, and lower mortality
prominent feature of UIP, is rare in NSIP.4,10 UIP rates.10 Although NSIP has a better prognosis
is characterized by heterogeneity, greater de- than IPF, mortality with fibrotic NSIP is high.
struction of the alveolar architecture, extensive British investigators followed 28 patients with
fibrosis, and minimal intra-alveolar inflamma- idiopathic NSIP up to 10 years after SLB.226 At a
tion.4 median follow-up of 42 months, 17 patients

(61%) had died; median survival was only 52 increasingly been used in lieu of SLB to diagnose
months. These data suggest that earlier studies UIP/IPF.5,18,164 However, SLB remains the gold
citing survival rates .90% with NSIP108 were standard for the diagnosis of UIP and assessment
overly optimistic. Similarly, a retrospective re- of prognosis.4 The role of SLB in clinical practice
view of 104 patients with IPF reclassified 61 is threefold: (1) to rule out other etiologies; (2) to
patients as having UIP and 43 (41%) as having better define the pattern of IIP (primarily UIP vs
fibrotic NSIP.173 At a median follow-up of 32 NSIP); and (3) to better define prognosis. VATS is
months, 25 of 43 NSIP patients (48%) had died, vs less invasive than open lung biopsies, and
48 deaths among 61 patients with UIP (79%). provides adequate histologic material.6,232 Tissue
Furthermore, the prognosis of fibrotic NSIP should be obtained from at least two sites (eg,
patients with severe functional impairment is upper and lower lobes of the same lung);
poor. Among NSIP patients with DLCO ,35% representative areas should be sampled (ie, avoid
predicted, 3-year survival was ,50%.173 Korean normal or very fibrotic areas).104,108,204,232 Specific
investigators cited 5-year survival rates of 56% histologic features or subtypes of IIPs have
among 48 patients with fibrotic NSIP and 34% prognostic value.108,226,232 Establishing the histo-
among 131 patients with UIP.175 Early studies logic diagnosis of UIP is a strong predictor of
cited favorable responses to CSs (alone or increased mortality and poor response to therapy
combined with immunosuppressive agents) in when compared with other IIPs.95,104,108 In one
60% to 83% of patients,211,221,227,228 whereas prospective study, long-term survival was worse
subsequent studies cited lower response rates in patients with greater degrees of FF, whereas
(25%–40%).108,158,226 Short-term (ie, 2-year) sur- the degree of alveolar cellularity or alveolar wall
vival rates underestimate long-term mortality fibrosis did not affect survival.232 In a cohort of 53
associated with NSIP.173,175,226 Additional studies patients with UIP, British investigators confirmed
are required to further elucidate the clinical that increasing FF correlated with mortality
features, outcomes, and rate of progression (P ¼ .006) and declines in FVC and DLCO at both
associated with NSIP and histologic subsets (eg, 6 and 12 months.222 Neither the extent of
cellular or fibrotic forms). established fibrosis nor intra-alveolar macro-
phage accumulation correlated with outcome.222
SLB In contrast, in a cohort of 99 patients with
idiopathic UIP, the extent of FF, established
The optimal staging and role of SLBs in IPF fibrosis, or intra-alveolar macrophage accumula-
are controversial. Video-assisted thoracoscopic tion did not predict survival.233 Another study of
surgical (VATS) lung biopsies are required to 43 patients with IPF found no relationship
establish the diagnosis of UIP unequivocally,6,229 between profusion of FF on SLB and survival.234
but many clinicians are reluctant to subject Variation in histologic features in individual
patients to the morbidity of surgery, particularly patients limits the prognostic accuracy of even
when therapeutic options for IPF are of limited SLB.104,203,204 Although SLB is touted as a gold
value. Although VATS is relatively safe, AE in standard, a minute fraction of the lung paren-
respiratory status was noted in 2.1% of 236 chyma is sampled. Evaluation of SLB is subject to
patients undergoing SLB for ILD.230 Further, interobserver and intralobar variation, even by
SLB was associated with rapid deterioration in expert pulmonary pathologists.104,204,226 Further,
respiratory status (consistent with AEs) in 3% to discriminating UIP from fibrotic NSIP is diffi-
4% of patients with idiopathic NSIP or CTD- cult.226 More importantly, foci of UIP and NSIP
associated ILD.231 Despite these caveats, SLB can may be found in individual patients.104,203 A
be justified in otherwise stable patients given the confident diagnosis of UIP or NSIP may be
potential for serious toxicities associated with difficult to make, particularly by pathologists
aggressive immunosuppressive therapy and the lacking expertise in pulmonary histology. Impor-
prognostic value of SLB. Clinical surveys have tantly, HRCT scans may corroborate the diagno-
found that SLB is performed in less than one- sis of UIP, provided that radiographic features
third of patients with IPF.164 HRCT scans have are classic.16 Further, the extent and pattern of
changes on HRCT scans have prognostic val- inflammation (alveolitis) in IPF and other inflam-
ue.140,164 Although the decision to perform VATS matory pulmonary disorders. However, even
lung biopsy should be individualized, we favor with careful quantification, 67Ga scans failed to
VATS biopsy (if no contraindications exist) in predict responsiveness to therapy.167Ga scans are
patients with recent onset of ILD of unknown expensive and inconvenient, and have no prac-
cause when transbronchial lung biopsies (TBBs) tical value. Clearance of 99Tc-DTPA aerosol is
are nondiagnostic. However, VATS biopsy is not accelerated in IPF and is a marker of increased
warranted in patients who have a prolonged lung permeability.240,241 However, increased
course (.2 years) and clinical, physiologic, and clearance of DTPA occurs in smokers and
HRCT features that are characteristic of IPF/UIP. patients with other inflammatory lung disorders;
Moreover, the risk of VATS lung biopsy is its clinical value is doubtful.241 Increased meta-
excessive in elderly (.70 years old) or debilitated bolic activity may be noted by PET scans in
patients, particularly when clinical and HRCT patients with IPF.163 At present, radionuclide
features strongly suggest UIP. In patients with imaging studies have no role in the management
ILD but without honeycombing on HRCT scans, of IPF.
increasing age and higher average total HRCT
scans interstitial score support the diagnosis of Pathogenesis
IPF (as opposed to other ILDs); by contrast, PFTs,
6MWT, presence of desaturation, or gender were The pathogenesis of IPF is complex and likely
not discriminative.235 Bronchoscopy with TBBs is involves myriad components including repetitive
most useful to diagnose alternative causes of ILD lung injury (particularly to AECs), destruction of
(eg, sarcoidosis, Langerhans cell granulomatosis, subepithelial basement membranes, inflamma-
pulmonary alveolar proteinosis [PAP], lymphan- tion, cytokines and chemokines, exaggerated
gitic carcinomatosis, COP). However, because of deposition of collagen and extracellular matrix,
the small sample size (2–5 mm), TBBs cannot recruitment and proliferation of FBs, inappropri-
substantiate the diagnosis of UIP, DIP, or NSIP ate wound-healing response, and excessive an-
and cannot be used to assess the extent of giogenesis.242 The fibrotic/inflammatory process
inflammation or fibrosis. in UIP has been likened to ‘‘abnormal wound
healing,’’243 with a vigorous fibroblastic response
BAL to AEC injury. Injury of AECs and destruction of
the subepithelial basement membranes lead to
BAL is useful to exclude alternative etiologies local recruitment, differentiation, and prolifera-
that may mimic IPF (eg, specific infections such tion of FBs.242 Excessive deposition of collagen
as Pneumocystis jirovecii, Mycobacteria, and fungi; and extracellular matrix contributes to the
PAP; and LCG),236 but has no role to diagnose or fibrotic process.242,244 A complex interplay be-
stage IPF.219,237 Increases in polymorphonuclear tween inflammatory and mesenchymal cell pop-
leukocytes, mast cells, alveolar macrophages, ulations amplifies and perpetuates the fibrotic
and myriad cytokines are noted in BAL fluid response.242,244 Early theories of pathogenesis
from patients with IPF; lymphocyte numbers are suggested that a heightened inflammatory re-
usually normal.237,238 However, BAL cell profiles sponse led to injury and fibrosis. Current theories
in IPF do not predict prognosis or therapeutic suggest a primary role for FB dysregulation;
responsiveness.2,237 BAL has yielded significant inflammatory cells may play a contributory,
insights into the pathogenic mechanisms respon- albeit minor, role.242,244 Soluble mediators (cyto-
sible for IPF, but BAL is of doubtful clinical value kines) produced by FBs and AECs amplify and
in assessing the extent or activity of IPF.237,239 perpetuate the fibrotic response. TGF-b likely
plays a critical role in IPF.242,244 Other cytokines
Radionuclide Scans that appear to be involved in the pathogenesis
include TNF-a, platelet-derived growth factor,
Historically, gallium (67Ga) citrate scanning connective tissue growth factor, IL-8, and CXC
was used as a surrogate marker of alveolar chemokines.242,244 Other possible mediators of

the fibrotic process in IPF include integrin- progressing IPF (symptoms .24 months) and
mediated intercellular adhesion molecule 1, 26 patients with the rapid variant (symptoms ,6
vascular cell adhesion molecule 1, surfactant months). Two genes, adenosine 2B receptor and
proteins, proteases, leukotrienes, oxygen radi- prominin-1/CD133, were expressed more strong-
cals, and myriad soluble mediators.1,242,243 Rela- ly in the rapid group. It is evident that the
tive deficiency of c-IFN, a cytokine that inhibits pathophysiology of IPF is complex, with diverse
collagen synthesis and fibrosis, may contribute to cell types/mediators participating in the initia-
the fibroproliferative process.1 The signals re- tion, orchestration, perpetuation, and evolution
sponsible for initiating and perpetuating this of the inflammatory/fibrotic process. Unfortu-
process are not known. However, the so-called FF nately, as will be discussed in greater detail
in IPF/UIP may be the leading edge of the below, therapeutic strategies designed to ablate
inflammatory/fibrotic process.4 Further, AEC inflammatory responses have had little or no
death is most prominent immediately adjacent impact on the outcome of IPF/UIP. In light of
to FF.242,244 Mesenchymal cells that form FFs in this, novel therapies targeted against FB prolif-
IPF/UIP are activated and display a contractile eration or other profibrotic mediators are being
phenotype, commonly referred to as myofibro- investigated (discussed later).
blasts.242,244 Myofibroblast differentiation and
fate are controlled by soluble growth factors Therapy
such as TGF-b1 and matrix-derived signals.244
Myofibroblasts in the lung in IPF may be derived Management of patients with IPF is frustrat-
from extrapulmonary fibrocytes and bone mar- ing, because the disease progresses inexorably
row-derived progenitor cells.245 Under the influ- and treatment has not been shown to alter the
ence of TGF-b1, myofibroblasts display increased natural history of the disease.1,5,18 Initial treat-
production of collagen, vimentin, beta-actin, and ment strategies, based upon the concept that
tissue inhibitors of metalloproteinases.1 This inflammation was a key factor in the pathogen-
leads to a bias towards excessive matrix produc- esis of IPF, utilized high-dose CSs and/or
tion and wound contraction in UIP. Additionally, immunosuppressive agents.224,232 However, ran-
a proangiogenic environment may favor fibrosis domized controlled trials (RCTs) were not per-
in IPF.1 IL-8 and c-IFN-inducible protein 10 (IP- formed. Several early studies cited response rates
10), members of the CXC chemokine family, of 10% to 30% with CSs, but these studies
affect fibrosis via angiogenic mechanisms.244 IL-8 included a mix of histologic entities (eg, UIP,
stimulates neovascularization whereas IP-10 in- DIP, RBILD, NSIP, HP), and cannot be extrapo-
hibits angiogenesis. In humans with IPF, IL-8 is lated to UIP. Studies that included only patients
markedly elevated in BAL fluid and serum,1 with UIP cited response rates of 0% to
whereas IP-10 levels in IPF lung biopsies were 17%.95,158,226 Importantly, a survival benefit with
reduced compared with control subjects.246 High CS therapy has not been demonstrated.5,9,17,18,232
plasma concentrations of biomarkers (ie, matrix Unfortunately, CSs are associated with a plethora
metalloproteinase-7, integrin-mediated intercel- of adverse effects, particularly in elderly or
lular adhesion molecule 1, IL-8, vascular cell debilitated patients.248 Given the significant
adhesion molecule 1, and S100A12) predicted toxicities, high-dose CSs should not be used to
poor overall survival in a cohort of 241 IPF treat IPF. Similarly, immunosuppressive or cyto-
patients.247 These assays are available only in toxic agents have not been shown to influence
research laboratories, but are promising markers mortality or clinical outcomes.1,18,93,249–251 Anec-
in the future to predict outcomes in IPF patients. dotal responses to AZA251,252 or CYC253 were
Genetic factors may be important in the patho- noted in early studies, but the preponderance of
genesis of the disease and its clinical expres- data suggest that these agents are ineffective as
sion.50 Differences in gene expression may therapy for IPF.1,18,93,249,250 Several large retro-
influence the severity and course of the dis- spective studies failed to document survival
ease.50,81 Selman et al81 examined gene expres- benefit with any form of therapy.17,18,232 In fact,
sion profiles in 88 patients with slowly as will be discussed below, the use of AZA plus
prednisone may increase mortality in IPF pa- ment may be offered to patients with severe
tients. symptoms and a declining course, provided that
the pros and cons of therapy are discussed
Expert Consensus Statements and honestly. We emphasize to patients that no
Recommendations for Therapy therapy has been proven to influence survival
or clinically important outcomes. N-acetylcyste-
An international consensus statement en- ine (NAC) is the most reasonable option, given
dorsed by the ATS and the ERS published in its lack of serious adverse effects. I do not
2000 concluded that existing therapies were of recommend high-dose prednisone as therapy
unproven benefit but acknowledged that physi- for IPF, because adverse effects outweigh bene-
cians may wish to treat patients with deteriorat- fit.248 Despite early anecdotal reports of apparent
ing disease.2 For patients who desire treatment, favorable responses to AZA,251,252 this agent
that statement recommended a trial (up to 6 (particularly when combined with CS) may have
months) of either oral AZA (2–3 mg/kg/d) or deleterious effects in patients with IPF. A NIH-
oral CYC (2 mg/kg/d) plus prednisone (0.5 mg/ sponsored trial randomized patients to one of
kg/d for 4 weeks, with subsequent taper).2 For three arms: (1) AZA þ low-dose prednisone
patients unable to take CS, AZA or CYC alone (pred) þ NAC, (2) NAC alone, or (3) placebo
were suggested. This approach represented a alone (http://clinicaltrials.gov/ct2/show/
substantial departure from earlier regimens NCT00650091). The triple-drug arm was stopped
advocating much higher doses of CS.224,251 This because of heightened mortality and morbidity
consensus statement represented expert opinion compared with IPF patients receiving placebo or
but was not validated in clinical trials. In 2011, an NAC alone. Compared with placebo, higher rates
international consensus statement endorsed by of mortality (11% vs 1%), hospitalizations (29% vs
the ATS, ERS, Japanese Respiratory Society, and 8%), and serious adverse effects (31% vs 9%)
Latin American Thoracic Association was pub- were noted in the triple therapy (AZA þ pred þ
lished,5 intending to replace the 2000 ATS/ARS NAC) cohort; further, PFTs did not improve in
statement. In this updated statement, ‘‘the com- the triple therapy cohort. CYC has potentially
mittee felt the preponderance of evidence to date serious toxicities,255 and I do not utilize CYC for
suggests that pharmacologic therapy for IPF is IPF. Mycophenolate mofetil (MMF) and other
without definite, proven benefit.’’5 In brief, the immunosuppressive agents have been utilized by
committee recommended against using CS some clinicians,256,257 but these agents have not
monotherapy, combined CS and immune-modu- been evaluated in clinical trials.
lator therapy, colchicine, cyclosporine A (CsA), c- In contrast to the dismal responses noted
IFN, bosentan, or etanercept. Evidence support- with immunosuppressive or cytotoxic therapy in
ing other strategies (eg, acetylcysteine [alone or IPF/UIP, favorable responses to CS (alone or
combined with AZA and prednisone], anticoag- combined with AZA) have been noted with NSIP
ulation, or pirfenidone) was weak, and these (particularly cellular variants).207,218 For NSIP
should not be used in most patients with IPF (either cellular or fibrotic), I treat with CS and
‘‘but may be a reasonable choice in a minority.’’ AZA for a minimum of 6 months. Patients failing
There was strong evidence supporting LT in or intolerant of AZA may be switched to MMF or
appropriate patients. CYC, but published data in this regard are
lacking.
My Recommendations for Therapy for IPF
Novel Therapeutic Options
Given the lack of survival benefit, and
potentially serious toxicities of CS or immuno- TNF-a antagonists (eg, etanercept and inflix-
suppressive therapy, I do not recommend these imab) have been tried in some cases of pulmo-
agents for IPF. LT is the preferred option for nary fibrosis (idiopathic and CTD-associated),
patients with severe IPF (unless contraindica- but data are unimpressive. In a prospective,
tions exist).254 However, pharmacologic treat- multicenter trial, 84 patients with IPF were

randomized to etanercept (twice weekly) or controversial. Nonetheless, NAC is inexpensive
placebo.258 At 48 weeks, there were no significant and has few side effects, making this an attractive
differences in primary endpoints (physiological option for IPF. A multicenter RCT sponsored by
parameters) between groups, but trends favoring IPFnet is currently underway to address the
etanercept were observed in some secondary impact of NAC in IPF.
endpoints.258 Anecdotal responses to infliximab Pirfenidone: Pirfenidone (5-methyl-1-phenyl-
were noted in case reports of CTD-associated 2-[1H]-pyridone) attenuates pulmonary fibrosis
pulmonary fibrosis.259,260 However, TNF-a an- in animal models, reduces synthesis of collagen I
tagonists are expensive and have serious poten- and III and TNF-a, inhibits TGF-b-stimulated
tial toxicities.257,260 Currently, these is no role for collagen synthesis, decreases extracellular ma-
these agents as therapy for IPF. trix, and blocks the mitogenic effect of profibrotic
Novel and Future Therapies: Major advances cytokines.265 Initial open label trials in IPF266,267
await the development of novel therapies that suggested that pirfenidone may slow the rate of
prevent fibroproliferation and enhance alveolar decline in the disease, but data were inconclu-
re-epithelialization.244 Agents that have been sive. Further, in a cohort of 11 patients with
tested in pilot studies include interferons, NAC, pulmonary fibrosis complicating Hermansky-
and pirfenidone (5-methyl-1-phenyl-2-[1H]-pyr- Pudlak syndrome (HPS), pirfenidone was asso-
idone) (discussed below). ciated with a slower rate of decline in PFTs (ie,
c-IFN: c-IFN is an endogenous cytokine that FVC, FEV1, DLCO) compared with 10 patients
down-regulates expression of TGF-b and may receiving placebo.268 However, a subsequent
have antifibrotic effects.244 Initial studies employ- RDBPC study in the United States that enrolled
ing recombinant c-IFN were encouraging,261,262 35 patients with HPS-associated pulmonary
but the INSPIRE trial, which randomized 800 fibrosis to pirfenidone (n ¼ 23) or placebo
patients with mild to moderate IPF to recombi- (n ¼ 12) found no differences between groups
nant c-IFN or placebo in a 2:1 ratio, showed no in the primary endpoint (rate of decline in FVC)
benefit. The study (conducted at InterMune, or secondary outcome measures.269 The study
Brisbane, CA) was ended because of ‘‘futility’’ was terminated because of futility. To date, 4
in March 2007. There is no role for c-IFN as RPCDB trials evaluating pirfenidone for IPF have
therapy for IPF.5 been published, but results are inconclusive. In
NAC: NAC is an antioxidant that stimulates 2005, Azuma et al270 reported a cohort of 107
glutathione synthesis, attenuates fibrosis in ani- patients with IPF randomized to pirfenidone or
mal models244 and augments glutathione levels placebo (2:1 ratio). That study was stopped
in BAL in IPF patients. A phase III multicenter, prematurely because AEs were noted in five
double-blind, placebo-controlled trial (IFIGE- patients receiving placebo (14%) compared with
NIA) in Europe evaluated the efficacy of oral no cases in the pirfenidone group. The primary
NAC in IPF.263 In this study, all patients received endpoint (change in lowest O2 saturation on
conventional therapy with prednisone (0.5 mg/ 6MWT over 6 or 9 months) was not met. There
kg/d, with taper) plus AZA (2 mg/kg/d). were no significant differences between groups
Patients were then randomized to oral NAC in mortality, TLC, DLCO, or resting PaO2. The rate
(1,800 mg/d) or placebo. At the end of 1 year, of decline in VC at 9 months was lower in the
PFTs had deteriorated in both cohorts. However, pirfenidone group (P ¼ .037) but differences
the rates of decline in FVC and DLCO were less in between groups were small and of doubtful
patients receiving NAC (P , .05).263 However, clinical significance. A larger study in Japan
these changes in PFTs were small (absolute randomized 275 IPF patients to placebo, high-
difference in FVC of 4.8% and in DLCO of 5.1%). dose, or low-dose pirfenidone (2:2:1 ratio) for 52
Assessment of the IFIGENIA supports a small weeks.271 Minor but statistically significant dif-
favorable effect of NAC on VC, DLCO, and CPI ferences in decline in VC at 52 weeks were noted
index; this effect was not evident in patients with among groups (0.16 L in placebo; 0.09 L, high-
more severe disease (CPI .50).264 The benefit (if dose pirfenidone; 0.08 L, low-dose pirfenidone).
any) of NAC as therapy for IPF remains No differences in mortality, rate of AEs, or
oxygenation were noted.271 Two concurrent mm Hg) or concomitant PAH were excluded. At
placebo-controlled DBRCT evaluating pirfeni- 12 months, the 6MWT worsened in both groups
done as therapy for IPF (CAPACITY-1 [study (no significant differences between groups).
004] and CAPACITY-2 [study 006]) were com- Mean changes from baseline in FVC at 12 months
pleted, with mixed results. 272 Both studies were 6.4% and 7.7% in the bosentan and
enrolled patients with mild to moderate IPF. In placebo groups, respectively. Mean changes from
study 004, 435 IPF patients were randomized as baseline in DLCO at 12 months were 4.3% and
follows: pirfenidone 2,403 mg/day (n ¼ 174); 5.8% in the bosentan and placebo groups,
pirfenidone 1,197 mg/day (n ¼ 87); placebo respectively. A trend in favor of bosentan was
(n ¼ 174). In this study, the decline in mean noted in the secondary endpoint of time to death
FVC at 72 weeks was less in patients receiving or disease progression (HR 0.63, P ¼ .12) and
pirfenidone (8.0%) compared with placebo quality of life (QOL) and dyspnea scores.274 In a
(12.4%). In study 006, patients were randomized larger study, patients with mild to moderate IPF
to pirfenidone 2403 mg/day (n ¼ 171) or placebo were randomized to bosentan (n ¼ 407) or
(n ¼ 173). The rate of change in FVC at 72 weeks placebo (n ¼ 209) for 12 months.275 Criteria for
was not significantly different between groups inclusion in that study included disease duration
(pirfenidone [9.0%]; placebo [9.6%]). In both ,3 years, SLB confirmation, and lack of extensive
studies, no significant differences were noted honeycombing on CT scans. No significant
between pirfenidone or placebo groups in sec- difference between groups were observed in the
ondary endpoints (eg, change in DLCO, dyspnea, primary endpoint (time to IPF worsening or all-
SO2 during 6MWT, time to worsening IPF, or cause death); further, no treatment effects were
fibrosis by HRCT scan). Overall mortality rates in noted on health-related QOL or dyspnea.275 A
both studies were 6% with pirfenidone and 8% subsequent RDBCT assessing ambrisentan (an-
with placebo. Although the authors concluded other ET-1 receptor antagonist) was stopped
‘‘pirfenidone has a favourable benefit-risk profile because of futility. Given these negative results,
and represents a suitable treatment option for ET-1 antagonists have no routine role as therapy
patients with idiopathic pulmonary fibrosis,’’272 for IPF. ET-1 antagonists could have a role in IPF
the changes in FVC between groups were small, patients with secondary PAH, but this has not
and I believe that the clinical benefit of pirfeni- been studied.
done has not been established. At present, these Phosphodiesterase-4 Inhibitors: Sildenafil, a
various studies266–268,270–272 are insufficient to phosphodiesterase-4 inhibitor, is effective thera-
assess the impact of pirfenidone on the course py for idiopathic PAH.276 Data regarding silde-
of IPF. Pirfenidone was approved for use in Japan nafil for PAH complicating IPF are limited to
and in the European Union (in December 2010) anecdotal cases and small series. In an open-label
but the FDA denied approval in May 2010, and RCT, 16 patients with PAH secondary to pulmo-
requested another clinical trial to assess the nary fibrosis underwent RHC to assess the acute
impact of pirfenidone (in progress). hemodynamic effects of vasodilators.277 Eight
ET-1 Receptor Antagonists: ET-1, a potent patients received sildenafil (50 mg oral dose) and
pulmonary vasoconstrictor, displays profibrotic eight received maximal tolerated dose of IV
effects and may play a role in the pathogenesis of epoprostenol. Pulmonary vascular resistance fell
IPF.273 Bosentan, an ET-1 receptor antagonist, equally in both groups: epoprostenol (36.9%);
reduced collagen deposition in animal models sildenafil (32.5%). Importantly, epoprostenol
(bleomycin-induced pulmonary fibrosis). 273 increased intrapulmonary V/Q mismatching
However, two DBRCT trials (ie, Bosentan Use whereas sildenafil maintained V/Q matching
in Interstitial Lung Disease [BUILD-1274 and and improved PaO2. However, this study only
BUILD-3275]) failed to show efficacy in patients assessed parameters 60 min after ingestion of
with IPF. In the first study, 158 IPF patients were sildenafil. Long-term effects of sildenafil in
randomized to bosentan or placebo.274 Patients patients with ILD (with or without PAH) are
with severe pulmonary dysfunction (FVC ,50% not known. Anecdotal responses were noted in
predicted, DLCO ,35% predicted, or PaO2 ,55 small series of patients with IPF and PAH,278 but

these data are inadequate to assess the role of group. Additional studies assessing BIBP 1120
sildenafil for patients with ILD. In one RDBPC are required to assess benefit (if any) with this
study, 29 patients with moderate IPF were agent. Mediators such as TGF-b, TNF-a, platelet-
randomized to placebo (n ¼ 15) or sildenafil derived growth factor, and other profibrotic
(n ¼ 14).279 At 6 months, 6MWT distance or cytokines may be involved in the pathogenesis
dyspnea scores were similar among groups.279 of IPF-associated PAH.189,286 Therapies targeting
In a multicenter trial, 180 IPF patients were specific cytokines are worthy of study, but data
randomized to sildenafil or placebo for 12 weeks, are lacking.
followed by open-label sildenafil for another 12 LT: LT is the best therapeutic option for
weeks.280 No differences were noted in the patients with severe IPF.254,287–290 Early listing
primary endpoint (20% improvement in for LT is urged in patients with progressive IPF,
6MWT distance). There were small, but statisti- because the waiting time for procuring donor
cally significant, differences in arterial oxygena- organs may exceed 2 years. Patients with severe
tion, DLCO, degree of dyspnea, and QOL favoring functional impairment (eg, FVC ,60% predicted,
sildenafil, but these changes were small and of DLCO ,40% predicted), oxygen dependency,
doubtful clinical significance. Sildenafil has no and/or a deteriorating course should be referred
role as routine therapy for IPF, but has possible, promptly for LT. The decision as to when to list
albeit untested, utility in the subset of IPF should be left to the transplant center, according
patients with secondary PAH. to local waiting times. Unfortunately, many
patients with severe IPF die while awaiting
Anticoagulants organs.
Data from the International Society of Heart
Inflammation and vascular injury in IPF may and Lung Transplantation evaluated .32,000
lead to a prothrombotic state that could exacer- lung transplant recipients worldwide from 1989
bate lung injury.281 Japanese investigators ran- through June 2009, of whom 22% had IPF.291
domized 56 IPF patients to anticoagulants Survival rates at 3 months post-LT were as
(warfarin) or placebo.282 Three-year survival follows: IPF (85%), idiopathic PAH (76%), cystic
and freedom from AEs were improved in the fibrosis (90%), and COPD (91%).291 Among
anticoagulated group. However, a multicenter patients surviving to 1 year, IPF and COPD had
RDBPCT in the United States was terminated the worst long-term survival, most likely reflect-
because of higher adverse effects in IPF receiving ing older age and comorbidities.291 Survival rates
warfarin compared with placebo. Given the risk, at 1, 3, and 5 years (all indications) were 79%,
anticoagulants have no role as therapy for IPF. 63%, and 52%, respectively.291 Importantly, sur-
Novel (Future) Agents: Unfortunately, current vival rates were lower in older recipients.
therapies for IPF are of unproven efficacy. Novel Survival rates at 1 and 5 years were 73% and
agents with potential antifibrotic properties have 36% in recipients aged older than 65 years,
theoretical value but have not yet been evaluated compared with 80% and 55% in recipients
in IPF (reviewed elsewhere).244,283 Imatinib me- younger than 50 years old.291 Consistent with
sylate, a tyrosine kinase inhibitor, was no better earlier studies, bilateral LT (BLT) was associated
than placebo in a multicenter, randomized trial in with improved survival compared with single LT
IPF patients.284 However, in a recent RDBPCT, (SLT) at later time points (.3 years) (all indica-
another tyrosine kinase inhibitor, BIBF 1120, was tions).291 Thabut et al292 reviewed survival times
associated with a trend toward a reduction in the and causes of death among 3,327 IPF patients
decline in lung function (at 12 months) and a who had SLT (n ¼ 2,146) or BLT (n ¼ 1,181) in the
lower incidence of AEs compared with place- United States from 1987 to 2009. Median survival
bo.285 In that study, FVC declined by 0.06 L in the time was longer after BLT (5.2 years) than SLT (3.8
high-dose BIBP 1120 cohort, compared with a years), but survival times did not differ after
0.19 L decline in the placebo group. There were adjustment for baseline differences between
no differences in DLCO or 6MWD between any of groups. BLT was associated with increased
the groups receiving BIBF 1120 and the placebo mortality in the first year, but survival benefit at
later time points. Cancer was a more common necessary to control peripheral edema in patients
cause of death in SLT (HR 3.60), likely reflected with cor pulmonale. Pulmonary rehabilitation
neoplasm arising from the native fibrotic lung. programs may improve walk distance and
Force et al293 retrospectively reviewed the UNOS symptoms or QOL in patients with IPF,298,299
database from 1987 to 2008; during that time even in patients with severe disease.298 The long-
frame, 3,860 IPF patients had LT (BLT n ¼ 2,431; term benefit of pulmonary rehabilitation remains
SLT, n ¼ 1.329). By multivariate analysis, there unclear.5
was no survival advantage with BLT (HR 0.90),
but 1-year conditional survival favored BLT (HR What Is the Relationship Between NSIP and UIP?
0.73, P ¼ .00064). Risk factors for early death
included recipient age .57 years and donor age Controversy exists as to whether NSIP is a
.36 years. A national database in the United separate disease entity or a continuum of disease
Kingdom evaluated 1,997 adults listed for LT related to IPF/UIP.4,9,217,218 Histologic features of
from 1995 to 2006; 1,143 underwent LT.294 NSIP overlap, and distinguishing fibrotic NSIP
Posttransplant mortality rates were highest from UIP is difficult.108,204,226 More importantly,
among patients with diffuse parenchymal lung both NSIP and UIP may coexist in individual
disease and lowest for patients with cystic patients. Review of SLB from patients with IIPs
fibrosis. For the diffuse parenchymal lung disease observed both NSIP and UIP (ie, discordant UIP)
group, adjusted for age, sex, and BMI, survival in 13% to 26% of patients.104,203 Further, both
immediately after LT was not significant different NSIP and UIP may be observed in pulmonary
for SLT or BLT patients. Late mortality was fibrosis complicating CTDs.300,301 NSIP and UIP
reduced in IPF patients receiving BLT compared may represent different points in the progression
with SLT. of a single disease or may represent distinct
Secondary PAH is not a contraindication to (albeit overlapping) processes. It is possible that
LT, but its presence may influence the operative cellular NSIP represents an early phase that may
and perioperative management. Whelan et al295 progress to fibrotic NSIP and ultimately UIP. If
reviewed 830 patients with IPF transplanted so, the survival advantage of NSIP may simply
between 1995 and 2002 in the IHSLT registry; represent lead-time bias.162,173 Until these ques-
77% had SLT, and 23% had BSLT. By multivariate tions are answered, I approach NSIP as a
analysis, mean PAP and BLT were independent potential reversible lesion, with both inflamma-
risk factors for mortality. Among SLT recipients, tory and fibrotic components. Unless specific
there was a linear relationship between PAP and contraindications exist, I treat NSIP with a
90-day mortality. However, only 8.3% of patients combination of CS (40 mg/day for 1 month, with
with SLT had mean PAP .40 mm Hg. The gradual taper) and AZA (2 mg/kg/day) for a 6-
decision as to which procedure (ie, SLT or BSLT) month trial. Responders are continued on med-
should be done depends upon the expertise of ical therapy, often for prolonged periods. Patients
the local transplant program.165 German investi- failing therapy and exhibiting a deteriorating
gators cited improved survival with BLT com- course are listed for LT (criteria for listing are
pared with SLT in a cohort of patients with IPF similar to IPF).
and secondary PAH.296 Given the improved
survival with BLT among patients with idiopath- Sarcoidosis
ic PAH,297 most centers perform BLT for IPF
patients with secondary PAH. Sarcoidosis is a poorly understood granulo-
Adjunctive Therapy: Supplemental oxygen is matous disease that involves the lung and
critical to optimize QOL and enhance exercise intrathoracic lymph nodes in more than 90% of
capacity in patients with IPF5; impact on survival patients.302–307 However, virtually any organ can
has not been studied. However, continuous be affected.307,308 Skin involvement,309–311 periph-
oxygen ameliorates pulmonary vasoconstriction eral lymphadenopathy, and eye312 involvement
and may delay the clinical development of cor each occur in 20% to 30% of patients.304 Clinically
pulmonale. Judicious use of diuretics may be significant involvement of spleen,313,314 liv-

Figure 11. Sarcoidosis. TBB specimen. Multinucleated giant Figure 12. Sarcoidosis. TBB specimen showing ‘‘burned out’’
cell in the center of a granuloma, surrounded by lympho- granuloma demonstrating nonnecrotizing granuloma con-
cytes and mononuclear cells in the periphery (hematoxylin- taining multinucleated giant cells and epithelioid cells in the
eosin). Reprinted with permission from ACCP Pulmonary center. In the periphery, no significant inflammatory cells
Medicine Board Review. 25th ed. Northbrook, IL: American are present, but concentric rings of collagen encircle the
College of Chest Physicians; 2009. granuloma (hematoxylin-eosin). Reprinted with permission
er,313,314 heart,315–318 CNS,319–323 or bone324,325 Northbrook, IL: American College of Chest Physicians; 2009.
occurs in 2% to 7% of patients with sarcoido-
sis.303,305,326 Lower mortality rates (0% to 0.5%)
sis.304 The clinical expression and course are
have been cited in nonreferral settings, when the
heterogeneous. One-third or more of patients are
diagnosis was made as part of routine radio-
asymptomatic, with incidental findings of bilat-
graphic screening.333,334 An epidemiologic study
eral hilar lymphadenopathy (BHL) on chest
in the United Kingdom identified 1,019 cases of
radiographs. Symptoms are protean, reflecting
sarcoidosis between 1991 and 2003.22 Mortality
the site of organ involvement. The natural history
rates at 3 and 5 years for sarcoid patients were
is usually favorable. Spontaneous remissions
5% and 7%, respectively, compared with 2% and
occur in nearly two-thirds of patients, and a
4% among age- and gender-matched control
waxing and waning course is common.302,305 The
subjects without sarcoidosis. Causes of death
presence of acute inflammatory manifestations
were not reported. A study in the United States
(ie, erythema nodosum, polyarthritis, and fever), assessed mortality rates in patients with sarcoid-
termed Löfgren syndrome, portends an excellent osis from 1988 to 2007.335 During that time frame,
prognosis, with high rates (.80%) of spontane- sarcoidosis-related mortality rates increased sig-
ous remission.302,326–328 Factors associated with nificantly, particularly in non-Hispanic black
poor prognosis and more aggressive disease women 55 years old. The average age- and
include black race, osseous involvement, lupus sex-adjusted sarcoidosis-related mortality rate
pernio (disfiguring nasolabial cutaneous lesions), was 4.32 per million population. Mortality rates
chronic hypercalcemia, and chronic pulmonary were uniformly greater (nearly 10-fold for both
sarcoidosis.303,304,326 Ethnic, geographic, and ge- male and female subjects) for non-Hispanic
netic factors influence prognosis.328–331 Lofgren blacks than non-Hispanic whites. Black dece-
syndrome is three to six times more common in dents with sarcoidosis were significantly youn-
women.328,332 Black race is associated with a ger than white decedents with sarcoidosis.
higher rate of chronic progressive disease, worse
long-term prognosis, extrapulmonary involve- Epidemiology
ment, and higher risk of relapses.302,326,327 In
10% to 15% of patients with sarcoidosis, the Sarcoidosis is worldwide in distribution, but
course is chronic and progressive, resulting in the prevalence varies according to racial and
permanent damage and fibrosis of affected geographic factors. Sarcoidosis is four to eight
organs; 1% to 6% of patients die of sarcoido- times more common in blacks than in
osis among World Trade Center (WTC) workers
was noted post-9/11.351 In a nested control study,
the risk of developing sarcoidosis was markedly
increased among workers on the WTC debris pile
compared with control subjects (OR 9.1) whereas
exposure to the WTC dust cloud was not
associated with a heightened risk (OR 1.0).352
Specific genetic polymorphisms may influence
prognosis. Human leukocyte antigen DQB1*0201
is a marker for a good prognosis in Dutch and
British patients with sarcoidosis.353 Polymor-
phisms of the C-C chemokine receptor gene
Figure 13. Sarcoidosis. Endobronchial lung biopsy specimen (CCR2 haplotype 2) were associated with
showing prominent multinucleated giant cells within the Löfgren syndrome and a good prognosis in
submucosa underlying the bronchioles (hematoxylin-eosin). Dutch patients.354 By contrast, in a Dutch
Reprinted with permission from ACCP Pulmonary Medicine population, severe pulmonary sarcoidosis was
Chest Physicians; 2009. strongly associated with the combination of
HLA-DQB1*0602 and DRB1*150101 haplo-
whites.336,337 In North America and Europe, types.330 In a large Swedish cohort of Löfgren
prevalence rates of 10 to 20 cases per 100,000 syndrome, DRB1*03-positive patients had a good
persons have been cited.337,338 In Scandinavia prognosis at 2 years (95% resolution) compared
and certain parts of the British Isles, prevalence with 51% among DRB1*03-negative patients.329
rates exceed 80 cases per 100,000.338,339 The Further, among DRB1*03-positive patients, there
incidence is much lower (,2 per 100,000) in was a pronounced seasonal component, with
southern Europe.338,340 Sarcoidosis has infre- much higher incidence in January, April, and
quently been reported in Central or South May.329
America341 or Africa,342,343 but whether this
Histopathologic Findings
represents underrecognition or reduced preva-
lence of the disease is not known. More than two-
The histologic hallmark of sarcoidosis is the
thirds of patients present between the ages of 20
noncaseating (nonnecrotizing) granuloma com-
and 40 years.337 There is a slight female predom-
posed of epithelioid cells and multinucleated
inance.337,344 Sporadic cases within families are
giant cells, surrounded by a cuff of lymphocytes
well recognized.345 Familial sarcoidosis (defined
and plasma cells355 (Fig 11). Fibrosis is present in
as having first- or second-degree relatives with
varying degrees (Fig 12). Disruption and destruc-
sarcoidosis) occurs in 17% of African American tion of parenchyma may be prominent. Because
patients with sarcoidosis, compared with 6% mycobacterial and fungal granulomas can cause
among Caucasian cases.346 Data from the multi- nonnecrotizing granulomas, special stains for
center ACCESS study noted that the familial acid-fast bacilli and fungi should be performed
relative risk of sarcoidosis was highest among to exclude these infectious etiologies. In the
siblings, followed by grandparents, and then respiratory tract, sarcoid granulomas are often
parents.336 A specific genetic defect has not been situated in the submucosa of bronchioles and
identified, but genes of the major histocompati- along bronchovascular bundles355 (Fig 13). Coa-
bility complex locus on chromosome 6p are lescent granulomas may give rise to confluent
believed to be involved.347 The inheritance mass lesions, nodules, or consolidation of lung
pattern is likely complex, with heterogeneous parenchyma.303 Exuberant granulomatous in-
alleles, polymorphisms, and linkages.348,349 The flammation may infiltrate and destroy affected
cause of sarcoidosis remains elusive, but genetic, organs, leading to significant and irreparable loss
environmental, and infectious causes have been of function. In the lung, progression to end-stage
suggested.350 An increased incidence of sarcoid- fibrosis (honeycomb lung) can occur. Fiber-optic

Figure 14. Sarcoidosis (stage I). Extensive bilateral hilar and
right paratracheal lymphadenopathy. Reprinted with per- Figure 16. Stage III sarcoidosis. Patchy reticulonodular
mission from ACCP Pulmonary Medicine Board Review. 25th densities throughout both lung fields. Lung volumes are
ed. Northbrook, IL: American College of Chest Physicians; well preserved. There is no definite lymphadenopathy.
2009. Reprinted with permission from ACCP Pulmonary Medicine
bronchoscopy with TBBs is the preferred diag- Chest Physicians; 2009.
nostic procedure to diagnose pulmonary sarcoid-

osis. Diagnostic yields are 60% to 95%.303 To avoid initial diagnostic bronchoscopy. When TBBs are
sampling error, I obtain several biopsy specimens nondiagnostic, mediastinoscopic lymph node
from both the upper and lower lobes at the time of biopsies may substantiate the diagnosis, provided
that enlarged mediastinal lymph nodes are
present. However, mediastinoscopy as a routine,
initial diagnostic procedure for hilar lymphade-
nopathy is not cost effective and has potential
morbidity. Percutaneous needle aspiration may be
an alternative to surgical biopsies. In one study of
19 patients with suspected sarcoidosis, endo-
sonography-guided fine-needle aspiration (FNA)
of enlarged mediastinal lymph nodes demonstrat-
ed nonnecrotizing granulomas in 100%; one
patient had tuberculosis (sensitivity and specific-
ity rates of 100% and 94%, respectively).356 In
another series, transbronchial FNA (TBFNA) with
a 26-gauge needle revealed cytological features
consistent with sarcoidosis in 88 of 116 patients
(76%) with mediastinal or hilar adenopathy.357
Figure 15. Stage II sarcoidosis. Extensive cystic radiolucen- Sensitivity of TBFNA cytology in this context was
cies (honeycombing) and fibrosis preferentially affecting 79%; specificity, 92%. Complications of TBFNA
upper lobes of both lungs. Linear fibrotic strands and include: pneumothoraces (10%–60%) or hemop-
volume loss are noted throughout. In addition, BHL is
tysis (5%–10%).358 Endobronchial ultrasound-
present. Reprinted with permission from ACCP Pulmonary
Medicine Board Review. 25th ed. Northbrook, IL: American guided (EBUS) transbronchial needle aspiration
College of Chest Physicians; 2009. (TBNA) of mediastinal lymph nodes may estab-
Figure 18. HRCT scan from a 48-year-old man with severe,
chronic pulmonary sarcoidosis. Cuts at the level of the main
carina show areas of bronchial thickening and consolidation
centrally, in an axial distribution. Large cystic, bullous
changes are evident in the posterior lung fields. The lung
architecture is distorted. Reprinted with permission from
ACCP Pulmonary Medicine Board Review. 25th ed. North-
brook, IL: American College of Chest Physicians; 2009.
granulomatous inflammation. Simultaneous or

subsequent excisional biopsies confirmed the-
diagnosis in 17 patients.362 Thus, FNA biopsy
can be an alternative to surgical biopsies in
selected patients. The optimal approach to diag-
nosing mediastinal lymph nodes (ie, TBNA,
EBUS-TBNA, or CT-guided FNA) depends upon
Figure 17. Top, Stage IV sarcoidosis. Posteroanterior chest the expertise and preference of the local institu-
radiograph demonstrates extensive cystic, bullous, and tion. SLB (ie, VATS or open) is rarely necessary to
fibrotic changes; upward retraction of the hilum; and
extensive pleural thickening in the left apex. Note surgical diagnose sarcoidosis. Biopsy of extrapulmonary
clips on the left lung from a previous left upper lobe sites may be appropriate when specific lesions or
lobectomy for a mycetoma. Bottom, HRCT scan demon- abnormalities are identified (eg, lymphadenopa-
strating a mycetoma (arrow) in the superior segment of the
left lower lobe in the same patient as in Figure 17, top, 8 thy, skin lesions, abnormal liver enzymes,
months after resection a left upper lobe mycetoma. Note the etc).304,308
bullae and cystic changes in the remaining lung parenchy-
ma. Reprinted with permission from ACCP Pulmonary Laboratory Features
Medicine Board Review. 25th ed. Northbrook, IL: American
College of Chest Physicians; 2009.
Laboratory features are nonspecific. Hyper-
lish the diagnosis of sarcoidosis in some pa- calcemia occurs in 1% to 4% of patients,
hypercalciuria in 15% to 40%.304,344,363 These
tients.359–361 In a randomized trial, EBUS-TBNA
derangements in calcium metabolism reflect
was superior to standard TBNA in patients with
enhanced production of 1,2-dihydroxycalciferol
mediastinal adenopathy and suspected sarcoido-
by mononuclear phagocytes from sarcoid gran-
sis.360 Diagnostic yield was 53.8% vs 83.3% in ulomas.304 Polyclonal hypergammaglobulinemia
favor of the EBUS-guided TBNA group occurs in 30% to 80% of patients with chronic
(P , .05).360 Tambouret et al362 performed 32 disease.304,326,344,363 Serum angiotensin-convert-
percutaneous FNA biopsies from a variety of sites ing enzyme (ACE) levels are elevated in 30% to
(eg, lymph nodes, salivary glands, lung, liver) in 80% of patients with sarcoidosis.303,344,363 False
28 patients with sarcoidosis; all aspirates showed positives are uncommon (,10%), but increased

serum ACE can occur in active histoplasmosis out intrathoracic lymphadenopathy.303 Some in-
and other granulomatous processes. The use of vestigators advocate defining patients with
serum ACE as a surrogate marker of disease extensive destruction, fibrosis, and volume loss
activity is discussed later. as stage IV.365 This radiographic staging system
may be useful as a prognostic guide, although
Chest Radiographs significant variability exists. Spontaneous remis-
sions occur in 60% to 90% of patients with stage I
Abnormalities are present on chest radio- disease, in 40% to 70% with stage II, and in 10%
graphs in more than 90% of patients with to 20% with stage III.302,303,366 Serious sequelae
sarcoidosis.303 BHL, often associated with en- are rare with stage I sarcoidosis, but may be
largement of right paratracheal lymph nodes, is appreciable in other stages. Virtually all fatalities
the classic radiographic feature, observed in due to pulmonary sarcoidosis occur in patients
more than two-thirds of patients153,303 (Fig 14). with radiographic stage II, III, or IV disease.303
Pulmonary parenchymal infiltrates are present in The course of the disease is usually dictated
25% to 50% of patients.303 Pulmonary parenchy- within the first 18 to 24 months of onset.303
mal infiltrates are typically bilateral and patchy, Spontaneous remissions occur in up to 40%
with a predilection for the mid and upper lung within the first 6 months303,366; .80% of sponta-
zones (Fig 15). Multiple focal nodular or alveolar neous remissions occur within the first 2 years.367
opacities in the upper lobes may mimic tubercu- Persistence of radiographic infiltrates beyond 2
losis and fungal pneumonia. Other disorders that years suggests that spontaneous remissions are
preferentially involve the upper lobes include unlikely to occur, and strongly warrants consid-
Langerhans cell granulomatosis, cystic fibrosis, eration of CS therapy.367 In some patients, the
silicosis, and chronic eosinophilic pneumonia. course is chronic, with multiple exacerbations or
Cavitation is rare.364 Pleural effusions occur in disease progression over years.303
,2% of patients.303 Pleural thickening on plain
chest films is rare, and usually reflects long- Chest CT Scans
standing chronic disease. Diffuse reticulonodular
or miliary infiltrates may be indistinguishable Chest CT scanning is far more sensitive than
from other chronic ILDs (eg, IPF, pneumoconio- conventional chest radiography in delineating
sis, pulmonary alveolar proteinosis, or lymphan- parenchymal details or detecting the extent of
gitic carcinomatosis) (Fig 16). Progression of the intrathoracic lymphadenopathy.153 Hilar or me-
lung lesion results in distortion and destruction diastinal lymph adenopathy is present in 47% to
of the lung architecture, with upward retraction 94% of patients with sarcoidosis.368 The most
of the hilae, broad coarse septal bands, bullae, commonly involved nodal stations (in order of
and end-stage honeycomb lung (Fig 17, top). decreasing frequency) are right lower paratrache-
With far advanced disease, mycetomas, bullous al, right hilar, subcarinal, and aortopulmonary
emphysema, and pulmonary hypertension may window.368 HRCT scans, using 1- to 2-mm slices,
be observed365 (Fig 17, bottom). Calcification of are superior to conventional CT scans in depicting
hilar or mediastinal nodes may be seen in long- parenchymal lesions and discriminating alveolitis
standing sarcoidosis. from fibrosis.153 Characteristic HRCT features of
sarcoidosis include nodular opacities and micro-
Radiographic Classification System nodules (,3 mm in diameter) along bronchovas-
cular bundles, central bronchovascular thickening
The radiographic staging system developed and nodularity, confluent nodular opacities with
more than four decades ago continues to be air bronchograms, GGOs, crowding and central
useful prognostically. This schema applies the retraction of bronchi and vessels near the hilae,
following criteria on plain chest radiographs: and pleural or subpleural nodules.153 Nodules are
stage 0, normal; stage I, BHL without parenchy- present in .80% of patients with sarcoidosis, and
mal infiltrates; stage II, BHL plus parenchymal represent aggregates of granulomas.153,368 Irregu-
infiltrates; stage III, parenchymal infiltrates with- larity or thickening of bronchovascular bundles,
occasionally with a ‘‘beaded’’ appearance, is a immunosuppressive agents. By contrast, patients
cardinal sign of pulmonary sarcoidosis.368 GGOs with large focal alveolar opacities and a ground-
were noted in 16% to 83% of patients with glass pattern are better candidates for therapy. CT
sarcoidosis153,368; both granulomatous and fibrot- patterns may evolve over time. Serial CT scans in
ic lesions may give rise to this CT feature.368 40 patients with pulmonary sarcoidosis showed
Progression of the sarcoid lung lesion may form several distinctive evolutionary patterns.371 Mac-
conglomerate masses, architectural distortion, roscopic nodules often disappeared or decreased
and cystic destruction (Fig 18). Cavitation was in size at follow-up. Consolidation and GGO
noted on CT scans in 2.7% of patients with resolved in some patients, but evolved into
sarcoidosis, typically in patients with advanced honeycombing in other patients (associated with
disease.364 In a retrospective study of 23 patients a decline in FVC). A conglomeration pattern
with cavitary sarcoidosis, 52% were in radio- shrank and evolved into bronchial distortion
graphic stage IV; 48% had severe extrapulmonary and a decline in FEV1/FVC ratio.
involvement.364 Active lesions (eg, consolidation Given the imprecise correlations between CT
or GGO) were present concomitantly in 19 scans and physiological parameters, direct mea-
patients (83%).364 Wall thickening during follow- surement of PFTs is critical to assess the extent
up suggests an infectious complication (particu- and degree of pulmonary functional impairment.
larly aspergillomas).364 Other nonspecific features
include irregular interfaces, thickened alveolar PFTs
septa or pleural surfaces, traction bronchiectasis,
and distortion or displacement of vessels, bron- Restrictive ventilatory defects are observed
chi, or interlobar tissues. The preferential distri- in 30% to 60% of patients with pulmonary
bution of parenchymal lesions in sarcoidosis sarcoidosis.303 Airway obstruction, with re-
along bronchovascular bundles and lymphatics, duced FEV1 and expiratory flow rates, occurs
with an upper lobe predominance,153 contrasts in 9% to 40% of patients.303,370 A prospective
sharply with IPF/UIP, which has a predilection study noted airflow limitation (defined as ,70%
for the basilar and subpleural (peripheral) regions FEV1/FVC ratio) in 20 of 228 consecutive
of the lungs. Emphysema may be observed in Japanese patients (8.8%) with sarcoidosis.372
advanced stage sarcoidosis (typically stage IV), Airflow limitation was more common in men,
but is more extensive in smokers.369 CT features of smokers, and radiographic stage IV. Airflow
airflow obstruction may include mosaic pattern of obstruction may reflect submucosal or endo-
attenuation; bronchial wall or peribronchiolar bronchial inflammation, parenchymal distortion,
thickening; bronchial distortion, compression, or bronchostenosis, or exaggerated bronchial reac-
stenosis; or bronchiectasis.370 Fibrosis and con- tivity.303,370,373 Increased airway hyperactivity in
glomerate masses may be present concomitantly, response to methacholine is common in patients
particularly in patients with bronchial disor- with sarcoidosis. 373 The D LCO is the most
tion.370 Specific CT features have prognostic sensitive of the PFT parameters,373 but the
significance. Focal nodular, alveolar, or GGOs degree of impairment is less severe in sarcoid-
suggest an active inflammatory component. In osis than in IPF.302 Hypoxemia is unusual, but
contrast, distortion of lung parenchyma, volume may be present in patients with advanced
loss, linear bands, bronchiectasis, cystic radiolu- disease. CPET findings are abnormal in up to
cencies, and bullae are characteristic of end-stage 50% of patients with sarcoidosis, even when
fibrosis.153 Because of its expense, I do not static PFT results are normal.374 However,
advocate routine HRCT scanning in the diagnosis CPETs are logistically cumbersome and have
or staging of sarcoidosis. However, HRCT scans doubtful practical value.
have a role in selected patients in assessing PFTs at a single time point cannot discrim-
prognosis and determining the likelihood of inate active from inactive disease and do not
response to therapy. Patients with extensive correlate with histologic findings. However,
fibrosis, honeycombing, and lung distortion are serial PFTs are important to follow the course
not likely to respond to therapy with CS or of the disease and assess response to therapy. VC

improves more frequently than DLCO, TLC, or inflammation (alveolitis). Characteristic patterns
arterial oxygenation.302 Changes in VC and DLCO of uptake have been noted in sarcoidosis (eg,
are concordant in .90 of patients.302,327 A increased uptake in lacrimal, salivary, and
prospective study in the United States of 193 parotid glands and hilar and mediastinal lymph
sarcoid patients cited excellent concordance nodes).375,376 However, 67Ga scans are expensive,
between changes in FVC and FEV1.327 Given inconvenient, and difficult to quantitate, and lack
the variability of DLCO and the expense of prognostic value.375,376 I see no role for 67Ga
obtaining lung volumes, spirometry and flow- scanning in either the initial staging or longitu-
volume loops are the most useful and cost- dinal follow-up of sarcoidosis. 67Ga scanning has
effective parameters to follow the course of been used in patients with normal chest radio-
pulmonary sarcoidosis. FVC is the most sensitive graphs and suspected sarcoidosis to detect
indicator of disease progression (or resolution). clinically silent extrathoracic sites of 67Ga uptake
Spirometry should be repeated at 6-month and provide sites for biopsies.376 However, PET
intervals for the first 2 years, even in patients scans are probably superior in this regard.377
with minimal or no pulmonary symptoms.
Patients with pulmonary symptoms or derange- PET Scanning
ments in pulmonary function require more
frequent studies. Deteriorating pulmonary func- Fluoro-2-deoxyglucose-PET scans may dem-
tion or persistence of severe derangements onstrate increased metabolic activity in patients
warrants a trial of CS therapy, regardless of with pulmonary378–380 or extrapulmonary sar-
whether radiographic abnormalities are present. coidosis380,381 (eg, bone,382 cardiac,316,383 or neu-
ral sites384). However, the clinical value of PET is
Ancillary Studies uncertain.368,377,378
BAL: BAL has provided significant insights
Serum ACE levels, radionuclide scans, and into the pathogenesis of sarcoidosis.385 BAL in
BAL cell profiles have been used to more sarcoidosis demonstrates increased numbers of
accurately determine the extent and activity of activated lymphocytes (typically CD4þ T cells),
the disease, but their role remains controversial. alveolar macrophages, and myriad proinflamma-
ACE: ACE, an enzyme normally produced by tory cytokines and mediators.307,385,386 BAL
endothelial cells, is produced in exaggerated lymphocytosis is present in .85% of patients
amounts by sarcoid granuloma macrophages.303 with pulmonary sarcoidosis; granulocytes are
Serum ACE levels may reflect total body granu- normal or low.302,385 BAL reveals increased
loma burden, but are not sensitive to active numbers of activated T lymphocytes (predomi-
localized disease. Changes in serum ACE often nantly CD4þ) and activated macrophages, with
parallel the course of the disease and may be reduced T-suppressor cells (CD8þ), in patients
used to guide treatment decisions, provided with active pulmonary sarcoidosis.385,386 In late
clinical information is taken into account. Isolat- phases of sarcoidosis, neutrophils and/or mast
ed elevations of serum ACE in the absence of cells may be increased.387 BAL cell profiles are
clinical symptoms do not require therapy. Im- not specific for sarcoidosis, but narrow the
portantly, serum ACE may be normal in patients differential diagnosis.385 Importantly, BAL cell
with active disease.302 I obtain a baseline serum profiles fail to predict prognosis or responsive-
ACE level in patients with sarcoidosis and obtain ness to CS therapy.302,385 High levels of T
serial levels in selected patients when clinical lymphocytes or lymphokines may reflect active
criteria are inadequate to judge disease activity. alveolitis, but do not imply that deterioration will
Radionuclide Scans: 67Ga citrate scans were inevitably occur.302 Because of the waxing and
used as a surrogate marker of disease activity in waning nature of sarcoidosis, BAL has limited
sarcoidosis and other inflammatory pulmonary prognostic value. Marked increases in CD4þ
disorders. 67Ga is taken up avidly by activated lymphocytes, consistent with an intensive alveo-
alveolar macrophages, and intrapulmonary up- litis, are characteristic of Löfgren syndrome, yet
take of 67Ga may be a marker of active alveolar spontaneous remissions occur in more than 85%
of patients in this setting.302 Serial bronchoscopy versial. Several prospective studies performed in
is invasive, expensive, and impractical for se- the 1970s failed to show a favorable effect on
quential evaluation of sarcoidosis. long-term prognosis. Although several studies
suggested short-term improvement with CS
Pathogenesis therapy, relapses often occurred following cessa-
tion of therapy. The lack of efficacy may reflect
The inciting signals responsible for the the study designs, as patients with stage I
exuberant granulomatous response, and its sub- disease, minimal or no symptoms, and normal
sequent progression to fibrosis (or resolution), lung function were often enrolled into treatment
have not been identified. Interactions between trials. In most of these studies, high rates of
activated mononuclear phagocytes (eg, mono- improvement or stabilization were noted in both
cytes and macrophages) and activated T helper/ treated and untreated patients. The long-term
inducer lymphocytes are responsible for the impact of CSs was difficult to assess, owing to the
induction and evolution of the granulomatous high rate of spontaneous remissions as well as
process.307,386 At sites of active disease, striking inclusion of patients with irreversible disease.
increases in helper/inducer (CD4þ) lymphocytes, These data cannot be extrapolated to patients
increased CD4þ/CD8þ ratios, and increased with severe or progressive pulmonary disease,
release of diverse lymphokines (consistent with who are the best candidates for therapy. A
a Th1 response), monokines, and biochemical multicenter, randomized trial of stage II or III
markers have been noted.307,386 Early in the sarcoidosis sponsored by the British Thoracic
course, Th1 cytokines (eg, c-IFN and IL-2) Society found that CS treatment in patients with
predominate at sites of disease activity; this persistent radiographic infiltrates after an initial
compartmentalization of the immune response 6-month observation period was associated with
(with a Th1 cytokine bias) may abate as the improved lung function, chest radiographs, and
disease remits.307,386 Lung T cells from patients symptoms compared with untreated control
with active pulmonary sarcoidosis release several subjects.366 Among 149 patients with stage II or
cytokines that contribute to the induction of the III pulmonary sarcoidosis eligible for the study,
immune response and facilitate T cell replication 33 patients required immediate CS therapy for
and mononuclear phagocyte activation.307,386 control of symptoms and were excluded. In
Alveolar macrophages from patients with pul- addition, 58 patients whose chest radiographs
monary sarcoidosis are activated, enhance anti- improved spontaneously within 6 months of
gen presentation, express receptors for IL-2, and entry served as an untreated observation group.
release growth factors that promote FB recruit- The remaining 58 untreated patients with persis-
ment and proliferation.386 Macrophages play a tent radiographic infiltrates after 6 months were
dual role in orchestrating the sarcoid lung lesion, randomly assigned to receive routine CS for 18
by producing monokines that may either amplify months (n ¼ 27) or selective therapy only (to
or down-regulate the inflammatory process. control symptoms or deteriorating pulmonary
symptoms; (n ¼ 31). No placebo group was
Therapy included. The dose of CS in the treated group
was modest (ie, prednisolone 30 mg daily for 1
CSs are the mainstay of therapy, and may month, tapered to 10 mg by 4 months; mainte-
produce dramatic remissions in patients with nance therapy with 10 mg daily was continued
severe or progressive sarcoidosis.302,307,388 Favor- for 9 months). Incremental doses were permitted
able responses to CSs are achieved in 60% to 90% as necessary to maximize radiographic improve-
of patients with symptomatic sarcoidosis, but ment. The results affirmed the benefit of treat-
relapses occur in 16% to 74% of patients after ment with CSs in patients with radiographic
cessation of therapy.302,303,388 Long-term efficacy stage II or III disease who failed to spontaneously
is less clear. Because of the potential for sponta- remit during the 6-month period of observation.
neous resolution and the toxicities associated These data support the use of CSs for patients
with CSs, indications for treatment are contro- with stage II or III disease who fail to improve

spontaneously within a reasonable period. The were randomly assigned to receive either oral
optimal observation period prior to deciding on prednisone for 3 months followed by inhaled
therapy has not been determined. A period of no budesonide or placebo.391 Among patients with
more than 6 to 18 months is appropriate, as stage II disease, chest radiographs did not differ
spontaneous remission beyond this point is between groups. Differences in PFTs (FVC, DLCO)
unlikely. More immediate institution of therapy between groups were minimal. A trend towards
is warranted for patients with severe or deteri- improvement in DLCO was noted in CS-treated
orating symptoms or pulmonary dysfunction. patients with stage II disease. These differences
CSs have potential toxicity, and routine were small, and did not achieve statistical
therapy for patients with mild or no symptoms significance. Changes in FVC over time were
is inappropriate. Indications for therapy should similar between groups. Long-term follow-up
be circumscribed and focused. Despite the lack of from the Finnish study, which randomized
consensus regarding efficacy of therapy, there is patients with stage I and II newly diagnosed
little doubt that CSs dramatically suppress or (,3 months) sarcoidosis to immediate treatment
reverse the disease in some cases. CSs are with placebo or prednisolone for 3 months,
warranted for myocardial,389 CNS,390 or ophthal- followed by inhaled budesonide for 15 months,
mologic (eg, uveitis) complications of sarcoido- found no differences in treated or placebo groups
sis.304,308 CSs are also indicated for chronic in chest radiographs at 1 year.392 However, at 5
hypercalcemia (to avert late complications of years, patients in the placebo cohort had lower
nephrocalcinosis and nephrolithiasis) and for mean FVC and DLCO and worse chest radio-
severe or progressive pulmonary or extrapulmo- graphs compared with treated patients. Differ-
nary dysfunction. The dose and duration of ences between groups were small, and the
therapy need to be individualized. Chronic significance of these observations is not clear. In
disease of mild to moderate severity can be another double-blind trial, British investigators
treated with modest dosages (eg, 40 mg every randomly assigned 44 adults with stage II or III
other day for 3–4 months, with subsequent pulmonary sarcoidosis to inhaled fluticasone
taper). Higher doses (eg, prednisone 1 mg/kg (1,000 lg bid) or placebo for 6 months.393
per day for 4 weeks, with a gradual taper) are Approximately 75% were taking oral CSs at the
appropriate for myocardial or CNS manifesta- start of the study. No significant differences in
tions. The duration of therapy and the rate of PFTs, mean dose of oral CS, or chest radiographs
taper need to be individualized according to were detected at any time point. These stud-
clinical response and presence or absence of ies391–393 suggest that inhaled CSs have minimal
adverse effects. A 3-month trial of CSs is usually value as primary therapy for pulmonary sarcoid-
adequate to judge efficacy. If no objective osis. However, given their low toxicity, a trial of
response has been shown within this time, CSs an inhaled CS is reasonable in patients with
can be tapered and discontinued. In contrast, significant endobronchial inflammation, cough,
among responders, CSs should be continued, or persistent pulmonary symptoms.
albeit in a tapering regimen, for 12 to 18 months. Immunosuppressive or Cytotoxic Agents: Immu-
Relapses may occur as the steroid dosage is nosuppressive or cytotoxic agents (eg, metho-
reduced or discontinued. In such cases, escala- trexate [MTX], AZA, leflunomide, MMF,
tion of the dose may be efficacious. Long-term cyclosporine, CYC, and chlorambucil) have been
CSs are indicated only for patients who have used, with anecdotal successes, in sarcoid pa-
shown unequivocal response to therapy yet tients failing or experiencing side effects from
relapse with attempts to stop therapy. CSs. However, randomized trials evaluating
Inhaled CSs: Inhaled CSs were associated with these agents are lacking, and the best agent has
anecdotal responses in patients with mild pul- not been determined.
monary sarcoidosis, but firm data supporting Immunosuppressive Agents: Both AZA and
their efficacy are lacking. In one double-blind, MTX may be useful for sarcoidosis refractory to
placebo-controlled trial in Finland, 189 patients CSs or as steroid-sparing agents in patients
with pulmonary sarcoidosis (stage I, II, or III) requiring high-dose CSs for control of the disease.
AZA: AZA (2–3 mg/kg/d), alone or com- these studies are not definitive, MTX has a role as
bined with CS, has been associated with anec- a steroid-sparing agent in sarcoidosis. Because of
dotal successes in sarcoidosis, even in patients potential toxicities, MTX should be restricted to
failing CS. However, randomized trials have not patients requiring unacceptably high doses of CS
been done. Further, studies directly comparing (.20 mg/d prednisolone or equivalent) or
AZA with alternative agents for sarcoidosis are experiencing serious side effects from CS. In this
lacking. In two early studies, 10 of 20 patients context, a 4- to 6-month trial of MTX is
failing CS responded to AZA.394,395 In one reasonable. I initiate therapy with 7.5 mg once
retrospective study, eight of 14 patients with weekly, and escalate the dose by 2.5-mg incre-
neurosarcoidosis responded to AZA.396 Diab et ments weekly (to a maximal dose of 20 mg) until
al397 treated seven patients with a combination of a clinical response or toxicity has occurred.
prednisone and AZA; all seven improved. In Serious adverse effects are rare (,1% of patients),
contrast, investigators from South Africa found but side effects requiring cessation of therapy
AZA to be of marginal benefit in a retrospective occur in 3% to 15% of cases.255 Adverse effects of
study of 10 patients with pulmonary sarcoido- MTX are dose dependent, and may be minimized
sis.398 All exhibited only partial (n ¼ 6) or no by addition of folic acid (1 mg/d). Adverse
(n ¼ 4) response to CS. In that study, AZA plus effects associated with MTX include gastrointes-
low-dose CS was associated with significant and tinal effects (eg, nausea, vomiting, and diarrhea),
sustained improvement in lung function in only stomatitis (eg, mucosal or oral ulcers), and rash.
two patients; two additional patients had tran- Less common complications, each occurring in
sient improvement and a steroid-sparing effect. 1% to 4% of patients, include megaloblastic
Two patients failing AZA subsequently respond- anemia, leukopenia, or thrombocytopenia; op-
ed to CsA and high-dose CS. No patient who portunistic infections; and interstitial pneumoni-
failed high-dose CS responded to AZA. German tis.255,257 In contrast to the alkylating agents,
investigators treated 11 patients with chronic MTX is not carcinogenic. MTX is teratogenic and
sarcoidosis with AZA plus prednisolone.399 All cannot be used in patients at risk of conception.
had symptomatic improvement; chest radio- The most worrisome side effect is hepatic
graphs improved in nine, and PFTs improved cirrhosis, which may occur in up to 2% of
in seven. Late relapses (8–22 months) occurred in patients with long-term use (.2 years).255 The
three patients. Although these data are limited, risk of permanent liver disease with long-term
AZA may be useful as a steroid-sparing agent or use of MTX (.2 years) has not been defined in
in selected patients with severe or progressive patients with sarcoidosis. A series of 68 patients
sarcoidosis refractory to CS. Extensive clinical with chronic sarcoidosis treated with long-term
experience with AZA in organ transplant recip- (.2 years) MTX therapy cited histologic features
ients and other immune disorders suggest that consistent with MTX toxicity in 14 patients
serious late sequelae associated with chronic (21%).403 Importantly, serial liver function tests
AZA use are uncommon.255 were not useful in determining which patients
MTX: MTX, a folic acid antagonist with both developed MTX toxicities. Contraindications to
immunosuppressive and antiinflammatory ef- MTX include ethanol abuse, concomitant liver
fects, has been efficacious for both pulmonary disease, history of hepatitis, unreliable patient,
and extrapulmonary sarcoidosis.302,400 MTX can renal failure, active infection, anemia, and leu-
be given parenterally (intramuscularly) or orally kopenia. Serial transaminase levels, CBC counts,
as a pulse once weekly. Dosages ranging from 10 and platelet counts should be monitored every 6
to 25 mg weekly have been used. In uncontrolled to 8 weeks in patients receiving MTX. Persistent
studies by investigators from the University of or progressive rises in hepatic enzymes, throm-
Cincinnati who evaluated more than 230 pa- bocytopenia, or leukopenia warrant discontinua-
tients, favorable responses to MTX were cited in tion of therapy or reduction of the dose. Given its
52% to 66% of patients.401,402 Relapses were potential for late, irreversible hepatotoxicity,
frequent with cessation of therapy, but usually MTX should be continued beyond 6 months only
responded to reinstitution of MTX. Although in patients demonstrating unequivocal objective

improvement. Enthusiasm for its use needs to be treatment of sarcoidosis are limited to sporadic
tempered by the high relapse rate noted on case reports and small retrospective series.
cessation of therapy. I prefer AZA for patients Chlorambucil, an alkylating agent of the nitrogen
with chronic, progressive sarcoidosis requiring mustard class, was associated with favorable
long-term treatment (.1 year). responses in a few nonrandomized studies in the
Leflunomide: Leflunomide has been used to 1970s and 1980s, but chlorambucil is oncogenic
treat sarcoidosis, but data are sparse.404 One and has numerous toxicities.255 Given the avail-
nonrandomized trial cited responses in 25 of 32 ability of alternative therapeutic agents, chlo-
sarcoid patients (78%) treated with leflunomide rambucil has no role in the treatment of
(alone or combined with MTX).405 Leflunomide sarcoidosis.
appears to be less toxic than MTX, and may be an CYC: CYC (oral or pulse) has rarely been used
alternative to MTX. to treat sarcoidosis. Anecdotal responses have
MMF: Responses to MMF were noted in been noted, but data are limited to a few case
anecdotal cases of extrapulmonary sarcoido- reports and small series.388,390 Lower and col-
sis406–409 but data are lacking in pulmonary leagues cited favorable responses in eight of 10
sarcoidosis. patients treated with IV pulse CYC for neuro-
CsA: CsA, a fungal decapeptide that exhibits sarcoidosis, eight of whom had concomitant lung
relatively selective inhibitory effects on T-cell involvement.390 Prior therapy included CS in all
activation, proliferation, and lymphokine re- 10 and MTX in eight. Thus, CYC has a role for
lease,255 has been used to treat sarcoidosis but severe sarcoidosis refractory to CSs or other
results have been disappointing. In a study from immunosuppressive agents. However, in light of
the National Institutes of Health, eight patients its oncogenic potential, I reserve CYC for severe
with symptomatic pulmonary sarcoidosis re- sarcoidosis refractory to CS and AZA or MTX.
ceived oral CsA (10 mg/kg/d) for 6 months.410 Further, infliximab may be used in lieu of CYC; in
Despite inhibitory effects on T-cell proliferation one study, infliximab was effective in four cases of
and cytokine release in vitro, pulmonary function CNS sarcoidosis refractory to CYC.414
or BAL results did not change. In another study,
six patients with CS-refractory CNS sarcoidosis Other Antiinflammatory and
were treated with CsA plus CS for 6 months.411 Immunomodulatory Agents
No patient achieved complete remission, but a
steroid-sparing effect was suggested. A subse- Nonsteroidal antiinflammatory agents have
quent study by these investigators cited favorable been used to treat the acute articular manifesta-
responses in 11 of 14 patients with neurosarcoi- tions of sarcoidosis, but have no role in treating
dosis treated with CsA.396 An RCT by Wyser and more severe cases of pulmonary or extrapulmo-
coworkers412 showed no benefit with oral CsA (5– nary sarcoidosis.
7 mg/kg/d) combined with prednisone as com- Antimalarial drugs (eg, chloroquine [CQ] and
pared with prednisone alone in a cohort of 37 hydroxychloroquine) have immunomodulating
patients with pulmonary sarcoidosis. CsA is very properties and are efficacious in treating rheu-
expensive and is associated with numerous matoid arthritis, systemic lupus erythematosus,
toxicities (eg, hypertension, renal insufficiency, and diverse immune-mediated diseases. Antima-
hirsutism, neuropathies, disorders in lipids, larials concentrate in cells of the reticuloendo-
heightened susceptibilities to infections, and thelial system and melanin-containing tissues
lymphoproliferative disorders).255 In light of the (eg, skin, spleen, leukocytes, kidney) and are
myriad complications associated with its use, and preferentially concentrated in epithelioid, mono-
the lack of demonstrated efficacy, cyclosporine nuclear, and giant cells comprising sarcoid
has no role as therapy for sarcoidosis. Topical granulomas. Anecdotal responses have been
cyclosporine eyedrops may be effective for noted with the antimalarials for cutaneous,415
sarcoid conjunctivitis.413 osseous,388 orbital,416 and neurologic417 sarcoid-
Alkylating Agents: Published data regarding osis and sarcoid-induced hypercalcemia,418 The
alkylating agents (eg, CYC, chlorambucil) for the role of antimalarials in treating pulmonary
sarcoidosis is less well established. However, a lupus pernio and extrapulmonary cas-
randomized trial of 23 patients with symptomatic es).309,379,408,414,426–430 In a RDBPC trial of patients
pulmonary sarcoidosis (radiographic stage II or with CS-refractory extrapulmonary sarcoidosis,
III) suggested benefit with CQ.419 Sixteen of the infliximab was superior to placebo; however, this
23 patients had previously been treated with benefit was not sustained after discontinuation of
high-dose CSs, without sustained improvement. therapy.428 Data in pulmonary sarcoidosis are
All 23 patients were treated with high-dose CQ limited.426,431 In a multicenter trial, 138 patients
(750 mg/d) for 6 months. Five patients withdrew with chronic pulmonary sarcoidosis were ran-
from the study before the 6-month acute phase domized to placebo or infliximab (3 mg/kg) or
(three because of intolerable side effects). After 6 infliximab (5 mg/kg) at weeks 0, 2, 6, 12, 18, and
months, the dose of CQ was tapered by 250 mg 24.426 At 24 weeks, the primary endpoint DFVC
every 2 months. Eighteen patients were then percentage predicted was slightly higher among
randomly assigned to a maintenance group (CQ, infliximab-treated patients (2.5% above baseline)
250 mg/d; n ¼ 10) or observation group (no CQ; compared with placebo-treated patients (no
n ¼ 8). After the initial 6-month treatment with change). This difference, although statistically
high-dose CQ, symptoms, PFT results, serum significant, is of doubtful clinical significance. In
ACE levels, and 67Ga scan findings improved. a RDBPC trial, 19 patients with pulmonary
Following randomization, the rate of decline in sarcoidosis failing or intolerant of CS were
PFTs was slower and there were fewer relapses in randomized to placebo or infliximab for 6 weeks,
patients receiving maintenance CQ vs no CQ and were then treated with open-label inflix-
therapy. Studies comparing CQ with CS therapy imab.430 At 6 weeks, mean FVC increased 15.2%
have not been done. The major toxicity of in infliximab-treated patients compared with
antimalarials is ocular (particularly CQ); dizzi- 8.4% in the placebo cohort (P ¼ .65).430 Anec-
ness and nausea may also occur.419 Unfortunate- dotal responses to adalimumab have been cited
ly, prolonged administration of CQ can lead to with chronic pulmonary and extrapulmonary
irreversible retinopathy and blindness. Given the sarcoidosis432,433 but data are sparse. Treatment
potential serious ocular toxicity associated with with TNF inhibitors is very expensive and has
CQ, hydroxychloroquine, which is less toxic, is been associated with a heightened risk of
preferred. The dose of hydroxychloroquine is 200 tuberculosis, other opportunistic infections, and
mg once or twice daily for a 6-month trial. Long- other adverse effects257 (including lymphoma
term maintenance therapy (100–400 mg daily) is development).257 Additional studies are required
reserved for patients manifesting unequivocal to establish the role of TNF-a inhibitors as
responses. Slit-lamp examinations should be therapy for sarcoidosis.
done by an ophthalmologist every 9 months to
rule out ocular toxicity. The combination of Rituximab
hydroxychloroquine with CS or immunosup-
pressive agents may enhance immunomodulato- Favorable responses to rituximab have been
ry effects compared with any of these agents cited in anecdotal case reports,434–436 but data are
alone. sparse.
Alternative Therapies: Anecdotal responses
have been cited with thalidomide420,421 (a seda- Pulmonary Hypertension
tive with teratogenic properties), but one pro-
spective study of 10 patients with pulmonary Pulmonary hypertension is a rare complica-
sarcoidosis showed no benefit.422 Responses tion of sarcoidosis, but may occur in patients
were cited with melatonin423 and pentoxifyl- with advanced radiographic stages.365,437–440 Al-
line424,425 in patients with sarcoidosis, but the though data are limited, favorable responses to
value of these agents is unproven. short- and long-term vasodilators have been
TNF-a: TNF-a inhibitors (particularly in- cited441 (eg, inhaled nitric oxide,438 IV epopro-
fliximab) have been used, with anecdotal suc- stenol,438,442 sildenafil,443 bosentan,444 and oral
cess, to treat refractory sarcoidosis (particularly calcium channel blockers438). Open, prospective

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Notes
Chapter 34. Rare Interstitial Lung Diseases:
Pulmonary Langerhans Cell Histiocytosis,
Lymphangioleiomyomatosis, and Cryptogenic
Organizing Pneumonia
Objectives: the lesions of PLCH are identical to Langerhans

Describe the salient epidemiologic, clinical, physiologic, cell histiocytosis (LCH; formerly termed eosino-
and radiographic features of Langerhans cell histiocyto- philic granuloma or histiocytosis X) involving
sis, lymphangioleiomyomatosis, and cryptogenic orga-
nizing pneumonia.
bone or extrapulmonary organs.3 However,
Compare and contrast the salient features seen on high- ,20% of adults with PLCH manifest extrapul-
resolution CT scans in these disorders. monary involvement.3–8 More importantly, LCH
Review the characteristic histopathologic features of each
predominantly affects children, whereas isolated
of these disorders, and the role of immunohistochemical
techniques or markers (for pulmonary Langerhans cell pulmonary LCH is rare in children.9 The clinical
histiocytosis and lymphangioleiomyomatosis). and radiographic features of PLCH overlap with
Review the differing therapeutic strategies for these those of myriad chronic ILDs.10 However, CT
disorders.
scans are highly characteristic and may distin-
guish PLCH from idiopathic pulmonary fibrosis
Key words: bronchiolitis obliterans organizing pneumonia;
cryptogenic organizing pneumonia; cystic lung diseases; and other chronic ILDs.
Langerhans cell granulomatosis; Langerhans cell histiocy-
tosis; lymphangioleiomyomatosis; pulmonary eosinophilic Epidemiology
granuloma
The prevalence of PLCH is estimated at two to

Synopsis:
five cases per million persons.1,3 Pulmonary LCH
Pulmonary Langerhans cell histiocytosis (PLCH; also
termed Langerhans cell granulomatosis) and lymphangio-
accounts for ,5% of cases of ILDs.3 Pulmonary
leiomyomatosis (LAM) are rare and poorly understood LCH typically occurs in adults aged 20 to 50 years;
chronic lung disorders characterized by extensive cyst children are rarely affected.3,4,8 Pulmonary LCH
formation within the lung parenchyma. These disorders
has been reported primarily in whites, suggesting a
share certain features, but LAM affects exclusively women,
while PLCH may affect either sex and almost exclusively genetic predisposition.3–5 However, no familial or
occurs in smokers. Cryptogenic organizing pneumonia inheritable trait has been identified. Further, PLCH
(COP), formerly termed bronchiolitis obliterans organizing occurs in Asian persons.11
pneumonia (BOOP), is a rare disease of unknown etiology
characterized by dense alveolar infiltrates, subacute course, Multisystemic LCH in children or adults is
and excellent responsiveness to corticosteroid (CS) therapy. monoclonal,12 whereas PLCH is polyclonal,
This chapter reviews the salient features of these disorders suggesting a reactive process.13 The low prolif-
and presents approaches to diagnosis and therapy.
erative rate of Langerhans cells (LCs) in PLCH
suggests a nonmalignant process.6,14 More than
90% of cases of PLCH occur in smokers,3–5,7,15–18
Pulmonary Langerhans Cell suggesting that constituents of cigarette smoke
Histiocytosis have a strong role in the pathogenesis. Some
studies suggest a distinct male predominance,5,19
Pulmonary Langerhans cell histiocytosis (PLCH) but others cite a slight female predominance.4,6,7
is a rare disorder usually seen in smokers, These variations in incidence by sex may reflect
presenting as chronic interstitial lung disease differences in smoking habits of the populations
(ILD) or with pneumothoraces.1,2 Histologically, studied.1

Clinical Features
The clinical features and natural history of

PLCH are variable. Symptoms of cough and
dyspnea are present in two-thirds of patients,
and often develop insidiously over several
months or years.1 Pneumothoraces occurs in 6%
to 20% of patients and may be the presenting
feature.1,4–6,20–22 Recurrent pneumothoraces may
require surgical pleurodesis for control.5,22 Rup-
ture of subpleural cysts or blebs accounts for the
predilection for recurrent pneumothoraces. He-
moptysis or wheezing occurs in ,5% of pa-
tients. 3 Constitutional symptoms of fever,
malaise, weight loss, or anorexia are present in Figure 1. LCH. Posteroanterior chest radiograph demon-
15% to 30% of patients.3–5 Ten percent to 25% of strating finely nodular densities throughout the lung
patients are asymptomatic, with incidental find- parenchyma, with a predominance in the middle and upper
ings on chest radiographs.1,4–6 Pulmonary arteri- lung fields, in a 44-year-old man with pulmonary LCH.
al hypertension (PAH) is common in severe Board Review. 25th ed. Northbrook, IL: American College of
PLCH23 and likely represents intrinsic pulmo- Chest Physicians; 2009.
nary vascular disease. In a series of 21 patients
with advanced PLCH and awaiting lung trans-
plant, all had PAH (mean pulmonary arterial patients with PLCH, five developed bronchogenic
pressure, 59 mm Hg) that was disproportionate carcinoma, for an annual risk of 1,040 per 100,000.27
to the degree of pulmonary functional impair- In contrast, none of 48 patients in a series from the
ment or hypoxemia.23 Histopathology demon- National Institutes of Health (NIH) had lung
strated proliferative vasculopathy involving cancer.7 Since virtually all patients are smokers,
muscular arteries and veins, with prominent cigarette smoke likely contributes to the cancer risk.
venular involvement. A fatal case of veno-
An association between lymphoma and PLCH has
occlusive disease complicating PLCH was de-
been suggested.28,30,31
scribed.24 Extrapulmonary involvement occurs in
,20% of patients with PLCH.3–7,19 Solitary
Chest Radiographic Features
punched-out lesions of bone and diabetes insip-
idus (from involvement of the pituitary) are the
Conventional chest radiographs usually dem-
most common sites of extrapulmonary involve-
onstrate diffuse reticular, reticulonodular, or
ment.1,3 Blood or serologic studies are not
cystic lesions with a predilection for the mid
helpful. In contrast to chronic eosinophilic
and upper lung zones (Fig 1).3–5 The costo-
pneumonia, peripheral blood eosinophilia is not
a feature of PLCH.1 phrenic angles are usually spared.4,5,18,20 Both
The prognosis of PLCH is generally good, but nodular and cystic components are usually
disparate results have been reported in the present concomitantly. The cystic radiolucencies
literature.16 The disease stabilizes or improves correspond to walls of cysts or dilated bronchi or
spontaneously in about two-thirds of patients, bronchioles. Reticular or reticulonodular lesions,
usually within 18 months of onset of symp- typically ranging in size from 1 to 5 mm,
toms.4–7,20,21 However, the disease progresses in represent the walls of cysts (from destroyed lung
15% to 30%, with destruction of lung parenchy- parenchyma) or peribronchiolar cellular lesions.1
ma and respiratory impairment; fatality rates With advanced disease, volume loss and fibrosis
range from 2% to 27%.4–7,19,21,25,26 may be extensive. Pneumothoraces occur in 6%
The risk for lung cancer appears to be increased to 20% of patients and may be the presenting
in patients with PLCH.27–29 In one study of 93 feature4–6 (Fig 2). Pleural thickening or effusions
558 Chapter 34. Rare Interstitial Lung Diseases (Lynch)

Figure 2. LCH. Posteroanterior chest radiograph demon-
strating far advanced cystic and nodular changes through-
out the lung parenchyma. A persistent right pneumothorax
is evident, despite the presence of a right thoracoscopy tube.
Surgical clips are from prior thoracotomies for attempted
pleurodesis. Reprinted with permission from ACCP Pulmo-
nary Medicine Board Review. 25th ed. Northbrook, IL:
American College of Chest Physicians; 2009. Figure 3. LCH. Posteroanterior chest radiograph demon-
strating finely nodular densities throughout the lung
parenchyma and hyperinflation in a 38-year-old woman
with pulmonary LCH. Reprinted with permission from
are uncommon.20 Cavitation of nodules is occa- ACCP Pulmonary Medicine Board Review. 25th ed. North-
sionally observed on CT scans1,20 but is not seen brook, IL: American College of Chest Physicians; 2009.
on plain radiographs. Hilar or mediastinal
lymphadenopathy is rare.1,4,32
Chest CT Imaging Characteristics
Certain findings on thin-section high-resolu-

tion CT (HRCT) scans are highly suggestive of
PLCH, and HRCT imaging is far superior to
conventional chest radiographs in discerning the
cystic nature of the disease3,33,34 (Figs 3–5). The
combination of cystic and nodular lesions, with a
proclivity to involve the upper lobes, strongly
suggests PLCH.1,35 There is no central or periph-
eral predominance. In adult PLCH, the costo-
phrenic angles are spared.18 Multiple thin-walled
cysts are observed in .85% of patients.11,20,33,36
These cysts are usually round and ,10 mm, but
may coalesce, occasionally exceeding 3 cm in
size.11,20,33 Nodules ranging in size from 1 to 15 mm
are a prominent component of PLCH, seen in two-
thirds of patients.20,33 A review of 27 cases of PLCH Figure 4. LCH. HRCT scan from the patient in Figure 3
in adults in Asia cited the following CT imaging reveals numerous cysts of various sizes throughout the lung
features: micronodules (89%), thin-walled cysts parenchyma. Multiple small nodules can also be seen
(82%), and thick-walled cysts (82%).11 The nodules dispersed throughout the peribronchial regions and alveolar
interstitium. Reprinted with permission from ACCP Pulmo-
surround small bronchioles and represent peri- nary Medicine Board Review. 25th ed. Northbrook, IL:
bronchiolar granulomas. As the disease progresses, American College of Chest Physicians; 2009.

Figure 5. LCH. HRCT scan of the upper lobes from a 56- Figure 6. Idiopathic pulmonary fibrosis. HRCT scan from a
year-old man with progressive cough and dyspnea. Note 55-year-old woman with UIP (documented by thoracoscopic
the multiple well-defined cystic spaces and coalescence of lung biopsy) demonstrates extensive honeycombing
blebs in the medial aspect of the right apex. A few tiny, throughout both lungs (upper lobes). Note that the cysts
scattered peribronchiolar nodules are also present. Trans- are distributed preferentially in the peripheral (subpleural)
bronchial lung biopsy specimens demonstrated typical regions of the lung, with relative sparing of the central
histologic features of LCH. S100 staining was also positive. regions. This pattern differs from the more uniform
Reprinted with permission from ACCP Pulmonary Medicine distribution of cysts seen in patients with pulmonary
Board Review. 25th ed. Northbrook, IL: American College of LCH. Reprinted with permission from ACCP Pulmonary
Chest Physicians; 2009. Medicine Board Review. 25th ed. Northbrook, IL: American
College of Chest Physicians; 2009.
the nodules are replaced by cysts, some of which

become confluent.11 The extent of nodular opacities
respiratory bronchiolitis interstitial lung disease is
on HRCT scanning correlates with the density of
often present.15 Pleural effusions and hilar adenop-
granulomatous inflammatory lesions in lung tis-
athy are rare.1,20,35 However, mediastinal or para-
sue; cystic lesions on CT scans correlate with the
density of cavitary lesions (both inflammatory and
fibrotic) on biopsy.8 Serial studies1,11,20,33,37 indicate
that lesions evolve from nodules to cavitary
nodules, and then to thick-walled and thin-walled
cysts. The extent of cystic lesions correlates with
severity of pulmonary dysfunction (DLCO and
FEV1).37 Even with thick-walled or bizarre cysts,
suggesting advanced/late-stage disease, LCs, and
granulomatous inflammation may be evident.11
These cysts or nodules are associated with areas of
intervening normal lung tissue.20,33 Both the
nodular and cystic lesions may resolve with
cessation of cigarette smoking.11 The cystic radio-
lucencies resemble lymphangioleiomyomatosis
(LAM), but the nodular component is lacking in
Figure 7. Idiopathic pulmonary fibrosis. HRCT scan from
LAM. In addition, LAM affects all lung zones, the patient in Figure 6 (lower lobes). Foci of honeycombing
including the basilar regions. The cysts of PLCH are noted throughout both lungs. Note the peripheral
lack the subpleural, peripheral, and basilar distri- (subpleural) distribution of honeycomb cysts, with relative
bution of the honeycomb cysts noted in idiopathic sparing of the central regions. In addition, prominent septal
pulmonary fibrosis (Figs 6 and 7).35 Ground-glass lines, bands, or fibrosis are apparent. This pattern differs
from the more uniform distribution of cysts seen in patients
opacities (GGOs) have been described in 3% to 20% with pulmonary LCH. Reprinted with permission from
of patients with PLCH3,15,20 but are rarely domi- ACCP Pulmonary Medicine Board Review. 25th ed. North-
nant. When GGOs are prominent, concomitant brook, IL: American College of Chest Physicians; 2009.

tracheal lymphadenopathy may be detected on CT
scans in up to one-third of patients.3
PET Scans
Increased metabolic activity on fluorodeoxy-

glucose PET scan imaging has been noted in
children with osseous LCH38 and adults with
pulmonary or disseminated LCH.39 Data for
adults with PLCH are limited, but positive PET
scan findings were cited for five patients with
PLCH.40 Patients with positive findings on PET
Figure 8. Photomicrograph of a subpleural granulomatous
scans had predominantly nodular inflammatory nodule in a patient with pulmonary LCH. The darker
lung disease (.100 nodules), whereas all patients staining areas within the nodule correspond to inflamma-
with negative findings on PET scans had pre- tory cellular infiltrates. The process extends into the alveolar
dominantly cystic lung disease with fewer interstitium. The pleural surface is at the lower left corner
(hematoxylin-eosin, low-power magnification). Reprinted
nodules (,25 nodules).40 with permission from ACCP Pulmonary Medicine Board
Review. 25th ed. Northbrook, IL: American College of Chest
Pulmonary Function Tests Physicians; 2009.
Pulmonary function test (PFTs) results are Histopathology

abnormal in .80% of patients with PLCH.1,4–
6,19,41
The DLCO is reduced in .75% of patients.3– Histologically, PLCH is characterized by
6,19,20,41
Severe reductions in DLCO are associated inflammatory, cystic, nodular, and fibrotic lesions
with a worse prognosis and correlate with distributed in a bronchocentric fashion.4,6,41,43
radiologic cyst formation. Reductions in vital Vasculitis is not a feature. The diagnosis of PLCH
usually requires thoracoscopic lung biopsy, but
capacity or total lung capacity (TLC) are present
transbronchial biopsies7,19 or CT-guided needle
in 50% to 80% of patients.4–7,19,41 Pure obstruc-
biopsies44 may be adequate provided the salient
tive or mixed obstructive-restrictive patterns are
features are present. Early in the course of the
present in one-third of patients.4–6,41 Air trap-
disease, proliferation of atypical histiocytes (his-
ping (increased residual volume) occurs in
tiocytosis X cells or LCs) dominates.4,6,45 Later,
nearly half of patients with PLCH, but hyperin-
granulomatous inflammation ensues. Fibrosis is
flation (TLC .110% of predicted) is rare.
the end result of the chronic inflammatory
Exercise tests typically demonstrate worsening
cellular lesions. In individual patients, several
gas exchange and increased dead space. 41 histologic features may be present concomitantly
Aberrations in PFTs do not consistently correlate (eg, histiocytic proliferation, granulomatous in-
with radiographic findings. However, a study of flammation, fibrosis, healing, and repair).
26 cases of PLCH noted correlations between The diagnosis of PLCH is suggested on low-
PFTs and CT imaging (semiquantitative).42 The power microscopy by numerous peribronchiolar
extent of cystic lesions on CT scans correlated nodules, numerous cysts, and a distinctive
inversely with FEV1 to FVC ratio, PaO2, and stellate or star-shaped pattern of fibrosis.4,6 The
DLCO, whereas nodular opacities did not. One stellate pattern of fibrosis was observed in 84 of
study of 12 patients with PLCH affirmed that the 100 cases of PLCH reported by Friedman and
extent of cystic lesions on CT scans correlated colleagues.4 The stellate border reflects extension
inversely with FVC and DLCO, whereas nodules of the cellular infiltrate into adjacent alveolar
did not.37 In most patients, PFTs improve or interstitium. Numerous discrete nodular infil-
stabilize over time, but this is variable. Serial trates distributed throughout the lung, inter-
PFTs should be performed to monitor the course spersed with large areas of normal lung
of the disease. parenchyma, can be seen under low-power

of cells.3,45 In PLCH, the cellular lesions are
composed of LCs, admixed with other inflam-
matory cells. Large numbers of macrophages
may be prominent in the alveolar spaces and
interstitium, simulating desquamative interstitial
pneumonia.3,5–7 Eosinophils are prominent in
some cases, mimicking chronic eosinophilic
pneumonia.5–7 However, in some patients, eo-
sinophils are sparse or absent.3 Early lesions
form in terminal and respiratory bronchioles that
invade and destroy the bronchial wall.1 Cavita-
tion may represent the lumen of the preexisting
Figure 9. Photomicrograph of pulmonary LCH. Scattered
bronchiole destroyed by the granulomatous
atypical histiocytes (LCs) are present within a cellular process.1 Bronchioles and alveolar walls are
nodule. LCs are moderately large cells with pale eosino- destroyed and replaced by fibrotic connective
philic cytoplasm and an indented, clefted nuclei (hematox- tissue. Dilated and distorted bronchioles and
ylin-eosin, oil immersion). From Lynch and Raghu.281
Reprinted with permission from ACCP Pulmonary Medicine alveolar parenchymal cysts result. Dense fibrosis
Board Review. 25th ed. Northbrook, IL: American College of (consisting of mature collagen) and intraluminal
Chest Physicians; 2009. fibrosis (consisting of young, organizing connec-
tive tissue within lumens of bronchioles and
magnification (Fig 8). These nodules are peri- alveoli) may be seen.4,7 Intraluminal buds of
bronchiolar in .80% of cases and subpleural in connective tissue resemble cryptogenic organiz-
70%.7 Because most patients with LCH are ing pneumonia (COP).7 Thus, the histopatholog-
smokers, respiratory bronchiolitis (RB) is a ic features of PLCH overlap with those of other
frequent concomitant finding.3,15 Under high- chronic ILDs. Identifying large numbers of LCs
power light microscopy, atypical histiocytes (LCs is the key to the diagnosis. However, late- or
or histiocytosis X cells) are prominent (encom- end-stage PLCH may be relatively acellular, with
passing up to 50% of cells), and are surrounded ,5% LCs and extensive alveolar and honeycomb
by variable numbers of eosinophils, lympho- cysts.1,45 In this context, distinguishing PLCH
from other end-stage chronic fibrotic lung
cytes, plasma cells, fibroblasts, and foci of
disorders is difficult, if not impossible. The
fibrosis.3,4,6 Aggregates of these LCs is the key
retention of a nodular or stellate configuration
histologic feature of PLCH and may be seen
is a clue to the diagnosis.4,6 Because the pattern
within the nodular lesions, air spaces, and
and distribution of lesions is a key to the
alveolar interstitium.4,6,45 LCs can be identified
diagnosis of PLCH, surgical lung biopsies are
by conventional stains (hematoxylin-eosin) on
often required to substantiate the diagnosis.3
high-power light microscopy by an experienced
Transbronchial lung biopsies (TBBs) or BAL are
pathologist.45 They are distinctive, large, ovoid
diagnostic in 10% to 40% of patients,3,7 but
mononuclear phagocytes with moderate significant potential for sampling error exists.1,46
amounts of eosinophilic cytoplasm, a promi- When bronchoscopic specimens are assessed,
nently grooved, folded nucleus, inconspicuous ancillary techniques, such as S100 or CD1a
nucleoli, and finely dispersed chromatin3,6 (Fig 9). stains, are important to substantiate the diagno-
Electron microscopy, which is not necessary sis (discussed below).
for clinical purposes, demonstrates distinctive
42-nm pentalaminar intracytoplasmic inclusions Immunologic Techniques
(termed X bodies or Birbeck granules) within
LCs.1,4,5 LCs also express CD1a antigen (the Immunohistochemical stains may be invalu-
common thymocyte antigen)3 and stain for S100 able in establishing the diagnosis of PLCH when
protein45 (discussed later). LCs are distributed in light microscopic features are not definitive.
normal lung, but rarely constitute more than 4% Positive staining for S100 protein, CD1a antigen,

and human leukocyte antigen DR identifies the structures and play a role in maintaining the
characteristic LCs.3,7 S100 protein can be assayed alveolitis in PLCH. 6,7 In addition to large
in paraffin-embedded biopsy specimens; some numbers of LCs within the cellular lesions,
monoclonal antibodies recognizing the CD1a immune complexes and other inflammatory cells
antigen require fresh or frozen tissue but anti- (eg, lymphocytes, plasma cells, eosinophils,
CD1a antibody O10 recognizes the antigen in mononuclear phagocytes, and foam cells) may
fixed and paraffin-embedded tissues.1 These be present. Interactions between these cells, and
immunohistochemical methods are less expen- release of cytokines, may drive the immune and
sive and less time-consuming than electron fibrotic response molecules.1 LCs serve as acces-
microscopy, and they avoid the sampling prob- sory cells, activating T lymphocytes and recruit-
lems associated with electron microscopy. Large ing other immune effector cells to the lung.1,45
aggregates of S100-positive histiocytes in stellate Tobacco smoke is strongly linked to PLCH. More
nodules or granulomatous lesions are virtually than 90% of patients are smokers,3–7,19,25 and
pathognomonic of PLCH.3 Small numbers of constituents of cigarette smoke are known to
S100-positive cells may be seen in normal lung serve as T-cell mitogens, stimulate macrophage
tissue or BAL fluid, but rarely exceed 4% of cytokine production,52 and induce epithelial cell
cells.47 Staining is most intense in active PLCH production of cytokines (eg, granulocyte-macro-
lesions, and diminishes in the fibrotic regions.47 phage-stimulating factor and transforming
Similarly, LCs express CD1a antigen (recognized growth factor b)1,3,53, that recruit LCs and
by the monoclonal antibody OKT6), but lympho- upregulate lymphostimulatory activity of
cytes and monocytes do not. Rare CD1a-positive LCs.1,45 The number of pulmonary LCs is
histiocytes may be found in BAL fluid from
increased in asymptomatic smokers.54 Cigarette
normal smokers or patients with chronic ILDs
smoking is associated with hyperplasia of pul-
(mean, 0.20%).47 A finding of .4% of cells
monary neuroendocrine cells and increased
expressing CD1a in BAL fluid is relatively
levels of bombesinlike peptides in the lower
specific for PLCH,1,47 but sensitivity is low
respiratory tract.55 Large numbers of bombesin-
(,25%).1 In one study,48 positive immunohisto-
positive neuroendocrine cells have been noted in
chemical staining to a murine monoclonal anti-
surgical lung biopsy specimens in patients with
body (Mab O10) was demonstrated in 33 of 34
PLCH.55 These neuroendocrine cells may con-
paraffin-embedded biopsy specimens from pa-
tribute to the recruitment and activation of
tients with LCH. Langerhans cells also express
mononuclear phagocytes and LCs to the lung
CD4 antigens and both CD1a and CD1c markers,
and stimulate growth of fibroblasts.3 Further,
a family of antigen-presenting molecules.49 In
addition, LCs in PLCH express surface markers cigarette smoke impairs CD10/neutral endopep-
associated with activation, such as B7 molecules, tidase, an enzyme that plays a role in inactivating
that are not present in normal pulmonary LCs.1 bombesinlike peptides.55 Exposure to cigarette
smoke in mice evoked interstitial granulomatous
Pathogenesis inflammation, with features consistent with
PLCH in humans.56 After cessation of exposure,
The pathogenesis of PLCH likely reflects an the density of pulmonary LCs in mice returned to
exaggerated immune response to cigarette smoke normal levels. These data support the assump-
that is initiated or regulated by LCs.36,45 LCs are tion that tobacco products are the major risk
specialized dendritic cells that express the CD1a factor for PLCH.57 However, most cigarette
receptor50 and function to regulate pulmonary smokers do not develop PLCH, in spite of having
responses to exogenous (inhaled) and endoge- an increased population of LCs, suggesting that a
nous (self) antigens.51 The striking bronchocen- ‘‘second hit’’ is necessary for the disease to
tric nature of the inflammatory process suggests occur.45 T lymphocytes (predominantly CD4þ)
a reaction to inhaled antigens or irritants.6,7 are abundant in LCH lesions, and associate
Accumulation of LCs is the earliest lesion to closely with LCs,1 suggesting local production
occur in PLCH.1 LCs replicate in the alveolar of antigen at these sites. The source of antigen is

unknown, but could be derived from cigarette plant (1%). Variables associated with worse
smoke-damaged airway epithelium.45 survival included older age, lower FEV1, high
residual volume, low FEV1 to FVC ratio, and
Course and Prognosis reduced DLCO.26 Another study from the Mayo
Clinic59 noted that the presence of PAH on
The natural history of PLCH is variable, but echocardiogram markedly increased mortality
most patients improve or stabilize within 6 to 12 (hazard ratio [HR], 28.8). This point bears
months of the onset of symptoms.1,2,4–7,20,21 emphasis, since PAH is common in advanced
However, data are limited to retrospective PLCH. In one study of 21 patients with PLCH
studies, with variable treatment regimens. In referred for LT, all patients had PAH (mean
1978, French investigators5 reported 78 cases of pulmonary arterial pressure, 59 mm Hg).23
PLCH. Among 67 cases with follow-up data,
outcomes were as follows: improved (13%), Therapy
stable (40%), worse (21%), and death (25%). The
following factors were associated with a worse Because of the rarity of PLCH and its highly
prognosis: multisystemic generalized disease, variable natural history, the role of therapy is
extensive honeycombing on chest radiographs, controversial.1 Smoking cessation is the primary
severe reductions in DLCO, extremes of age, and and essential component of therapy; the role of
multiple pneumothoraces.4,5,19,25 In 1981, Fried- pharmacologic agents has not been studied in
man et al4 reviewed 100 cases of PLCH con- randomized trials.16,45 A variety of chemothera-
firmed by surgical lung biopsy. Follow-up was peutic regimens have been used to treat dissem-
available in only 60 patients (both treated and inated LCH in children, including vinca alkaloids
untreated). Complete resolution of symptoms (eg, vincristine or vinblastine), etoposide, cladri-
was noted in 33 patients (55%); 22 (37%) had bine (2-chlorodeoxyadenosine), cyclophospha-
persistent symptoms, 5 had a worsened condi- mide, methotrexate, cyclosporine A, and
tion, and only 1 (2%) died. A European study19 antithymocyte globulin.16,60–62 International pro-
followed up 45 patients with PLCH for a median spective randomized trials by the Histiocyte
of 6 years; 12 patients (27%) died or required Society have been conducted since the 1990s in
lung transplant. Median survival from the time children with multisystemic LCH.16,61,63–65 For
of diagnosis was 13 years. Reduced FEV1 to FVC infants or children with high-risk organ involve-
ratio (FEV1/FVC) was an independent predictor ment, intensive multiagent chemotherapy was
of mortality by multivariate analysis. Investiga- more effective than less aggressive regimens65;
tors from the Mayo Clinic58 identified 87 patients however, this approach would not be appropriate
with isolated PLCH diagnosed between 1946 and for adult PLCH. Anecdotal responses were cited
1996 (83 were adults; 84 were smokers). Of these with interleukin 266 and etanercept67 in children
87 patients, 74 (85%) ultimately achieved ‘‘dis- with disseminated LCH, but data are sparse. In
ease-free survival.’’ Treatment regimens included several case reports or small series of bone, skin,
prednisone (58%), chemotherapy (10%), surgical or disseminated LCH, anecdotal responses were
excision (7%), and no treatment (25%). Ten achieved with single-agent therapy with
patients (11%) died; an additional three patients 2-chlorodeoxyadenosine, a purine nucleoside
developed progressive pulmonary disease. A that is toxic to lymphocytes and mono-
subsequent review of 102 cases of PLCH in cytes.60,68–71 Further, favorable responses were
adults from the Mayo Clinic from 1976 to 1998 noted in four adults with PLCH treated with
cited a median survival of 12.5 years; 5- and 10- 2-chlorodeoxyadenosine. 69,71–73 Additionally,
year survival rates after the diagnosis were 74% imatinib mesylate, a tyrosine kinase inhibitor,
and 64%, respectively.26 Only 15 patients (15%) was associated with anecdotal responses in two
died from respiratory failure. Treatment regi- adults with PLCH39 and one with cerebral
mens included smoking cessation (100%), pred- LCH.74 Anecdotal responses in adults with
n i s o n e a l o n e ( 3 9 %) , p r e d n i s o n e p l u s disseminated, skin, or lymph node LCH have
chemotherapeutic agents (15%), and lung trans- been cited with cyclophosphamide and other

cytotoxic agents.16 Importantly, PLCH in adults context, an initial trial of CS (0.5 to 0.75 mg/
likely has a different pathogenesis than child- kg/d, with gradual taper) for 2 to 4 months is
hood LCH, and optimal therapy for PLCH has reasonable. Prolonged therapy should be contin-
not been elucidated. No controlled or prospective ued only for patients manifesting unequivocal
studies have been performed. However, given and objective improvement. For patients with
the strong link between cigarette smoking and severe PLCH recalcitrant to CS therapy and
PLCH in adults, patients must be urged in the cessation of smoking, cladribine,73 imitinib mes-
strongest possible terms to discontinue smoking.3 ylate,39 or immunosuppressive agents could be
In most patients, the disease will stabilize or even considered. Pneumothoraces occur in 15% of
improve after cessation of smoking.3,45 Anecdotal patients with PLCH, and rate of recurrence
responses have been noted in PLCH treated with exceeds 50% when managed conservatively by
corticosteroid (CS) therapy and immunosuppres- observation or chest tube without pleurodesis.22
sive and cytotoxic agents,5,7,9,19,21,25 but the data Therefore, early surgical pleurodesis is justified
may be confounded by the impact of smoking in managing pneumothoraces in patients with
cessation or the potential for spontaneous remis- PLCH. PAH is relatively common in PLCH59 and
sion. One uncontrolled study25 cited radiograph- may reflect a primary vasculopathy (including
ic improvement in 12 of 14 patients treated with veno-occlusive disease).24 Given the high inci-
prednisone for progressive PLCH; the other two dence of PAH in PLCH, I recommend transtho-
patients were stable. In another study, CS therapy racic echocardiography in newly diagnosed cases
was associated with worse survival,19 but this
to estimate right ventricular systolic pressures.
may reflect a selection bias. In the cohort of
The use of vasodilators for treating pulmonary
PLCH reported from the Mayo Clinic, 54 of 102
hypertension in patients with PLCH has not been
patients (53%) were treated with prednisone
extensively studied.23 However, two patients
(alone or combined with immunosuppressive
with PLCH treated with IV epoprostenol devel-
agents).26 Although data were not provided, the
oped acute pulmonary edema.23
authors stated that ‘‘no specific therapeutic
Lung transplant (LT) has been successfully
interventions have been shown to improve
accomplished in patients with PLCH and severe
survival.’’ Given the rarity of PLCH, randomized
respiratory failure refractory to medical therapy.76,77
therapeutic trials are lacking. Radiation therapy
Data from the International Society for Heart and
may be effective for solitary lesions of bone, but
Lung Transplantation (ISHLT) Registry from Janu-
has no role in pulmonary LCH. The role of
immunosuppressive or cytotoxic agents in iso- ary 1995 to June 2004 identified only 39 patients with
lated PLCH in adults has not been established. PLCH among 13,007 lung transplant recipients
The International Histiocyte Society initiated a (0.3%).78 French investigators77 reported that 39
registry of LCH in adults.75 That registry identi- patients with PLCH who had undergone LTat seven
fied 274 adults with LCH from 13 countries: 44 centers in France had 1-, 2-, and 5-year survival rates
(16%) had isolated pulmonary involvement and of 77%, 64%, and 54%, respectively. The disease
188 (69%) had multisystemic disease.75 Treatment recurred in eight patients (20.5%), but did not
regimens varied. Most commonly used therapies influence survival. Recurrent PLCH appears to be
included vinblastine (with or without CS) in 30% more common among those who resume cigarette
and etoposide in 10%. Only 13 patients (30%) smoking76,79,80 or patients with extrapulmonary
with isolated PLCH were treated. Five-year involvement.77 Patients must be vigorously coun-
survival rates were 89% among patients with seled not to resume smoking after LT. Criteria for
isolated PLCH and 92% among patients with listing patients with PLCH for LT are lacking. I
multisystemic involvement. The impact of ther- believe LTshould be considered when the following
apy for PLCH could not be ascertained. Given factors are present: (1) severe respiratory failure
the paucity of data, and the potential for PLCH to despite smoking cessation (eg, FVC ,55% predict-
remit spontaneously or after cessation of smoked; FEV1 ,40% predicted; DLCO ,40% predicted);
ing,1 I reserve therapy for patients with severe, (2) need for supplemental oxygen; and (3) poor and
progressive, or debilitating disease. In this declining quality of life, severe PAH.81

LAM 2004 to 2008 ranged from 0.23 to 0.31 cases per
million women per year.
LAM is a rare disorder characterized by The seminal articles describing pulmonary
hamartomatous proliferation of atypical smooth LAM were published in 1974 and 1975, compris-
muscle along lymphatics in the lung, thorax, ing 32 patients105 and 28 patients, 99 respectively.
abdomen, and pelvis.82–85 Sporadic LAM occurs In 1990, Taylor et al98 described 32 patients with
virtually exclusively in women.84,86,87 LAM can LAM followed up at Stanford and the Mayo
also complicate tuberous sclerosis complex (TSC), a Clinic. In 1995, Kitaichi and colleagues97 de-
genetic disorder discussed later.88–90 Only four scribed 46 patients with LAM from Japan, Korea,
cases of biopsy-confirmed LAM have been report- and Taiwan. Subsequent series from the United
ed in male subjects; three had definite or probable Kingdom,106 France,96 Korea,107 and the United
TSC,91–93 whereas one did not.94 Mean age of onset States83,95 elucidated the clinical spectrum and
of sporadic LAM is between 30 and 45 years; .90% natural history of this disorder. In the United
of cases have been in premenopausal wom- States, a national registry studied 230 patients
en.82,85,86,95–99 Pulmonary LAM may cause progres- enrolled into a national registry established by
sive airflow obstruction, pneumothorax, the National Heart, Lung, and Blood Institute
hemoptysis, or chylothorax.86 Sporadic LAM is (NHLBI). 83 The LAM Foundation (www.
exceptionally rare, with an estimated prevalence of thelamfoundation.org) maintains a separate
1 to 5 per million in the United States,100 United registry in the United States.86
Kingdom,101 France,96 and Asia.97,102,103 A study in
Korea87 cited a surge in diagnosed LAM after 2004, Clinical Features
reflecting enhanced screening with chest CT scan.
Harknett et al104 assessed the prevalence of LAM by The most common symptom of LAM is
using databases from seven countries. The preva- dyspnea, which usually begins in the third or
lence ranged from 3.4 to 7.8 cases per million fourth decade of life and progresses inexorably
women, but there was significant variation be- over years.83–85,95–98 Pneumothorax occurs in 50%
tween countries. Incidence rates in the United to 80% of patients.85,95–98 The rate of recurrent
States, United Kingdom, and Switzerland from pneumothorax is .70%, the highest among all
chronic lung diseases.86,108 Recurrent pneumo-
thoraces in women of childbearing age may be a
clue to the diagnosis.109 Chylous effusions,
resulting from rupture of involved lymphatics
of the pleura, mediastinal lymph nodes, or
thoracic ducts, have been noted in 7% to 39% of
women with LAM.83,85,95–98 Chyloptysis, with
expectoration of white, sticky sputum, may also
occur.83,101,105 Hemoptysis or focal alveolar hem-
orrhage, due to obstruction of venules, occurs in
28% to 40% of patients with LAM.83,95–98 The
course of LAM is usually indolent but inexorable;
most patients ultimately die of respiratory failure
(typically more than 10 years after diagnosis).102
However, the prognosis of LAM is heteroge-
neous, and the impact of therapy is controversial
(discussed later).
Figure 10. LAM. HRCT scan from a 33-year-old woman with
a history of recurrent pneumothoraces shows numerous well- Differential Diagnosis
defined cysts scattered throughout the lung parenchyma.
Board Review. 25th ed. Northbrook, IL: American College of Because of the rarity of LAM and the
Chest Physicians; 2009. nonspecificity of clinical features, the diagnosis

Figure 12. LAM. CT scan from the patient in Figure 11
demonstrates multiple thin-walled cysts of varying sizes in
the lower lobes, with several large confluent cysts. Note that
cysts are scattered relatively evenly throughout the lung,
with neither peripheral nor central predominance. A
nodular component is lacking. Reprinted with permission
Figure 11. LAM. Posteroanterior chest radiograph demon- Northbrook, IL: American College of Chest Physicians; 2009.
strating modest hyperinflation and some cystic and emphy-
sematous changes in a 42-year-old woman with LAM.
Surgical clips are present in the left lung from a previous inflation develops as the degree of airway
thoracotomy for the treatment of recurrent pneumothorax.
obstruction worsens and may be seen in up to
Board Review. 25th ed. Northbrook, IL: American College of two-thirds of patients late in the course of the
Chest Physicians; 2009. disease. Pleural effusions (often chylous due to
is often delayed for 3 to 5 years after the onset of

symptoms.85,86,102 Symptoms may be erroneously
ascribed to chronic bronchitis, asthma, emphyse-
ma, PLCH, or chronic ILD.110 Pulmonary lesions
identical to LAM may occur in patients with
tuberous sclerosis complex (TSC), an autosomal-
dominant familial disorder associated with neu-
rologic and cutaneous manifestations.88,90 By
contrast, sporadic LAM is not familial and is
not associated with either cutaneous or neuro-
logic manifestations.85,110
Chest Radiographic Changes
Plain chest radiographs in LAM are nonspe-

cific but may demonstrate pneumothoraces,
cystic or reticulonodular shadows, pleural effu-
sions, or hyperinflation.85,95–98 Pneumothorax
has been noted in 39% to 53% of patients at the
time of presentation and occurs in approximately
Figure 13. LAM. Posteroanterior chest radiograph from a 41-
80% of patients during the course of the year-old woman with a history of recurrent pneumothora-
disease85,95–98 (Fig 10). Reticulonodular infiltrates ces demonstrates marked hyperinflation and emphysema-
are evident in 47% to .85% of patients.95–98 The tous changes. A reticular pattern is noted in the lower lobes,
which likely reflects the walls of cysts. Reprinted with
reticulation actually represents summation of
numerous cystic walls. Cysts or bullae are 25th ed. Northbrook, IL: American College of Chest
detected in 41% to 58% of patients.95–98 Hyper- Physicians; 2009.

Figure 16. LAM. CT scan (upper lobes) from a 36-year-old
Figure 14. LAM. CT scan from the patient in Figure 13 woman demonstrates small (1 to 3 mm) round cysts
demonstrates multiple thin-walled cystic radiolucencies throughout both lung fields, which is consistent with early
throughout lung parenchyma consistent with LAM. Note changes in LAM. A diffuse background haze (ground-glass
that both the central and peripheral regions of the lungs are opacification) is present, which is consistent with alveolar
involved. Reprinted with permission from ACCP Pulmonary hemorrhage. She had a 12-month history of intermittent
Medicine Board Review. 25th ed. Northbrook, IL: American hemoptysis. Transbronchial lung biopsy specimens demon-
College of Chest Physicians; 2009. strated hemosiderin-laden macrophages (which is consis-
tent with previous hemorrhage) and clusters of smooth
muscle cells (positive for HMB-45), which is consistent with
lymphatic obstruction) occur in 7% to 39% of LAM. Reprinted with permission from ACCP Pulmonary
patients. 83,85,95–98,111 Mediastinal and hilar Medicine Board Review. 25th ed. Northbrook, IL: American
lymphadenopathy are not features of LAM.85,97 College of Chest Physicians; 2009.
normal35,85,95–98,101 (Figs 11–14). Cysts are usu-

HRCT Scans
ally round, but may assume polygonal or
bizarre shapes as multiple cysts coalesce (Fig
Thin-section HRCT scans in LAM reveal
12). In LAM, the cysts are distributed diffusely
numerous thin-walled cysts, ranging in size without predilection for specific regions or
from a few millimeters to 6 cm, throughout lobes. Cavitation is not a feature of pulmonary
both lungs; the intervening lung parenchyma is LAM. Nodules, interstitial fibrosis, or irregular
lung-pleural interfaces—features commonly ob-
served in other chronic ILDs—are absent or a
minor feature in LAM.35 Ground-glass opacities
were not cited in early reports of HRCT imaging
in LAM,98,112 but were noted in 12% (8 of 66)96
and 59% (22 of 37)97 of patients in two series.
GGOs may reflect foci of alveolar hemorrhage,
pulmonary hemosiderosis, or diffuse prolifera-
tion of smooth muscle cells95,96,101 (Figs 15 and
16). Mediastinal or intrathoracic lymphadenop-
athy is unusual.35,97,113 However, retrocrural
adenopathy is common, found in 26% of
Figure 15. LAM. HRCT scan in a 44-year-old woman with patients with LAM in one series.95 Semiquanti-
LAM demonstrates multiple, thin-walled cystic radiolucen- tative and quantitative analyses of extent of
cies bilaterally. Note the two large lesions, representing disease by thin-section CT scan correlate well
confluent cysts. From Lynch and Raghu.281 Reprinted with
with physiologic parameters (eg, FEV1, DLCO,
25th ed. Northbrook, IL: American College of Chest and gas exchange at rest and exercise)114 and
Physicians; 2009. exercise performance.115 Abdominal CT imaging

findings may reveal cysts or angiomyolipomas predictor of exercise-induced hypoxemia.128 Pro-
(AMLs) in the kidney, spleen, or pelvic organs, liferation of smooth muscle cells within the
or retrocrural or para-aortic lymphadenopa- pulmonary interstitium may cause airway obstruc-
thy.95,110,116,117 Pleural calcifications or masses tion, dilation of proximal air spaces, and destruc-
may be sequelae of pleurodesis.117 tion of pulmonary capillaries. Air space cystic
lesions appear to be more important than muscular
Differential Diagnosis of HRCT Imaging proliferation in small airways as a cause of airflow
obstruction.115 Loss of alveolar support and paren-
Cystic radiolucencies may be observed in chymal interdependence may be an important
pulmonary LCH, emphysema, and any chronic contributory mechanism of airflow obstruction. In
end-stage lung disease. However, salient differenc- one study of 143 patients with LAM, a predomi-
es distinguish these entities from LAM. Cysts in nantly solid (as opposed to cystic) histologic pattern
PLCH are preferentially distributed in the upper of LAM lesions in lung biopsy specimens was
and mid lung zones, and a nodular component is associated with a more rapid decline in FEV1.124
usually evident.3,15,110 Honeycomb cysts, a prom- Interestingly, airway inflammation did not corre-
inent feature of idiopathic or collagen vascular late with severity of airflow obstruction or response
disease-associated pulmonary fibrosis, are distrib- to bronchodilators.124
uted in the peripheral (subpleural) regions of the In a retrospective review of the NIH experi-
lungs and are nearly invariably accompanied by ence,102 response to bronchodilators was associated
linear bands, distortion of lung parenchyma, or with a greater rate of decline in FEV1 and DLCO in
GGOs.118 Severe, end-stage LAM may give rise to patients with LAM than in nonresponders. Reduc-
large cysts that may resemble bullous emphysema; tions in FEV1 to FVC ratio and increased TLC have
however, emphysematous lesions lack discernible been associated with a worse prognosis and poor
walls and typically have an upper lobe predomi- survival.97,125 By contrast, FVC, FEV1, arterial blood
nance. The cysts in LAM are more regular and have gases, and alveolar-arterial gradient did not predict
well-formed walls.95,98 Other rare causes of cystic survival.97,125 The rate of progression of airflow
lung disease include lymphocytic interstitial pneu- obstruction is highly variable, ranging from a few
monia,119 Sjogren syndrome,120 hypersensitivity years to more than two decades.102,103,124 A review
pneumonitis,121 amyloidosis,120 light chain deposi- of 47 patients with LAM in the United Kingdom
tion disease,122 and Birt-Hogg-Dubé syndrome.123 cited a mean fall in FEV1 of 118 mL/y, but there was
marked variability between patients.106 French
PFTs investigators96 cited a mean decline in FEV1 of 106
mL/y among 31 patients with LAM. A study of 275
Early in the course of LAM, spirometry results patients with LAM in the United States followed up
may be normal.83,86,96,97 The DLCO is reduced in for 5 years cited annual declines in FEV1 ranging
.65% of patients.83,95–98,124 An obstructive ventila- from 52 to 119 mL.129 The most significant
tory defect, often with air trapping, has been cited predictors of functional decline were initial lung
in 29% to 78% of patients; lung volumes are normal function and age. The rate of decline in FEV1 was
or increased.95–98,125 Restrictive defects in LAM lower in older patients. Conversely, patients with
may reflect chylous pleural effusions or effects of higher initial FEV1 and DLCO (less severe disease)
prior pneumothoraces or pleurodesis.114,124,126 Im- had more rapid declines in DLCO.129 A nationwide
pairments in exercise performance and gas ex- study in Japan103 of 173 patients with LAM cited a
change correlate with the extent of cystic disease on slower rate of decline in lung function among
quantitative CT imaging.115,127 Cardiopulmonary patients presenting with pneumothorax. However,
exercise testing typically demonstrates impair- another study in the United States130 showed that
ments in maximum oxygen uptake (V̇O2max).128 pneumothorax was associated with a lower FEV1
Reductions in V̇O2max correlate with increasing and more rapid decline in FEV1 than for those
severity of disease by CT imaging and histologic without pneumothorax.
criteria.128 By multivariate analysis, FEV1 and DLCO Airflow obstruction is the most important
correlate with V̇O2max.128 Reduced DLCO is the best factor responsible for exercise limitation, but

pulmonary vascular involvement plays a con-
tributory role.115 PAH at rest in LAM is uncom-
mon (,10% of cases),131 but may be elicited by
exercise.132 In one study,132 echocardiography
was performed at rest and during exercise in 95
patients with LAM. By echocardiographic crite-
ria, PAH was present (systolic pulmonary artery
pressure .40 mm Hg) in eight patients at rest but
was elicited by exercise in 56 (59%). Exercise
arterial oxygen saturation (SaO2) was the best
predictor of exercise-induced PAH.
Pathology Figure 17. Photomicrograph of LAM. Open-lung biopsy

specimen demonstrating the proliferation of atypical
smooth muscle cells within the alveolar interstitium, which
Grossly, the lungs in LAM may first appear
is consistent with LAM (hematoxylin-eosin, high-power
emphysematous. However, as the disease pro- magnification). Reprinted with permission from ACCP
gresses, the entire lung is replaced by cysts. Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
Histologically, LAM is characterized by prolifer- American College of Chest Physicians; 2009.
ation of atypical interstitial smooth muscle and
thin-walled cysts within lung, renal parenchyma, proliferation or hemosiderosis do not correlate
uterus, lymph nodes, or affected organs.85,99,105,110 with survival.97,125 LAM histology scores, based
Unlike other forms of ILD, there is very little on the extent of replacement of lung tissue by
fibrosis in LAM. The smooth muscle cells are cystic lesions and infiltration of LAM cells, are a
heterogeneous and may exhibit features of large predictor of mortality.102,113
spindle cells, smaller cells with little cytoplasm, or
epithelioid cells.85,110 The LAM cells grow in a Immunohistochemical Stains and Ancillary
haphazard arrangement, unlike the orderly pat- Diagnostic Techniques
terns of organization of normal smooth muscle
cells.133 In pulmonary LAM, surgical lung biopsy Smooth muscle cells in pulmonary LAM are
specimens demonstrate both cystic lesions and similar histologically and by immunohistochem-
muscular lesions (ie, proliferation of immature ical analysis to AMLs, which are benign mesen-
smooth muscle cells)97,102 (Fig 17). Nodular chymal tumors consisting of blood vessels,
proliferations of immature smooth muscle sur- abnormal smooth muscle, and fat.84,134–136 Im-
round airways, blood vessels, and lymphatics, munohistochemical staining is positive for mus-
and extend into bronchioles and alveolar intersti- cle-specific actin, desmin, human melanoma
tium. Destruction of alveolar parenchyma forms black-45 (HMB-45),84,136–139 other melanoma-as-
cysts, which are surrounded by immature smooth sociated antigens (eg, gp100 and melanoma
muscle. The walls of the cysts are typically ,2 antigen recognized by T cells [MART-1]), and
mm thick.84,102 Pneumothoraces result from rup- tyrosinase-related proteins TRP-1 and TRP-2.137,138
ture of subpleural cysts.84,96 Proliferating smooth HMB-45 immunoreactivity in smooth muscle is
muscle may obstruct pulmonary venules (causing highly specific for LAM, AMLs, and clear cell
focal edema and pulmonary hemorrhage) or tumor of the lung, but is never found in normal
lymphatics (leading to chylothorax).96,98,99 Hemo- smooth muscle.84 The immunohistochemical reac-
siderin-laden macrophages within alveolar spac- tivity of LAM cells is localized more frequently in
es or interstitium may be a clue to previous the large epithelioid cells.113 LAM cells also express
episodes of hemorrhage.96,97 The extent of cystic two lymphangiogenic growth factors, vascular
or smooth muscle lesions on surgical lung biopsy endothelial growth factor (VEGF) C and VEGF-
has prognostic significance. Predominantly cystic D,100 and spread through lymphatic channels.140
LAM lesions suggest a worse prognosis and Receptors for progesterone and estrogen have been
survival, whereas grades of smooth muscle noted in the nuclei of proliferating smooth muscle

cells in some patients with LAM,96,98 but these including podoplanin, VEGF receptor-3 and
findings are not uniform.102,141 VEGF-C.140 VEGF-D is elevated more than three-
fold in serum of patients with LAM136,147 and may
Diagnosis of LAM prove to be a useful biomarker for LAM. Possible
sources of LAM cells include AMLs, lymphatic or
Historically, the diagnosis of pulmonary bone marrow cells, uterine or ovarian cells, or cells
LAM required surgical lung biopsy.98,99,105 It of neural crest origin.86
was often diagnosed inadvertently, at the time Renal or abdominal AMLs (HMB-45 posi-
of thoracotomy for recurrent pneumothoraces.98 tive), have been noted in 15% to 54% of patients
The presence of innumerable small cysts with pulmonary LAM and often antedate the
throughout the lung surface without nodularity diagnosis of pulmonary LAM.95,96,116,117,148 Uter-
or interstitial fibrosis is virtually pathognomonic ine leiomyomas were cited in 41% of patients
for LAM.98 Transbronchial lung biopsy speci- with LAM in one study.96 In a recent histologic
mens may substantiate the diagnosis in some study,146 LAM lesions were detected in the uterus
cases but requires a skillful pathologist.96–98 in 9 of 10 women with pulmonary LAM and in 0
Unless the pathologist is familiar with the salient of 10 women without pulmonary LAM. Ryu et
histologic features, the abnormal smooth muscle al149 evaluated chest CT scans from 176 subjects
cells are often misinterpreted as fibrocytes. Given with sporadic renal AMLs (no prior history of
the sampling variability, we do not recommend
LAM or TSC) seen at the Mayo Clinic between
TBBs to diagnose suspected pulmonary LAM.
1997 and 2006 and from176 controls without renal
Surgical lung biopsy is the gold standard, but is
AMLs (matched for age, sex, and smoking
usually not necessary, provided HRCT imaging
history).149 Interestingly, 81.8% of subjects with
features are characteristic, clinical criteria are
renal AMLs were women. Nine women (5.1%)
consistent, and any of the following features are
with renal AMLs had 4 cystic lesions on chest
present: typical renal AMLs, chronic chylous
CT scan whereas none of the controls had 4 or
ascites with abdominal lymphadenopathy, and
more cystic lesions. Angiomyolipomas are often
characteristic histopathologic findings on lymph
incidental findings on CT, but growth of these
node biopsy.85,86 Commercially available blood
smooth muscle tumors may cause local pain,
tests have no diagnostic value in LAM. However,
bleeding, chylous ascites, or compression of
serum VEGF-D may be an excellent screen for
contiguous structures.136,148 AMLs are hyper-
pulmonary cyst development in women with
echogenic on ultrasonography and reveal fat
TSC142 and may distinguish LAM from other
cystic lung disease.143 attenuation on CT.95,101 CT scanning is the best
screening test to assess the presence, size, and
Extrapulmonary Involvement extent of renal or intraabdominal cysts or AMLs
in patients with pulmonary LAM.116 In one
AMLs or cysts may involve abdominal or prospective study,116 eighty patients with LAM
retroperitoneal lymph nodes, spleen, kidney, had chest and abdominopelvic CT, and abdom-
periadrenal blood vessels, liver, uterus, and inopelvic ultrasonography. Intraabdominal le-
ovaries.116,133,135,144 The source of LAM cells sions were detected in 61 patients (76%),
(atypical proliferating smooth muscle cells) is including renal AMLs in 43 (54%), enlarged
not known, but there is direct evidence for abdominal lymph nodes in 31 (39%), lymphan-
blood-borne and lymphatic dissemination of giomyoma in 13 (16%), ascites in 8 (10%),
LAM.86,135,140,145 The frequent presence of LAM dilatation of the thoracic duct in 7 (9%), and
lesions in uterus and retroperitoneal lymph nodes hepatic AMLs in 3 (4%).116 Ultrasonography and
in women with pulmonary LAM suggests that the abdominal CT scans may have complementary
uterus or pelvic cavity may be the primary site of roles in the diagnosis and follow-up of abdom-
origin of LAM.146 Induction of lymphangiogenesis inal and pelvic manifestations of LAM.85,116 The
may be important.136 Lymphatic endothelial European Respiratory Society Guidelines on
markers are expressed abundantly in LAM, LAM recommend an initial abdominal CT scan

to detect AMLs, lymphangioleiomyomas, or with LAM if they have ‘‘symptoms compatible
lymphadenopathy in all patients with LAM.85 with meningioma’’ or if progesterone is being
Appropriate management of renal AMLs or administered or its use is planned.85
cysts depends on size, growth rate, and presence or
absence of symptoms. AMLs are often incidental TSC
findings noted on CT scans but may cause pain,
local bleeding, compression of renal parenchyma, TSC, an autosomal-dominant disorder with
and impaired renal function.95,136,148 The risk for high penetrance and variable expressivity, shares
local complications is increased for lesions .4 cm in some features with LAM (eg, extrapulmonary
size.136,148 Asymptomatic patients with lesions ,4 AMLs; hamartomatous proliferation of smooth
cm in greatest dimension can be followed up with muscle; pulmonary LAM).86,88,90 TSC affects 1 in
yearly ultrasonography or CT scanning; lesions .4 5,800 individuals90,153 and is far more common than
cm in size or causing symptoms should be followed sporadic LAM (S-LAM).86 Both S-LAM and TSC
up no less often than at 6-month intervals.85,148 are caused by mutations in the tuberous sclerosis
Expanding or symptomatic lesions .4 cm in size genes TSC1 and TSC2 that control cell growth,
should be treated with embolization or sur- survival, and motility through the Akt/mammali-
gery.85,148 Partial or total nephrectomy may be an target of rapamycin signaling pathway.86,90
required to manage complications (eg, hemorrhage TSC affects the migration and differentiation
and refractory pain).85,148 An increased risk for of neural crest cells and affects multiple tissues
renal cell carcinoma has been noted in patients with including skin, central nervous system, lymphat-
TSC and AML.131 ics, bone, and lung.90 Up to 60% of cases of TSC
LAM involving lymphatics may lead to ade- are sporadic, with no family history.88,90 Both
nopathy, lymphangioleiomyomas, or chylous effu- males and females can be affected with TSC.
sions (pleural or peritoneal).85,135,136 Adenopathy is Clinical features commonly observed with TSC
found in 39% of patients with sporadic LAM.116,136 include mental retardation, seizures, digital
Histologically, lymph nodes are replaced by atyp- fibromas, sebaceous adenomas, ash-leaf-shaped
ical smooth muscle cells.136 CT scans may reveal depigmented skin lesions, sclerotic bone lesions,
enlarged lymph nodes with areas of low attenua- and cranial calcifications.88,90 These features are
tion that represent collections of chyle (lymphatic not present in sporadic LAM.88,153 The pheno-
fluid).116,136 Lymphangioleiomyomas appear on typic expression of TSC is variable, but 75% of
CT scans as circumscribed lobular masses.116,133 patients die by the age of 20 years.148 However, in
Chyle-filled cystic lesions may result from the 12% to 20% of patients with TSC, the diagnosis is
obstruction of lymphatic vessels by proliferating made in adulthood,88,154 often after TSC was
LAM cells.116,136 Lymphangioleiomyomas are more identified in an offspring.88
common in sporadic LAM (26%) than LAM Sporadic LAM and TSC-associated LAM
complicating TSC (9%).150 Expanding lesions can (TSC-LAM) share many common clinical and
displace abdominal vicera, causing pain, obstipa- radiographic features. Early studies96,101,155,156
tion, urinary frequency, or ascites.116,136 There is no cited pulmonary lesions indistinguishable radio-
treatment of lymphangioleiomyomas, but a clinical graphically and histopathologically from LAM in
trial using octreotide, a somatostatin analogue used 1% to 4% of patients with TSC. Subsequent
to treat chylothorax in neonates and children,151 is studies113,153,157 suggest that the prevalence of
in progress.136 pulmonary LAM among women with TSC is
Brain involvement is not a feature of LAM. much higher (26%–39%). However, pulmonary
However, the prevalence of meningiomas ap- manifestations are typically milder in TSC-LAM
pears to be increased in LAM and TSC.152 In one and the rate of progression is slower.102,110 In one
prospective study, 152 meningiomas were found prospective study,113 screening HRCT scans were
in 8 of 250 women with LAM by MRI (three had performed in 48 patients with TSC who had no
TSC; five had been treated with progesterone). pulmonary symptoms, no prior history of LAM,
The European Respiratory Society Guidelines on and normal PFTs. Pulmonary cysts consistent
LAM recommend brain MRI scans in women with LAM were detected in 13 of 38 female

patients (34%) but in none of 10 male patients mutation is not found in LAM, sequential somatic
with TSC. Similarly, a retrospective study of 78 mutations of the TSC2 gene likely occur in LAM.
women with TSC detected pulmonary LAM in 20
(26%) (by CT imaging in 13, by surgical lung Pathogenesis
biopsy or autopsy in 7).157 Since a minority of
patients with TSC develop pulmonary LAM, Significant advances in the understanding of
additional mutations or environmental factors the pathogenesis of the smooth muscle pro-
are likely required for disease expression. Renal liferation in LAM have been made within the past
or abdominal AMLs are found in 15% to 45% of decade (discussed in detail else-
patients with S-LAM95,96,116,117,148,150 and in where).86,102,153,160,161 Since sporadic LAM only
.80% of patients with TSC.96,112,150,156 Patients affects females (with rare exceptions), estrogens
with TSC-LAM have a higher frequency of likely play a key role in the pathogenesis.82,86 LAM
hepatic (33% vs. 2%) and renal (93% vs. 32%) occurs nearly predominantly in premenopausal
AMLs than S-LAM but have a lower incidence of women, and exogenous or endogenous estrogens
pleural effusion (6% vs. 12%) or ascites (6% vs. accelerate the course of the disease.82,86 LAM cells
10%) than S-LAM.150 Interestingly, AMLs in both and AML cells express estrogen receptors.161,162
LAM and TSC express the antimelanoma mono- One postulate is that estrogen signals through Akt
and releases the tuberin-deficient or hamartin-
clonal antibody HMB-45, suggesting a common
deficient cell from feedback inhibition, resulting
origin from a progenitor smooth muscle
in abnormal proliferation.86 Estrogen and tamoxi-
cell.88,96,148,153 Identical chromosomal abnormal-
fen stimulate growth of LAM-associated AML cells
ities (13q14 and 14q24) are noted in TSC, S-LAM,
in culture.163 In mice, estrogens (ie, 17b-estradiol)
and uterine leiomyomas.86,153 Both leiomyomas
promoted growth and metastasis of TSC2-null
and S-LAM involve proliferation of smooth
tumors, via activation of p42/44 MAPK path-
muscle in women of childbearing age.86,153
way.164 Thus, estrogen may promote the survival
In both TSC and S-LAM, mutations in one of
and metastasis of TSC2-deficient cells in LAM.165
two genes (TSC1 or TSC2) are present (mutations in
LAM cells have high mitotic and low apoptotic
TSC2 are more common in both disorders).86,90,153
activities, which are important in their proliferative
Tumor suppressor genes TSC1 and TSC2 encode
behavior.166 LAM cells consist of two subpopula-
proteins known as hamartin and tuberin, respec- tions: myofibroblastlike spindle-shaped cells and
tively.86,153 In TSC, a germ line mutation (ie, first hit) epithelioidlike polygonal cells.82,135 Spindle-
is present in all cells in the body.90 Neoplasms and shaped cells express smooth muscle-specific pro-
dysplasias occur when somatic ‘‘second-hit’’ mu- teins (ie, smooth muscle a-actin, desmin, and
tations result in ‘‘loss of heterozygosity’’ for the vimentin), and display high rates of proliferation.82
normal allele.86,153 This results in loss of function of By contrast, the epithelioidlike cells exhibit lower
either TSC1 (hamartin) or TSC2 (tuberin) pro- rates of proliferation.82 Both cell types express
teins.153 Because TSC genes suppress tumor melanoma-associated proteins HMB-45 and
growth, this additional mutation allows cellular CD63.153 LAM-derived cells express lymphangio-
proliferation and the formation of hamartomas.153 genic growth factors (VEGF-C and VEGF-
TSC1 mutations in general are associated with D).140,142,147 Expression of VEGF-C in LAM cells
milder disease severity than TSC2 mutations.158 correlated with the histologic severity of the lung
Germ line mutations are present in all cells of the lesion.140 Further, serum concentrations of VEGF-D
body in TSC or TSC-LAM, whereas in sporadic were elevated in patients with LAM and correlated
LAM, both the first-hit and second-hit mutations negatively with pulmonary function.147 Young et
are confined to lesions in the lung, kidney, and al142 affirmed elevated serum VEGF-D levels in
lymph nodes.86 Loss of heterozygosity for TSC2 pulmonary LAM but not miscellaneous cystic lung
(but not TSC1) was found in renal AMLs from 7 of diseases. In one study,167 serum VEGF-D levels
14 patients with LAM without clinical features of were elevated in patients with LAM, compared to
TSC.159 A similar lesion was found in AMLs in healthy volunteers, but only in patients with
patients without LAM or TSC.101 Since a germ line lymphatic involvement. Elevated VEFG-D levels

correlated with greater lymphatic involvement, disease. Data from Asia cited survival rates of
lower initial DLCO, more severe extent of disease .70% at 5 years after the onset of LAM but only
on chest CT scan, and low incidence of AMLs.167 In 38% (10 of 26 patients) at 8.5 years.97 A study of
patients with pulmonary LAM without lymphatic 69 patients with LAM in France cited survival
involvement, serum VEGF-D levels were similar to rates (by Kaplan-Meier analysis) of 91% at 5
those of healthy controls. Interestingly, VEGF-D years, 79% at 10 years, and 71% after 15 years.96
levels were lower in patients with AML than those In a study of 57 LAM patients from the United
without AMLs. These data suggest that serum Kingdom, 10-year survival from the onset of
VEGF-D is not a sensitive marker to diagnose symptoms was 91%.173 Similarly, a report of 227
isolated pulmonary LAM, but may be a marker of patients with LAM in the United States cited a
lymphatic involvement. In one study of pulmonary 10-year survival rate of 92%.130 Italian investiga-
LAM,100 VEGF-D levels were reduced after treat- tors174 followed up 36 women with LAM for a
ment with sirolimus. Matrix metalloproteinases mean of 9.8 years; 5- and 10-year survival rates
(MMPs) likely play a role in the development of were 97% and 90%, respectively.
pulmonary cystic lesions in LAM.168 LAM cells
contain increased amounts of MMPs, especially Treatment
MMP-2, but also MMP-1 and MMP-9.168
Until recently, LAM was considered benign. Owing to the rarity of LAM, optimal therapy
However, LAM cells may be found in multiple has not been determined.175,83,86,129 With the
sites (eg, renal AMLs, lung, chylous effusions, exception of sirolimus (discussed later), no
lymph nodes, blood, and urine), suggesting randomized or controlled studies have been
metastatic behavior.135,153,166 Despite a benign performed. Corticosteroids, immunosuppressive
histologic appearance, LAM shares neoplastic agents, cytotoxic drugs, and radiation therapy
characteristics including unregulated growth, have no role in LAM. Because LAM is exclusive-
lymphatic or vascular spread, and tissue destruc- ly a disease of women and appears to be
tion.86,102,169 LAM cells express several melano- exacerbated by estrogens, physicians should
ma markers (eg, gp100, MART-1)138 and HMB- counsel against pregnancy or the use of exoge-
45,153 consistent with a neoplastic origin. Further, nous estrogens.96,101,106,175 However, any final
LAM lesions display enhanced expression of decision regarding pregnancy must be left to the
metastasis-associated CD44 splice variant 6,170 patient.85 Historically, diverse estrogen-ablative
supporting the hypothesis that multiorgan in- therapies were tried (eg, oophorectomy; admin-
volvement in sporadic LAM reflects metastatic istration of antiestrogen regimens—eg, proges-
spread. Recurrent LAM cells displaying the terone, tamoxifen, androgens, lynestrenol,
identical TSC mutations noted in the explanted luteinizing hormone-releasing hormone antago-
lung have been observed in the donor lung,171,172 nists [eg, goserelin], gonadotropin-releasing hor-
consistent with metastases. mone agonists [eg, leuprolide acetate], and
somatostatin).95–98,101,106,107 However, these ther-
Course and Prognosis of LAM apies are of unproven benefit. Data are discour-
aging but are limited by retrospective analyses
The course of LAM is indolent, but most and small numbers of patients. In a retrospective
patients ultimately die of respiratory fail- review from Stanford and the Mayo Clinic,98
ure.84,85,102 However, the pace of the disease is oophorectomy alone was ineffective in all 16
extremely variable. Early retrospective re- patients. None of nine patients treated with
views99,105 cited 5- and 10-year survival rates of tamoxifen improved, while 2 of 19 treated with
only 60% and 20%, respectively. Subsequent intramuscular medroxyprogesterone acetate
studies noted improved survival, which likely alone stabilized or improved.98 In 1995, Kitaichi
reflects earlier diagnosis (particularly with the et al97 retrospectively evaluated 40 treatment
advent of CT scans). In 1990, Taylor et al98 courses in patients with LAM. Only 2 patients
reported that 25 of 32 patients with LAM (78%) improved; 9 remained stable, while 29 deterio-
were alive a mean of 8.5 years after onset of the rated. Oophorectomy or progesterone alone was

never effective. The combination of oophorecto- Sirolimus, a macrolide with immunosuppres-
my and progesterone was associated with dete- sive properties, inhibits the activity of the mamma-
rioration in nine, stability in one, and lian target of rapamycin, suppresses smooth
improvement in one. Gonadotropin-releasing muscle proliferation, and suppresses DNA synthe-
hormone agonists were ineffective in all six sis of LAM cells in vitro.153,176 Further, sirolimus
patients. Tamoxifen (alone or in combination induced remission of renal AMLs in patients with
with other agents), was given to 13; only one TSC or LAM.144,177 In one nonrandomized open-
improved. Tamoxifen has partial estrogen ago- label trial,144 16 patients with TSC or LAM were
nist activity, which raises concerns about its treated with oral sirolimus for up to 2 years. AML
potential to exacerbate the proliferative process.101 diameters were reduced in all 16 patients; most
French investigators96 identified 69 women with shrinkage occurred during the first year of treat-
LAM from 1973 to 1996. Diverse hormonal ment. In another open-label trial,134 25 patients with
therapies were administered in 57 patients (84%). AMLs were treated with sirolimus for 12 months; 5
Treatments included progesterone (n ¼ 46), ta- had TSC only and 18 women had LAM (sporadic or
moxifen (n ¼ 22), gonadotropin-releasing hor- associated with TSC). After 12 months of therapy,
mone agonists (n ¼ 14), somatostatin (n ¼ 6), and the mean volume of AML lesions fell by nearly 50%.
oophorectomy (n ¼ 5). Among 34 patients with Further, among 11 female patients with LAM, mean
serial PFTs, FEV1 improved by 15% in only four FEV1 increased above baseline by 118 mL and FVC
patients. A retrospective analysis of 43 patients increased by 390 mL at 12 months.134 These
beneficial effects tended to reverse after the drug
with LAM in the United Kingdom suggested that
was withdrawn. In the Multicenter International
progesterone may slow the rate of decline of
LAM Efficacy of Sirolimus (MILES) Trial,100 a total
pulmonary function tests (FEV1, TLC),106 but
of 89 patients with LAM were randomly assigned
differences did not achieve statistical significance.
to sirolimus or placebo for 12 months, followed by a
In a subsequent retrospective study by these
12-month observation period (without therapy).
investigators,173 factors influencing disease pro-
During the treatment period, the FEV1 slope was
gression were assessed in a cohort of 57 LAM
12 mL/mo in the placebo group compared to þ1
patients, 36 of whom had been treated with
mL/mo in the sirolimus group. The absolute
progesterone. There was more rapid progression
between-group difference in the mean change in
of dyspnea among patients treated with proges-
FEV1 during the treatment group was 153 mL.
terone (HR, 2.2), those who became pregnant after
Further, in the sirolimus group, statistically signif-
the onset of symptoms (HR, 2.7), and cigarette icant improvements from baseline to 12 months
smokers (HR, 2.0). These associations were of were noted in FVC, functional residual capacity,
borderline statistical significance. These data do serum VEGF-D levels, quality of life, and functional
not support a beneficial effect of progesterone on performance. There was no significant difference
lung function. A larger study from the United between groups in change in 6-minute walk
States129 followed up 275 patients with LAM for distance or DLCO. After discontinuation of siroli-
approximately 4 years. Overall, 139 patients (50%) mus, the decline in lung function in the sirolimus
were treated with progesterone (67, oral; 72, IM). group paralleled that of the placebo group. Thus,
No benefit in rates of decline in FEV1 or DLCO was consistent with the earlier study,134 the beneficial
noted among patients receiving progesterone effect of sirolimus was not sustained. An off-label
compared to untreated patients. Absolute annual study from the NIH affirmed the efficacy of
declines in FEV1 were 59 mL among patients not sirolimus in a cohort of 19 women with progressive
treated with progesterone versus declines of 119 LAM or chylous effusion(s).126 After beginning
mL/y and 76 mL/y among patients treated with sirolimus therapy, 12 patients with chylous effu-
oral or IM progesterone, respectively.129 Data from sions and 11 patients with lymphangioleiomyomas
these various clinical series96–98,106,107,129,173 sug- experienced almost complete resolution of these
gest that estrogen-ablative therapies are of limited conditions.126 Consistent with the MILES study,100
or no value. I do not recommend antihormonal during sirolimus therapy (for a mean of 2.6 years),
therapies for LAM. FEV1 increased by 50 mL/y compared to 100 mL

decrease in FEV1 over a mean duration of 2.5 years Bronchodilators and supplemental oxygen
before sirolimus therapy.126 Neurohr et al178 treated have adjunctive roles in selected patients with
10 women with progressive pulmonary LAM with pulmonary LAM.95,96,101 Sildenafil or vasodila-
sirolimus. The mean change in FEV1 was2.30 mL/ tors have a theoretical role among patients with
d before therapy and þ1.19 mL/d gain after PAH complicating LAM,132 but data are lacking.
sirolimus therapy. At 3 and 6 months, FEV1 had
increased by 220 mL and 345 mL from baseline, Management of Chylous Effusions and
respectively. Sirolimus was discontinued in three Pneumothoraces in LAM
patients because of adverse effects. Additional case
reports cited improvement with sirolimus for Pneumothoraces complicate LAM in 50% to
chylothorax,179,180 retroperitoneal AML,181 abdom- 80% of patients; chylothoraces, in 10% to
inal and pelvic masses and chylous effusion,182 and 39%.83,95,96,101,189 Both complications may occur
pulmonary LAM.180,183 These various studies are repetitively in individual patients, mandating an
encouraging and support a role for sirolimus for aggressive surgical approach to therapy. Thora-
patients with progressive LAM or chylous effu- costomy tubes may be adequate for pneumotho-
sions. However, given the potential for serious rax or chylothorax in some patients, but
adverse effects with long-term use of sirolimus, recurrences are common.86,95,96,111 Video-assisted
appropriate patient selection, indications for ther- thoracoscopic surgery (VATS) with pleurodesis is
apy, and dose and duration of therapy have not yet warranted for recurrent pneumothoraces or
been elucidated. Importantly, sirolimus may impair chylothoraces complicating LAM.111 Manage-
wound healing and should be discontinued for ment of chylous pleural effusions or ascites in
several weeks for patients listed for lung transplant. patients with LAM is difficult. Dietary fat
The use of statins has been considered, since restriction, peritoneal-jugular shunts, and scle-
simvastatin inhibits migration of human LAM cell rosing agents have been tried but are usually
cultures and LAM cell proliferation.153 Further, ineffectual.95,96,101,111 Given the rarity of LAM,
combined treatment with simvastatin and siroli- optimal management of chylous effusions is
mus abrograted cell proliferation to a greater controversial. The approach should be individu-
degree than either agent alone.153 However, El- alized, taking into account the severity or
Chemaly and colleagues184 retrospectively evalu- persistence of chylothorax, comorbidities, and
ated 335 patients with LAM followed up at the NIH local expertise.111 I recommend a trial of medical
since 1996 (44 had taken statins). After adjusting for therapy with sirolimus. For refractory chylotho-
age, rates of decline in FEV1 were similar between rax, I favor VATS with talc pleurodesis and
both groups; annual rate of decline in DLCO was thoracic duct ligation. Placement of a pleuro-
greater among patients taking statins than matched venous shunt led to successful resolution of
controls.184 Another clinical trial in progress at the chylous pleural effusions in one patient with
NHLBI is evaluating octreotide,86 which has shown LAM and persistent chylothoraces refractory to
promise for treating chylous complications in other pleurodesis and thoracic duct ligation.190
diseases.185
Doxycycline, an inhibitor of MMPs, inhibited LT for LAM
MMP-2 secretion from human LAM cells and
TSC2-null mouse embryonic fibroblasts in vitro.186 Single- or double-lung transplant has been
Doxycycline was associated with improvement in successful in patients with LAM and end-stage
FEV1 in one patient with LAM.187 A potential role of pulmonary insufficiency.191–195 Data from the
doxycycline as therapy for LAM is being examined ISHLT Registry from January 1995 to June 2009
in a placebo-controlled trial in England.102 identified 274 patients with LAM among 25,938
LAM cells express melanoma-associated an- lung transplant recipients worldwide (1.1%).196
tigens, and a subset of LAM cells are susceptible Survival rates following LT for LAM are similar
to cytotoxic T cells directed against melanoma to other indications (3-year survival, 73%-
antigens.137 Thus, immunotherapy (eg, vaccines) 76%).191–194 When to list patients with LAM for
may be an option,138,188 but studies are lacking. LT is difficult, as the prognosis is highly variable

among patients. Guidelines for LT in LAM therapy,220,221 chemotherapy,222–225 malignan-
include the following: disease progression de- cy,226–228 lung cancer,229 hematopoietic stem cell
spite medical therapy, FEV1 to FVC ratio ,50%, transplants,230–233 lung or heart-lung234 trans-
TLC .130%, FEV1 ,30%, and severe cystic plants, or may be a reaction to pharmacologic or
disease on HRCT scanning.197 LAM-associated exogenous agents.204,235–237 I will discuss only
complications of LT include massive operative idiopathic (cryptogenic) OP, a disorder in which
hemorrhage due to extensive pleural adhesions, no specific etiology can be established.
pneumothorax in the native lung (for single-lung
transplant recipients), and postoperative chylo- Epidemiology
thorax.189,193,194 Prior pleurectomy or talc pleu-
rodesis can create difficulties with tissue plane The incidence of COP is difficult to ascertain,
dissection and bleeding during removal of the as historically a variety of terms were used
native lung(s).189 In one study of 80 patients with interchangeably to refer to this disorder (eg,
LAM who had LT, pleural-related postoperative organizing pneumonia, cryptogenic organizing
bleeding occurred in 13 of 45 patients with prior pneumonia, bronchiolitis obliterans organizing
pleurodesis, compared to 1 of 35 without prior pneumonia, bronchiolitis obliterans, and resolv-
pleurodesis.189 LAM recurrence in the donor ing pneumonia). Nonetheless, COP (or idiopathic
lung allograft has been noted in 3% to 8% of LT BOOP) is rare, and most referral centers see no
recipients.86,193,194 Molecular techniques con- more than two to five cases per year. In 1983,
firmed that foci of LAM in lung allografts were Davison and colleagues238 described eight pa-
derived from the recipient,171,172 indicating that tients with ‘‘cryptogenic organizing pneumonia.’’
LAM cells can migrate or metastasize despite In 1985, Epler and colleagues203 described 67
histologically benign features.135 patients with BOOP (including 50 with the
idiopathic form) gleaned from more than 2,500
COP open lung biopsies performed from 1950 to 1980.
A retrospective review of pathologic files at the
COP is a rare immune disorder characterized University of Alabama identified 24 cases from
by granulation tissue that obstructs small bron- 1972 to 1984; five had connective tissue disease
chioles and extends into the distal alveolar ducts (CTD).239 French investigators240 at a leading
and alveoli.198–202 The term bronchiolitis obliter- referral center identified 16 patients with idio-
ans organizing pneumonia (BOOP) is synony- pathic BOOP/COP in 6 years. A survey in Japan
mous,203 but the use of this historical term is detected 29 cases of BOOP/COP from 200
discouraged.200,204 Clinical features of COP in- hospitals from 1986 to 1988; five patients had
clude focal alveolar infiltrates, cough, fever, CTD.241 In a Spanish community hospital, 33
dyspnea, and a subacute course, mimicking cases of COP were observed in 19 years.229 A
community-acquired pneumonia.199,200,205 Oblit- survey at a leading referral hospital in Vancou-
erative bronchiolitis (OB), which is characterized ver, British Columbia, from 1985 to 1992, detected
by obstruction of bronchioles and small airways 25 cases of COP.198 This represented a prevalence
but lacks the organizing pneumonia (OP) compo- of 1.2 per 10,000 admissions. Their review of 63
nent, is a distinct disorder with differing clinical published articles identified 296 patients with
and radiographic features and prognosis.200,204 COP (24 were single case reports). Of the
Organizing pneumonia (with or without OB) may published cases, 218 were idiopathic and 29
complicate collagen vascular disease,206–209 Sjo- had CTD. Gudmundsson et al242 retrospectively
gren syndrome,210 inflammatory bowel dis- evaluated all biopsy-proven cases of OP diag-
ease,211,212 Wegener granulomatosis,213 lower nosed in Iceland between 1984 and 2003. The
respiratory tract infections (eg, legionellae, virus- mean annual incidence of OP per 100,000
es, Mycoplasma spp),201,214 actinomycosis,215 cryp- population was 1.10 for COP and 0.87 for
tococcal pneumonia,216 Pneumocystis jirovecii secondary OP. Most patients with idiopathic
infection,217,218 human immunodeficiency virus COP present in the fourth through sixth decade
(HIV) infection,219 toxic fume inhalation, radiation of life, but all ages may be affected.198–200,203

There is no predominance by sex.242 COP is more
common in nonsmokers (2:1 ratio).199
Clinical Features
Predominant symptoms are cough (typically

nonproductive) and dyspnea.198,199,203 Extrapulmo-
nary involvement does not occur, but fever, weight
loss, and malaise may be prominent.198–200,203 The
course is subacute, with symptoms developing
over a 2-week to 6-month period.198,199,203 An
antecedent upper or lower respiratory tract infec-
tion precedes the onset of symptoms in at least
one-third of patients.198,203 The constellation of
these features simulates an infectious etiology. The
diagnosis is often not suspected until repetitive
courses of antibiotics fail. Physical examination
reveals midinspiratory squeaks or rhonchi in 40%
of patients; wheezing does not occur.198,203 Rales
may be present, but frank consolidation changes
on chest auscultation are lacking.199,200 Clubbing is
not a feature of COP.199 No consistent laboratory
aberrations are present. The erythrocyte sedimen-
tation rate is usually elevated; peripheral blood
leukocytosis is noted in one-third.198,199,203
Chest Radiographs
Focal lobar or segmental alveolar infiltrates,

often with air bronchograms, are the cardinal
features, observed in 60% to 80% of patients with
COP198–200,203,205,238 (Figs 18 and 19). These Figure 18. BOOP. Top, A, Posteroanterior chest radiograph
infiltrates are often in the periphery of the lung from a 75-year-old woman with a 6-month history of
(resembling chronic eosinophilic pneumo- recurrent ‘‘pneumonias,’’ demonstrating focal right lower
nia)200,243 but lack the striking upper-lobe predi- lobe consolidation. A patchy left lower lobe infiltrate is also
present. Bottom, B, Posteroanterior chest radiograph from
lection characteristic of that disorder. The the same patient as in top, A, demonstrates right upper lobe
infiltrates may wax and wane, even before and left lower lobe alveolar infiltrates; a patchy right lower
initiation of therapy. A more diffuse pattern, lobe infiltrate is also present. A transbronchial lung biopsy
specimen demonstrated the classic features of BOOP. After
associated with reticulonodular infiltrates, occurs
the initiation of therapy with prednisone 40 mg/d, complete
in 20% to 30% of patients.198,200,203 In this context, radiographic and symptomatic resolution was evident
focal opacities are lacking and the pattern within 3 weeks. Reprinted with permission from ACCP
resembles other chronic ILDs. Chest radiograph Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
findings are normal or reveal only hyperinflation
in 4% to 10% of patients.198,199,203 Focal air space
disease with consolidation is associated with an sions,244 miliary lesions,245 or cavitary nod-
improved prognosis and higher rate of respon- ules246,247 have been noted in anecdotal cases.
siveness to corticosteroids than other radiograph- HRCT scans depict the salient features of COP
ic patterns.199 Pleural effusions, cavitation, and more clearly than conventional chest radio-
intrathoracic lymphadenopathy are not features graphs.199,248 Typically, multiple segmental or lobar
of COP. However, multiple nodular mass le- dense alveolar opacities, with air bronchograms,

Figure 20. Photomicrograph of BOOP. Open-lung biopsy
specimen demonstrating a plug of organizing granulation
tissue within a respiratory bronchiole. A peribronchiolar
Figure 19. BOOP. Posteroanterior chest radiograph demon- mononuclear inflammatory cell infiltrate is also evident
strating extensive patchy alveolar infiltrates in the left lung (hematoxyline-osin, high-power magnification). From Nea-
and a patchy infiltrate in the right lower lobe in a 58-year- gos and Lynch.282 Reprinted with permission from ACCP
old man. The open-lung biopsy specimen was consistent Pulmonary Medicine Board Review. 25th ed. Northbrook, IL:
with BOOP. After 4 weeks of therapy with prednisone 60 American College of Chest Physicians; 2009.
mg/d, he was asymptomatic, and the infiltrates seen on
chest radiographs had almost completely resolved. From Increased uptake of fluorodeoxyglucose on
Neagos and Lynch.282 Reprinted with permission from
PET scan is characteristic for patients with
ACCP Pulmonary Medicine Board Review. 25th ed. North-
brook, IL: American College of Chest Physicians; 2009. OP250,253; however, this finding has no clinical
value.
are seen in the peripheral regions of the lungs.199,243
In some cases, a feeding vessel or bronchus leading PFTs
into the area of consolidation or nodular opacity
may be seen. Reticulonodular infiltrates are noted PFTs in COP demonstrate reductions in lung
in one-quarter of patients. Other findings include volumes (eg, vital capacity and TLC) and DLCO
GGOs and peribronchiolar nodules extending into and a widened alveolar-arterial oxygen gradi-
the lung parenchyma in a centrifugal pattern from ent.198–200,203 Despite the involvement of small
the involved airways.199,240,243,245 Honeycombing is airways, an obstructive component is rare in
rare. One study of 38 patients with COP noted the nonsmokers.199,203 The lack of an obstructive
following features on CT: consolidation (87%), defect in COP has been ascribed to the patchy
GGOs (58%), bronchial dilatation (58%), nonseptal nature of involvement. Some regions are com-
linear or reticular opacities (45%), nodules or mass pletely obstructed (resulting in loss of entire
lesions (32%), and peribronchial distribution of units and proportionate reduction in lung
consolidation (29%).243 Mediastinal lymphadenop- volumes), whereas other units are spared.
athy may be present, but is usually minor (lymph Bronchodilators are generally ineffective. These
nodes ,15 mm in size). The presence of consolida- deficits usually reverse promptly with cortico-
tion on CT scans predicts a favorable prognosis, steroid therapy.198–200,203
with complete or partial resolution with CS
therapy; by contrast, reticular patterns suggest an Histology
incomplete response or progression to fibrosis.249
Occasionally, COP presents as a solitary focal mass The cardinal histologic feature of COP is an
lesion, mimicking neoplasm.199,250–252 In this set- exuberant inflammatory and fibrotic process in-
ting, the diagnosis is usually established after volving terminal and respiratory bronchioles.199,201
surgical excision.250,251 Medical therapy is usually Tufts of granulation tissue, aggregates of neutro-
not required for isolated OP noted incidentally at phils, edema, debris, fibrin, connective tissue,
surgery.250–252 myofibroblasts, and fibroblasts plug the terminal

fied on lower-power magnification) is a clue to the
diagnosis. Extension of the process to contiguous
alveolar ducts and spaces results in the ‘‘organizing
pneumonia’’ component199,201 (Fig 22). Despite the
presence of extensive granulation tissue and
edema, the alveolar architecture is preserved and
fibrosis is absent. The lesions in COP appear to be of
uniform age, suggesting a stereotypic response to
prior injury. By contrast, constrictive bronchiolitis,
also termed obliterative bronchiolitis, lacks the
organizing pneumonia component of COP and is
associated with a distinctly worse prognosis.200 In
Figure 21. Photomicrograph of BOOP. Open-lung biopsy OB, the small airways and bronchioles are obliter-
specimen demonstrating a plug of granulation tissue within ated by transmural fibrosis and inflammation, but a
the bronchioles. A peribronchiolar inflammatory cellular prominent inflammatory component is lacking.200
infiltrate is present extending into the alveolar interstitium The airway lumens are narrowed by concentric
(hematoxylin-eosin, high-power magnification). Reprinted
with permission from ACCP Pulmonary Medicine Board deposition of collagen and fibrous connective
Review. 25th ed. Northbrook, IL: American College of Chest tissue. The histologic lesions of OB may be seen as
Physicians; 2009. a complication of rheumatoid arthritis, toxic fume
inhalation, bone marrow or lung transplant, and
bronchioles (Figs 20 and 21). Inflammatory cells are diverse exposures.201,204,236 In contrast to COP, OB
present within bronchiolar lumens and extend into is associated with a poor prognosis and low rate of
the peribronchiolar regions, alveolar ducts, and responsiveness to corticosteroids or cytotoxic
alveolar spaces. Mononuclear cells predominate, agents. The course is characterized by progressive
but scattered neutrophils and eosinophils are seen. airflow obstruction, eventually resulting in respi-
Multinucleated giant cells are present in up to 20% ratory failure and death. This entity is beyond the
of cases. Foamy alveolar macrophages within the scope of this chapter.
alveolar spaces may simulate desquamative inter- The histologic features of COP overlap with
stitial pneumonitis.254 The disease is patchy, but the those of several other entities, including desqua-
peribronchiolar distribution (which can be identi- mative interstitial pneumonia, chronic eosinophil-
ic pneumonia, hypersensitivity pneumonitis,199
cystic fibrosis,255 infectious etiologies,199 and more
recently described entities such as airway cen-
tered interstitial fibrosis,256 idiopathic bronchiolo-
centric interstitial pneumonia,257 and bronchiolitis
interstitial pneumonitis.258 The differentiating
features of these entities is beyond the scope of
this chapter and is addressed elsewhere.256–258
Given the patchy nature of COP, fiberoptic
bronchoscopy with TBB is usually not adequate
to establish the diagnosis with certainty. In such
cases, VATS lung biopsy is required. However, the
diagnosis can sometimes be confirmed with TBB if
Figure 22. Photomicrograph of BOOP. Open-lung biopsy clinical features are consistent and infectious
specimen demonstrating a plug of granulation tissue within etiologies are reliably excluded.199,205 Gross mac-
the bronchioles. A peribronchiolar inflammatory cellular roscopic findings at the time of bronchoscopy and
infiltrate is present extending into the alveolar interstitium
analysis of BAL fluid are helpful in excluding
(hematoxylin-eosin, low-power magnification). From Lynch
and Chavis.283 Reprinted with permission from ACCP infectious etiologies. The absence of bronchitis or
Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: purulent secretions within airways and negative
American College of Chest Physicians; 2009. smear and culture results of BAL fluid make

infection less likely. BAL in COP often reveals MMP-2 expression in BAL fluids and tissues.
increases in lymphocytes (20% to 40%), polymor- MMP-2 activity in COP correlated with increases
phonuclear leukocytes (5% to 15%), or eosinophils in BAL lymphocytes.263 Japanese investigators264
(5%), sometimes with plasma cells or mast noted elevated serum levels of KL-6 (a mucinlike
cells.198–200,205 The CD4 to CD8 ratio is de- glycoprotein) in 17 of 30 patients with COP. KL-6
creased.199,200 These aberrations are nonspecific may be produced by damaged or regenerating type
and do not distinguish COP from other infectious II epithelial cells, and may be elevated in diverse
or immune-mediated disorders. Percutaneous CT- idiopathic interstitial pneumonias (including UIP
guided needle biopsy may establish the diagnosis and nonspecific interstitial pneumonitis).265
in some patients with COP,259 but caution should The pivotal factors that initiate, direct, and
be applied owing to small sample size. regulate the inflammatory and reparative process
in COP have yet to be elucidated. However,
Pathogenesis therapies that ablate the inflammatory response
are usually highly efficacious in COP.
The pathogenesis of COP has not been eluci-
dated but likely represents an exaggerated host Therapy
response to a variety of inflammatory or injurious
stimuli.199,200 The uniformity of the histologic Corticosteroids are the cornerstone of therapy
lesion and the peribronchiolar distribution suggest for COP.201,229,266 The optimal dosage and dura-
that inhaled stimuli (eg, possibly inhaled antigens tion of CS therapy for COP have not been studied
or noxious agents) may initiate lung injury. This is in randomized trials. In early studies, initial
followed by activation and recruitment of inflam- treatment with high-dose prednisone (1 mg/kg/
matory cells and an attempt to repair. The frequent d) was advocated,203 but lower doses (eg, 0.5 to
association of antecedent viral or respiratory tract 0.75 mg/kg/d) are often adequate in patients
infection in COP suggests that inhaled viral or with mild to moderate disease.201,229,266 Respons-
bacterial antigens may elicit an intense local es to CS are often dramatic (symptomatic
immune response. BAL in patients with COP often improvement within a few days).201 Radiograph-
demonstrates lymphocytic alveolitis with expan- ic clearing is usually evident within 1 to 4 weeks
sion of CD8þ cells and increased levels of Th1- after institution of CS therapy.198,201,203 Complete
related cytokines including interferon c, interleukin remissions occur in more than 80% of pa-
12, and interleukin 18.260 Newly formed intralumi- tients.201,229,265,266 In the remaining patients,
nal fibromyxoid tissue in COP demonstrates minor impairments persist, but serious sequelae
increased capillarization, compared with fibroblas- are uncommon. Pulmonary fibrosis occurs in
tic foci of usual interstitial pneumonia (UIP).261 ,2 0 % o f p a t i e n t s , a n d d e a t h i n
Angiogenesis may be mediated by growth factors, ,5%.198,200,203,229,266 The dose and rate of taper
VEGF, and basic fibroblast growth factors.261 of CS should be individualized according to
Regulation of angiogenesis may influence revers- clinical symptoms, chest radiographs, and PFTs.
ibility of the fibrotic lesions. Imbalance between Among responders, the dose of prednisone can
MMPs and tissue inhibitors of metalloproteinases be tapered to ,20 mg within 2 to 3 months.266
(TIMPs) may play a role in the airway remodeling Relapses may occur as the steroid is tapered or
observed in COP.262 Concentrations of MMP-9 and discontinued. 199,229,266 In one retrospective
TIMP-1 were increased in BAL fluid from patients study,266 one or more relapses (mean, 2.4)
with COP and UIP compared with controls, but the occurred in 58% of 48 patients with COP. Among
highest concentrations were observed in COP. patients experiencing multiple (3) relapses, the
Lymphocytes are important cellular sources of mean delay between first symptoms and treat-
MMP-9. It is possible that MMP-2 preferentially ment onset was significantly longer than for
degrades collagens and TIMPs play a role in patients who never had a relapse (22 vs. 11
remodeling after parenchymal damage.262 Suga et weeks, respectively; P ¼ .02).266 Most relapses
al263 also found increased expression of MMP-9 in occurred within 1 year of the initial episode of
UIP, whereas COP cases showed predominant COP; only two patients experienced relapses .15

months after the initial episode.266 Another ry failure developing within a few days or
study229 noted responses to steroids in 32 of 33 weeks.278,279 This syndrome is rare; only 10 such
patients (97%); relapses occurred in 18 (56%). In patients were identified in a retrospective anal-
both series, treatment of relapses was highly ysis at three medical centers from 1979 to 1992.278
efficacious. Relapses did not affect survival or In that sentinel report, nine patients required
result in long-term functional morbidity.229,266 In mechanical ventilatory support. Despite CS
one study,264 relapse rates were higher for therapy in all cases, seven patients died of
patients with COP who had elevated serum KL- progressive respiratory failure. Five patients
6 levels (37.5%) than for those with normal KL-6 received additional therapy with cyclophospha-
levels. mide or azathioprine. Possible risk factors in-
Although the optimal duration of therapy has cluded underlying CTD (n ¼ 3) and exposure to
not been studied, I advise a minimum of 6 to 12 drugs or environmental agents (n ¼ 4). Nine were
months of treatment.201 I prefer to continue low- current or former smokers. Histologic features of
dose CS (10 to 15 mg prednisone every other day) COP were present in all cases. In addition,
for 12 months unless adverse effects require necropsies in six patients revealed prominent
earlier discontinuation. Patients with a propensi- alveolar septal inflammation, diffuse alveolar
ty for relapse each time CSs are tapered require damage, interstitial fibrosis, and honeycombing.
chronic low-dose CS therapy.200 Factors associat- Korean investigators280 reported six patents with
ed with a worse prognosis include a predomi- rapidly progressive, ultimately fatal, OP from a
nantly interstitial pattern on chest radiographs or
cohort of 45 patients with OP. Because of the high
HRCT imaging199 and lack of lymphocytosis on
mortality rate associated with rapidly progres-
BAL.267 Immunosuppressive or cytotoxic agents
sive COP, I recommend intravenous pulse meth-
(eg, azathioprine, cyclophosphamide, cyclospor-
ylprednisolone (1,000 mg daily for 3 days),
ine A) are reserved for patients whose condition
followed by high-dose prednisone (1 mg/kg/d
fails to respond or who experience adverse effects
or equivalent, with a gradual taper). The dura-
from CSs.199,268–270 Data evaluating these agents
tion of therapy may be relatively brief once a
are limited to anecdotal cases and small series.
clinical response has been achieved. For patients
Macrolide antibiotics (particularly azithromycin)
with CS-recalcitrant disease, cyclophosphamide
have been used to treat obliterative (constrictive)
or azathioprine should be added.
bronchiolitis complicating lung234,271 or bone
marrow transplant,230 with favorable responses
Nothing to Disclose
in small series. The efficacy of macrolides reflects
immunomodulatory properties,272–274 rather than
antimicrobial activity. While data are limited for
COP, Stover et al220 cited favorable responses to
azithromycin in six patients with OP (three due to whose products or services may be discussed in
radiation therapy; three, cryptogenic). Others this chapter.
noted favorable responses with macrolides for
COP,275–277 but data are limited to a few cases. References
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Chapter 35. Pulmonary Vasculitis and Alveolar
Hemorrhage
Ulrich Specks, MD
Objectives: A systematic diagnostic approach to the patient with DAH

is described.
Understand the principles of classification of vasculitis.
Describe the spectrum of pulmonary vasculitides and
their clinical manifestations.
Describe the principles of treatment for the antineutro-
phil cytoplasmic autoantibodies (ANCA)-associated vas- Pulmonary Vasculitis
culitis syndromes.
Describe the differential diagnostic approach to the Vasculitis is defined as inflammation of vessel
patient presenting with diffuse alveolar hemorrhage.
Review specific diseases that can cause diffuse alveolar walls. Primary, or idiopathic, vasculitis is sepa-
hemorrhage. rated from secondary vasculitis. The primary
systemic vasculitides are a heterogeneous group
Key words: alveolar hemorrhage; ANCA-associated vascu- of immune-mediated syndromes of unknown
litis; antiglomerular basement membrane disease; Behçet etiology that share a clinical response to immu-
disease; capillaritis; eosinophilic granulomatosis with poly- nosuppressive therapy. Their wide spectrum of
angiitis (Churg-Strauss); giant cell arteritis; granulomatosis
with polyangiitis (Wegener); idiopathic pulmonary hemo-
frequently overlapping clinical manifestations is
siderosis; microscopic polyangiitis; Takayasu arteritis defined by the size and location of the affected
vessels as well as by the nature of the inflamma-
Synopsis: tory infiltrate. Secondary vasculitis may occur in
Pulmonary vasculitis, defined as inflammation of the the context of a well-defined underlying disorder
pulmonary vessels, is usually but one manifestation of a (eg, systemic lupus erythematosus) or have a
systemic vasculitis. The vasculitis syndromes are separated specific etiology such as infection, or therapeutic
into primary (unknown etiology) and secondary (known
etiology or related to another defined syndrome such as a
or illicit drug use.
collagen vascular disease) vasculitides. The systemic vascu- The classification and definitions of the
litides are further classified by the size of vessels predom- vasculitides are based on the size of the most
inantly affected: large-vessel, medium-sized-vessel, and prominently affected vessels. Definitions, no-
small-vessel vasculitides. The small-vessel vasculitides are
further divided into those that are associated with immune- menclature, and classification schemes are sub-
complex deposits versus those that are not (pauci-immune). ject to change as our knowledge about
The pauci-immune small-vessel vasculitides are usually pathogenesis increases. The terms used in this
associated with antineutrophil cytoplasmic autoantibodies chapter are based on the nomenclature and
(ANCA), and consequently also called ANCA-associated
vasculitides. The ANCA-associated vasculitides, granulo- definitions put forth by the Chapel Hill Consen-
matosis with polyangiitis (Wegener), microscopic polyan- sus Conference in 1992 and modified by the
giitis (MPA), and eosinophilic granulomatosis with second Chapel Hill Consensus Conference held
polyangiitis (EGPA) (Churg-Strauss) most commonly affect
in 2010 (Table 1).1
the respiratory tract. The spectrum of their clinical presen-
tations and their management is described in detail. Not all Pulmonary vasculitis is defined as inflamma-
respiratory manifestations in patients with vasculitis are tion of vessels in the lung, including pulmonary
caused by the vasculitis. Diffuse alveolar hemorrhage arteries, veins, capillaries, and bronchial arteries.
(DAH) results from the disruption of the alveolar-capillary
Pulmonary vasculitis is usually but one manifes-
basement membrane. This can be caused by immune-
mediated systemic disease processes that cause capillaritis, tation of a systemic disorder and should be
by the direct toxic effects of inhaled or blood-borne agents, evaluated and treated as such, even if at the time
by coagulopathies, or by mitral valve disease. The small- of presentation, disease manifestations appear to
vessel vasculitides, granulomatosis with polyangiitis (We-
be limited to the respiratory tract. Moreover, not
gener), and MPA are the vasculitis syndromes that most
commonly lead to capillaritis with DAH, but many other all respiratory symptoms occurring in patients
systemic autoimmune disorders can also cause capillaritis. with vasculitis are caused by inflammation of

Table 1—Pulmonary Vasculitis Syndromes: Classification inflammatory disorder that is often associated
and Diagnostic Features with polymyalgia rheumatica. It is the most
Primary vasculitis syndromes
common form of vasculitis in the Northern
Large vessel vasculitis hemisphere and affects predominantly elderly
Medium-sized vessel vasculitis patients. The typical features of the disease
Small-vessel vasculitis include new-onset headache and a palpably
Pauci-immune
ANCA-associated vasculitides tender or nodular temporal artery with de-
Granulomatosis with polyangiitis (Wegener)a creased pulsation. The clinical illness appears
Microscopic polyangiitisa gradually with the development of nonspecific
Eosinophilic granulomatosis with polyangiitis
systemic symptoms such as low-grade fever,
(Churg-Strauss)b
Idiopathic pauci-immune pulmonary capillaritisb malaise, and weight loss. Headache, variable
Immune complex associated but often severe, is the most common symptom
Anti-GBM diseaseb in GCA. Amaurosis fugax is observed in 20% of
IgA-vasculitis (Henoch-Schönlein)b
Cryoglobulinemic vasculitisb,c
patients and visual loss in 10%. There is no
Hypocomplementemic urticarial vasculitis specific laboratory marker for the disease, but
(anti-C1q vasculitis)c markedly elevated erythrocyte sedimentation
Other: Behçet diseaseb rate is a typical finding. Granulomatous inflam-
Secondary vasculitis
Systemic lupus erythematosusb mation of the vessel wall is found in 60% of
Antiphospholipid syndromeb temporal artery biopsy specimens. The aorta may
Rheumatoid arthritisb also be affected by the disease and GCA should
Drug-induced vasculitisb
be considered as the cause of thoracic aortic
a
Frequent cause of alveolar hemorrhage. aneurysms in the elderly.5 Mortality of patients
b
Rare cause of alveolar hemorrhage. with GCA is not different from that of the general
c
May be primary or secondary population, but patients can die from dissection
of thoracic aortic aneurysms.6,7
pulmonary vessels. Respiratory symptoms and Respiratory symptoms have been reported in
disease manifestations are most common in the up to 25% of patients but rarely require manage-
small-vessel vasculitis syndromes. ment by a pulmonologist.8 However, respiratory
symptoms may be the initial presentation of
Large-Vessel Vasculitis GCA and should be considered in any elderly
patient with new onset of cough, hoarseness, or
The primary large-vessel vasculitides affect throat pain without other identifiable cause and
predominantly the aorta and its branches, but the erythrocyte sedimentation rate should be
medium-sized and even small vessels can also be measured in such patients.9,10 Cough, hoarse-
ness, and throat pain usually resolve promptly
affected. They comprise giant cell arteritis (GCA)
with glucocorticoid therapy. Isolated cases with
and Takayasu arteritis (TAK). Even though there
pleural effusion or multinodular pulmonary
are substantial clinical differences between GCA
lesions have also been reported in GCA. Such
and TAK, they cannot be distinguished histo-
cases are difficult to interpret and granulomatosis
pathologically, and some2,3 have suggested that
with polyangiitis (Wegener; GPA) should be
these two syndromes may represent two differ- considered in the differential diagnosis because
ent phenotypes of the same disease resulting it may also involve the temporal arteries.
from senescence of the immune and vascular Therapy for GCA continues to be based on the
systems. use of glucocorticoids without proven alterna-
GCA: This has also been referred to as tive. The glucocorticoid-sparing role of metho-
temporal arteritis, cranial arteritis, and granulo- trexate (MTX) for GCA remains controversial.11
matous arteritis, but these terms should no TAK: Takayasu arteritis predominantly af-
longer be used because they do not adequately fects the aorta and its major branches in young
reflect the disease process or may cause confu- patients. TAK has also been called pulseless
sion with other disorders.4 GCA is a generalized disease, aortic arch syndrome, or reversed
596 Chapter 35. Pulmonary Vasculitis and Alveolar Hemorrhage (Specks)

coarctation but these terms are obsolete. TAK sion to areas affected by severe arterial stenoses,
affects predominantly young women. However, but the results are only temporary.16
sex distribution and predominantly affected
vascular territories may vary with ethnicity.12 Medium-Sized-Vessel Vasculitis
Early disease manifestations include constitu-
tional symptoms, low-grade fever, and arthral- Classic Polyarteritis Nodosa (PAN): PAN is a
gias. Variable pulses of the extremities and necrotizing arteritis of medium or small arteries.
claudication of affected vascular territories are It does not affect arterioles, capillaries, or
typical. Renovascular hypertension, pulmonary venules. Therefore, it is not associated with
hypertension, and ischemia of affected organs pulmonary capillaritis leading to alveolar hem-
may be the more disabling complications of this orrhage, or with glomerulonephritis. PAN is also
chronically relapsing disease.12 not associated with antineutrophil cytoplasmic
autoantibodies (ANCA).1 However, classic PAN
Pulmonary complications are the result of a
can on rare occasions affect the bronchial or
unique arteriopathy, predominantly of the large-
bronchiolar arteries, causing lung hemorrhage
and medium-sized pulmonary vessels.13 Progres-
by that mechanism. Most cases of classic PAN
sive defects in the outer media of the arteries and
diagnosed today are associated with viral
ingrowth of granulation tissue-like capillaries
infections, specifically hepatitis B and C. Con-
associated with thickened intima and subendo-
sequently, antiviral therapy plays a prominent
thelial smooth muscle proliferation lead to
role in the management of such cases in addition
pulmonary artery stenoses and occlusion. The
to immunosuppression.17 Classic PAN is far less
inflammatory infiltrate of the vessel wall is
likely to relapse than MPA, and therefore can
predominantly lymphoplasmacytic with variable
generally be treated with a shorter course of
amounts of giant cells. The involvement of
immunosuppression.
pulmonary arteries is common but often asymp-
tomatic. Various degrees of pulmonary hyper- Small-Vessel Vasculitis
tension may affect up to half of all patients. Chest
radiograph findings are often normal but com- By the revised Chapel Hill Consensus Con-
puted tomography may show areas of low ference nomenclature, small-vessel vasculitis is
attenuation as a result of regional hypoperfusion, categorized into two major groups by their
subpleural reticulolinear changes, and pleural histopathologic immune phenotype: (1) ‘‘pauci-
thickening. Fistula formation between pulmo- immune’’ small-vessel vasculitides and (2) ‘‘im-
nary artery branches and bronchial arteries, as mune complex’’ small-vessel vasculitides. The
well as nonspecific inflammatory interstitial lung term pauci-immune indicates absence or scarcity
disease, has also been reported. Conventional as of immune deposits in the affected tissues. On
well as CT angiography, ventilation-perfusion lung biopsy specimens, few or no immune
scanning, or magnetic resonance angiography deposits can be detected in lesions caused by
may all be useful in selected patients. these syndromes, which essentially comprise the
Therapy for TAK consists primarily of im- ANCA-associated vasculitides. Pauci-immune
munosuppression with glucocorticoids. Other glomerulonephritis is the typical renal lesion of
immunosuppressive agents including methotrex- ANCA-associated vasculitis. The term pauci-
ate are used in conjunction with glucocorticoids immmune is used to differentiate these lesions
for remission induction and as glucocortocoid- from syndromes that also cause small-vessel
sparing agents for remission maintenance.14 vasculitis but are associated with readily detect-
Unfortunately, many patients will have relapse able immunoglobulin (Ig) or complement
when the glucocorticoid dose is reduced below deposition in affected tissues, including the
15 mg daily. The use of antitumor necrosis factor- vessel walls. Immune complex vasculitides
a agents may be beneficial for patients whose include anti-glomerular basement membrane
condition is refractory to standard therapy.15 (anti-GBM) disease, cryoglobulinemic vascu-
Vascular bypass procedures may restore perfu- litis, IgA vasculitis (Henoch-Schönlein), and

hypocomplementemic urticarial vasculitis. Most hemorrhage occur frequently in both, but are
secondary vasculitides, that is, those associated more common in MPA than in GPA. The
with a well-defined other systemic disease such vasculitis of MPA is indistinguishable from that
as collagen vascular disease are also immune of GPA, and consequently there may be substan-
complex mediated. tial clinical overlap.1 For these reasons, the
The ANCA-associated (pauci-immune) vas- therapeutic approach to patients with GPA and
culitides are the most common systemic small- MPA is governed by the same principles and
vessel vasculitides and most frequently affect the most clinical studies and therapeutic trials have
respiratory tract. In contrast, the immune com- combined both diseases.
plex vasculitides are more rare and only rarely Histopathologic features that define GPA and
affect the lung, anti-GBM disease being the separate it from MPA include discrete or conflu-
notable exception. ent necrotizing granulomatous inflammation
ANCA-Associated Vasculitis: The primary sys- with vasculitis. Fibrinoid necrosis, microabscess-
temic small-vessel vasculitides are GPA (Wege- es, focal vasculitis, thrombosis, and fibrous
ner), MPA, and eosinophilic granulomatosis with obliteration of the vascular lumen may be seen.
polyangiitis (Churg-Strauss; EGPA). In contrast Giant cells are a hallmark of the necrotizing
to the other forms of systemic vasculitis with granulomatous inflammation of GPA. Atypical
predilections for larger vessels, most patients and rare histopathologic features of GPA include
with active GPA and MPA, and more than half of bronchiolitis obliterans organizing pneumonia,
patients with active EGPA, have ANCAs. Of all bronchocentric inflammation, or a marked num-
systemic vasculitides, the ANCA-associated vas- ber of eosinophils in the inflammatory infiltrates.
culitides are most likely to cause respiratory Both GPA and MPA are chronically relapsing
manifestations. GPA and MPA share many diseases, with GPA having the higher propensity
clinical features and the same diagnostic and for relapses. Therefore, treatment is divided into
therapeutic principles apply. Because of its remission induction therapy and remission main-
unique clinical features, EGPA will be discussed tenance therapy. Remission induction therapy
separately. needs to be tailored to the severity and acuity of
the disease process (Table 2). To this end,
GPA and MPA treatment-active disease is categorized as non-
DEFINITIONS AND NOMENCLATURE: Polyangiitis is severe (limited) disease or severe disease. Severe
common to both GPA and MPA. The term disease is either life-threatening or threatening an
implies that vessels of different size can be organ with irreversible loss of function. Thus,
involved. The most commonly affected vessels alveolar hemorrhage, glomerulonephritis, eye
in MPA and GPA are capillaries, venules, involvement (except mere episcleritis), nervous
arterioles, and arteries.1 Necrotizing vasculitis system involvement including sensorineural
of medium-sized vessels may occur in both, and hearing loss, all qualify as severe disease mani-
the wall of the aorta may also rarely be affected festations. Limited disease includes essentially all
by necrotizing granulomatous inflammation in patients who have nonsevere disease. The term
GPA. The presence of necrotizing granulomatous limited disease used in the United States com-
inflammation, usually involving the respiratory prises what European investigators have referred
tract, is what distinguishes GPA from MPA.1 to as early-systemic disease as well as localized
Histopathologic documentation of granuloma- disease. The term limited should be phased out
tous involvement of the respiratory tract is not in favor of nonsevere because it is potentially
explicitly required.1 Radiographic evidence or misleading. Even though the separation of severe
clinical examination findings highly predictive of versus nonsevere is not based on well-defined
granulomatous pathology are sufficient. Conse- biological distinctions, most disease manifesta-
quently, the diagnosis of GPA depends on a tions leading to the categorization as severe
correlation of clinical, pathologic, and serologic disease are caused by capillaritis. In contrast,
features. Necrotizing glomerulonephritis and most symptoms leading to the classification as
pulmonary capillaritis resulting in alveolar nonsevere (limited) disease are the result of

Table 2—Treatment Options for GPA and MPA
Disease Presentation Remission Induction Remission Maintenance
Nonsevere (limited) GPA Pred þ MTX MTX or AZA

Severe GPA or MPA, new Dx Pred þ CYC AZA or MTX
Pred þ RTX Nothing (?)
Severe GPA or MPA, relapse Pred þ RTX RTX (?)
Refractory GPA Pred þ RTX RTX
Fulminant GPA or MPA Pred þ RTX or CYC As for severe disease
Consider adding PLEX
Dx ¼ diagnosis; Pred ¼ prednisone.
necrotizing granulomatous inflammation. Pa- MPA. Other organ and disease manifestations are
tients with nonsevere GPA have a more protract- covered in detail elsewhere.28–30
ed disease course, a greater likelihood of The median age of patients at diagnosis is 45
experiencing a disease relapse following a period years, but children as well as octogenarians may
of remission, and a higher prevalence of destruc- be affected. The average age of onset of GPA is
tive upper respiratory tract disorders (eg, saddle- about 10 years younger than for MPA. Men and
nose deformity). Consequently, even the term women are affected equally. Greater than 90% of
nonsevere may appear as a misnomer to the patients with GPA are white. The clinical
affected patient and may require explanation. presentation of GPA varies from subacute non-
Tracheobronchial disease involvement is also a specific respiratory illness to rapidly progressive
feature of GPA not shared with MPA; it may alveolar hemorrhage syndrome.28,29 Necrotizing
represent unique treatment challenges (discussed granulomatous inflammation causes the charac-
below). teristic disease manifestations of GPA affecting
ETIOLOGY AND PATHOGENESIS: The etiology of the respiratory tract. Ear, nose, and throat
symptoms are initially noted by .85% of
ANCA-associated vasculitis remains unknown.
patients. These may include rhinorrhea, purulent
There seems to be a multifactorial genetic
or bloody nasal discharge, nasal mucosal drying
predisposition for the development of autoim-
and crust formation, epistaxis, and otitis media.
munity and a specific phenotype of ANCA-
Deep facial pain from paranasal sinus involve-
associated vasculitis.18 In such genetically pre-
ment, nasal septal perforation, and ulceration of
disposed patients, environmental factors may
the vomer are important signs. Other signs
then trigger the onset of the disease. Occupa-
include aphthous lesions of the nasal and oral
tional exposures have been suggested as possible
mucosa and inflammation and destruction of the
triggers, including inhalation of silica-containing
nasal cartilage, leading to a saddle-nose defor-
compounds, grain dust, and heavy metals, but mity. Ulcerated lesions of the larynx and trachea
these associations are weak.19–21 In contrast, are present in 30% of untreated cases.31 These
infections, in particular with Staphylococcus aure- may cause hemoptysis. Bland stenoses may
us, have long been linked to the onset of GPA as represent scarring that occurs during the healing
well as to relapses.22,23 The various mechanisms process of the active inflammatory lesions and
by which infections may lead to the loss of give rise to postobstructive complications.32
tolerance and the development of ANCAs and Alveolar hemorrhage occurs in about 25% of all
thus trigger the onset of disease are gradually patients with GPA and MPA.33
becoming better understood.24,25 ANCAs seem to DIAGNOSTIC EVALUATION: The diagnostic evalu-
play a pathogenic role in the development of ation of patients suspected of having GPA or
vasculitis by directly inducing this activation of MPA should include imaging of the chest,
neutrophils and injury to endothelial cells.26,27 pulmonary function testing if the patient has
CLINICAL PRESENTATION: This paragraph focus- any respiratory symptoms or chest radiographic
es only on respiratory manifestations of GPA and abnormalities; measurement of erythrocyte

sedimentation rate and C-reactive protein, com- antigen-specific test result (PR3-ANCA or MPO-
plete blood count, serum chemistry panel, urine ANCA) by immunofluorescence, or vice ver-
analysis and microscopy, and ANCA testing. sa.36,37 Only the PR3-ANCA with C-ANCA
Respiratory symptoms are usually associated combination and the MPO-ANCA with P-ANCA
with unilateral or bilateral radiographic abnor- combination are sensitive and specific for ANCA-
malities. Alveolar infiltrates suggesting the pos- associated vasculitis.
sibility of alveolar hemorrhage may occur in GPA The diagnostic utility, that is, positive and
and MPA. Nodules or mass lesions (which may negative predictive values, of ANCA testing for
or may not cavitate) ranging from a few GPA and MPA is critically dependent on the
millimeters to several centimeters in size are the pretest probability of the disease in the patient
hallmark of GPA. Solitary nodules may also tested, as well as on the analytic accuracy of the
occur. Lymphadenopathy and large pleural effu- test method. If applied to patients with clinical
sions are unusual. Lobar consolidation should features indicating a high pretest probability of
prompt consideration of postobstructive pneu- GPA or MPA, ANCA testing has a very high
monia resulting from an endobronchial stenosis. positive predictive value. However, occasional
Tracheobronchial lesions are common in false-positive ANCA test results have been
GPA, but not a feature of MPA. They may be reported in a variety of infections. Most infec-
asymptomatic or mistaken for asthma.32 Pulmo- tions reported with ANCA either lack the right
nary function testing including inspiratory and pairing of immunofluorescence test results with
expiratory flow-volume loops may provide im- their corresponding antigen specifity or have
portant clues to the presence of airway narrow- clinical features that are distinct from GPA or
ing and should be part of the initial evaluation.32 MPA.34 However, subacute bacterial endocarditis
Bronchoscopic inspection of the tracheobronchial may represent a diagnostic challenge because it
tree is recommended for patients with unex- may mimic small-vessel vasculitis clinically and
plained respiratory symptoms, abnormalities on has been reported with C-ANCAs/PR3-AN-
pulmonary function tests, or radiographic abnor- CAs.38 For patients undergoing evaluation for
malities.32 necrotizing glomerulonephritis, with or without
Patients with GPA or MPA have variable alveolar hemorrhage, ANCAs may occur in
degrees of elevation of erythrocyte sedimentation conjunction with anti-GBM.39,40 These ANCAs
rate or C-reactive protein. Urine analysis and are usually MPO-ANCAs, and the presence of
microscopy as well as serum creatinine levels anti-GBM seems to determine the prognosis of
should be obtained for all patients because early such patients with double-positive results.39,40
renal involvement may be clinically silent yet Most patients with severe GPA or MPA have
progress rapidly. a positive ANCA test result (sensitivity .95%),
In GPA and MPA, diagnostically relevant but up to 30% of patients with limited GPA may
ANCAs come in two flavors.34 Antibodies not have detectable ANCAs.35 Even though there
reacting with proteinase 3 (PR3; PR3-ANCAs) is an association between ANCA titers and
and causing a cytoplasmic immunofluorescence disease activity, changes in ANCA levels do not
pattern (C-ANCAs) on ethanol-fixed neutrophils reliably predict the disease activity in individual
are found in most patients with GPA.35 Antibod- patients.41 Therefore, serial titers of ANCAs
ies reacting with myeloperoxidase (MPO), caus- should not be used to plan long-term therapy
ing a perinuclear immunofluorescence pattern with conventional cytotoxic agents.
(P-ANCAs) on ethanol-fixed neutrophils, are the REMISSION INDUCTION IN GPA AND MPA: GPA
predominant ANCA type encountered in MPA.34 and MPA have been combined in many random-
Of note, a variety of antibodies can cause a P- ized controlled trials that inform our current
ANCA pattern, but only those that also react approach to therapy in affected patients. Patients
with MPO have diagnostic value in the context with GPA are categorized by disease activity and
of ANCA-associated vasculitis. Consequently, extent into having nonsevere (limited) or severe
maximal diagnostic accuracy of ANCA testing disease, whereas most disease manifestations of
requires corroboration of a positive target MPA lead to the categorization of severe disease.

For nonsevere (limited) GPA, glucocorticoids induction with the intermittent pulse regimen
in combination with MTX at a dose of up to 25 than for the oral application of CYC. A meta-
mg once a week is considered the standard of analysis of earlier cohort studies also found that
care.42 There is only one prospective randomized IV pulse CYC therapy may be safer because of a
controlled trial comparing MTX to cyclophos- lower cumulative dose but a higher relapse rate
phamide (CYC) for remission induction in such was also observed after discontinuation.48 In the
patients.43 This trial also documented that early author’s experience-based opinion, IV CYC
discontinuation of immunosuppression in pa- should be avoided in the intensive care unit
tients with ANCA-associated vasculitis is associ- setting. However, its use is preferred over oral
ated with a high relapse rate. The largest CYC for patients with questionable compliance,
reported group of patients with nonsevere in young women with fertility issues, and in
(limited) GPA was treated with MTX for remis- patients who have gastrointestinal problems with
sion induction in the context of the Wegener’s oral CYC application.
Granulomasosis Etanercept Trial (WGET).44 Going forward, patients with GPA and MPA
Greater than 90% of patients achieved remission may no longer require exposure to CYC at all
with this regimen, and .70% achieved a sus- because the 4-decade-old standard use of CYC
tained remission (lasting longer than 6 months). for remission induction in severe GPA and MPA
These rates are equivalent to those achieved with has been challenged by the results of two
CYC in severe disease (see below).44 randomized controlled trials.33,49
CYC at a dose of 2 mg/kg/d in combination The RAVE (Rituximab for ANCA-Associated
with glucocorticoids has been the standard Vasculitis) trial33 was a randomized double
regimen for remission induction in patients with blind, double placebo-controlled, multicenter
severe GPA or MPA until recently. In contrast to trial that compared oral CYC (2mg/kg/d) to
the original regimen introduced 40 years ago by rituximab (RTX; 375 mg/m2 of body-surface area
Fauci, the current consensus is to limit the per week for 4 weeks) for remission induction in
duration of CYC therapy, if used at all, to the severe GPA or MPA in 197 patients. Once
first 3 to 6 months of remission induction.44,45 remission was achieved between 3 to 6 months,
Whenever CYC is used for remission induc- patients randomly assigned to CYC were subse-
tion, consideration should be given to the quently given azathioprine (AZA) for remission
patient’s fertility. Young men should be offered maintenance for 18 months, whereas patients
sperm banking before therapy is initiated. If time receiving RTX were given placebo. There was no
allows, ovarian protection should be offered to difference in rates of achieving remission at the
young women in addition to minimizing the end of 6 months and maintaining remission at 18
cumulative exposure as much as possible. In months between the two treatment arms. How-
women, the risk of infertility is directly related to ever, among the 101 patients who entered the
the cumulative dose of CYC received. Yet, even trial with severe relapsing disease, RTX proved
the limited exposure to CYC of 3 to 6 months’ superior to CYC. The results of the RAVE trial led
duration has a substantial effect on womens’ to approval by the US Food and Drug Admin-
fertility.46 istration of RTX for remission induction in severe
When CYC is applied as IV pulse therapy, the GPA and MPA. The long-term results of the
cumulative dose of CYC is lower than daily oral RAVE trial indicate that one course of RTX is as
therapy applied over similar time periods. One effective as 18 months of conventional immuno-
randomized controlled trial compared a regimen suppressive therapy.50
of IV pulse application of CYC to daily oral use.47 Another randomized controlled open-label
The pulse regimen was noninferior to the oral trial conducted in 44 patients with newly
application of CYC for remission induction, and diagnosed severe ANCA-associated vasculitis
the frequency of leukopenia, but not infection, with active renal disease, RITUXVAS (Rituximab
was lower. However, even though the trial was Versus Cyclophosphamide for ANCA-Associated
not powered to detect a difference in relapses, the Renal Vasculitis), showed complementary results
relapse rate was higher following remission to those of the RAVE trial.49 In this trial, patients

were randomly assigned in a ratio of 3:1 to PLEX, salvage therapy with recombinant activat-
receive RTX (together with two pulses of CYC) ed factor VII may be considered.55
compared to standard IV pulse CYC therapy REMISSION INDUCTION IN PATIENTS WITH ‘‘REFRAC-
followed by oral AZA. The primary outcome was TORY’’ D ISEASE: The term refractory disease is
sustained remission (of .6 months’ duration) at commonly used in the context of patients who
month 12. No difference between the treatment have persistent disease activity on the maximal
arms was found (RTX, 76% vs CYC, 82%). tolerated dose of CYC or who have contraindi-
Mycophenolate mofetil (MMF) may represent cations for the use of CYC. A variety of agents
an alternative to CYC (and RTX) for patients with have been proposed for use in addition or
MPA who have MPO-ANCAs and mild renal instead of the failing regimen in such patients.
disease (creatinine ,3.5 mg/d) and no other life During the last decade, RTX has emerged as the
or organ-threatening disease manifestation. This treatment of choice for such patients, on the basis
statement is supported by data from one ran- of .20 case series and cohort studies comprising
domized controlled trial with 35 patients from .200 patients.56
China comparing oral MMF (1.5–2 g/d) to IV REMISSION MAINTENANCE IN GPA AND MPA:
CYC (0.75–1.0 g/m2 once monthly). In addition, First, it is of note that the propensity for relapse is
all patients received IV methylprednisolone much higher in GPA than in MPA and the same
bolus therapy (0.5 g/d for 3 days) followed by can be said for patients with PR3-ANCAs versus
oral prednisone (0.6–0.8 mg/kg for 4 weeks MPO-ANCAs. Once remission has been induced
and the prednisone taper is well under way, CYC
tapered by 5 mg/wk to 10 mg/d). The efficacy
should be switched to either AZA (preferred for
of these regimens was equivalent, but MMF was
patients with renal involvement and any degree
better tolerated than CYC.51 A prospective pilot
of renal insufficiency) or MTX. The first option is
trial with 17 patients conducted at the Mayo
supported by the results of a randomized trial,45
Clinic found similar results.52
which showed that AZA is as good as CYC for
REMISSION INDUCTION IN PATIENTS WITH FULMI-
remission maintenance to 18 months. Another
NANT DISEASE: For some patients with GPA and
randomized controlled trial57 has shown that
MPA, the combination of glucocorticoids and
MTX and AZA are equivalent for remission
CYC or RTX may not be sufficient to induce a
maintenance. In contrast, a recent randomized
remission quickly. Plasma exchange (PLEX)
controlled trial58 that compared MMF to AZA for
should be considered early for patients who remission maintenance has shown that MMF is
present with rapidly progressive glomerulop- inferior to AZA for this purpose. Thus, the use of
nephritis and renal failure as well as for patients MMF for remission maintenance can only be
who present with diffuse alveolar hemorrhage. supported for patients whose therapy with MTX
The results from two studies currently support and AZA has failed, or who have contraindica-
the use of PLEX. The MEPEX (Methylpredniso- tions for both agents. The WGET trial in which
lone Versus Plasma Exchange) trial53 in 156 MTX was used for remission maintenance
patients who presented with a serum creatinine confirmed that long-term remission remains an
level of 5.5 mg/dL or greater was conducted to elusive goal for many patients with GPA, as
compare 3 pulses of IV methylprednisolone to 2 remission was maintained in less than half of the
weeks of PLEX (7 3 60 mL/kg) in addition to patients.44 It is currently unclear what to do for
standard therapy for severe disease (oral pred- remission maintenance when RTX is used for
nisone and CYC). PLEX was superior to methyl- induction. The long-term results of the RAVE
prednisolone with respect to renal recovery. A trial indicate that one course of RTX is as effective
single-center cohort study54 of 20 patients pre- as 18 months of conventional immunosuppres-
senting with alveolar hemorrhage described sive therapy. RTX may also be effective for
100% survival of the patients when PLEX was remission maintenance in refractory disease.
added to standard immunosuppressive therapy. MANAGEMENT OF TRACHEOBRONCHIAL DISEASE IN
If alveolar hemorrhage is uncontrolled despite GPA: The management of large airway involve-
aggressive immunosuppressive therapy and ment in GPA may represent unique challenges.32

Subglottic stenosis may require dilation proce- available rates in the general population, patients
dures paired with local injection of long-acting with lupus, and patients with rheumatoid arthri-
glucocorticoids, with or without mitomycin tis. This increased risk of thromboembolic dis-
C. Stenoses of the large airways may require ease has also been documented for the other
bronchoscopic interventions, including balloon ANCA-associated vasculitides.61
dilation by flexible fiberoptic bronchoscopy or Heart involvement of GPA may go unrecog-
rigid bronchoscopy with YAG-laser treatment, nized until a complicating event occurs. A high
and the placement of silicone airway stents. frequency of echocardiographic abnormalities
Patients with tracheobronchial disease manifes- attributable to GPA and associated with an
tations of GPA may also benefit from high-dose increased mortality was observed in a study62
inhaled glucocorticoids as well as antimicrobial of 85 patients with confirmed GPA. Lesions
therapy targeted to culture and susceptibility directly related to GPA included regional wall
results obtained from sputum or bronchial motion abnormalities not matching coronary
washings. distributions, left ventricular systolic dysfunction
OTHER MANAGEMENT ISSUES: For patients with with decreased ejection fraction, pericardial
GPA and MPA, significant morbidity and mor- effusions, valvulitis, left ventricular aneurysm,
tality related to organ damage is caused not only and a large intracardiac mass. Evaluation of
by the disease itself but also by treatment unexplained dyspnea in patients with GPA
toxicities. To avoid unnecessary exposure to should therefore include echocardiography.
immunosuppressive drugs, it is important to EGPA (Churg-Strauss): The Chapel Hill Con-
differentiate symptoms arising from damage sensus definition for EGPA is ‘‘eosinophil-rich
from those caused by active disease. Permanent and granulomatous inflammation involving the
complications have been reported to occur in respiratory, and necrotizing vasculitis affecting
86% of patients from GPA itself, including end- small to medium-sized vessels, and associated
stage renal disease, chronic pulmonary dysfunc- with asthma and eosinophilia.’’1 EGPA is includ-
tion, diminished hearing, destructive sinus dis- ed among the ANCA-associated vasculitides, but
ease, saddle-nose deformities, proptosis, and only 40% to 70% of patients with active EGPA
blindness. Among the treated patients, 42% have detectable ANCA.63–65 EGPA is primarily
experienced permanent treatment-related prob- distinguished from GPA and MPA by a high
lems including chemical (drug-induced) cystitis, prevalence of asthma and peripheral blood and
osteoporotic fracture, bladder cancer, myelodys- tissue eosinophilia. Three distinct disease phases
plasia, and avascular necrosis.28 In the WGET of the disease have been described.66 The first is a
trial59 (180 patients), reflecting more recent prodromal allergic phase with asthma. This
standard practice, damage that occurred despite phase may last for a number of years. Second is
(or because of) therapy included visual impair- an eosinophilic phase with prominent peripheral
ment, hearing loss, nasal blockade, pulmonary and tissue eosinophilia. This phase may also last
fibrosis, hypertension, renal insufficiency, periph- a number of years and the manifestations may
eral neuropathy, gonadal failure, and diabetes remit and recur over this time period. The
mellitus. Only 11% of the enrolled patients did differential diagnosis for patients in this phase
not have a single point on the vascular damage of the disease includes parasitic infection and
index (which was developed from 61 items) after chronic eosinophilic pneumonia. The third and
1 year of study enrollment.59 The WGET also vasculitic phase consists of systemic vasculitis
concluded that patients with limited GPA are at a and may be life-threatening. The three phases are
higher risk of GPA-related damage than are those not seen in all patients, do not necessarily occur
with severe disease.59 in this order, and may even concur. However,
Patients with GPA and MPA are at increased asthma usually predates vasculitic symptoms by
risk for venous thromboembolic disease. In the a mean of 7 years (range, 0–61 years).63
WGET cohort60 of 180 patients with GPA, the The classic histopathologic picture consists of
incidence rate of venous thromboembolism was necrotizing vasculitis, eosinophilic tissue infiltra-
found to be elevated when compared with tion, and extravascular granulomas. However,

not all features are found in every case, and they dose reductions or discontinuation of oral gluco-
are not pathognomonic of the condition.67 The corticoid therapy.70,71 There is no evidence
classic histopathologic features of EGPA may suggesting that these agents directly cause the
also be mitigated and modified by glucocorticoid disease.
therapy of asthma.67 Moreover, the finding of a The prognosis of EGPA is better than that of
Churg-Strauss granuloma on skin biopsy should GPA or MPA because, the overall mortality is
not be confused with the diagnosis of EGPA. This lower and not significantly different from that of
type of necrotizing extravascular granuloma may the normal population.63 Most deaths are sec-
be seen in EGPA as well as in other systemic ondary to cardiac involvement.72
autoimmune diseases including GPA and rheu- Systemic glucocorticoids remain the mainstay
matoid arthritis. of therapy. There are no clinical trials that
Pulmonary parenchymal involvement occurs provide clear guidance. Treating EGPA according
in 38% of patients. Transient alveolar-type infil- to the principles of the management of GPA and
trates are most common. These have a pre- MPA appears most appropriate.73 Accordingly,
dominantly peripheral distribution and are in- CYC should be added to glucocorticoids for
distinguishable from infiltrates seen in chronic remission induction in all patients with disease
eosinophilic pneumonia. Occasionally, nodular manifestations that threaten the patient’s life or
lesions may be seen in EGPA. In contrast to GPA the function of a vital organ, that is, particularly
and MPA, alveolar hemorrhage is exceedingly those with central or peripheral nerve involve-
rare.63,68 Renal involvement in EGPA is less ment, glomerulonephritis, heart involvement, or
prominent than in GPA or MPA and does not alveolar hemorrhage. MTX, AZA, or MMF have
generally lead to renal failure.63–65,68 In contrast, been used as glucocorticoid-sparing agents in
peripheral nerve involvement, typically in the less severe disease and for remission mainte-
form of mononeuritis multiplex, is more fre- nance. Refractory disease and disease dominated
quent. Skin, heart, central nervous system, and by difficult-to-control eosinophilic inflammation
abdominal viscera may also be involved. have been reported to respond to interferon alfa
If ANCAs are present, they are usually therapy.74 However, continued long-term inter-
P-ANCAs reacting with MPO.63–65 The ANCA feron alfa therapy may be necessary, and this
status appears to correlate with disease activity treatment carries the risk of substantial toxicity.75
and MPO-ANCAs seem to be very sensitive to RTX has also been used successfully in EGPA,
glucocorticoid therapy in EGPA.63 Recent stud- particularly for ANCA-positive patients with
ies64,65 suggest a more vasculitic disease pheno- renal disease, but the data are still scarce and it
type in the presence of ANCAs, but this was not cannot be recommended to use RTX instead of
confirmed by all studies.63 There remains sub- CYC for patients with severe EGPA.76,77 Anti-IL-5
stantial overlap of organ manifestations between therapy has also recently been reported as a
patients with EGPA who are ANCA positive and promising agent for treatment of EGPA.78
those who are ANCA negative. Idiopathic Pauci-Immune Pulmonary Capillaritis:
Glucocorticoid therapy given for asthma may Occasionally patients presenting with isolated
partially suppress or delay the onset of the diffuse alveolar hemorrhage caused by capillaritis
complete syndrome. The term formes frustes of have negative serology test results for any known
EGPA has been associated with patients in whom autoantibodies, including ANCAs. Direct immu-
the full-blown picture of systemic eosinophilic nofluorescence studies79 of the lung tissue in such
vasculitis and/or granulomatosis was masked by patients did not reveal immune deposits. Hence,
glucocorticoid therapy asthma.69 In recent years this clinicopathologic presentation has been re-
significant attention has been devoted to EGPA ferred to as idiopathic pauci-immune pulmonary
detected in patients using leukotriene receptor capillaritis and represents a diagnosis of exclu-
antagonists. Available case studies and limited sion. This form of isolated pulmonary capillaritis
population-based incidence estimates suggest is histopathologically indistinguishable from that
that these agents may lead to unmasking of of ANCA-associated vasculitis, and patients are
vasculitic symptoms in asthmatics by allowing best treated with an immunosuppressive regimen

according to the principles outlined for severe disease.85 The pulmonary outcome of anti-GBM
GPA and MPA.79 disease is generally favorable, whereas end-stage
Anti-GBM Antibody Disease: Anti-GBM dis- renal disease is common.83
ease is a rare autoimmune disease characterized IgA Vasculitis (Henoch-Schönlein): Formerly
by the presence of autoantibodies directed known as Henoch-Schönlein purpura, anaphylactoid
against the NC1 domains of the alpha-3 and purpura, allergic purpura, or IgA-associated disease,
alpha-5 chains of basement membrane collagen IgA vasculitis is a syndrome characterized by
type IV. The term Goodpasture syndrome should be acute purpura of the skin, arthritis, colicky
reserved for anti-GBM disease affecting both the abdominal pain, and glomerulonephritis. Patho-
kidneys and lungs. The term antiglomerular logic findings include acute arteriolitis and
basement membrane disease is a misnomer, but it venulitis in the superficial dermis and the bowel.
is maintained because of its widespread use and Proliferative and necrotizing glomerulonephritis
acceptance. representing capillaritis is usually mild. The
The pathogenicity of anti-GBM antibodies renal lesion is indistinguishable from IgA ne-
has been proven by classic primate transfer phropathy, which may represent a renal-limited
experiments in the 1960s.80 The target epitope variant of the disease. Other single organ
for anti-GBM antibodies is only accessible in the manifestations (skin) have been described and
basement membranes of the kidneys because of such cases may progress to the systemic disease.
the unique fenestrations of the kidney endothe- IgA deposits in vessel walls of affected
lial layer.81 In all other organs, the endothelial
organs detectable by direct immunofluorescence
layers effectively prevent access for the circulat-
microscopy are the hallmark of IgA vasculitis.86
ing anti-GBM antibodies. For these reasons the
Although it is more common in children (mean
kidneys are affected in virtually all cases, and
age of patients, 17 years), adults may also be
isolated lung involvement is the rare exception.
afflicted. Palpable purpura, which are usually
The lungs are affected in about half of patients
distributed over the buttocks and lower extrem-
with anti-GBM disease, causing the clinical
ities, and fever are generally the first signs. The
presentation of DAH. Lung involvement is
purpura may precede, accompany, or follow
contingent upon an additional, usually inhala-
arthralgias and abdominal colic. The triad of
tional, injury such as smoking or volatile hydro-
purpura, arthritis, and abdominal pain is present
carbon exposure or an infection leading to
exposure of the antigen to the anti-GBM antiin approximately 80% of patients. Joint involve-
bodies.82,83 ment is typically monoarticular and transient,
Anti-GBM disease is classified as a vasculitis involves the large joints, and causes pain out of
because it affects the capillaries in the kidneys proportion to the objective evidence of synovitis.
and the lung, even though neutrophil infiltration Peritonitis and melena are common. Pulmonary
in the lungs is much less prominent than in manifestations of IgA vasculitis are rare. Capil-
capillaritis associated with ANCA-associated laritis has been documented histopathologically
vasculitis. In fact, lung histopathology in anti- only in a minority of these cases.87
GBM disease is often described as bland. Cryoglobulinemic Vasculitis: This type of vas-
However, capillaritis as a secondary histopatho- culitis is characterized by the presence of
logic feature has been documented.84 circulating cryoglobulins and their deposits in
Circulating autoantibodies to basement mem- small vessels, predominantly capillaries, venules,
brane are detectable in the serum, but the and arterioles. Fifty percent of cases are linked to
diagnosis of anti-GBM disease hinges upon the hepatitis C virus infection.88 Skin and peripheral
histopathologic documentation of linear IgG nerve involvement as well as glomerulonephritis
deposits along the basement membranes in lung are common. In contrast, lung involvement in the
or kidney. form of capillaritis leading to DAH is rare (3%)
Early implementation of immunosuppressive but portends a poor prognosis with high mortal-
therapy in conjunction with PLEX is the key to a ity (80%).88 RTX is emerging as primary immu-
favorable outcome in patients with anti-GBM nosuppressive agent for cryoglobulinemic

vasculitis, including those cases associated with consequence of mucosal inflammation, has also
hepatitis C virus infections.89 been described.
Hypocomplementemic Urticarial Vasculitis Therapy of the underlying disease consists of
(Anti-C1q Vasculitis) (HUV): HUV is a systemic immunosuppression.99 Prednisone alone may
disorder characterized by urticaria, hypocomple- not be sufficient to control the vasculitis. The
mentemia, anti-C1q antibodies, and vasculitis of addition of other drugs such as colchicine and
small vessels.90,91 Signs and symptoms consist of conventional immunosuppressive agents is usu-
fever, arthralgias, arthritis, angioedema, uveitis, ally necessary. The use of biologic agents, in
episcleritis, abdominal pain, glomerulonephritis, particular anti-tumor necrosis factor agents, has
and seizures occurring at variable frequencies also been reported recently. The addition of AZA
and combinations.92,93 HUV has been associated or CYC to glucocorticoids may result in resolu-
with pulmonary complications not directly tion of pulmonary aneurysms. Once pulmonary
caused by vasculitis. Obstructive pulmonary arteritis has been identified, anticoagulation
disease occurring in up to two-thirds of these should be avoided. The prognosis of pulmonary
patients is thought to result from a combination involvement is poor. About one-third of patients
of smoking and an unknown immunologic die within 2 years of developing pulmonary
process. Emphysematous changes in the basal involvement, most from fatal pulmonary hemor-
regions may occur in some patients.94,95 HUV, rhage. Embolization therapy may be used as
with or without hypocomplementemia, can also treatment and prevention of hemorrhage from
occur in patients with systemic lupus erythema- pulmonary artery aneurysms.
tosus. Secondary Vasculitis: Many of the rheumato-
logic diseases exhibit a secondary vasculitic
Other Vasculitis Syndromes process in the organs involved. Infectious pro-
BEHÇET DISEASE (BD): BD is a rare, chronically cesses, particularly secondary to infection with
relapsing systemic inflammatory disorder char- Aspergillus and Mucor species, invade vascular
acterized by recurrent aphtous oral ulcers and at structures and produce secondary vasculitis.
least two of the following: recurrent genital Certain drugs and chemicals can induce vascu-
ulcers, uveitis, cutaneous nodules or pustules, litis. Other uncommon secondary vasculitic
or meningoencephalitis that have no other entities include benign lymphocytic angiitis and
explanation.96 There is a strong association with granulomatosis, bronchocentric granulomatosis,
the major histocompatibility complex antigen and necrotizing sarcoid angiitis. Systemic lupus
HLA-B51.97 The mean age of patients at the erythematosus (SLE) and the antiphospholipid
onset of BD is 35 years. Most studies have syndrome (APS) will be highlighted here because
reported a predominance of men with the disease they can cause DAH.
over women. Respiratory manifestations are SLE AND OTHER COLLAGEN VASCULAR DISORDERS:
common in BD and include cough, hemoptysis, The disease manifestations of SLE are highly
chest pain, and dyspnea.98 Hemoptysis is often variable. Pulmonary capillaritis leading to diffuse
massive and fatal. The vasculitis of BD is DAH is rare in SLE but is usually a severe
immune-complex mediated and may affect ves- complication of the disease. Direct immunofluo-
sels of all sizes. Secondary thrombosis with major rescence microscopy reveals prominent immune
venous occlusion can occur. Thrombosis may not complex deposits in the affected tissues including
be preventable in BD by anticoagulation, but the lungs. The onset of DAH in patients with SLE
aspirin 80 mg/d has been advocated. Destruction is usually abrupt and seldom the first sign of the
of the elastic lamina of pulmonary arteries, disease. The rapid development of pulmonary
causing aneurysm formation, secondary erosion infiltrates is usually associated with fever. He-
of bronchi, and arterial-bronchial fistulae, may moptysis may be absent in up to half of the
result in massive hemoptysis. CT scan or mag- patients.100 Consequently, the differentiation of
netic resonance angiography is used to detect DAH from infection may be difficult in SLE and
pulmonary artery aneurysms. Recurrent pneu- may require a diagnostic BAL. Mechanical
monia, as well as bronchial obstruction as a ventilation, infection, and CYC therapy were

identified by univariate analysis as negative anticoagulation may need to be interrupted to
prognostic factors in one cohort.100 The reported control the hemorrhage. Early PLEX in addition
mortality associated with DAH in SLE ranges to immunosuppressive therapy should be con-
from 0% to 90%.101–104 Treatment consists of sidered in patients with APS and DAH.
glucocorticoids and CYC. The use of PLEX has
been suggested but its benefit remains unproven. Diffuse Alveolar Hemorrhage
While respiratory complications are very
common in all other types of collagen vascular General Approach to DAH
or connective tissue disorders, pulmonary capil-
laritis presenting as DAH is extremely rare. Only Diffuse hemorrhage into the alveolar spaces
isolated cases have been reported with polymyo- is often referred to as diffuse alveolar hemor-
sitis, rheumatoid arthritis, and mixed connective rhage syndrome because DAH usually results
tissue disease.105,106 Consequently, serologic test- from an underlying or associated condition that
ing performed as part of an evaluation of DAH causes a disruption of the alveolar-capillary
should include studies aimed at the identification basement membrane integrity. Mechanisms lead-
of these rare but potential underlying disease ing to DAH include immunologically mediated
entities. inflammatory conditions causing capillaritis (eg,
ANTIPHOSPHOLIPID SYNDROME: APS is defined by the vasculitis syndromes described in the pre-
arterial and venous thromboses, or recurrent ceding section of this chapter), direct chemical or
miscarriages occurring in patients with antiphos- toxic injury (eg, from toxic or chemical inhala-
pholipid antibodies (anticardiolipin antibodies, tion, abciximab use, all-trans-retinoic acid, tri-
lupus anticoagulant, or both). If APS occurs in mellitic anhydride, smoked crack cocaine),
the context of another autoimmune disease, physical trauma (eg, pulmonary contusion), or
malignancy, or drug exposure, it is labeled increased vascular pressure within the capillaries
secondary APS. In the absence of other coexisting (eg, mitral stenosis, severe left ventricular fail-
disorders it is considered primary.107 Hyperco- ure).
agulability can cause pulmonary embolism and The clinical course of DAH is unpredictable
infarction, pulmonary microthrombosis, and pul- and may progress rapidly to respiratory failure; it
monary arterial thrombosis with secondary pul- is always potentially life-threatening. Conse-
monary hypertension as consequence.108–110 quently, it should be considered in the differen-
However, primary pulmonary hypertension and tial diagnostic evaluation of any patient with
adult respiratory distress syndrome have also alveolar infiltrates on chest radiograph. The
been reported as complications of APS. DAH is symptoms of DAH are nonspecific. Patients
thought to be rare in APS but serology testing to usually seek care because of dyspnea and cough,
look for APS should be included in the evalua- possibly associated with fever. Diffuse alveolar
tion of any patient with DAH. The clinical infiltrates on chest radiograph are the first
presentation is nonspecific and consists of cough, diagnostic hallmark. Depending on the severity
dyspnea, fever, and bilateral pulmonary infil- of the disease process at the time of evaluation,
trates. DAH can also occur in the context of adult anemia and hypoxemia may be prominent.
respiratory distress syndrome and hemoptysis is Hemoptysis is a common presenting symptom
absent in greater than half of the reported of DAH, but it is absent in many patients with
patients with APS and DAH. Therefore, an early DAH at the time of presentation.
BAL may help in the differential diagnosis. DAH is best confirmed by BAL. Progressively
Tissue necrosis from microthrombosis as well as more bloody return indicates alveolar origin of
pulmonary capillaritis has been implicated as the blood; the presence of .20% hemosiderin-
cause of DAH in APS. As in SLE, the capillaritis laden macrophages among the total number of
of APS is immune complex mediated. Most alveolar macrophages recovered by BAL is
patients respond to glucocorticoids.108 Yet, the reported to indicate alveolar hemorrhage even
coexistence of thrombosis and capillaritis with in the absence of ongoing active bleeding.111,112
DAH represents a therapeutic dilemma because The diagnostic approach to the patient with DAH

is aimed at the rapid identification of the associated with pulmonary capillaritis and those
underlying cause and at prompt implementation that lack pulmonary capillaritis (bland histolo-
of appropriate therapy. gy). Pulmonary capillaritis refers to the specific
The history of present illness and past histopathologic finding of alveolar wall infiltra-
medical history may provide the first clues to tion, with inflammatory cells centered on capil-
an underlying etiology. Pulmonary alveolar lary walls and small veins.113 The inflammatory
hemorrhage is significantly associated with the cells are predominantly neutrophils, but eosino-
following: thrombocytopenia (,50,000 cells/lL), phils or monocytes may also be encountered.
other abnormal coagulation variables, renal Capillaritis usually causes fibrinoid necrosis of
failure (creatinine concentration 2.5 mg/dL), alveolar and vessel walls and may culminate in
and a history of heavy smoking. Exposure to the destruction of the underlying lung architec-
inhalational toxins such as trimellitic anhydride ture.113 The interstitial infiltration by neutrophils
or pyromellitic dianhydrate and drug abuse, seen in the context of capillaritis needs to be
including crack cocaine abuse, should be identi- distinguished from the predominant intra-
fied. The past medical history will also uncover alveolar neutrophilic infiltration commonly asso-
preexisting comorbidities that can cause DAH, ciated with active infections. Another hallmark of
including mitral stenosis, coagulation disorders, capillaritis is the presence of pyknotic cells and
recent bone marrow or hematopoietic stem cell nuclear fragments from neutrophils undergoing
transplant, preexisting autoimmune disorders, apoptosis.113 This feature, referred to as leukocy-
and the use of specific therapeutic agents. toclasis, allows the distinction of true capillaritis
Similarly, the initial physical examination should from neutrophil margination related to surgical
include a careful search for signs of comorbidities trauma, which can simulate capillaritis.114
and possible systemic autoimmune disorders.
Initial blood and urine testing should screen Specific Etiologies of DAH
for other organ involvement, particularly kidney
involvement (complete blood count, chemistry Vasculitides: The vasculitis syndromes associ-
group, urine analysis, and microscopy), and ated with pulmonary capillaritis leading to DAH
determine the current coagulation status. Base- have been discussed in the previous section of
line markers of inflammation (erythrocyte sedi- this chapter. The most common cause of capil-
mentation rate and C-reactive protein) are laritis and pulmonary renal syndrome, defined as
helpful for monitoring subsequent responses to DAH with glomerulonephritis, is ANCA-associ-
therapy. At the same time, specific serologic ated vasculitis, either GPA or MPA. In contrast,
testing for potential underlying systemic disease DAH is rare in the context of EGPA.63,65 If EGPA
processes should be initiated. This includes gives rise to DAH, patients are usually MPO-
testing for ANCAs, anti-GBM antibodies, anti- ANCA positive.64
nuclear antibodies, anti-double-stranded DNA Mitral Valve Disease: DAH is a well-known
antibodies, antiphospholipid antibodies, cryo- feature of mitral stenosis, even though the
globulins, as well as determination of comple- possibility is rarely considered in clinical prac-
ment levels, rheumatoid factor, and creatinine tice. Severe mitral insufficiency can also produce
kinase. alveolar hemorrhage. Hemoptysis can be the
The decision to obtain a biopsy specimen presenting feature. It is caused either by the
needs to be considered carefully by weighing the rupture of dilated and varicose bronchial veins
risks of the biopsy procedure, the likelihood of early in the course of mitral stenosis or as a result
obtaining a diagnostic piece of tissue, the of the stress failure of pulmonary capillaries.115
likelihood of the biopsy findings to alter the In surgically untreated patients, recurrent epi-
therapeutic approach, and the risks associated sodes of DAH may lead to chronic hemosiderosis
with the chosen therapy. In most cases of DAH, a of the lungs, fibrosis, and punctate calcification/
lung biopsy is not warranted. ossification of the lung parenchyma.
The DAH syndromes can be broadly sepa- Idiopathic Pulmonary Hemosiderosis: IPH is a
rated into those in which DAH is caused by or rare disorder of unknown cause. It is a diagnosis

of exclusion. Many cases reported before the (BMT) recipients, usually during the first 30 days,
discovery of ANCAs probably represented with most episodes occurring around day 12
ANCA-associated vasculitis. Most cases diag- after BMT.126–128 Recipients of autologous BMT
nosed as IPH today are probably associated with are at higher risk than recipients of allogeneic
gluten-sensitive sprue (celiac disease). The com- BMT. DAH and diffuse alveolar damage are the
bination of alveolar hemorrhage and celiac two major complications following BMT. The
disease has also been called Lane-Hamilton overall incidence of diffuse alveolar damage is
syndrome.116 In contrast to DAH of other 5% to 7%. An autopsy series has found DAH in
etiologies, the DAH of IPH may be subtle and 24% of post-BMT recipients.129 Risk factors for
not necessarily associated with hemoptysis. Iron- the development of DAH include intensive
deficiency anemia is a hallmark of IPH. It is conditioning chemotherapy and older age (.40
thought to be the result of malabsorption of iron years). Post-BMT alveolar hemorrhage is a form
in the gastrointestinal tract rather than of of noninfectious pneumonitis characterized by
recurrent lung hemorrhage. IPH can occur in sudden onset of dyspnea, nonproductive cough,
children or young adults. Patients suspected of fever, and hypoxemia. Hemoptysis is rare and its
IPH should be tested for antigliadin antibodies, absence may lead to incorrect diagnosis. Many
particularly since gastrointestinal symptoms may
cases are identified only at autopsy.130 The
be absent or very subtle. Most patients with IPH
clinical presentation is nonspecific. Chest imag-
attributable to celiac disease respond to gluten-
ing shows diffuse but patchy alveolar densities
free diet and do not need immunosuppressive
with central predominance. Lung biopsy is rarely
therapy.116 Repeated DAH in IPH has been
indicated. BAL is important to detect DAH and
reported to progress to lung fibrosis; early
to exclude infections. DAH is a potentially fatal
appropriate therapy may prevent this out-
respiratory complication with a reported mortal-
come.117
ity in excess of 50%.126,131 Data that support high-
Toxic Alveolar Hemorrhage: DAH can result
dose parenteral glucocorticoid use as beneficial
from toxic fume inhalation or from blood-borne
toxins. Fumes or dust of trimellitic anhydride (a therapy are not convincing; yet, it remains
component of certain plastics, paints, and epoxy standard practice.
resins) cause acute rhinitis and asthmatic symp-
toms if exposure is minor; with greater exposure, Miscellaneous Causes of Alveolar Hemorrhage
alveolar hemorrhage occurs.118,119 The trimellitic
anhydride-hemoptysis anemia syndrome occurs The following rare disease entities have also
after ‘‘high-dose exposure’’ to fumes.120,121 Iso- been reported to occasionally cause alveolar
cyanates have caused lung hemorrhage. Illicit hemorrhage. Therefore, they should be consid-
drug use, particularly crack cocaine inhalation, ered in the differential diagnosis: pulmonary
has also been linked to DAH.122 lymphangioleiomyomatosis,132 pulmonary veno-
Many medications have been associated with occlusive disease,133,134 pulmonary capillary he-
the development of DAH. These include drugs mangiomatosis,135 and tumor emboli.136
with antiplatelet or anticoagulant effects includ-
ing abciximab; immunosuppressive and chemo- Relationships Disclosed
therapeutic agents, including D-penicillamine,
sirolimus, and all-trans-retinoic acid; antithyroid The author has disclosed the following
drugs such as propylthiouracil; or continuous IV relationships: Grant monies (from sources other
infusion of epoprostenol for primary pulmonary than industry): NIAID, NIAMS. Consultant fee,
hypertension.121,123,124 Antithyroid drugs can speakers bureau, advisory committee, etc: con-
cause an ANCA-associated vasculitis with sulting fees from Genentech Inc. Product/proce-
DAH.125 dure/technique that is considered research and
DAH Following Bone Marrow Transplant is not yet approved for any purpose: All
(BMT): DAH occurs in both allogeneic and medications/interventions used for the treat-
autologous hematopoietic stem cell transplant ment of ANCA-associated vasculitis except the

use of glucocorticoids and rituximab represent an individual patient data meta-analysis. Arthri-
off-label use for this indication. tis Rheum. 2007;56(8):2789–2797.
12. Maksimowicz-McKinnon K, Clark TM, Hoffman
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Notes

Chapter 36. Lung Cancer
Gerard A. Silvestri, MD, MS, FCCP
Objectives: Epidemiology
Understand the epidemiology of lung cancer and
etiologic factors that cause this disease. Lung cancer is the leading cause of cancer death
Review the latest information on screening for lung cancer,
using chest radiography and chest CT scan imaging.
in the United States and worldwide. In 2010, a
Review the techniques and strategies used to diagnose total of 222,520 patients were diagnosed with
lung cancer. cancer and 157,300 died of this disease.1 World-
Understand the importance of accurate staging and review wide the numbers are staggering. Two million
the methods used to stage a patient before treatment.
Understand the appropriate preoperative evaluation for persons per year die of lung cancer and this is a
patients who are being considered for surgical resection conservative estimate. Estimates indicate that by
of a lung cancer. the year 2030, a total of 10,000,000 people will die
Review the treatment options by stage and cell type of
from this disease yearly. The full consequences of
lung cancer.
the tobacco epidemic are not yet known. In
developing nations, the epidemic has not yet
Key words: bronchogenic carcinoma; bronchoscopy; che-
motherapy; computed tomography; endobronchial ultra- reached its peak. For example, 350,000,000 Chi-
sound; mediastinoscopy; non-small cell lung cancer; nese persons smoke cigarettes, which is more than
positron emission tomography; radiation therapy; sterotac- the number of persons living in the United States.
tic body radiotherapy; tyrosine kinase inhibitors; video-
assisted thoracoscopic surgery
On average, they consume 11 cigarettes per day,
an amount equivalent to estimates of the Amer-
Synopsis: ican population in the late 1950s and early 1960s.
Lung cancer is the leading cause of cancer death in the
In males, prostate cancer has the highest
United States and worldwide, accounting for 157,000 deaths incidence, followed by cancer of the lung and
in the United States in 2011. Screening using chest bronchus, while colon cancer remains the third
radiograph does not reduce mortality. A recent randomized
most commonly diagnosed cancer in both men
trial showed that screening with chest CT scan imaging
reduces mortality by 20%. The diagnosis of lung cancer can and woman. For women, the incidence of breast
be made by using a myriad of tests, depending on the size cancer is higher than that of lung cancer.
and location of the primary tumor and/or the presence and However, mortality from lung cancer is higher
site of metastases. The initial biopsy analysis should attempt
to both make a diagnosis and confirm the most advanced
than from breast and prostate cancer in women
stage simultaneously. Lung cancer is classified as small cell and men, respectively. Colorectal is the third
(20%) and non-small cell (80%). Adenocarcinoma is the most leading cause of cancer death in men and
common histologic subclass (30%–35%), then squamous cell women. More people in the United States will
(25%), large cell (10%–15%), and poorly differentiated non-
small cell lung cancer (NSCLC) (10%–15%). Staging with CT die of lung cancer than of breast, prostate, and
and PET scans should be performed in most cases of lung colon cancer combined. Nearly twice as many
cancer. Tissue confirmation of positive findings is needed. women will die of lung cancer than breast cancer
Accurate staging of the mediastinum is critical and can be
each year in the United States. Lung cancer is
accomplished with transbronchial needle aspirate, endo-
bronchial ultrasound with fine needle aspiration, mediasti- decreasing in incidence owing to the decrease in
noscopy, mediastinotomy, or video-assisted thoracoscopic tobacco consumption. This has occurred more
surgery. Treatment regimen and prognosis depend upon rapidly in males than in females.
stage. Small cell lung cancer is treated with chemotherapy
for advanced stage and chemoradiotherapy for limited- Tobacco use is responsible for 80% to 90% of
stage disease. Stage 1 NSCLC is treated with surgery alone; the cases of lung cancer. There is a clear dose/
stage 2, with surgery followed by chemotherapy; stage 3, response relationship. Five percent of all lung
with chemoradiotherapy; and stage 4, with chemotherapy
cancers may be related to passive smoke, more so
alone. Newer treatment with targeted agents, such as the
tyrosine kinase inhibitors, is warranted for those with a in never-smokers. There is an individual genetic
sensitizing receptor on the surface of the tumor. susceptibility to lung cancer and 10% to 15% of

never-smokers who develop lung cancer have a lung cancers and its incidence has been decreas-
strong family history of this disease. Controlling ing over time. Non-small cell lung cancer
for cigarette smoking, genetic susceptibility (NSCLC) accounts for the other 80%. Within
probably accounts for a two- to three-fold NSCLC, adenocarcinoma is the most common
increase incidence of lung cancer. The etiology cell type, with approximately 30% to 35% of all
of lung cancer has also been related to other lung cancers designated as an adenocarcinoma.
causes including asbestos, radon, polycyclic Squamous cell carcinoma accounts for 20% to
hydrocarbons, chloromethyl ether, chromium, 25% of all lung cancers. Large cell carcinoma
nickel, and arsenic. Of these, asbestos has the accounts for 10% to 15%, and the remainder are
tightest association with lung cancer. It should be unclassified or poorly differentiated. There are
remembered that asbestos alone can cause some clinical and radiographic differences be-
mesothelioma irrespective of cigarette smoking. tween the subtypes of lung cancer. Squamous cell
The combination of asbestos and cigarette smok- carcinoma occurs in 95% of patients who smoke
ing is multiplicative, that is to say, asbestos alone cigarettes. It is usually a centrally located lesion
raises the risk of lung cancer only slightly (2–33 that grows locally. Squamous cell cancers can
normal), cigarettes alone raise it a great deal (20– cavitate. They are also associated with the
403 normal, depending on the amount and paraneoplastic syndrome of hypercalcemia and
length of the exposure), and the combination of hypertrophic pulmonary osteoarthropathy. Ade-
smoking and asbestos exposure increases the nocarcinoma has an increased incidence in never-
likelihood of lung cancer nearly 100-fold. Age is a smokers and is usually located peripherally. It
risk factor for lung cancer, and the average age of has a higher rate of metastatic disease at
diagnosis for lung cancer is 70 years. COPD is presentation. Small cell lung cancer is uniformly
another risk factor for lung cancer even after found in smokers. It is usually a centrally located
controlling for tobacco use. Patients with COPD tumor with more than 70% of cases presenting as
have a 4 times higher likelihood of lung cancer metastatic disease. Nearly all of the paraneoplas-
than those with a similar smoking exposure tic syndromes related to lung cancer are found in
without COPD. Lung cancer occurs in never- patients with small cell-type histology. Large cell
smokers and accounts for 10% to 15% of all lung carcinoma is usually found peripherally. It has a
cancer cases. Worldwide, 15% of men and nearly high predilection for metastatic disease and
50% of women with lung cancer are never- occurs most often in smokers. Bronchoalveolar
smokers. It is believed that the high incidence cell carcinoma is a subtype of adenocarcinoma. A
of lung cancer among women who are never- new classification does away with the designa-
smokers is due to the use of biomass cooking tion bronchoalveolar cell carcinoma (BAC). This
fuels in poorly ventilated residences. If consid- disease is often found in nonsmokers and is more
ered separately, lung cancer in never-smokers commonly found in females. It may have one of
would rank as the seventh most common cause three radiographic presentations: (1) solitary
of cancer death worldwide.2 There are differenc- pulmonary nodule, (2) lobar consolidation (ap-
es in response to treatment of lung cancer in pears to mimic pneumonia), or (3) multiple
never-smokers (they live longer even after nodules. Different presentations may be distinct
controlling for stage at presentation), and it biological diseases with different presenting
should be noted that females, light smokers or features, treatment options, and prognoses. It is
never-smokers, and Asian persons respond bet- staged and treated as adenocarcinoma and has a
ter to the tyrosine kinase inhibitors (erlotinib). higher response rate to the epidermal growth
factor receptor (EGFR) inhibitors. Solitary, pul-
Histologic Classification of Lung monary nodules that present as BAC are often
Cancer very slow growing and have a lower likelihood
of revealing a high uptake on PET scan. Another
As a general grouping, lung cancer is interesting feature of the multifocal bronchoal-
classified as either small cell or non-small cell. veolar cell carcinoma is bronchorrhea. Patients
Small cell accounts for approximately 20% of all can also have complaints of salty-tasting sputum.
618 Chapter 36. Lung Cancer (Silvestri)

Table 1—Categories of New Adenocarcinoma Classification pulmonary nodule (defined as .4 mm); most
for Which Former BAC Concept Was Used
results (96.4%) were false-positives. Most of the
1. Adenocarcinoma in situ, which can be nonmucinous
false-positive scans needed only radiographic
and rarely mucinous follow-up. Only 1% mortality with surgery was
2. Minimally invasive adenocarcinoma, which can be reported for those undergoing screening. Cur-
nonmucinous and rarely mucinous rently, there is no guideline recommendation for
3. Lepidic-predominant adenocarcinoma (nonmucinous)
4. Adenocarcinoma, predominantly invasive with some screening and we await the recommendation of
nonmucinous lepidic component (includes some the US Preventive Services Task Force. However,
resected tumors, formerly classified as mixed subtype, it seems clear that some form of lung cancer
and some clinically advanced adenocarcinomas,
screening using low-dose CT scanning will be
formerly classified as nonmucinous BAC)
5. Invasive mucinous adenocarcinoma (formerly mucinous undertaken in the future.
BAC)
Diagnosis
The new classification for BAC can be found in
History
Table 1.3
Patients with lung cancer most commonly
Screening for Lung Cancer
have complaints of cough, dyspnea, chest pain,
and/or hemoptysis. Less common symptoms
Until recently, lung cancer screening using
include clubbing, hoarseness, dysphasia, or
any modality was not recommended. Three
wheezing. Only 5% to 15% of patients with lung
randomized trials in the 1970s, using chest
cancer are asymptomatic. Fifteen percent have
radiography vs community care, revealed no
extrapulmonary symptoms, the most common
benefit from lung cancer screening. Those trials being neurologic (headache), bone pain, weight
are criticized for contamination (ie, the patients loss, or other complaints related to the site of
in the control arm received periodic chest metastatic disease. Up to 10% may present with a
radiographs) and for being underpowered to paraneoplastic syndrome. One aspect to note in
detect a reduction in mortality, if present. Still, the history of a patient with lung cancer is a
the US Preventive Services Task Force did not change in the character of the cough. As cough
recommend screening with chest radiography. quite commonly is present in patients who
Recently, the results of the prostate, lung, colon, smoke cigarettes, it is often a change in that
ovarian screening trial revealed that screening cough that alerts the clinician that lung cancer
using chest radiography was not beneficial for may be present. Patients with lung cancer often
patients with lung cancer. That study randomly describe that the cough has changed in character
assigned approximately 140,000 patients to re- (deeper, unrelenting), the sputum quantity has
ceive radiography vs no radiography.4 changed, or that there is now blood streaking in
Recently, the results of the National Lung the sputum.
Screening Trial were reported. That trial enrolled
53,454 participants between the ages of 55 and 74 Physical Examination
who were current or former smokers with a 30-
pack-year history of smoking.5 They randomly Findings on physical examination usually
assigned that population to receive low-dose CT parallel symptoms, for example, facial swelling
scanning vs chest radiography. Participants were associated with superior vena cava syndrome;
scanned for 3 years and the average follow-up papilledema for patients with cranial metastasis;
was another 3.5 years. The study was stopped and lymphadenopathy, particularly supraclavic-
early because the mortality end point was ular lymphadenopathy, for those with advanced
reached. There was a reduction in both lung cancer. Positive findings are only found late in
cancer mortality (20%) and overall mortality the course of the disease. Generally, by the time
(6.7%). Nearly 25% of persons in the group who one can find significant physical examination
received a low-dose CT scan had a solitary findings, the patient has metastatic disease. Fifty

percent of patients have evidence of unresect- toid nodule, and granulomatosis with polyangii-
ability at the time of their diagnosis. Once the tis (Wegener). This is but a short list of the
patient undergoes further testing, another 15% potential causes of solitary pulmonary nodules.
will be deemed to have unresectable disease. An Adenocarcinoma accounts for nearly 60% of
additional 5% to10% will be found to have malignant solitary pulmonary nodules. Squa-
unresectable disease at the time of surgery. mous cell cancer occurs in 20%, solitary metas-
Therefore, only approximately 20% to 30% of tasis in 10%, undifferentiated non-small cell
patients are surgical candidates. cancer in 10%, and very rarely, small cell
The common paraneoplastic syndromes are carcinoma presents as a solitary pulmonary
hypertrophic pulmonary osteoarthropathy. The nodule.6
physical examination findings for this entity There are three clinical characteristics and
include clubbing and painful shins. Hypercalce- three radiographic characteristics that make
mia, often due to a production of parathyroid cancer more likely. The clinical characteristics
hormone-like hormone, is more common in include the age of the patient, the smoking status,
squamous cell carcinoma than in the other and a history of extrathoracic malignancy. The
cancers. Another paraneoplastic syndrome is older the patient, the higher the pack-year history
syndrome of inappropriate ADH secretion, of smoking; moreover, a history of cancer
which is most commonly found in small cell elsewhere makes lung cancer more likely. Radio-
lung cancer. Eaton-Lambert syndrome, a neuro- graphically, there are three findings that increase
muscular disorder resulting in progressive weak- the probability that the nodule in question is
ness, is also found more commonly in small cell malignant: diameter, with an increasing diameter
lung cancer. Cushing syndrome is another more likely to indicate cancer; spiculation, which
common paraneoplastic syndrome found with also increases the likelihood of cancer; and upper
small cell lung cancer. The findings of paraneo- lobe location of the nodule. Nodules greater than
plastic syndrome do not preclude treatment of 20 mm have an 80% chance of being malignant,
the lung cancer with curative intent, as patients whereas nodules between 2 to 5 mm have a 1%
with paraneoplastic syndrome can improve chance of being malignant. If a nodule is calcified
dramatically with treatment of the underlying completely, the likelihood that it is cancer is nil.
disease. However, eccentric calcification is worrisome and
patients with eccentric calcification should not be
Solitary Pulmonary Nodule dismissed without further evaluation or serial
radiographic follow-up. In general, if the pretest
With the increased utilization of CT scanning probability is low, serial CT scan to follow up the
of the chest for a myriad of indications, the lesion is recommended. If the pretest probability
incidence of solitary pulmonary nodule has risen is intermediate one could consider further
dramatically in the United States. Should screen- imaging with PET scan; if the lesion is 1 cm or
ing for lung cancer be undertaken on a broad greater, transthoracic needle aspiration or bron-
scale, this incidence will rise even further. When choscopy should be considered. If the pretest
one is evaluating solitary pulmonary nodule, the probability is high (. 60%), one should consider
pretest probability of cancer is quite important. excisional biopsy with a frozen section, followed
The differential diagnosis of benign solitary by lobectomy if the patient is found to have
pulmonary nodules includes nonspecific or cancer. Of note, the sensitivity of the transtho-
healed granulomas (25% infectious granulomas) racic needle aspiration is approximately 90%,
and benign neoplasms (15%). Within the benign with the specificity approaching 100%. It is also
neoplasms, hamartoma, lymphoma, fibroma, and important to note that finding nondiagnostic
other countless benign neoplasms can occur. biopsy results is five times more likely in persons
Other causes of noncancer solitary pulmonary eventually found to have benign disease, but a
nodules include lung abscess, pseudotumor, nondiagnostic biopsy result does not rule out
rounded atelectasis, arteriovenous malformation, malignancy. The rate of pneumothorax is ap-
infarct, mucoid impassion, hematoma, rheuma- proximately 15%, with 5% of patients requiring

Table 2—Recommendations for Follow-up and Management of Nodules Smaller Than 8 mm Detected Incidentally at
Nonscreening CT Scan
Nodule Size (mm) Low-Risk Patient High-Risk Patient
4 No follow-up needed Follow-up CT scan at 12 mo; if unchanged, no

further follow-up
.4–6 Follow-up CT scan at 12 mo; if unchanged, no Initial follow-up CT scan at 6-12 mo, then at
further follow-up 18–24 mo if no change
.6–8 Initial follow-up CT scan at 6-12 mo, then at Initial follow-up CT scan at 3–6 mo, then at 9–
18–24 mo if no change 12 and 24 mo if no change
.8 Follow-up CT scan at around 3, 9, and 24 mo; Same as for low-risk patient
dynamic contrast-enhanced CT scan, PET
scan, and/or biopsy
chest tube placement. Table 2 describes the examination of pleural fluid. If pleural fluid is
recommended course of follow-up for nodules present, a diagnostic thoracentesis should be
that are monitored with serial CT scan. Follow-up performed. Initially, only 50% of cases are
is recommended on the basis of the size of the cytologically positive. If the pleural fluid is
nodule and the risk of cancer. For low-risk cytologically negative, in the right clinical setting,
patients with a very small pulmonary nodule a second cytology specimen should be obtained.
(,4 mm), no follow-up is necessary. However, There is no evidence that sending more than 50
for high-risk patients, follow-up is recommended mL of fluid to the pathology service improves the
more frequently and earlier biopsy is recom- diagnostic yield. If both pleural fluid examina-
mended.7 tion results are negative, the recommendations of
the American College of Chest Physicians
Diagnosis of Lung Cancer (ACCP) in its lung cancer guidelines is to
proceed to pleuroscopy or thoracoscopy via
Sputum Cytology video-assisted thoracoscopic surgery (VATS).
Blind pleural biopsy is not recommended as it
Though rarely performed, sputum cytologic only increases the yield by 8%. In considering the
findings diagnostic in 20% of patients with lung diagnosis of lung cancer, one should always
cancer, in 74% with central lesions, and in only biopsy the site that can provide the diagnosis and
5% with peripheral lesions. It is a reasonable first the highest stage of disease simultaneously.
step for central lesions, particularly for patients Therefore, it is recommended that if there is
who are not candidates for treatment but for evidence of distant metastatic disease, such as
whom a diagnosis can be informative (for them the presence of a supraclavicular lymph node, a
and their family) and for whom supportive care liver lesion, or an adrenal lesion, that this entity
services can be offered. Bronchoscopy has an be biopsied first, thereby providing not only a
overall sensitivity of 88% in cases with central diagnosis, but also the stage of the disease as
lesions. The sensitivity for diagnosis is highest stage IV, with a single diagnostic test.8
when combining direct endobronchial biopsy,
endobronchial brush, and bronchial wash. For Staging
peripheral lesions, bronchoscopy is not useful for
patients with lesions ,2 cm (20%). Bronchoscopy Staging lung cancer is critically important
has a better yield for larger, peripheral lesions because it allows the clinician to estimate
(60%). The yield of bronchoscopy is also im- prognosis, select treatment options, and report
proved if there is a radiographic bronchus sign outcomes. It gives clinicians a common, easily
extending to the lesion, by using fluoroscopy and understood nomenclature with which to com-
by obtaining 5 biopsies. The diagnosis of lung pare patients between institutions and enroll
cancer can be obtained with a high accuracy by eligible patients in clinical trials. Recently, in July

Table 3—Proposed Definitions for T, N, and M Descriptors tumors ,2 cm, while T1B tumors are between 2
to 3 cm. T2 tumors have been subclassified to
T2A if they are between 3 and 5 cm, and to T2B if
they are between 5 and 7 cm. Finally, tumors .7
cm are now classified at T3 tumors. T3 tumors
also include a second nodule in the same lobe
and atelectasis of the whole lung. T4 tumors
invade the mediastinum directly or the great
vessels. In addition, a T4 tumor has an ipsilateral
nodule in a different lobe. Finally, pleural
effusions, which were previously designated as
T4 lesions, are now designated as M1 lesions. In
addition, nodules present in different lobes but in
the same lung, previously designated as M1
disease, are now downstaged to T4, as their
prognosis is better than previously thought.
There are no changes in the N component of
the staging classification. N0 is designated as no
hilar or mediastinal adenopathy; N1 disease, as
intrapulmonary or hilar lymph nodes; N2 dis-
ease, as ipsilateral mediastinal lymph node
involvement; and N3 disease, as contralateral
mediastinal lymph node involvement. The M or
metastatic component of lung cancer staging
system is now designated M1A and M1B. M1A
includes metastatic disease within the chest and
M1B includes metastatic disease outside the
chest. From a practical standpoint, treatment for
both of these M-classified diseases is the same.
Prognostically, however, M1B disease has a
worse prognosis. Once the TNM status is
documented, a stage classification is then devel-
oped (Tables 3 and 4 for stage classification).
Pathologic 5-year survival in the new revised
staging system is 73% for stage IA disease, 58%
for stage IB, 46% for stage IIA, 36% for stage IIB,
24% for stage IIIA, 9% for stage IIIB, and 13% for
stage IV. Small cell lung cancer can use the TNM
classification for staging. However, for practical
reasons, many clinicians still use the old Veterans
Administration Lung Cancer Study Group stag-
ing system, which breaks the staging of small cell
lung cancer into extensive stage disease, that is,
disease outside of a single hemithorax, or limited
stage disease within a hemithorax, which can
include a supraclavicular lymph node. At the
2009, the 7th edition of the TNM classification of time of diagnosis, 70% of patients with small cell
malignant tumors was published.9 The interna- lung cancer are found to have extensive disease.
tional staging system was changed significantly After a history and physical examination are
(see Table 3). T1A tumors are designated as those performed, staging tests are often dictated by the

Table 4—Descriptors, Proposed T and M Categories, and noscopy alone. The sensitivity of EBUS-NA is
Proposed Stage Groupings approximately 93%, with a specificity of 100%.
The sensitivity of mediastinoscopy is also ap-
proximately 90%. Mediastinotomy and VATS are
the only methods that can access level-5 lymph
nodes.
Before surgery a combined CT-PET scan
should be performed. In one randomized pro-
spective trial, futile thoracotomies were reduced
by half for patients who had a preoperative PET
scan. The most common reason for avoiding
thoracotomy was the discovery of unsuspected
metastatic disease. For every five PET CT scans
performed, one futile thoracotomy was averted.
Preoperative Pulmonary Evaluation

findings of that examination and pretreatment
chest CT scan. In general, two noninvasive and From the evaluation thus far, one can assign a
several invasive staging tests can be per- clinical TNM status, classify the patient as to a
formed.10,11 All patients with lung cancer usually stage of disease, and suggest a treatment ap-
undergo a CT scan of the chest through the proach. Should a treatment approach include
adrenal glands with contrast enhancement. Most consideration of surgery, one has to ask the
question of whether the tumor is resectable, and
patients who are going to be considered for
if it is resectable, whether the patient can
treatment will also undergo a PET scan. This is
undergo surgery.12 Operative risks include im-
particularly true if those patients are being
mediate or short-term perioperative morbidity
evaluated for surgical resection. CT scanning
and mortality. However, there is future long-term
has a poor sensitivity and specificity for medias-
risk including postoperative pulmonary disabil-
tinal involvement with tumor. The sensitivity is
ity and resultant decrements in quality of life.
50% and specificity is 86%. PET scans have both a
The most important parameter to assess before
higher sensitivity and specificity. However, PET
consideration of operability is pulmonary func-
scanning is not infallible. False-positive findings
tion studies. In general, if the FEV1 is .2 L or
in the mediastinum on PET scan occur for up to 60% of predicted, the patient should be able to
20% of patients. Therefore, tissue acquisition is tolerate most surgical procedures. If the diffusion
critical to avoid any possibility that a patient be capacity is 60% of predicted, postoperative
deemed as having inoperable disease, when in outcome is usually excellent as well. To improve
fact he or she may be a candidate for surgery. our ability to predict outcome, we calculate a
There are a myriad of methods of obtaining postoperative predicted FEV1 and diffusion
tissue within the mediastinum. They include capacity. If they are both greater than 40% of
mediastinoscopy, mediastinotomy (Chamberlain predicted, the patient will usually tolerate resec-
procedure), thoracoscopy, transbronchial needle tion quite well. High-risk patients include those
aspiration, endoscopic ultrasound with fine with a CO2 .45, a PO2 ,50, and a postoperative
needle aspiration (EUS-NA), and endobronchial predicted FEV1 or diffusion capacity ,40%
ultrasound with fine needle aspiration (EBUS- predicted. Age alone is a factor but it should
NA). Depending on the expertise within your not preclude patients from undergoing lung
institution, these tests can be complementary. A cancer resection. Poor exercise tolerance is an
recent randomized trial of needle acquisition of independent risk factor. The calculation of
mediastinal lymph nodes, using a combination of postoperative predicted FEV1 and diffusion
EBUS-NA and EUS-NA, found that this modality capacities is obtained by multiplying the preop-
was better than surgical staging with mediasti- erative value by the percentage of lung function

Figure 1. ACCP algorithm for preoperative evaluation for lung cancer patients.
that will remain after surgery. This can be 20, the mortality of surgery is not increased;
calculated by using differential ventilation per- however, the morbidity related to surgery is, and
fusion scanning; the ACCP has an algorithm (Fig that should be a consideration. For those with a
1). For borderline cases, for which the postoper- maximum oxygen consumption of .20 mL/kg/
ative predicted FEV1 and diffusion capacity are min, surgery is reasonable.
borderline (around 40%), a cardiopulmonary
exercise testing should be performed. For those Treatment
who have a maximum oxygen consumption of
,10 mL/kg/min, alternatives to surgery should Treatment of small cell lung cancer is related
be strongly considered. For those between 11 and to the stage at diagnosis, with 70% of patients

having extensive disease at presentation.13 Those For those patients with early-stage NSCLC,
patients are eligible for chemotherapy alone. who are not candidates for surgery, radiation
Palliative radiotherapy is included to treat therapy with curative intent can be offered.
symptoms related to most metastatic sites. These Stereotactic body radiotherapy (SBRT) is a new
patients generally have an excellent response to noninvasive cancer treatment in which numer-
chemotherapy. However, disease nearly always ous, small, highly focused, and accurate radia-
recurs. This stage of small cell lung cancer is not tion beams are used to deliver potent doses of
curable. The average survivorship is approxi- radiation in 1 to 5 treatments to tumor targets.
mately 9 months. The 1-year survival is 20% and In a landmark study by Timmerman et al,14
there is virtually no 5-year survivorship. The published in JAMA in 2010, the local control
treatment of limited stage small cell cancer rate for patients with stage I and II tumors
includes chemotherapy and thoracic radiation treated with SBRT was 97%. This is much better
therapy. If patients have a complete response, than was found with traditional radiation
they are also offered prophylactic cranial radia- therapy.15 Randomized trials are now underway
tion. The median survival is 16 to 24 months. that randomly assign patients to surgery vs
Two-year survival is from 40% to 50% and in SBRT for patients with marginal pulmonary
some studies, up to 20% are cured (this is function. Stage IIIA NSCLC encompasses a
approximately the same cure rate as those with heterogeneous group of patients; however, most
stage IIIA NSCLC). patients in this grouping have a tumor with
ipsilateral mediastinal lymphadenopathy (N2
The treatment of NSCLC differs significantly
disease). There is some controversy regarding
by stage. Stage IA, IB, IIA, and IIB cancers are all
the treatment of these patients.16 In general, the
candidates for surgery.14 The proper surgery for
gold-standard treatment is combined chemo-
lung cancer includes a lobectomy or pneumo-
therapy with thoracic radiation to both the
nectomy with mediastinal lymph node dissec-
tumor and the mediastinum. Some have advo-
tion. Three or more lymph node stations should
cated for neoadjuvant therapy, which is pre-
be sampled. Whenever possible, a VATS surgery
treatment chemotherapy, or radiotherapy
should be performed. Cure rates are similar to
followed by surgery. However, two large ran-
those for open thoracotomy, with a better quality
domized trials found no survival benefit for
of life and decreased pain by using a VATS
patients given several cycles of chemotherapy
approach. Lesser resections, such as a wedge or a and/or radiotherapy before surgery. Patients
segmentectomy, can be performed in appropriate who have incidental mediastinal lymph node
patients with marginal lung function. For pa- involvement discovered unexpectedly at the
tients with stage II disease and resected stage time of surgery are candidates for postoperative
IIIA disease, adjuvant chemotherapy should be adjuvant chemotherapy with consideration of
offered. There is no benefit to providing adjuvant adjuvant radiation therapy. The treatment of
therapy for patients with stage 1A disease. In stage IIIB lung cancer includes combined
fact, they do worse with chemotherapy postop- chemoradiotherapy, similar to that for patients
eratively. The additional benefit of chemotherapy with stage IIIA, though the outcome is worse.17
after surgery in patients with stage II and Special considerations for the treatment of stage
resected stage T3 disease is at least 5% and IIIA disease include the Pancoast or superior
may be as high as 15%. Patients should be sulcus tumor. This is a clinical presentation for
offered four cycles of chemotherapy, which which data show that preoperative chemora-
should start within 6 weeks of surgery. The diotherapy improves the 5-year survivorship to
follow-up after surgery should include a history approximately 50%. If the disease is not
and physical examination plus chest CT scan completely resectable, chemoradiotherapy is
every 6 months for 2 years, then yearly until 5 the treatment of choice.
years. Postoperative imaging with PET scan is Stage IV NSCLC is a difficult disease to
not recommended unless a new lesion is discov- treat.18 In general, the 5-year survivorship is
ered on CT scan. ,5%. For patients with a good performance

status, chemotherapy provides a small but who have an abnormal alteration of that
definite survival benefit. The median survival pathway present within their tumor.19,20
is improved by 4 months. At 1 year, the survival
is doubled from 10% to 20% with chemothera- Radiation Therapy for Lung Cancer
py. There is also a quality-of-life benefit. In
several studies, treatment of stage IV lung As previously discussed, SBRT is useful for
cancer with chemotherapy has been found to patients with stage I lung cancer who have been
be cost-effective. Patients with stage IV disease deemed unsuitable for surgery as a consequence
who have a poor performance status do not of poor pulmonary function. Radiation therapy
benefit from chemotherapy and should be has an important role in the treatment of stage III
treated with best supportive care alone. Che- lung cancer when it is combined with chemo-
motherapy for stage IV disease includes a therapy. Radiation therapy is extremely useful in
platinum-based doublet. Four cycles of chemo- palliating bony metastasis, hemoptysis, superior
therapy is as good as six cycles of chemother- vena cava syndrome, and in patients who
a p y. Tu m o r s t re a t e d w i t h s e c o n d - l i n e develop atelectasis from endobronchial obstruc-
chemotherapy for stage IV lung cancer, and tion with tumor.
which have progressed on first-line therapy,
have a lower response rate. Docetaxel in this
Summary
setting improves survival by about 2 months.
In summary, lung cancer is the leading
Erlotinib (a tyrosine kinase inhibitor) also adds
cause of cancer death in the United States.
a 2-month survival benefit.
While the incidence of lung cancer is decreasing
There are new approaches to NSCLC that
in the United States, an epidemic is at hand in
include targeted therapy. The concept is to direct
developing nations. Screening for lung cancer
treatment at specific cell-signaling and regulato-
with chest radiography is of no benefit. There is
ry pathways that are altered in neoplastic cells.
a 20% reduction in lung cancer mortality by
The single most studied target is the epithelial
using low-dose CT scan screening. While there
growth factor receptor. It is overexpressed in a
are no current guidelines in favor of screening
significant minority of lung cancers. Binding to
using low-dose CT scan, it is likely that
the epidermal growth factor receptor triggers screening will be recommended for those who
intracellular signaling events through at least meet inclusion criteria of the national lung
three major pathways (the AKT, MAPK, and screening trial. The diagnosis of lung cancer
STAT pathways). The tyrosine kinase receptor is depends upon the clinical presentation and
responsible for proliferation, invasion, angiogen- radiographic findings. The tools used for tissue
esis, metastasis, and inhibition of apoptosis. diagnosis depend on the easiest access for the
These all lead to uncontrolled tumor growth. patient and the least invasive way to confirm
Gefitinib and erlotinib are the best-studied malignancy and to provide the most advanced
tyrosine kinase inhibitors. Clinical factors that stage with a single diagnostic test (eg, biopsy of
predict response include adenocarcinoma sub- an adrenal gland). Intrathoracic staging should
type, never-smokers, women, and Asian heri- include a CT and a PET scan. False-positive CT
tage. Patients with adenocarcinoma who are and PET scan findings occur and clinicians
EGFR-positive benefit from first-line erlotnib as should not base their treatment strategy on a
opposed to those without the mutation, who do PET scan without tissue confirmation. The
worse when treated with a tyrosine kinase treatment of stage 1 NSCLC includes surgery
inhibitor and better with traditional chemother- for patients deemed suitable for this interven-
apy. Other targets have been recently identified, tion, and stereotactic body radiotherapy for
including the benefit of targeting the EML 4 those who have severe pulmonary dysfunction
ALK receptor with crizotnib. The general trend or other comorbidities that preclude safe surgi-
in lung cancer research is to identify pathways cal resection. The treatment of stage II disease is
that can be targeted for treatment in patients surgery with adjuvant chemotherapy. The treat-

ment of stage III disease is combined radiation when is it lung cancer: ACCP Evidence-Based
and chemotherapy. The treatment of stage IV Clinical Practice Guidelines (2nd edition). Chest.
disease is chemotherapy or targeted therapy if 2007;32(3 suppl):108S–130S.
the patient has a reasonable performance status. 7. MacMahon H, Austin JH, Gamsu G, et al.
If performance status is poor, best supportive Guidelines for management of small pulmonary
care should be used. Palliative radiation thera- nodules detected on CT scans: a statement from
py should not be excluded for any patient with the Fleischner Society. Radiology. 2005;237:395–400.
any stage disease if necessary. 8. Rivera MP, Mehta AC. Initial diagnosis of lung
Multidisciplinary tumor boards often provide cancer: ACCP Evidence-Based Clinical Practice
the best possible recommendations for treatment- Guidelines (2nd edition). Chest. 2007;132(3 suppl):
related issues and should be used when avail- 131S–148S.
able. 9. Goldstraw P, Crowley J, Chansky K, et al. The
IASLC Lung Cancer Staging Project: proposals for
Relationships Disclosed the revision of the TNM stage groupings in the
forthcoming (seventh) edition of the TNM classi-
The author has disclosed the following fication of malignant tumours. J Thorac Oncol.
relationships: Monies (from sources other than 2007;2(8):706–714.
industry): Duke Endowment; virtual tumor 10. Silvestri GA, Gould MK, Margolis ML, et al.
board NCI – K24 DOD computer aided cancer Noninvasive staging of non-small cell lung
detection. Grant Monies (from industry related cancer: ACCP evidenced-based clinical practice
sources): Allegro diagnostics Olympus America, guidelines (2nd ed). Chest. 2007;132(suppl):178S–
Boston Scientific Corporation. Consultant fee, 201S.
speakers bureau, advisory committee, etc: Olym- 11. Detterbeck FC, Jantz MA, Wallace M, Vansteen-
pus America. Speakers Bureau: Olympus Amer- kiste J, Silvestri GA. Invasive mediastinal staging
ica diagnostics. The ACCP Education Committee of lung cancer: ACCP evidence-based clinical
has reviewed these relationships and resolved practice guidelines (2nd ed). Chest. 2007;
any potential conflict of interest. 132(suppl):202S–220S.
12. Colice GL, Shafazand S, Griffin JP, et al. Physio-
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Chapter 37. Pathology of Lung Cancer, COPD, and
Diseases of the Airways
Andrew Churg, MD
Objectives: This is a very brief overview of the pathology of

Review the different morphologic types of smoking- lung cancer, COPD, asthma, and airway diseases.
related lung cancers. It purposely includes no pictures, but pathology
Review major highlights of the new (and not universally
cannot be understood without morphologic
adopted) classification of lung adenocarcinomas.
Review the pathologic features of COPD. images, and, when going through this chapter,
Review the pathologic features of asthma. the reader should refer to the images in the
Review the pathologic features of bronchopneumonia. PowerPoint presentations that are part of the
Review the pathologic features of infectious bronchiolitis
material included in the Board Review Course, if
and constrictive bronchiolitis.
Review the pathologic features of aspiration. possible.
Key words: adenocarcinoma in situ; asthma; bronchiolitis; Carcinoma of the Lung

bronchoalveolar cell carcinoma; bronchopneumonia; COPD;
emphysema; lung cancer; small airway remodeling Smoking-Related Carcinomas
Synopsis: Carcinoma of the lung, as the term is com-

The common smoking-induced lung cancers include squa- monly used (meaning tumors generally related to
mous cell carcinoma, adenocarcinoma, small cell carcinoma, cigarette smoking) are classified histologically as
and large cell undifferentiated carcinoma. Bronchoalveolar
cell carcinoma is a variant of adenocarcinoma in which there shown in Table 1. There are distinct microscopic
is growth of carcinoma cells along alveolar walls. A new requirements for diagnosing each histologic
classification of pulmonary adenocarcinomas proposes to type.1,2 Squamous cell carcinomas produce keratin
replace the term bronchoalveolar carcinoma with adenocar-
and/or show intercellular bridges. Adenocarcino-
cinoma in situ because these tumors are noninvasive and are
100% curable with local excision. Carcinoids are nonsmoking- mas make glands and/or produce mucus, al-
related neuroendocrine tumors that are usually low grade though the definitions of adenocarcinoma have
malignancies, most commonly found in the large airways. recently been expanded in complex ways to cover
COPD includes the pathologic entities of emphysema, small
airway remodeling, bronchial mucus gland hypersecretion
other morphologic patterns3 that potentially have
(clinical chronic bronchitis), and vascular remodeling associ- prognostic significance. Small cell carcinomas have
ated with pulmonary hypertension, of which emphysema and small cells with scanty cytoplasm and a distinctive
small airway remodeling are associated with airflow obstruc- immunohistochemical profile. Large cell carcino-
tion. In asthma a variable combination of increased airway
smooth muscle, thick basement membrane, mucus metaplasia
ma is a term reserved for tumors that do not show
with mucus hypersecretion, epithelial denudation, and any of the features of squamous cell, adenocarci-
eosinophil infiltration are found. Infectious bronchiolitis is noma, or large cell carcinomas.
characterized most commonly by an acute luminal neutrophil
About 95% of lung cancers are smoking-
exudate with a chronic inflammatory cell infiltrate in the
airway wall. Bronchopneumonia shows neutrophils in the related; however, carcinoma of the lung does
lumens of respiratory bronchioles and surrounding paren- occur in nonsmokers, and most such tumors are
chyma. In aspiration, food particles and bronchiolitis obliter- adenocarcinomas.
ans organizing pneumonia are often present in addition to
Bronchoalveolar Carcinoma and the Concept of
neutrophils, but pure acid aspiration can lead to diffuse
alveolar damage (clinical ARDS). Constrictive bronchiolitis Adenocarcinoma In Situ: Bronchoalveolar carcino-
demonstrates narrowing or complete obliteration of the ma (BAC) is a form of adenocarcinoma that
lumens of respiratory bronchioles by fibrous tissue with exhibits lepidic growth, meaning that the tumor
resulting fixed airflow obstruction.
cells grow along pre-existing alveolar walls and
are not invasive. Studies from Japan in the 1990s

Table 1—Histologic Classification of Carcinoma of the Table 2—Current and Proposed Nomenclature for Small
Lung Adenocarcinomas
Squamous cell carcinoma Current Name Proposed Name

Adenocarcinoma (including bronchoalveolar carcinoma)
Small cell carcinoma Bronchoalveolar carcinoma Adenocarcinoma in situ
Large cell carcinoma Adenocarcinoma with less Minimally invasive
than 5 mm of invasion adenocarcinoma
and from other parts of the world in the 21st

century have shown that,4–7 if this strict defini- and squamous cell carcinomas do not respond to
tion of BAC is followed, the tumor behaves as an pemetrexed. In addition, molecular testing for
in situ lesion that is 100% curable by local mutations for which specific therapies are avail-
excision.8 On the basis of these observations, it able is based in large part on the histologic type
has recently been proposed that tumors with a of tumor. For example, EGFR mutations are
pure lepidic growth pattern should be called found in a proportion of adenocarcinomas and
adenocarcinoma in situ7 (Table 2). It is too early never in squamous cell carcinomas.
to tell whether this nomenclature will be widely To help in the diagnosis of tumors that are
adopted, therefore the practicing clinician should not histologically obvious, many immunhisto-
expect to see both terms in pathology reports, at chemical markers have been extensively evalu-
least for the immediate future. It should be noted ated in the pathology literature. Some of the more
that, although they represent adenocarcinoma in useful ones are listed in Table 3. Their application
situ, BACs are still staged as T1 tumors. It has is complex and generally is based on a panel of
been proposed that staging schemes should be stains. Details are beyond the scope of this
changed to reflect biologic behavior.7 chapter, but some familiarity with the names of
Minimally Invasive Adenocarcinoma: The same the various stains is useful in understanding
studies that showed 100% survival for BAC also pathology reports.
produced the interesting observation that, given
time, BAC will become focally invasive, but that Carcinoid Tumors
BAC with less than a 5-mm invasive focus also
have an excellent prognosis.4–6 This has led to the Carcinoid tumors are nonsmoking-related
proposed term minimally invasive adenocarci- neoplasms that mostly arise in large airways.
nomas for such tumors with the suggestion that They are neuroendocrine tumors, meaning that
wedge resection (rather than complete lobecto- they contain neurosecretory granules that stain
my) might be adequate treatment. Again it is too for synaptophysin and chromogranin. They also
soon to tell whether this terminology or this stain for the markers CD56 and TTF-1.
surgical approach will be widely adopted. Pulmonary carcinoid tumors are malignant,
Immunohistochemistry in the Diagnosis of Car- but the majority are low grade neoplasms with
cinoma of the Lung: Although the histologic 10-year survival in excess of 90%. A minority of
subtype of many lung cancers is obvious on carcinoids are high grade tumors with a worse
routine pathology stains, a significant proportion prognosis. These lesions show necrosis, cytologic
is hard to classify, particularly on small bronchial
Table 3—Immunohistochemical Stains Useful in Histologic
or transbronchial biopsies or cytology specimens. Classification of Carcinoma of the Lung
The older concept that lung cancers should
simply be diagnosed as ‘‘small cell’’ or ‘‘non- Markers of Markers of
Markers of Squamous Small Cell
small cell’’1 has given way to the realization that
Adenocarcinoma Cell Carcinoma Carcinoma
adenocarcinomas and squamous cell carcinomas
need different chemotherapeutic approaches and TTF-1 p63 TTF-1
that some treatment modalities may be contrain- Napsin A Cytokeratin 5/6 CD56
Cytokeratin 7 Synaptophysin
dicated. For example, bevacizumab can cause Chromogranin
massive hemorrhage in squamous carcinomas9
630 Chapter 37. Pathology of Lung Cancer, COPD, and Diseases of the Airways (Churg)
atypia, and a high mitotic count when examined Table 4—Morphologic Types of Emphysema
microscopically. Pulmonary carcinoid tumors
Centrilobular emphysema
occasionally can secrete serotonin and cause Panlobular emphysema
carcinoid syndrome, but this is very uncommon, Paraseptal (also called distal acinar) emphysema
and even more uncommonly can produce adre- Scar or cicatricial emphysema
nocorticotropic hormone and cause Cushing’s
syndrome.
alveolar walls that would normally be attached
to small airways leads to loss of tethering and
Pathology of COPD premature collapse of the airways on expiration.
Anatomic Lesions in COPD
Small Airway Remodeling
COPD encompasses four anatomic lesions:
Small airway remodeling consists of fibrous
emphysema, small airway remodeling (also
thickening of the walls of membranous and, to a
called small airways disease), mucus gland
lesser extent respiratory, bronchioles such that
hyperplasia and mucus hypersecretion, and
the bronchiolar lumen is narrowed and distorted,
vascular remodeling. Emphysema and small
causing increased resistance to flow. Smooth
airway remodeling are associated with airflow
muscle may be increased as well. In addition,
obstruction, whereas mucus hypersecretion re-
sults in the clinical picture of chronic bronchitis. there is a chronic inflammatory infiltrate and
Chronic bronchitis is not a cause of airflow sometimes an acute inflammatory infiltrate in the
obstruction but appears to predispose to acute airway wall, mucus metaplasia of the airway
exacerbations, possibly because infectious organ- epithelium, and production of mucus that be-
isms colonize the excess mucus. Vascular remod- comes inspissated as mucus plugs, again causing
eling leads to pulmonary hypertension. airflow obstruction.11 Recent data using micro-
CT images suggest that, in addition to becoming
Emphysema narrowed, small airways are actually obliterated
in COPD, and that this process occurs before the
There are four main types of emphysema development of emphysema.12
(Table 4)10 and their descriptions are based on
location within the pulmonary lobule. In centri- Mucus Gland Hyperplasia and Mucus
lobular emphysema (CLE) one sees a hole that Hypersecretion
represents a destroyed and dilated respiratory
bronchiole with surrounding relatively normal There is no good anatomic measure of mucus
parenchyma. CLE emphysema typically starts in gland hyperplasia. The Reid index, which was
the upper zones but can extend to the lower used in the past, has been shown to produce poor
zones when severe. In panlobular emphysema discrimination between those with chronic bron-
(PLE), enlarged airspaces are present throughout chitis and those without. The real definition of
the lobule. PLE typically is more severe in the mucus hypersecretion is based on the clinical
lower zones. Paraseptal emphysema consists of signs and symptoms that constitute chronic
enlarged airspaces aligned along the pleura. Scar bronchitis.
emphysema consists of enlarged airspaces
caused by retraction of scars of any kind. CLE, Vascular Remodeling
PLE, and paraseptal emphysema are strongly
associated with cigarette smoking, but PLE is Vascular remodeling leading to thick-walled
also seen in patients who are a1-antitrypsin pulmonary arteries and muscularized pulmo-
deficient. nary arterioles causes pulmonary hypertension.
The exact role of emphysema in producing Although pulmonary hypertension in COPD has
airflow obstruction is somewhat controversial, been ascribed to loss of vessels caused by
but the usual explanation is that destruction of emphysema and hypoxia, current thinking is

Table 5—Etiologies of Constrictive Bronchiolitis ing infectious bronchiolitis include constrictive
(Bronchiolitis Obliterans)
bronchiolitis (bronchiolitis obliterans), bronchiec-
Inhalation of toxic gases and fumes
tasis, and lung abcess, as well as airway
(for example, nitrogen oxide causing silo filler’s disease) hyperreactivity.
Collagen vascular diseases, especially RA
Post viral and mycoplasma infections Bronchopneumonia
Inflammatory bowel disease involving the lung
Drug-induced
Associated with bronchiectasis Bronchopneumonia can be viewed as a
Lung transplantation special type of infectious bronchiolitis in which
Idiopathic there is, early on, an extensive neutrophil
infiltrate in the lumen of the bronchiole and also
extending out into the alveolar spaces distal to
that vascular remodeling is a direct effect of the bronchiole. As the pneumonia resolves, the
cigarette smoke.13 neutrophils are replaced by macrophages.
Viewed at a gross level, bronchopneumonia is
Asthma distinctly patchy with relatively uninvolved
parenchyma between bronchioles. Lobar pneu-
The morphologic findings in asthma are monia does not differ microscopically from
variable from patient to patient. Increased airway bronchopneumonia, but in lobar pneumonia the
smooth muscle (which causes abnormal degrees neutrophilic infiltrate occupies large regions of
of bronchoconstriction) is seen in most asthmat- the lung. Treated pneumonia may simply disap-
ics. In addition there may be marked thickening pear or may lead to a picture of organizing
of the epithelial basement membrane, denuda- pneumonia, a process that is microscopically
tion of the airway epithelium, mucus metaplasia identical to BOOP (hence the origin of the name
(increased goblet cells) of the epithelium leading BOOP: bronchiolitis obliterans organizing pneu-
to mucus hypersecretion and mucus plugs, and monia).
an infiltrate of eosinophils and chronic inflam-
matory cells. It should be remembered that Constrictive Bronchiolitis
treatment with steroids will cause rapid disap-
pearance of eosinophils, therefore their absence is Constrictive bronchiolitis is the current pre-
not against a diagnosis of asthma. More impor- ferred pathologic term for fibrous narrowing or
obliteration of the lumens of membranous and
tant, however, asthma is not a diagnosis that is
respiratory bronchioles. The corresponding clin-
based on biopsy, but rather on clinical and
ical term is bronchiolitis obliterans. However, in
pulmonary function findings.
lung transplant biopsies, the pathologic term
bronchiolitis obliterans is still used.
Infections Involving the Airways Etiologies of constrictive bronchiolitis are
shown in Table 5. Because the bronchiolar
Infectious Bronchiolitis
lumens are narrowed by fibrous tissue, there is
no response to bronchodilators, and patients
The findings in infectious bronchiolitis are
with bronchiolitis obliterans typically have fixed
extremely variable. Viral and mycoplasma infec- airflow obstruction as well as evidence of air
tions typically produce a picture of neutrophils in trapping on CT scan. Constrictive bronchiolitis is
the bronchiolar lumen and chronic inflammatory the major cause of lung transplant failure in long-
cells in the airway wall,14 but this same appear- term transplant survivors.
ance can be seen with noninfectious bronchiolitis,
for example, in inflammatory bowel disease Aspiration
involving the lung. Some cases of infectious
bronchiolitis show only a chronic inflammatory Aspiration can appear pathologically as a
cell infiltrate. Long-term sequelae of nonresolv- bronchiolitis or a pneumonia, or both. The most
common pathologic pattern is BOOP, typically peripheral adenocarcinoma of the lung. Ann
with associated giant cells or granulomas. De- Thorac Surg. 2000;69(3): 893–897.
pending on exactly what has been aspirated, 6. Yim J, Zhu LC, Chiriboga L, Watson HN, Gold-
neutrophils may or may not be present. If only berg JD, Moreira AL. Histologic features are
gastric acid without food particles has been important prognostic indicators in early stages
aspirated, diffuse alveolar damage may be found lung adenocarcinomas. Mod Pathol. 2007;20(2):
and the clinical picture may be that of ARDS. 233–241.
Important clues to the diagnosis of aspiration 7. Travis WD, Brambilla E, Noguchi M, et al.
are the finding of foreign material, most com- International Association for the Study of Lung
monly vegetable particles or sometimes meat Cancer/American Thoracic Society/European
fibers (muscle). If lipid is aspirated, it produces Respiratory Society. International multidisciplin-
an initial giant cell reaction, but over time leads ary classification of lung adenocarcinoma. J Thorac
Oncol. 2011;6(2):244–285.
to scarring of the parenchyma.
8. Arenberg D; American College of Chest Physi-
Nothing to Disclose cians. Bronchioloalveolar lung cancer: ACCP
evidence-based clinical practice guidelines (2nd
edition). Chest. 2007;132(3 Suppl):306S–313S.
9. Azzoli CG, Baker S Jr, Temin S, et al. American
Society of Clinical Oncology. American Society of
Clinical Oncology Clinical Practice Guideline up-
this chapter.
date on chemotherapy for stage IV non-small-cell
lung cancer. J Clin Oncol. 2009;27(36):6251–6266.
References 10. Wright JL, Thurlbeck WD. Thurlbeck’s Chronic
Airflow Obstruction, 2nd ed. Hamilton, Ontario:
1. Travis WD, Brambilla E, Muller-Hermelink HK,
BC Dekker; 1999.
Harris CC. Tumors of the Lung, Pleura, Thymus, and
11. Hogg JC, Chu F, Utokaparch S, et al. The nature of
Heart. Lyon: IARC Press; 2004.
small-airway obstruction in chronic obstructive
2. Colby TV, Koss MN, Travis WD. Tumors of the
pulmonary disease. N Engl J Med. 2004;350(26):
Lower Respiratory Tract. Washington DC: Armed 2645–2653.
Forces Institute of Pathology; 1995. 12. McDonough JE, Yuan R, Suzuki M, et al. Small-
3. Yoshizawa A, Motoi N, Riely GJ, et al. Impact of airway obstruction and emphysema in chronic
proposed IASLC/ATS/ERS classification of lung obstructive pulmonary disease. N Engl J Med.
adenocarcinoma: prognostic subgroups and im- 2011;365(17):1567–1575.
plications for further revision of staging based on 13. Wright JL, Levy RD, Churg A. Pulmonary
analysis of 514 stage I cases. Mod Pathol. 2011; hypertension in chronic obstructive pulmonary
24(5):653–664. disease: current theories of pathogenesis and their
4. Noguchi M, Morikawa A, Kawasaki M, et al. implications for treatment. Thorax. 2005;60(7):605–
Small adenocarcinoma of the lung. Histologic 609.
characteristics and prognosis. Cancer. 1995;75(12): 14. Myers JL. Other diffuse lung diseases. In: Churg
2844–2852. A, Myers JL, Tazelaar HD, Wright JL, eds.
5. Suzuki K, Yokose T, Yoshida J, et al. Prognostic Thurlbeck’s Pathology of the Lung. 3rd ed. New
significance of the size of central fibrosis in York: Thieme Medical Publishers; 2005;601–674.

Notes
Chapter 38. Pathology of Diffuse Lung Disease
Andrew Churg, MD
Objectives: cysts with a partial lining of abnormal smooth muscle cells

that are positive for HMB-45 on immunostaining. In
Define the pathologic features of ARDS (pathologic pulmonary alveolar proteinosis the alveoli are filled by
diffuse alveolar damage). densely eosinophilic granular material. In chronic eosino-
Define the pathologic features of bronchiolitis obliterans philic pneumonia, the alveolar are filled by eosinophils, but
organizing pneumonia. acute eosinophilic pneumonia looks like diffuse alveolar
Define the pathologic features of usual interstitial damage with small numbers of eosinophils.
pneumonia.
Define the pathologic features of nonspecific interstitial
pneumonia.
Define the pathologic features of Langerhans cell This is a very brief overview of the pathology of
histiocytosis. diffuse lung disease. It purposely includes no
Define the pathologic features of hypersensitivity pneu-
pictures, but pathology cannot be understood
monitis.
Define the pathologic features of sarcoid. without morphologic images, and, when going
Define the pathologic features of lymphangioleiomyo- through this chapter, the reader should refer to
matosis. the images in the PowerPpoint presentations that
Define the pathologic features of pulmonary alveolar
proteinosis.
are part of the material included in the Board
Define the pathologic features of acute and chronic Review Course, if possible.
eosinophilic pneumonia.
ATS/ERS Classification of the
Key words: BOOP; diffuse alveolar damage; eosinophilic Idiopathic Interstitial Pneumonias
pneumonia; hypersensitivity pneumonitis; Langerhans cell
histiocytosis; lymphangioleiomyomatosis; pulmonary alve-
olar proteinosis; NSIP; saroid; UIP Anyone dealing with diffuse lung disease
will encounter what has been called the ‘‘alpha-
Synopsis: bet soup’’ of abbreviated names for different
Pathologists use the term acute lung injury to refer to both types of diffuse lung disease. Some of these are
diffuse alveolar damage, the pathologic finding in ARDS, incorporated in the (ATS/ERS) classification of
and to bronchiolitis obliterans organizing pneumonia. This the idiopathic interstitial pneumonias (Table 1).1 I
should be discouraged because in almost all cases the
will not specifically refer to idiopathic interstitial
combination of morphology, imaging, and clinical features
will separate these entities. Usual interstitial pneumonia is pneumonias in this chapter because they really
characterized by peripheral macroscopic honeycombing and represent a very heterogeneous group of entities
fibrosis, microscopic honeycombing, patchy fibrosis, and that are (1) not related to each other; (2) not
fibroblast foci. In contrast, nonspecific interstitial pneumo-
nia shows uniform involvement of the alveolar walls and
necessarily idiopathic (respiratory bronchiolitis
can be cellular, fibrotic, or mixed. Respiratory bronchiolitis with interstitial lung disease [RBILD] and des-
with interstitial lung disease consists of smoker’s macro- quamative interstitial pneumonia [DIP] are
phages in the lumens of respiratory bronchioles with or smoking-related diseases); (3) not necessarily
without fibrosis of the walls of the bronchioles. Desquama-
tive interstitial pneumonia looks like respiratory bronchiol-
interstitial as the term is generally thought of
itis with interstitial lung disease writ large, with filling of (diffuse alveolar damage as the pathologic
airspaces by smoker’s macrophages over a large area. manifestation of acute interstitial pneumonia is
Langerhans cell histiocytosis shows a combination of not really an interstitial lung disease); and (4)
cellular centrilobular nodules containing, early on, Lan-
gherns cells, often with cysts, and stellate fibrosis in the have completely different prognoses. However,
healed stage. In hypersensitivity pneumonitis, there is a the ATS/ERS classification does make the im-
centrilobular interstitial inflammatory infiltrate, usually but portant point that for many types of diffuse lung
not always associated with small noncaseating granulomas.
disease, consultation among pathologists, radiol-
Sarcoid has numerous noncaseating well-defined granulo-
mas that follow the bronchovascular bundles and interlob- ogists, and pulmonologists is necessary to arrive
ular septa. In lymphangioleiomyomatosis, the lung shows at a meaningful diagnosis.

Table 1—The ATS/ERS Classification of the Idiopathic Interstitial Pneumonias
Histologic Pattern Clinical-Radiol-Pathol Diagnosis
Usual interstitial pneumonia Idiopathic pulmonary fibrosis (IPF)

Nonspecific interstitial pneumonia Nonspecific interstitial pneumonia (NSIP)
Organizing pneumonia (OP) Cryptogenic organizing pneumonia (COP, BOOP)
Diffuse alveolar damage Acute interstitial pneumonia (AIP)
Respiratory bronchiolitis Respiratory bronchiolitis with interstitial lung disease (RBILD)
Desquamative interstitial pneumonia Desquamative interstitial pneumonia (DIP)
Adapted from Travis et al.1
Diffuse Alveolar Damage/ARDS there are hyaline membranes in the alveolar

ducts and, often, parenchymal collapse second-
Diffuse alveolar damage (DAD) is the patho- ary to loss of surfactant. In the organizing phase
logic pattern seen in patients with ARDS and of DAD one finds granulation tissue in various
acute interstitial pneumonia (AIP) and is reason- degrees of organization. In the fibrotic phase
ably specific to ARDS/AIP, but occasionally can (rarely seen because of the use of lung protective
be seen with diffuse alveolar hemorrhage. Diffuse respirator settings) the parenchyma develops
alveolar damage has a large number of etiologies cysts with fibrous walls.
(Table 2). There is no pathologic difference
between diffuse alveolar damage in ARDS and Bronchiolitis Obliterans Organizing
in AIP, rather AIP is simply idiopathic ARDS in a Pneumonia
patient with no predisposing causes for ARDS.
Bronchiolitis obliterans organizing pneumo-
Pathologic Features nia (BOOP) is a misnomer that reflects outdated
pathologic usage of the term bronchiolitis ob-
Grossly, lungs with DAD are very heavy, literans. It is now known that the granulation
often more than 1,000 g each, and have the firm tissue plugs seen in respiratory bronchioles in
consistency of liver. Microscopically DAD has BOOP do not lead to the fixed airflow obstruc-
three phases. In the acute or exudative phase tion of true bronchiolitis obliterans, but rather
can resolve. The ATS/ERS classification1 has
Table 2—Causes of Diffuse Alveolar Damage (Clinical suggested the morphologically more correct
ARDS/AIP) term cryptogenic organizing pneumonia to re-
place BOOP, but this has not caught on. BOOP or
Idiopathic ¼ acute interstitial pneumonia
Infections cryptogenic organizing pneumonia is really
Sepsis (usually Gram negative bacteria) meant to refer to an idiopathic condition, but
Viral, fungal, pneumocystis pneumonias the same pathologic pattern is seen in a variety
Severe bacterial pneumonia
Aspiration of gastric contents (acid) of settings (Table 3) and strictly speaking the
Inhalation of toxic gases pathologic pattern in this situation should be
Fire smoke, oxygen, many chemicals called organizing pneumonia pattern. However,
Shock
Lung, head trauma BOOP or secondary BOOP is also widely used in
Metabolic disorders this situation.
Pancreatitis, uremia
High exposure to sensitizing agent
Acute eosinophilic pneumonia Pathologic Features
Drug reactions
Miscellaneous (burns, fat, and amniotic fluid emboli, BOOP, whether idiopathic or secondary, is
collagen vascular disease, near drowning, IV, or
lymphatic contrast material) characterized by granulation tissue plugs in the
lumens of respiratory bronchioles and alveolar
636 Chapter 38. Pathology of Diffuse Lung Disease (Churg)

ducts. These are always accompanied by some Table 3—Causes of a Microscopic Picture of BOOP
degree of interstitial chronic inflammation.
Idiopathic
Organizing pneumonia (including aspiration)
Usual Interstitial Pneumonia Drug reactions
Infections
Reactions to inhaled toxins, especially noxious gases
In theory usual interstitial pneumonia (UIP)
Chronic eosinophilic pneumonia (look for eosinophils)
is a pathologic term that refers to the clinical Hypersensitivity pneumonitis
entity of idiopathic pulmonary fibrosis.1 How- Collagen vascular disease
Distal to airway obstruction (especially slow-growing tumors)
ever, UIP is used by both pathologists and
Inflammatory bowel disease
clinicians and is a perfectly acceptable clinical Around other inflammatory or mass lesions (tumors,
term. Most cases with a pathologic picture of UIP abcesses, infarcts)
are idiopathic, but an identical picture is seen in
patients with collagen vascular diseases. Familial
UIP refers to UIP in two or more closely related Pathologic Features
family members. Some pneumoconioses, such as
asbestosis, can resemble UIP, but usually the In NSIP there is generally no architectural
morphologic resemblance is not very close. distortion, rather the alveolar walls are widened
either by an infiltrate of chronic inflammatory
Pathologic Features
cells (cellular NSIP), fibrous tissue (fibrotic
NSIP), or both (mixed cellular and fibrotic NSIP).
Grossly, UIP shows disease that is more
Honeycombing is uncommon in NSIP. The
marked in the periphery of the lung and usually
pathologic pattern is of importance, as patients
more marked in the lower zones. This consists of
with purely cellular NSIP appear to have an
macroscopic honeycombing (cystic spaces with
excellent prognosis, whereas in fibrotic NSIP the
thick fibrous walls) and sheets of fibrous tissue.
prognosis is much worse, albeit probably better
Microsopically UIP shows a combination of
than in UIP. Whether NSIP is at all related to UIP
microscopic honeycombing (microscopic cystic
is much disputed, but a recent article3 claims that
spaces with thick fibrous walls), patchy pauci-
some cases do progress to a UIP picture.
cellular interstitial fibrosis, and fibroblast foci, the
latter small foci of granulation tissue that are
believed to be the sites of injury and eventual
Respiratory Bronchiolitis With
fibrosis in UIP. In acute exacerbations of UIP the Interstitial Lung Disease and
pathologic picture is one of diffuse alveolar Desquamative Interstitial Pneumonia
damage or BOOP superimposed on UIP. There
is also a markedly increased risk of lung cancer RBILD and DIP are diseases of cigarette
in lungs with UIP. smokers, although they are included in the ATS/
ERS classification of idiopathic interstitial pneu-
Nonspecific Interstitial Pneumonia monias.1 RBILD is a confusing concept because
pathologically it shows a picture of smoker’s
As opposed to UIP, which is a fairly specific respiratory bronchiolitis (RB); however the patient
disease, nonspecific interstitial pneumonia has either a mixed obstructive/restrictive func-
(NSIP) is a reaction pattern that may be the tional abnormality, or a markedly decreased
pathologic manifestation of a variety of condi- diffusing capacity, or reticulation on CT imaging
tions.2 The most important of these are collagen (ie, evidence of an interstitial lung disease), and no
vascular disease where NSIP is the most common other cause in the biopsy to account for the clinical
pathologic pattern of interstitial lung disease, and radiologic findings. In this circumstance a
some cases of hypersensitivity pneumonitis, and diagnosis of RBILD is applied.4
drug reactions. Idiopathic NSIP is relatively It is believed that in some patients, over time
uncommon. (and with continued smoking), RBILD progresses

Table 4—Names and Etiologic Agents for Some Types of disease of cigarette smokers, and appears to be
Hypersensitivity Pneumonitis caused by smoke-induced chemoattraction of Lan-
Clinical Condition Exposure (Agent)
gerhans cells, a form of dendritic cell, to the lung.
Bird fancier’s lung Bird droppings (avian proteins) Pathologic Features

or feathers
Pigeon breeder’s lung
In early LCH there are rounded or stellate
Farmer’s lung Moldy hay (Micropolyspora faeni)
Mushroom worker’s Mushroom compost cellular nodules centered on bronchioles. Micro-
lung scopically they contain a mixture of Langerhans
Maple bark disease Maple bark (Cryptostroma corticale) cells, eosinophils, and smoker’s macrophages.
Malt worker’s lung Moldy barley (Aspergillus sp.)
Coffee worker’s lung Coffee bean (coffee bean dust)
Langerhans cells stain strongly for the markers S-
Humidifier fever Fungal spores (thermophilic 100 and CD1a and these are useful in proving
actinomycetes) that a given case is LCH. Over time early LCH
Pituitary snuff taker’s Bovine/porcine pituitary snuff lesions may develop cysts, and the combination
lung (bovine, porcine antigens)
Chemical worker’s Trimellitic anhydride, toluene of cysts and nodules often allows a confident
lung diisocyanate diagnosis of LCH on CT scan. LCH lesions tend
Other chemicals for manufacturing to scar and may produce stellate, predominantly
plastics, rubber, epoxies
centrilobular scars. Because the scar is in the
centrilobular region, it can obliterate both bron-
to cover large areas of lung parenchyma and thus chioles and pulmonary artery branches, and the
becomes DIP. latter leads to pulmonary hypertension, a com-
mon long-term finding in LCH.6
Pathologic Features
Hypersensitivity Pneumonitis
RBILD shows the pathologic features of
smoker’s respiratory bronchiolitis, namely an Hypersensitivity pneumonitis (HP) is caused
infiltrate of pale gold-colored alveolar macro- by a reaction to inhaled antigens, often microor-
phages in the lumens of respiratory bronchioles, ganisms that grow in wet warm conditions, but
often accompanied by some degree of fibrosis of also avian proteins, and occasionally even inor-
the bronchiolar walls. Occasionally the fibrosis ganic chemicals7 (Table 4). There are numerous
extends away from the bronchioles toward the causes of HP (Table 4), of which the common
pleura. Smoker’s RB is found in every cigarette ones are pet birds, farming, household molds,
smoker and probably causes no functional effects and hot tubs contaminated by atypical mycobac-
or at most produces very mild airflow obstruc- teria (‘‘hot tub lung’’). Very specialized occupa-
tion. The process is only called RBILD when it tional groups also get HP, for example, maple
meets the clinical/radiologic criteria of an inter- bark strippers, but typically such cases are only
stitial lung disease, as outlined previously. seen in the local regions where these industries
In DIP there are smoker’s macrophages filling occur.
large areas of lung, always accompanied by some
degree of interstitial inflammation and often Pathologic Features
some degree of interstitial fibrosis. Some cases
of DIP progress to a fibrotic NSIP pattern5 and Acute HP is caused by massive exposure to
some probably end up looking something like an antigen and clinically appears as a febrile
UIP, but overall, many cases appear to stabilize or illness that resolves in 2 to 3 days. Such cases are
regress with smoking cessation/steroids. rarely biopsied but pathologically may show
diffuse alveolar damage, bronchiolitis, or poorly
Langerhans Cell Histiocytosis formed granulomas.
Most cases of HP are subacute and appear
Langerhans cell histiocytosis (LCH), also clinically as a fairly mild interstitial lung disease.
known as eosinophilic granuloma of lung, is also a Pathologically they show a chronic interstitial

inflammatory infiltrate that is centered around the Lymphangioleiomyomatosis
bronchovascular bundles in the centers of the
lobules (and hence appear as centrilobular ground Lymphangioleiomyomatosis (LAM) is a dis-
glass opacities on CT imaging). The inflammatory ease of women and is seen as sporadic cases and
infiltrate is accompanied by small noncaseating in patients with tuberous sclerosis.
granulomas in about 70% of patients. LAM is caused by proliferation of abnormal
Chronic HP (as generally used) refers to HP smooth musclelike cells, not only in the lung, but
in which there is radiologic or pathologic systemically. The reason for the proliferation is a
evidence of fibrosis.7 Pathologically these cases mutation in the tuberous sclerosis complex I or II
may resemble UIP or fibrotic NSIP but often with gene9; this defect can be functionally corrected
marked fibrosis around the bronchovascular with mTOR inhibitors and sirolimus has been
bundles. reported to improve function in LAM.10
Although the prognosis of subacute HP is LAM cells are not clonal but they circulate
very good, chronic HP tends to have a poor through the lymphatic system and can form
prognosis, whatever the pathologic pattern.8 lymphangiomyomas anywhere in the lymphatic
system. LAM can obstruct the thoracic duct,
Sarcoid leading to chylous effusions. Patients with LAM
also have a high incidence of renal angiomyoli-
Sarcoid has numerous clinical manifestations, pomas. Recent data suggest that serum VEGF-D
but pathologically pulmonary sarcoid can be is elevated in LAM11 and this may be a useful
divided into ordinary sarcoid and nodular/ way of diagnosing conditions that appear as
necrotizing sarcoid. cysts on imaging or that are pathologically
equivocal.
Pathologic Features
Pathologic Features
Sarcoid is characterized by the presence of
well-formed, discrete, noncaseating granulomas In the lung LAM appears as cysts lined to a
that follow the bronchovascular bundles and the greater or lesser degree by abnormal smooth
interlobular septa (ie, the routes of lymphatics in muscle cells. The cells stain with the marker
the lung). Because the sarcoid granulomas are HMB-45, which is diagnostically useful, and they
immediately around the airways, the diagnostic may also be positive for estrogen and progester-
yield is high on transbronchial biopsies. As one receptors. When LAM cysts are subpleural,
opposed to HP, in which there is a prominent they tend to rupture and produce a pneumotho-
interstitial infiltrate with small granulomas or no rax, and a very large proportion of patients with
granulomas, in sarcoid there are prominent LAM present with spontaneous pneumothorax.
granulomas and usually no interstitial infiltrate.
Sarcoid granulomas commonly aggregate Pulmonary Alveolar Proteinosis
and over time these aggregates can scar, result-
ing in hyalinized nodules. In the past nodules Pulmonary alveolar proteinosis (PAP) is
were thought to be unusual in sarcoid, but CT caused by filling of alveoli by partially degraded
imaging has shown that they are in fact surfactant. Alveolar macrophages normally de-
extremely common. When the nodules are larger grade surfactant and require GM-CSF to do so.12
than 1 cm the disease is referred to as nodular The defect in PAP arises from an absence of
sarcoid; when the nodules have necrosis in the functional GM-CSF or GM-CSF receptors, or the
centers, it is called necrotizing sarcoid. Nodular development of antibodies to GM-CSF (so-called
and necrotizing sarcoid clinically/radiologically acquired or autoimmune PAP). Acquired PAP is
mimic metastatic tumors, but they have a good the most common type. Consequently treatment
prognosis, probably similar to that of stage I with GM-CSF can be used to treat PAP, although
sarcoid. whole lung lavage appears to work equally well.

Pathologic Features References
In PAP the alveoli are filled by dense 1. Travis WD, King TE, Bateman ED, et al. ATS/ERS
intensely eosinophilic granular material (which international multidisciplinary consensus classifi-
is the partially degraded surfactant) and dense cation of idiopathic interstitial pneumonias. Gen-
bodies that represent dying alveolar macro- eral principles and recommendations. Am J Respir
phages. Occasionally there is also a mild inter- Crit Care Med. 2002;165(4):277–304.
stitial inflammatory infiltrate. Digested PAS stain 2. Schneider F, Hwang DM, Gibson K, Yousem SA.
is useful to confirm the diagnosis as proteinosis
Nonspecific interstitial pneumonia: a study of 6
material is strongly PAS-positive, whereas ede-
patients with progressive disease. Am J Surg
ma, a morphologic differential diagnosis, does
Pathol. 2012;36(1):89–93.
not stain with digested PAS.
3. Travis WD, Hunninghake G, King TE Jr, et al.
Idiopathic nonspecific interstitial pneumonia:
Eosinophilic Pneumonias
report of an American Thoracic Society project.
Eosinophilic pneumonias are divided into
acute eosinophilic pneumonia (AEP) and chronic 4. Churg A, Müller NL, Wright JL. Respiratory
eosinophilic pneumonia (CEP). AEP appears bronchiolitis/interstitial lung disease: fibrosis,
clinically/radiologically as ARDS, but with pulmonary function, and evolving concepts. Arch
.25% eosinophils in lavage and a dramatic Pathol Lab Med. 2010;134(1):27–32.
response to steroids. CEP is a chronic process 5. Tazelaar HD, Wright JL, Churg A. Desquamative
commonly associated with systemic symptoms interstitial pneumonia. Histopathology. 2011;58(4):
such as fever and weight loss as well as 509–516.
pulmonary symptoms, blood eosinophilia, and 6. Vassallo R, Ryu JH, Colby TV, Hartman T, Limper
dense peripheral consolidation on imaging. AH. Pulmonary Langerhans’-cell histiocytosis. N
Many patients with CEP are asthmatic. Both Engl J Med. 2000;342(26):1969–1978.
AEP and CEP are hypersensitivity reactions that 7. Selman M, Churg A. Hypersensitivity pneumoni-
can be caused by inhaled organic antigens but tis. In: Pawankar R, Colgate ST, Rosenwasser LJ,
also by systemically administered drugs. eds. Allergy Frontiers: From Epigenetics to Future
Perspectives. Tokyo: Springer; 2009;275–294.
Pathologic Features 8. Churg A, Sin DD, Everett D, Brown K, Cool C.
Pathologic patterns and survival in chronic
Pathologically AEP looks like diffuse alveolar
hypersensitivity pneumonitis. Am J Surg Pathol.
damage but with eosinophils (cells not seen in
2009;33(12):1765–1770.
ordinary diffuse alveolar damage) visible in the
9. McCormack FX. Lymphangioleiomyomatosis: a
tissue sections. CEP appears as sheets of eosino-
clinical update. Chest. 2008;133(2):507–516.
phils filling alveolar spaces. Therefore, it resem-
10. Bissler JJ, McCormack FX, Young LR, et al.
bles a bacterial pneumonia but with eosinophils
Sirolimus for angiomyolipoma in tuberous scle-
substituted for neutrophils. BOOP is also very
commonly a part of the pathologic reaction in CEP. rosis complex or lymphangioleiomyomatosis. N
Engl J Med. 2008;358(2):140–151.
Nothing to Disclose 11. Young LR, Inoue Y, McCormack FX. Diagnostic
potential of serum VEGF-D for lymphangioleio-
The author has disclosed that no relation- myomatosis. N Engl J Med. 2008;358(2):199–200.
ships exist with any companies/organizations 12. Borie R, Danel C, Debray MP, et al. Pulmonary
whose products or services may be discussed in alveolar proteinosis. Eur Respir Rev. 2011;20(120):
this chapter. 98–107.

Chapter 39. Pleural Disorders
Michael H. Baumann, MD, MS, FCCP
Objectives: fluid in a 70-kg man, with the space being about

Describe the pathophysiology of pleural fluid formation. 18–20 lm from the mesothelial cell-lined visceral
Describe practical aspects of thoracentesis and pleural to the parietal pleural surfaces. In the human
fluid analysis including pleural fluid interpretation.
Describe the roles and limitations of various imaging there is about 0.5 mL/h of pleural liquid entering
tools in pleural disease. the pleural space, or about 12 mL/day in an
Describe the roles and limitations of invasive diagnostic adult. Much of this information is extrapolated
and therapeutic tools in pleural disease.
Describe the pathogenesis, clinical features, and man- from animal studies.1,3,9,10 The total white cell
agement of patients with the most common causes of count of pleural fluid in normal nonsmoking
transudative and exudative pleural effusions. subjects extrapolated from thoracoscopic lavage
Describe the pathogenesis and management of patients
with spontaneous and iatrogenic pneumothoraces. is 1.7 3 103 cells/mL. Differential counts (median
percentages) note a prominence of macrophages
Key words: exudate; pleura; pneumothorax; thoracentesis; (75%) and lymphocytes (23%). Additional cells
thoracoscopy; transudate include mesothelial cells (2%), neutrophils (0%),
and eosinophils (0%). Smokers have a small but
Synopsis:
statistically significant increase in neutrophils to
Pleural disorders are common and present ongoing man-
agement challenges. This chapter will review the patho-
a median of 1%.10 Normal pleural fluid protein is
physiology of pleural fluid formation and practical aspects less than 1.5 g/dL.3 Normal pleural fluid is
of thoracentesis and pleural fluid evaluation. Various reported to be alkaline with a higher bicarbonate
imaging tools and invasive diagnostic/therapeutic tools
will be reviewed and their optimal applications delineated.
than plasma.1
An emphasis on the diagnosis and management of the most Several key points of normal pleural physi-
common causes of transudative and exudative effusions ology should be kept in mind and assist in
will be featured, with several uncommon causes highlighted
briefly. Lastly, the management of spontaneous and iatro-
understanding the genesis of pleural fluid in the
genic pneumothoraces will be described. abnormal state. Intrapleural pressure is lower
than interstitial pressure, thus creating a gradient
for fluid movement into the pleural space.
Pleural membranes leak liquid and protein and
Introduction offer little resistance to either. Despite this, the
protein concentration of normal pleural liquid is
This chapter will provide a review of pleural low, implying some sieving of protein across a
diseases. The reader is referred to several addi- gradient. The pleural mesothelial cells appear to
tional references1–7 to complement this review. I
have no role in reabsorption of effusions. The
have tailored the selection of information present-
entry of pleural fluid is slow and consistent with
ed here utilizing the American Board of Internal
known interstitial flow rates. The majority of
Medicine website8 for likely material to be covered
pleural fluid exits the pleural space by bulk flow
by the Pulmonary Board Examination and for
and not by diffusion or active transport, as
information that can lead to meaningful changes in
the care of your patients. This chapter will evidenced by the protein concentration remain-
sequentially address the objectives outlined above. ing constant as an effusion is absorbed. The
primary exit route is via parietal pleural stomata
Pleural Anatomy, Cellular Elements, leading to the pleural lymphatics. There is a 30-
and Physiology fold reserve for fluid removal, indicating that for
pleural fluid to form in excess, both an increased
The normal pleural space is filled with rate of fluid formation and an impaired removal
approximately 7 to 14 mL of low-protein pleural likely must exist.1,6

Understanding these key points in addition for pleural fluid.13 Interestingly, chest ultrasound
to the Starling law assists in understanding the adoption is based on variable-quality evidence
formation of a transudate or exudate. Generally, a but the tool does provide a useful assessment
transudate forms by leakage of fluid across an adjunct not only for patients with pleural fluid
intact capillary barrier because of increased but also for patients with pneumothorax, pro-
hydrostatic pressure or decreased osmotic pres- vided proper training and knowledge have been
sure. Transudates exist in the presence of normal acquired.14
pleural membranes with a relatively limited Without chest ultrasound, the rate of
differential as to their etiology. Conversely, an thoracentesis-associated iatrogenic pneumo-
exudate forms because of fluid leakage across an thorax (IP) ranges from 4% to 30%, with 20% to
impaired capillary barrier with increased perme- 50% of these receiving a chest tube.15 Ultrasound
ability, allowing transfer of protein and liquid, assists with site selection and ideally increases the
with a large potential list of causes.1,3 safety of pleural procedures. Nonradiologists and
specifically pulmonologists safely and effectively
Thoracentesis incorporate ultrasound with high diagnostic
accuracy (99.6%) and a minimum of complica-
One of the first steps to be considered in the tions (0.5%) in managing pleural fluid.16 Physical
assessment of a patient with a pleural effusion is examination to detect pleural fluid when com-
the performance of a thoracentesis. However, pared with ultrasound in selecting a diagnostic
prior to the performance of a thoracentesis an thoracentesis site is sensitive only 76.5% of the
often forgotten step must be taken. Thoracentesis time, with a specificity of only 60.3% with a
without a carefully considered history and positive predictive value of 85.5% and negative
physical examination will not be as illuminating. predictive value of only 45.6%. In this study,
What do you think the pleural fluid analysis will ultrasound prevented potential organ damage in
yield? What is your pretest probability of the 15% of procedures and increased accuracy by
effusion being a transudate or an exudate? There 26%.17 Similarly, a meta-analysis notes that
are a limited number of causes of transudative ultrasound reduces the risk of thoracentesis-
effusions compared with exudative effusions, but associated pneumothorax from approximately
a thorough knowledge of the patient’s situation 9% without ultrasound to 4% with ultrasound
will assist you in better interpreting the pleural (P ¼ .001).18 Interestingly, no prospective assess-
fluid results. Pleural fluid analysis in conjunction ment of ultrasound use in large effusions vs small
with clinical information can provide a definitive effusions has been published. A practical ap-
diagnosis in 18% of cases and a presumptive proach may be to proceed with thoracentesis in a
diagnosis in 56% of cases, and can be nondiag- large effusion, without ultrasound, but if no fluid
nostic in 26% of cases.11 Various tools may assist is obtained to incorporate ultrasound.3
in the performance of a thoracentesis, including Ultrasound is also useful in diagnosing
ultrasound and manometry. pneumothorax, with the suggestion that only
the absence of both the lung sliding sign and the
Ultrasound for Pleural Fluid and Pneumothorax comet tail sign safely lead to the diagnosis of
pneumothorax.19 Compared with chest radiogra-
Effective July 2012, the Accreditation Council phy, ultrasound is at least as accurate with
for Graduate Medical Education notes that a operator skill central to successful pneumothorax
pulmonary/critical care fellow ‘‘must demon- diagnosis.14,19
strate competence in procedural and technical
skills, including: use of ultrasound techniques to Manometry
perform thoracentesis and place intravascular
and intracavitary tubes and catheters.’’12 Addi- The measurement of pleural space elastance
tionally, the 2010 British Thoracic Society (BTS) by pleural manometry has been suggested to be
Pleural Disease Guidelines strongly recommend of value.20–24 The BTS guidelines13 make no
ultrasound guidance for all pleural procedures specific recommendation for the use of pleural
642 Chapter 39. Pleural Disorders (Baumann)

manometry, noting that manometry is not SEEK) volume XIX (question 93)28 for additional
currently in clinical practice in the United information.
Kingdom and that there are no comparative
studies and no commercially available equip- Pleural Fluid Analysis
ment for manometry. Elastance is the inverse of
compliance and represents the change in pleural Once you have obtained pleural fluid, anal-
pressure related to the volume of pleural fluid ysis pitfalls should be avoided. For example,
removed. Marked negative drops in pleural pleural fluid pH plays a major role in manage-
pressure generally represent a lack of appropri- ment of parapneumonic effusions and errors in
ate lung reexpansion commiserate with the fluid analysis can lead to management missteps.29 Air
removed.20–24 This may have clinical application within the sampling syringe clinically and
in the diagnosis of trapped and entrapped lung statistically significantly increases the measured
(covered later in this chapter) and arguably may pH value. Similarly, time delay (4 and 24 h but
be related to the development of reexpansion not 1 h) clinically and statistically significantly
pulmonary edema (RPE). increases the measured pH value. Lidocaine
within the sampling syringe clinically and
How Much Fluid (Air) to Remove and statistically significantly decreases the pleural
Reexpansion Pulmonary Edema fluid pH. Heparin decreases the pH but not in a
clinically significant fashion. Glucose is not
Development of marked drops in pleural clinically significantly impacted by air, time,
pressure may be related to the development of lidocaine, or heparin. As glucose has a good
reexpansion of pulmonary edema (RPE). This in correlation with pleural fluid pH values, it may
turn may be related to the volume of fluid (or serve as a surrogate for pleural fluid pH.29
air, in a pneumothorax) removed. Older recom-
mendations, as in the American Thoracic Society Transudate or Exudate?
statement on malignant pleural effusions, pre-
Dr. Light’s 1972 publication30 allows the
scribe a preset volume of fluid to be removed in
separation of pleural fluid type into a transudate
order to avoid RPE. The American Thoracic
or an exudate. Subsequent publications31,32 point
Society suggests removal of only 1 to 1.5 L of
out other potential criteria (modified Light’s
fluid as long as the patient does not have
criteria) and the need to recognize that we are
increasing dyspnea, cough, or chest pain.25 The
artificially dividing a spectrum of pleural fluid
BTS guidelines similarly note that thoracentesis
abnormalities into two distinct entities (taking
should be stopped when no more fluid (or air)
continuous variables such as pleural fluid protein
can be aspirated, the patient develops symp-
and creating a dichotomy, a transudate, or an
toms of cough or chest discomfort, or 1.5 L has
exudate). Table 1,3,30,31 which is taken from
been withdrawn.13 In contradistinction to these
ACCP-SEEK volume XVII (question 19),33 has a
two statements, a large (185-patient) study26 of
summary of these variables. Novel technologies
large volume thoracentesis with volumes of up
are evolving, thereby allowing for more specific
to 3 L or more removed notes only four patients diagnoses that will make this discrimination of a
developed radiographic RPE (2.2%) not requir- transudate vs an exudate less important and
ing intervention and only one patient developed potentially obsolete.4
clinically significant RPE (0.5%). RPE occurrence
is found to be independent of the pleural fluid Pleural Fluid Values
volume removed and pleural elastance. The
symptom most closely associated with signifi- Pleural Fluid pH: Pleural fluid pH has
cant drops in pleural pressure (not definitively potential diagnostic and management determi-
shown to be related to RPE) is vague chest nation value.3,34–36 Focusing diagnostically, there
discomfort and not cough or sharp chest pain.27 are relatively few causes of low pleural fluid pH
Refer to ACCP-SEEK Pulmonary Medicine (ACCP- and these are summarized in Table 2.3,34–36 Refer

Table 1—Transudate or Exudate?: Light’s Criteria and Modified Light’s Criteria
PF Test Meta-analysis Cut Points Previously Reported Cut Points
Pleural fluid protein .2.9 g/dL (.29 g/L) .3 g/dL (.30 g/L)
Pleural fluid/serum protein ratio .0.5a .0.5b
Pleural fluid LDH .0.45 upper normal limita .2/3 upper normal limitb
Pleural fluid/serum LDH ratio .0.6a .0.6b
Pleural fluid cholesterol .45 mg/dL (.1.16 mmol/L) .45, 54, 55, or 60 mg/dL (.1.16, 1.40, 1.42,
or 1.55 mmol/L)
Taken from ACCP-SEEK volume XVII, question 19.33

a
Modified Light’s criteria.
b
Light’s criteria.
to ACCP-SEEK volume XIX (question 4)28 for be of value as a marker of worsening inflamma-
additional information. tion. LDH isoenzymes are of no clinical value.3
Pleural Fluid Glucose: As noted above, there is The pleural fluid albumin (or protein) gradi-
good correlation between pH and glucose values, ent is of value particularly in diagnosing a
that is, if the pH is low the glucose is low, at least transudative effusion due to congestive heart
in parapneumonic effusions.16,37 Likely this failure (CHF) in a patient who has undergone
correlation holds in other circumstances. There- diuresis.3,40–42 Movement of pleural fluid based
fore, the causes of a low pH listed in Table 2 upon diuretic effects may impact measured
overlap with those seen to cause a low glucose pleural fluid values. The formula to incorporate
value seen in Table 3.3 An elevated pleural fluid is serum albumin (or protein) minus pleural fluid
glucose is found in a limited number of clinical albumin (or protein). Using albumin, if the value
situations (Table 3).38,39 is 1.2 g/dL, the effusion is classified as an
Pleural Fluid Protein, Lactic Acid Dehydrogenase exudate; if .1.2 g/dL, the effusion is compatible
(LDH), and Albumin (Protein) Gradient: The main with a transudate. Given the ready availability of
value of pleural fluid protein is in the discrimi- a pleural fluid and serum protein (vs an albumin)
nation of a transudative vs an exudative effu- from their use in Light’s criteria during an
sion.3,30 Similarly, the main value of a pleural evaluation of a pleural effusion, the use of the
fluid LDH is in this discrimination, although one protein gradient is recommended.3 If the protein
key point to remember is that an effusion that is gradient value is greater than 3.1 g/dL in the
exudative by LDH alone (not by protein as well) setting of patient who has undergone diuresis for
may be a clue to the presence of a parapneumonic CHF, the effusion is likely transudative and due
effusion or a malignant effusion.3 Additionally, to CHF.
pleural fluid LDH may reflect the level of pleural Pleural Fluid Amylase, Cholesterol, and Triglyc-
inflammation and serially rising LDH values may eride: See later sections.
Table 2—Exudative Pleural Effusions With a pH ,7.30
Disorder pH – SEM (% Associated) Comment
Esophageal rupture 6.12 – 0.08 (100) Likely due to infection

Parapneumonic effusions/ 6.83 – 0.08 (100) Low pH with therapeutic implications; Proteus: high pH
proteus/infection
Collagen vascular 7.06 – 0.05 (100) ,7.2 rheumatoid; lupus .7.35
Malignant 7.16 – 0.02 (33) Low pH generally poor prognosis;
pH not useful to predict pleurodesis success
Tuberculosis 7.17 – 0.12 (20) ...
Hemothorax 7.27 (unknown) ...
Paragonimiasis ,7.10 (unknown) Associated with eosinophilia
Disorders are listed from lowest to highest pH from top to bottom of table.

Table 3—Causes of Low or High Glucose Effusions
Disorder Comment
Cause of low glucose effusions (,60 mg/dL)

Parapneumonic effusion/infection Remember therapeutic implications of low pH
Malignancy 15%–25% of cases
Rheumatoid disease 42% ,10 mg/dL; 78% ,30 mg/dL; note: lupus usually normal
Tuberculosis Variable finding
Rare cause to consider: paragonimiasis, hemothorax,
Churg-Strauss, lupus
Causes of high-glucose effusions
Peritoneal dialysis Glucose 200–2,000 mg/dL; PF/S .2
Extravascular central line PF/S .1
Esophageal rupture: consume soft drink PF/S .7
PF/S ¼ pleural fluid/serum ratio.
Pleural Fluid Cellular Analysis (Abnormal Find- the pleural fluid hematocrit is greater than equal
ings): Please see above regarding normal pleural to the peripheral blood hematocrit.1,3,47
fluid cellular elements and physiology. Common
abnormalities causing an elevation in pleural Pleural Imaging
lymphocytes and eosinophils are summarized in
Tables 4 1,4,43,44 and 5 1,3,43–46 respectively. Lym- As chest imaging is to be covered by other
phocytosis is variably defined from greater than chapters in the board review, only key points will
50%6 to greater than 80%1,3,43 of pleural fluid be made here. The reader is referred to a
cells present. Determining the percentage of T or comprehensive review of the major imaging
B lymphocytes is not diagnostically useful, as modalities of the pleural space.48
most lymphocytic effusions contain a predomi-
nance of CD4þ T cells regardless of whether the Chest Radiography
diagnosis is TB or malignancy. Such a determi-
nation may be useful if leukemia or lymphoma is A chest radiograph is the most often first
suspected.1 Remember to measure a hematocrit radiographic investigation obtained in a patient
in pleural effusions appearing bloody, as very with a suspected pleural fluid collection. The
little blood may make the fluid appear like pure chest radiograph is the most sensitive radio-
blood; pleural fluid can appear to be pure blood graphic technique for detecting very small
but frequently the hematocrit of the fluid will be effusions because a lateral decubitus film can
less than 5%.3,4 A hemothorax is defined when demonstrate as little as 5 to 10 mL of fluid. A
standard lateral film can demonstrate blunting of
Table 4—Causes of Elevated Pleural Fluid Lymphocytes the posterior costophrenic sulcus with 25 to 50
mL of fluid present. In contrast, an upright
Lymphocytosis Differential Considerations posterior-anterior film can only reliably demon-
strate fluid volumes in excess of 200 mL.48
Defined variably Most common:
as .50% TB
and .80% Malignancy Ultrasonography
Post–coronary arterial bypass graft
(after first month postoperatively) See above regarding the role of ultrasound
Others to consider:
Chylothorax
for thoracentesis and the detection of pneumo-
Yellow nail syndrome thorax. Ultrasonography can confirm very small
Chronic rheumatoid effusion volumes of fluid, is particularly useful in the
Sarcoidosis
supine critically ill patient, and may assist in
Uremia
Radiation differentiating a pleural fluid transudate from an
exudate. Transudates are often anechoic but may

Table 5—Causes of Elevated Pleural Fluid Eosinophils differentiate benign from malignant pleural
thickening. Malignant disease is suggested by
Eosinophilia Differential Considerations
parietal pleural thickening greater than 1 cm,
Defined as 10% Most common: nodular, circumferential, and mediastinal pleural
Pneumothorax thickening.48
Blood
Others to consider:
MRI and PET
Idiopathic (1/3 of all eosinophilic
effusions)
Malignancy (6%–40% of malignant MRI has a limited role in pleural disease. It
effusions) can be useful in the assessment of extrapleural
Drug reaction
Benign asbestos pleural effusion:
extension of pleural malignancy in patients
30% of these effusions with up to allergic to IV contrast. PET scan can distinguish
50% eosinophilia malignant from benign pleural disease, but false
Paragonimiasis (low glucose) positive scans may occur because of infection
Churg-Strauss (low glucose)
and talc pleurodesis. False-negative scans may
occur with slow-growing or low-grade cancers.
show septations. Exudates vary in their echo- PET scan may be of particular value in mesothe-
genic properties, with fibrin strands and septa lioma to differentiate types of mesothelioma,
frequently present with these findings often provide prognostic information, and assess dis-
associated with infected or malignant fluid ease response to chemotherapy.48
collections.48 Ultrasound has a sensitivity of
73%, a specificity of 100%, a positive predictive Invasive Pleural Tests
value of 100%, and a negative predictive value of
79% for the diagnosis of pleural malignancy. Common invasive pleural tests for diagnosis
Highly suggestive findings include pleural thick- of pleural disorders include thoracentesis, closed
ening greater than 1 cm, pleural nodularity, and pleural biopsy, and thoracoscopy. Medical thora-
diaphragmatic thickening more than 7 mm.49 coscopy consists of thoracoscopy performed by a
nonsurgeon, generally without general anesthe-
Chest CT Scan sia, with one or two entry ports utilizing conscious
sedation, often in a nonoperating room environ-
Chest CT scan is more sensitive and specific ment such as the bronchoscopy suite. This is in
for defining pleural disease found on plain film contradistinction to a surgical thoracoscopy,
than ultrasonography. Importantly, there should which is usually done with multiple entry ports
be an IV contrast delay of 60 to 90 s to optimize (utilizing larger-sized ports), with general anes-
pleural enhancement. The most frequent finding thesia, and in an operating theater.50,51 In the tables
in empyema or complicated parapneumonic that follow I will not differentiate between surgical
effusion is parietal pleural enhancement. This and medical thoracoscopy for pleural diagnosis,
finding is found in 90% of these cases. These as yield is very likely interchangeable. These
infected pleural effusions are most commonly invasive tests are often performed to diagnosis
lenticular in shape, with obtuse angles where the malignancy and TB. The diagnostic sensitivity for
fluid meets the chest wall. Adjacent lung tissue these procedures in pleural malignancy and TB
shows passive atelectasis. In contrast, a lung settings are summarized in Tables 6 3,50,52–54 and
abscess is more commonly spherical in shape, 7 6,50,51,55,56 respectively.
with a thicker wall that replaces rather than
displaces the lung parenchyma. The split pleura Pleural Malignancy (Nonprimary and
sign of thickened parietal and visceral pleura Mesothelioma)
separated by pleural fluid is valuable in differ-
entiating the diagnosis of pleural rather than Thoracentesis with cytological evaluation
parenchymal disease.48 Contrast chest CT scan is should usually be the first diagnostic step for
the imaging tool of choice to demonstrate and to suspected pleural malignancy. The yield is

Table 6—Diagnostic Yield Comparison for Pleural Malignancy
Diagnosis Thoracentesis, % PB, % Thoracentesis þ PB, % Thoracoscopy, %
Cancer (nonpleural primary) 40–87 57 73–90 Sensitivity: 91

Specificity: 100
Mesothelioma 0 definitive (but 25 called malignant) 21 ... .90
PB ¼ pleural biopsy.
variable based on a number of potential factors CT-scan-guided pleural biopsy offers an

including higher yield in more advanced disease, alternative to traditional blind pleural biopsy. In
nature of the malignancy, and the skills of the the setting of cytology negative effusions sus-
cytopathologist.25 Serial thoracentesis may in- pected of malignancy, CT-scan-guided cutting
crease the yield presumably because of newly needle biopsy compared with Abrams’ blind
shed intact malignant cells, with two additional pleural biopsy has a greater sensitivity and
taps increasing yield by about 17%.53 The negative predictive values (87% vs 47%, 80% vs
cytological diagnosis of malignancy may be 44%, respectively), and identical (100%) specific-
made with a volume of fluid as little as 10 mL ity and positive predictive values. This approach
and with no more than 50 mL usually being may be used successfully even if pleural thick-
necessary.57–59 Pleural biopsy has a generally ening is less than 5 mm.63
lower yield than thoracentesis because of the
distribution of involvement of the pleura by TB
malignancy in areas not accessible by pleural Pleural effusions due to TB are primarily
biopsy in nearly half of patients, less frequent from a delayed hypersensitivity response to TB
involvement of the parietal than visceral pleura proteins present in the pleural space.3,6 As this
with metastatic disease and less advanced stage may occur from only a few bacteria, it may
of malignancy at the time of biopsy.50,51,60,61 explain why the acid-fast smears and cultures of
Adding pleural biopsy to thoracentesis cytolog- pleural fluid have a relatively low yield. TB
ical studies may increase yield by only 7% to pleuritis is likely the primary area where closed
12%.25 Medical thoracoscopy has a higher yield pleural biopsy still has a significant diagnostic
for pleural malignancy and the added benefit of role today, especially given the need for culture
potentially incorporating simultaneous talc pou- of the TB to ascertain resistance patterns in this
drage for fluid recurrence prevention. But gen- age of increased TB resistance.50,64–66 The diag-
erally, pleural cytology via thoracentesis should nostic yield of thoracoscopy is not significantly
be the first invasive diagnostic step.50,51 A different from the combination of pleural biopsy
particular concern is the seeding of the pleural and pleural fluid studies.50,51,55
biopsy or thoracoscopy tract with malignant cells
in the setting of mesothelioma. Routine admin- Transudative Pleural Effusions
istration of radiotherapy in this setting is
debated. Close monitoring of pleural puncture Table 8, adapted from Dr. Light’s text,3
sites postprocedure and treating only those summaries the approximate yearly incidence of
patients developing symptomatic deposits seems transudative and exudative pleural effusions of
to be a balanced approach.62 differing etiologies in the United States.
Table 7—Diagnostic Yield Comparison for Pleural TB
Diagnosis Thoracentesis, % PB, % Thoracentesis þ PB, % Thoracoscopy
TB Smear: 10 Granuloma: 50–80 95 Similar to thoracentesis þ PB

Culture: 25–75 Culture: 55–80
Combination: 87

Table 8—Yearly Incidence of Pleural Effusions in the United peptide on pleural fluid does not add diagnos-
States tically to the measurement of this peptide in the
serum.3,41 In the patient with cardiomegaly and
Disease/Etiology Incidence T or E
bilateral pleural effusions who is afebrile without
Congestive heart failure 500,000 T pleuritic chest pain, treatment of CHF can
Parapneumonic effusion 300,000 E proceed without the need for thoracentesis
Malignant pleural effusion 200,000 E
unless the effusion does not respond to therapy.3
Lung 60,000
Breast 50,000 Unresponsive patients with CHF and other
Lymphoma 40,000 benign treatment-resistant pleural effusions may
Other 50,000 be considered for chest tube-directed pleurodesis
Pulmonary embolism 150,000 E
Viral disease 100,000 E
but often have a poor short-term outcome.67
Cirrhosis with ascites 50,000 T Chronic indwelling pleura catheters and shunts
(hepatic hydrothorax) may be considered in selected patients.3
(consider spontaneous
bacterial pleuritis)
Postcoronary artery bypass 50,000 E
Hepatic Hydrothorax (HH)
graft surgery
Gastrointestinal disease 25,000 Variable A pleural effusion occurs in about 5% to 6%
Tuberculosis 2,500 E
of patients with cirrhosis and ascites.3 In approx-
Mesothelioma 2,300 E
Asbestos exposure 2,000 E imately 20% of patients with HH, an effusion will
occur without clinically detectable ascites.68 Fluid
Adapted from Light,3 Table 8.2. E ¼ exudate; T ¼ transudate. arrives in the pleural space by transfer of fluid
‘‘T or E’’ column indicates which type is more common. See
text for more information. from the peritoneum to the pleural space via
diaphragmatic defects (pores), driven by a
CHF favorable pressure gradient from the abdomen
(positive pressure) into the pleural space (cyclical
CHF is likely the most common cause of a negative pressure).3,68 Although patients often
pleural effusion, with left-sided failure being a have decreased plasma oncotic pressure due to
far more common etiology than right-sided heart low plasma protein, this does not appear to play
failure. Most of the pleural fluid arrives in the a significant role in pleural fluid formation.3 As
in CHF, the symptoms of the underlying cirrhosis
pleural space from the alveolar capillaries and
and ascites predominate.3,68 The chest radio-
moves via the lung interstitium because of
graph most commonly demonstrates a right-
increased pulmonary capillary pressure. Elevat-
sided effusion (80%), with 17.5% being left sided
ed systemic venous pressure decreases parietal
and 3% being bilateral.68
pleural lymphatic clearance of the arriving
Both thoracentesis and paracentesis should
pleural fluid. Clinically, the patient presents with
be performed in these patients given concerns
the usual signs and symptoms of CHF, with the
for the potential of spontaneous bacterial peri-
level of dyspnea appearing greater than the size
tonitis and spontaneous bacterial pleuritis
of the effusion would indicate. The chest radio- (SBPL).1,3,68 SBPL occurs in about 13% of
graph most commonly demonstrates a bilateral patients with cirrhosis and HH.69 Uncomplicat-
effusion (69%) with a unilateral right-sided ed HH pleural effusions are transudative but
effusion occurring in about 21% of cases and with the protein level usually lower than in the
unilateral left in 9% of cases.3,41 ascites fluid and low LDH level.3 Treatment of
Pleural fluid analysis most commonly yields uncomplicated HH is through management of
a transudative effusion (80%–85%). The 15% to the underlying cirrhosis and ascites.1,3,68 Gener-
20% of patients classified as an exudate are likely ally, chest tube placement should be avoided as
so classified because of having received diuresis.3 this can lead to significant protein depletion,
Please see above regarding the use of the electrolyte imbalance, and cardiovascular com-
albumin and protein gradient in this setting. promise by ongoing drainage of ascitic fluid via
Measurement of N-terminal pro-brain natriuretic the chest tube.1,3,70 In advanced disease where

transjugular intrahepatic portal systemic shunt Peritoneal Dialysis
or liver transplantation is not possible, surgical
closure of the diaphragmatic defects and pleu- Pleural effusion occurs in 1.6% of patients
rodesis may be considered but carries a 30% undergoing chronic ambulatory peritoneal dial-
mortality in the 3 months following surgery.3 ysis (CAPD) on average 1 day to 8 years after
SBPL is diagnosed by finding culture-positive initiating CAPD.3,39,75 An effusion develops
pleural fluid and the presence of more than 250 within 30 days of starting CAPD in 50% of
neutrophils/mm3 in the pleural fluid, or by the patients. Eighteen percent of patients are under-
presence of .500 neutrophils/mm3 (and a going dialysis greater than a year before an
negative culture) in the pleural fluid.3,69,71 effusion develops. As with HH, the majority of
Paradoxically, the treatment of choice of SBPL CAPD patients with an effusion have a right-sided
is antibiotic therapy alone, with chest tube effusion (88%)3,75 because of the PD fluid moving
placement seldom required.2,3,69,71 Refer to from the peritoneal cavity to the pleural space as
ACCP-SEEK volume XXI (question 109)72 for ascites fluid moves to the pleural space in HH.3,39
additional information. Pleural fluid analysis reveals a transudate
with a protein level consistently lower than 1.0
Nephrotic Syndrome g/dL with a range between 0.07 and 0.50 g/dL.
LDH levels range from 6 to 55 IU/L. Few
Pleural effusion occurs in approximately 20% mononuclear cells are found (,100 cells/lL).
of patients with nephrotic syndrome. These Glucose concentrations range from 200 to 2,030
effusions arise from a combination of decreased mg/dL.39 Glucose is generally midway between
oncotic pressure and increased hydrostatic pres- the dialysate fluid value and the serum value.3
sure arising from increased salt retention and Management includes stopping CAPD for 2
hypervolema.2,3 In nephrotic patients with hypo- to 6 weeks. CAPD can then be restarted in more
proteinemia, interstitial oncotic pressure is re- than 50% of patients without recurrence of the
effusion.3,76 If the effusion recurs, chest tube-
duced in parallel with plasma oncotic pressure.
directed pleurodesis may be considered.3,77
Therefore, Starling forces will remain in balance
Thoracoscopic-directed correction of the pleural
across the vessel wall until plasma albumin drops
peritoneal connection can be attempted and/or
below 2.0 g/dL.73 Pleural effusions likely will not
thoracoscopic talc poudrage may be attempted to
occur until this level of protein depletion develops
control pleural fluid accumulation due to
with all else being equal. A prospective screen of
CAPD.3,78,79
152 patients (not specifically selected for nephrotic
syndrome) with chest radiographs and protein Trapped and Entrapped Lung
determinations concluded that hypoalbuminemia
is an uncommon cause of pleural effusion. Finding Trapped and entrapped lung can represent a
a pleural effusion in an patient with a low albumin continuum of a disease process; entrapped lung
should prompt an evaluation for other potential may proceed to a trapped lung. In both processes
causes.74 Pleural effusions tend be bilateral and the normal reexpansion of the lung during
may be infrapulmonary (subpulmonic) in loca- pleural fluid removal is impaired by visceral
tion.1 Pulmonary emboli may develop in up to pleura restriction.20,21 Entrapped lung (also
22% of patients with nephrotic syndrome due to known as lung entrapment) occurs in the setting
acquired protein deficiency prompting a hyperco- of an active inflammatory or malignant pleural
agulable state.1,3,73 Some suggest that a CT process and represents a mechanical complica-
angiogram should be obtained in patients with tion of that process. The visceral pleura surface
nephrotic syndrome and a pleural effusion that is impacted by the active process impairs reexpan-
exudative to assess for pulmonary emboli.2,3 Serial sion of the lung (visceral pleural restriction)
thoracentesis should be avoided as it will exacer- during pleural fluid removal resulting in a drop
bate the protein loss; treatment should be focused in pleural pressure. The pleural pressure curve as
on management of the nephrotic syndrome.3 measured by manometry has an initial normal

portion (normal unimpacted reexpanding lung) visceral and parietal pleural surfaces will reap-
followed by a steep drop reflecting limited lung proximate and pleurodesis will likely be more
reexpansion (Fig 1).20,21 See the section above successful if the underlying condition warrants.
regarding manometry. Specific therapy is direct- As the use of manometry appears limited,13 a
ed toward the active process such as infec- chest radiograph or a CT scan of the chest after
tion.20,21 In the setting of malignancy, the thoracentesis showing incomplete lung reexpan-
limited reexpansion of the lung hampers the sion and thickened visceral pleura suggests
success of pleurodesis efforts, as reapposition of either a trapped or an entrapped lung.21 Refer
the visceral and parietal pleural surfaces is ideal to ACCP-SEEK volumes XIX (question 58)28 and
for successful pleurodesis.22 XXI (question 125)72 for additional information.
Trapped lung is a relatively uncommon but
likely underrecognized condition related to a Other Transudative Effusions With Key Points
remote pleural inflammatory process creating a
fibrous visceral pleural peel that prevents lung Urinothorax80: Definition: Presence of urine in
reexpansion. Conditions producing initial pleu- the pleural space. Incidence: Rare. Etiology:
ral inflammation (and potential initial entrapped Obstructive uropathy due to bilateral obstruction
lung) such as pneumonia (including empyema), of the urinary tract or common distal obstruction.
hemothorax, ongoing uremia, rheumatoid pleu- May occur secondary to trauma. Extravasated
risy, and prior thoracic surgery including coro- urine moves retroperitoneal into the pleural
nary artery bypass grafting (one of the most space. Pleural fluid: Only cause of a low-pH
common causes) precede the development of a transudative pleural effusion. Smells like urine.
trapped lung and usually have an accompanying Pleural creatinine/serum creatinine ration .1.0
exudative effusion. As this inflammatory process (sensitive but not specific). Treatment: Relieve
becomes temporally remote and the visceral obstruction. Refer to ACCP-SEEK volume XXI
pleural fibrosis does not resolve, the part of the (question 19) for additional information.72
lung impacted becomes trapped and will not Duropleural Fistula39: Definition: Duropleural
fully reexpand. The space between the lung and fistula or subarachnoid pleural fistula is a
parietal pleura fills with fluid because of an communication between the subarachnoid space
imbalance of hydrostatic pressures.20,21 Pleural and the pleura. Incidence: Rare, but may be more
fluid analysis in patients with a trapped lung common than reported; potential complication of
often reveals borderline exudative values, with spinal cord surgery. Etiology: Positive pressure of
one series finding a mean pleural fluid pH of subarachnoid space drives fluid to lower-pres-
7.30, LDH of 124 IU/L, and a protein level of 2.9 sure pleural space. Most are due to blunt or
g/dL.21 Few cells are found with a mononuclear penetrating trauma. Diagnosis: High degree of
predominance including an elevated lymphocyte suspicion required, but symptoms of cerebrospi-
predominance (.50%) in most patients.21 The nal fluid leak present including postural head-
initial pleural pressure is usually negative and aches, nausea, and vomiting. Pleural fluid: Looks
upon fluid removal falls steeply (Fig 1).20,21 As like water with total protein less than 1 g/dL.
with an entrapped lung, limited lung reexpan- Beta transferrin is a specific and sensitive marker.
sion makes pleurodesis ill advised and likely Treatment: No strong consensus.
unsuccessful. 22 Patients often have chronic
asymptomatic pleural effusions and surgical Exudative Pleural Effusions
intervention should only be pursued if the
patient has limiting dyspnea proven because of Parapneumonic Effusion and Empyema
the effusion and trapped lung.20,21
A normal pressure/volume curve (pleural Any pleural effusions associated with bacteri-
elastance) measured by manometry indicates the al pneumonia, bronchiectasis, or a lung abscess is
lung is reexpanding with pleural fluid removal considered a parapneumonic effusion.1,3 Para-
with a minimal drop in pleural pressure (Fig 1).20 pneumonic effusions are probably the most
In this setting, if enough fluid is removed, the common cause of an exudative effusion in the

(47%) mortality rate when compared with com-
munity-acquired pleural infections (17%).83 Such
information should be used to empirically select
appropriate initial antibiotic therapy.
Parallel pathophysiologic and clinical divi-
sion of pleural infection into three temporal
stages may be done1,81 but may no longer be
relevant given recent findings of the second
Multicenter Intrapleural Sepsis Trial (MIST) study
(see below).82 This division represents a contin-
uum and transition from one stage to another that
may be rapid and unpredictable.1,81 Simple para-
pneumonic effusions (physiologic exudative
stage) may be turbid in appearance, with values
Figure 1. Pleural manometry curves. Adapted from ACCP- of pH .7.30, glucose .60 mg/dL, and LDH
SEEK volume XIX, question 58.28
potentially elevated with neutrophils usually
,10,000/lL. Gram stain and culture are negative.
United States.1 Up to 57% of cases of pneumonia
The effusion is free flowing without evidence of
will have an associated parapneumonic effu-
loculation.1,81 Complicated parapneumonic effu-
sion.81 Empyema is pus in the pleural space and sions correlate with the early fibrinopurulent
may be defined as thick purulent appearing physiologic stage and may be cloudy with values
pleural fluid.3 Approximately 60% of empyemas of pH ,7.20, glucose ,35 mg/dL, and LDH
are parapneumonic in origin, with an additional .1,000 IU/L. Neutrophil levels are usually
20% from thoracic surgical procedures and the last .10,000/lL and the culture and Gram stain
20% from complications of trauma, thoracentesis, may both be positive. Fibrinous septations are
esophageal perforation, and other conditions.1,3 forming and loculations may be present. The term
Mortality from pleural infection is up to 20% and complicated refers to the requirement for a chest
chest tube drainage and antibiotic administration tube or surgery to likely resolve the pleural
fail in approximately one-third of patients, who effusion.81,84 Empyema correlates with the phys-
then require surgery.82 Community-acquired and iological late fibrinopurulent stage and is defined
hospital-acquired pleural infections exhibit mi- by the presence of pus representing bacterial and
crobiological patterns that differ significantly.81,83 inflammatory cell death regardless of the bio-
Also, community-acquired and hospital-acquired chemical parameters.29 A pleural peel (thickened
microbiological patterns of infections of the membrane on the visceral and parietal pleural
pleural space differ in their patterns from the surface) may be present.1 The presence of pus
microbiological patterns of their respective should prompt drainage.1,29,84
community- and hospital-acquired pneumo- Pleural fluid pH value of ,7.2 is the single
nias.81,83 Pleural infections acquired from the most powerful indicator for the need for chest
community are most frequently due to strepto- tube drainage in the setting of parapneumonic
coccal infection (Streptococcus pneumonia, 71 of 336 effusion, with pleural fluid LDH (.1,000 IU/L)
[21%]; Streptococcus intermedius, 80 of 336 [24%]; and glucose (,3.4 mmol/L) levels not improving
other species, 25 of 336 [7%]). Anaerobes comprise predictive accuracy.84,85 However, when pH is
approximately 20% of community-acquired pleu- not available, glucose and LDH may serve as
ral infections compared with only 8% in the alternative markers for the need for chest tube
hospital setting. Pleural infections due to Staphy- drainage.84 The BTS guidelines utilize a pH value
lococcus aureus and enterococci are more prevalent of ,7.2 and/or a Gram stain-positive and/or
in hospital-acquired infections. Fifteen of 60 culture positive as the primary indicators for
(25%) isolates in hospital acquired infections are placement of a chest tube.84 Importantly, a large-
due to methicillin-resistant Staphylococcus aureus. bore chest tube is not required, and small-bore
Hospital-acquired pleural infections have a higher tubes suffice, with image guidance potentially

improving success.84,86,87 The BTS guidelines very poor, with a median survival of 4 months in
note that there is no indication for the routine a meta-analysis of over 400 patients.36 Prediction
use of intrapleural fibrinolytics in patients with of survival based on pleural fluid characteristics
pleural infection.84 MIST 1, published in 2005, has been limited, with a low pH not reliably
found no clinically significant benefit of strepto- predicting survival or of value in selecting
kinase including for the outcomes of death and patients for pleurodesis.36,89 The Karnofsky
the need for surgery88 and appears to largely performance score is significantly associated with
form the basis of this BTS recommendation.84 The survival, with a median survival of 34 days with
subsequent MIST 2 study, however, finds a a score 30 and a median survival of 395 days
statistically significant improvement in radio- with a score of 70.89,90
graphic appearance, lower surgical referral rate, Malignancy likely produces pleural effusions
and a reduction in hospital stay in patients by increasing permeability of pleural vessels,
receiving the sequential combination of intra- increased pulmonary vessel permeability by
pleural tissue plasminogen activator and deoxy- infection or pulmonary embolism (PE), increased
ribonuclease (DNase) compared with patients hydrostatic forces due to venous obstruction
receiving a saline placebo vs those receiving and/or hypoproteinemia, and entry of fluid into
either tissue plasminogen activator or DNase the pleural space by disruption of the thoracic
alone. Importantly, the DNase alone group had duct. Fluid exit from the pleural space may also
an increased surgical referral rate (odds ratio be reduced by parietal pleural and mediastinal
2.9).82 As noted above, given there is no evidence lymphatic invasion, by atelectasis lowering pleu-
of differential treatment effect between purulent ral pressure, and by elevated central venous
vs nonpurulent pleural fluid found in the MIST 2 pressure, as by superior vena cava syndrome.2,3
study,82 staging of pleural fluids may not be Dyspnea is the most common symptom associ-
clinically important. Patients with persistent ated with malignant pleural effusion.2 Massive
sepsis and a residual pleural collection despite pleural effusions (complete or near-complete
drainage and antibiotics should receive a surgical opacification of the hemithorax) are most com-
consultation.84 Refer to ACCP-SEEK volume XXI monly associated with pleural malignancy.89
(question 139)72 for additional information. Pleural fluid is most commonly exudative and
may meet only the LDH criteria (ratio or total)
Pleural Disease Due to Metastatic Malignancy and not the protein criteria.2,3,30 The effusion may
be bloody, with malignant disease being the most
Although malignant pleural disease may common cause of bloody effusions.2,43 See the
exist without an effusion, effusions are found in discussion above and Table 6 regarding the
55% to 60% of cases.2 Malignant disease of the diagnostic yield of different invasive approaches.
pleura is the second leading cause of an Diagnosis is most commonly accomplished by
exudative effusion after parapneumonic effu- demonstrating malignant cells by cytological
sions.3 Cancer of the pleural space can be examination of the pleural fluid or by biopsy of
primary or secondary. Secondary malignancy is the pleura.3
due to metastatic spread of a malignancy to the Management of malignant pleural disease
pleura. In contrast, mesothelioma is a primary should be selected based upon patient symptoms,
malignancy of the pleural space and will be performance status, tumor type, response to
discussed later. Table 9 summarizes five separate systemic therapy, and the degree of lung reexpan-
studies with 2,040 patients and lists the most sion and symptom relief after therapeutic thora-
common causes of secondary (metastatic) malig- centesis.2,89 Malignant effusions due to breast
nant pleural disease.89 Lung and breast cancers cancer, small cell lung cancer, and lymphoma
are the most common, followed by lymphoma may be responsive to chemotherapy.2 Manage-
(both Hodgkin and non-Hodgkin), with lympho- ment options range from observation to pleurec-
ma likely the most common cause in younger tomy.2,3,89 Observation is recommended for the
adults.2 In aggregate, the overall prognosis for patient who is asymptomatic or for whom the
pleural disease due to metastatic malignancy is cancer type is unknown.89 Therapeutic thoracen-

Table 9—Origin of Malignant Pleural Effusions In patients with a good performance status,
thoracoscopy can be used for the diagnosis of a
Malignant (Tumor)
Origin Frequency, %
suspected malignancy, drainage of the effusion,
and application of pleurodesis via talc poudrage.89
Lung 37.5 Placement of a chronic indwelling pleural catheter
Breast 16.8 also offers effective control of recurrent symptom-
Lymphoma 11.5
Gastrointestinal 6.9
atic malignant pleural effusions.89 The original
Genitourinary 9.4 study by Putnam and colleagues94 remains the
Other 7.8 only prospective randomized trial to date and
Unknown primary 10.7 demonstrates shorter hospital time (by design)
Adapted from Roberts et al,89 Table 1.
and similar effusion recurrence rates compared
with chest tube-directed doxycycline pleurodesis
(13% and 21%, respectively; not statistically
tesis is associated with a high rate of effusion
different). Forty-six percent of the indwelling
recurrence at 1 month and is not recommended
catheter group had spontaneous pleurodesis at a
management if the patient’s life expectancy is more
median of 26.5 days.94 When to choose chest tube-
than 1 month.89 Conversely, if the patient’s life
directed pleurodesis vs an indwelling pleural
expectancy is less than 1 month, repeated thera-
catheter has yet to be defined. The decreased
peutic thoracenteses are suggested.89 Small-bore
hospital days of an indwelling pleural catheter
chest tubes (10–14F) followed by pleurodesis are
will likely favorably financially outweigh the cost
preferred to repeated thoracentesis. Large-bore
of the required indwelling pleural catheter-related
chest tubes are not necessary in malignant effu-
disposable vacuum drainage bottles when com-
sions, as efficacies of small- and large-bore chest
pared with the total days in hospital for chest
tubes are equivalent.89 If upon therapeutic thora-
tube-directed pleurodesis.89 Open pleurectomy
centesis the lung appears trapped, pleurodesis is
carries a significant morbidity and has operative
not indicated.89 However, if at least partial pleural
mortality of 10% to 19%. The BTS guidelines note
apposition can be achieved, pleurodesis may still that insufficient evidence exists to recommend
be attempted. If after placement of the small-bore pleurectomy as an alternative to pleurodesis or a
chest tube the effusion is drained and the lung re- chronic indwelling pleural catheter for a recurrent
expands, as confirmed by chest radiograph, malignant pleural effusion.89
pleurodesis should not be delayed. The amount
of daily fluid drainage before pleurodesis (eg, Pleural Disease Due to Malignant
,150 mL/d) is less important than radiographi- Mesothelioma
cally confirmed fluid removal and lung reexpan-
sion.89 Talc is the most effective sclerosant Approximately 2,500 to 3,000 cases of malig-
available, with graded talc being recommended nant pleural mesothelioma are diagnosed each
to avoid small talc particles and the slight potential year in the United States.2,95,96 This frequency
of acute lung injury. Talc application by slurry or will likely continue to increase and peak in 2020
poudrage is equally effective.89 Patient rotation is in the United States and Europe.2,96 Reduction in
not necessary after intrapleural application of a asbestos exposure, the prime environmental
sclerosant.89,91–93 If a malignant pleural effusion agent driving mesothelioma development, and
fails to drain because of multiple loculations and the long latency period between exposure and
the patient remains dyspneic, intrapleural fibrino- development of mesothelioma (several decades)
lytics may be of value.89 In the setting of limited explain this late peak after the asbestos abate-
pleural apposition or trapped lung, a chronic ment efforts in the 1970s to 1990s.2 Minimal
indwelling pleural catheter provides a good asbestos exposure may lead to mesothelioma.2,96
option.89 Refer to ACCP-SEEK volume XIX (ques- Although tobacco smoke and asbestos inhalation
tion 58)28 for additional information. synergistically increase the development of lung
As noted above, thoracoscopy can play a diag- cancer, tobacco smoke plays no role in the
nostic and therapeutic role in pleural malignancy. development of mesothelioma.2 The mean age

of onset is 60 years of age with a larger male Surgery trial.98 Patients were assigned to EPP or
predominance.2,96 Nonpleuritic chest pain of a no EPP in the context of trimodal therapy where-
severe aching quality and dyspnea are the main in all patients received induction platinum-based
clinical symptoms.2,96 Most commonly, the chest chemotherapy. After induction chemotherapy,
radiograph shows a moderate to large unilateral patients were then randomly assigned to EPP
pleural effusion or unilateral pleural thickening. followed by postoperative hemithorax irradia-
Pleural plaques are found in less than 20% of tion or to no EPP. All randomized patients,
patients with mesothelioma.2 including those in the no-EPP group, continued
The median survival of untreated cases is to receive management according to local policy
between 6 and 9 months, with less than 5% 5- including potentially chemotherapy, palliative
year survivors.96 Cell type correlates with prog- radiotherapy, or further surgery. For a patient to
nosis, with the epithelial type doing best and the be eligible for EPP, there had to be no evidence on
sarcomatous type the worst; the mixed or preoperative CT scan staging of unresectable
biphasic type falls between the two.2 Other disease or of distant metastases. A high morbid-
negative prognostic factors include male gender, ity found associated with EPP (as in other
elevated serum LDH, serum leukocytosis, poor nonrandomized studies) suggests that EPP with-
performance status, chest pain, thrombocytosis, in trimodal therapy offers no benefit and may
and age .75 years.95 Table 6 lists diagnostic harm patients.98
yields of various invasive approaches. Cytology
yield is poor. Immunohistochemistry may assist Pulmonary Embolism
the potentially difficult differentiation between
adenocarcinoma and mesothelioma. Calretinin PE is the most commonly overlooked diag-
and cytokeratin 5/6 positivity favor mesothelio- nosis in patients with an undiagnosed pleural
ma, and CEA and MOC-31 positivity favor effusion.1 Approximately 300,000 to 500,000
adenocarcinoma. Such staining usually makes patients develop a pleural effusion due to a PE
electron microscopy unnecessary.2 The exact role each year in the United States.99 A pleural
of pleural fluid and serum markers remains effusion occurs in 20% to 50% of patients with a
undetermined but they may predict which PE, is usually small, and occupies less than one-
asbestos-exposed individuals develop mesotheli- third of the hemithorax in 90% of cases.99 PE is
oma. Markers include soluble mesothelin-related associated with radiographically evident consol-
peptide, osteopontin, and megakaryocyte poten- idation and/or atelectasis with or without an
tiating factor.95,97 Soluble mesothelin currently effusion in roughly 50% of cases. Atelectasis
appears the most promising available biomarker alone may be the only abnormality in 6% of
but its lack of sensitivity for early-stage disease cases.100 PE-associated effusions are almost al-
and for all malignant mesothelioma histologies ways exudative and primarily arise from in-
(only elevated in epithelial subtype) and its lack creased permeability of lung capillaries. This
of specificity (positive soluble mesothelin test increased lung interstitial fluid then crosses the
seen in other tumors such as pancreatic, lung, visceral pleural. Ischemia of the pulmonary
and ovarian) are limiting factors.95,97 capillaries distal to embolus may contribute to
The best therapeutic approach to mesotheli- this increased permeability. Pleural fluid findings
oma remains undefined. Surgery, radiation, vary widely and do not assist in establishing the
chemotherapy, and combinations of these are diagnosis.99 The fluid is not consistently bloody,
reported. Chemotherapy can provide a signifi- with one study noting the red cell count to be
cant increase in response rate, moderate increase below 10,000/lL in 33%, between 10,000 and
in life expectancy, and symptom relief with no 100,000/lL in 49%, and above 100,000/lL in
deleterious impact on quality of life. A combina- 18%.101
tion of an antifolate (ie, pemetrexed) with a Patients with PE may be divided into three
platinum-based agent seems optimal.96 The role categories based upon their presenting symp-
of extrapleural pneumonectomy (EPP) has been toms. These in turn have an associated effusion
better defined by the Mesothelioma and Radical incidence. Patients presenting with pleuritic

chest pain or hemoptysis (infarction group, 65%) the pleura (30%) more commonly than of the
have an effusion 56% of the time; the group pulmonary parenchyma (23%).65 Within the Unit-
presenting with isolated dyspnea (22%) have an ed States the foreign-born proportion of pleural
effusion in 26% of cases; and the group present- TB patients compared with pulmonary parenchy-
ing with circulatory collapse (8%) do not have an mal TB patients increased from 1993 to 2003 (1993,
associated effusion.1,102 27%; 2003, 46%). This is in large part because of
The presence of a bloody pleural effusion is the decrease in case numbers of United States-
not a contraindication to anticoagulation or to the born TB patients. Émigrés from the Indian
administration of thrombolytic therapy in the subcontinent to the United States proportionally
setting of a PE. The majority of patients will not have pleural involvement nearly twice as often as
have significant bleeding into the pleural space pulmonary parenchymal TB (9.3% vs 4.4%,
with anticoagulation.1,99,100 PE-related effusions respectively).65
without complications reach their maximal size TB effusion may be due to primary or
early, with one study noting no fluid increase reactivation disease.66,104 Primary disease results
after the third admission day.1,100 If hemothorax from rupture of a subpleural caseous focus in the
does occur, anticoagulation should be stopped lung into the pleural space. Myobacterial anti-
and consideration given to chest tube insertion.99 gens entering the pleural space react with
primarily CD4þ lymphocytes, prompting a de-
Post-Coronary Artery Bypass Graft Surgery- and layed hypersensitivity reaction.66,104 Pleural fluid
Post-Cardiac Injury Syndrome (PCIS)-Related accumulates predominantly because of increased
Effusions capillary permeability and less so from impaired
lymphatic clearance due to occlusion of pleural
The terminology and etiology for these two stomata. Reactivation disease is frequently asso-
causes of pleural effusion can be confusing. Table ciated with pulmonary parenchymal disease.66
10 1,3,103 compares these two entities. In fact, Clinically, in contrast to parenchymal pulmonary
there can be overlap in these entities. Dressler103 TB, most pleural TB effusions present as an acute
in 1958 described a syndrome of fever, chest pain, illness, with approximately one-third of patients
electrocardiac evidence of pericarditis, pneumo- being symptomatic for less than 1 week and two-
nitis, and pleurisy occurring within days after a thirds for less than 1 month. The most common
myocardial infarction. Sahn103 coined the term presenting symptoms are pleuritic chest pain and
PCIS in 1983 to include chest pain, fever, nonproductive cough in 75% and 70% of patients,
pericarditis or pleuritis, left-sided pleural effu- respectively. TB effusions are most commonly
sions and infiltrates, leukocytosis and increased unilateral and small to moderate in size, occu-
erythrocyte sedimentation rate after myocardial pying less than two-thirds of a hemithorax.66
infarction, cardiac surgery, penetrating chest HIV-positive patients tend to have different
trauma, or pacemaker placement. PCIS may clinical manifestations including a longer dura-
occur early after coronary artery bypass graft tion of illness and a lower incidence of chest pain.
surgery. Also, pleural fluid is more likely to be smear- and
culture-positive for mycobacteria. If the CD4
Tuberculous Pleuritis count is less than 100 cells/lL, approximately
half of patients will have a positive smear for
In 2004, there were 9 million new cases of TB acid-fast bacteria on pleural fluid analysis.104
and approximately 2 million deaths. The frequen- These patients may also have mesothelial cell
cy of pleural TB as part of the total cases varies counts .5% (see below).104
geographically, with approximately 4% being Please see above and Table 7 regarding the
reported in the United States and 23% in Spain.66 yield of invasive diagnostic tools in TB-related
TB-related effusions are the second most common effusions. Other caveats regarding diagnosis
type of extrapulmonary TB, with lymph node include the following: Sputum examination plays
involvement being the most common.66 Patients a diagnostic role in apparently sole pleural TB
older than 65 years of age have TB involvement of effusions. Sputum induction yields a positive

Table 10—Post-CABG- and PCIS-Related Effusions
Characteristic CABG PCIS
Incidence 30 days post op: 57% with effusion Acute myocardial infarction (AMI) related: 3%–4%
Size: 25% of hemithorax in 10% of patients (68% with effusion); more likely 1% incidence;
particularly if transmural
.17% for post op especially if disrupt pericardium:
usually 3 weeks post op
Clinical Dyspnea (fever and chills uncommon) Pericarditis, pleuritis, pneumonitis, fever
(¼ Dressler’s)
Pathogenesis Early (first 30 days): larger effusion Injury: myocardium or pericardium
due to surgical trauma Antimyocardial antibodies: association strongest post
Late (. 30 Days): unknown but unlikely PCIS surgical; no clear-cut relation with AMI
Pleural fluid Early: bloody (eosinophilic) Normal glucose and pH
Late: clear (lymphocytic) Bloody: 30%
Chest radiograph Unilateral left (67%) at day 30 75% pulmonary infiltrate; small effusion—unilateral
or bilateral
Diagnosis Early: rule out heart failure, PE, Diagnosis of exlusion: rule out heart failure, PE,
parapneumonic effusion pneumonia
Late: same plus TB, malignancy, and chylothorax
Treatment Serial thoracentesis Aspirin, indomethacin; severe: consider steroids
Rarely consider surgery: trapped lung
AMI ¼ acute myocardial infarction; CABG ¼ coronary artery bypass graft.
culture in 55% (35 of 64) of patients for is .60 mg/dL in 80% to 85% of cases and is ,30
Mycobacterium tuberculosis in patients with a chest mg/dL in about 15% of cases.66 During the initial
radiograph showing only an effusion.105 This 2 weeks of illness, the fluid may be neutrophil
finding challenges the past supposition that predominant but then shifts to lymphocyte
patients with pleural TB effusions are not predominant.66 A mesothelial cell count of more
contagious.106 These findings have been support- than 5% is rarely compatible with pleural TB;
ed in a subsequent study107 utilizing CT scanning however, this finding is not specific to pleural TB
finding parenchymal lung lesions in 86% of because there are other causes of a low mesothe-
patients being assessed for TB pleuritis and lial cell count. Any entity causing chronic pleural
finding 31% of patients with TB pleuritis with a inflammation may prevent exfoliation of pleural
sputum or bronchial washings positive for TB by mesothelial cells into the pleural space and a low
culture. Skin testing using purified protein mesothelial cell percentage.66,104
derivative (PPD) showing a positive test is only Other pleural fluid markers or tests may be
supportive and not a diagnostic finding. PPD considered to diagnose pleural TB. Commonly
testing has its greatest value in areas of low considered options include pleural fluid adeno-
prevalence or no vaccination for TB.66 In the sine deaminase (ADA), interferon gamma, and
United States, a relatively low-prevalence coun- polymerase chain reaction (nucleic acid amplifi-
try (with some discrete areas of higher preva- cation testing) assessment.66 A pooled analysis of
lence), PPD was found to be positive in 61% of nucleic acid amplification testing from 20 studies
patients with pleural TB and 58% of patients with using pleural fluid notes a high specificity of 97%
pulmonary TB; however, roughly one-quarter of for commercial assays and 91% for in-house
all patients did not have a PPD reported.65 assays but a low and variable sensitivity of 62%
Pleural fluid analysis is nearly always exu- for commercial and 76% for in-house assays.
dative and generally yields a clear, straw-colored ADA is perhaps the most useful pleural fluid
fluid that is almost never grossly bloody.66 marker. ADA is abundant in lymphocytes and
Pleural fluid protein frequently exceeds 5 g/dL therefore a potential good marker for pleural
and suggests pleural TB.104 Pleural fluid pH TB.66 A pleural fluid ADA level of .70 IU/L
usually falls between 7.30 and 7.40, with about highly suggests pleural TB and a level of ,40
20% of cases having a pH ,7.30.66 Fluid glucose IU/L virtually excludes the diagnosis.66 The

most widely accepted cutoff value for ADA is 40 Connective Tissue Disorders and the Pleura
IU/L.104 Sensitivity and specificity of ADA by
meta-analysis for the diagnosis of pleural TB are Table 11 1,3,111–119 shows a comparison of the
92% and 90% respectively.104 However, the features of pleural effusions due to RA and to
predictive value of ADA depends on the preva- systemic lupus erythematosus (SLE).
lence of disease. In a generally low pleural TB
prevalence area such as the United States, the Chylothorax and Pseudochylothorax
strength of a high-sensitivity test such as ADA is
its negative predictive value.108 The positive Table 12 3,5,39,120–123 lists a comparison of the
predictive value of the test may be best used in features of pleural effusions due to chylothorax
young patients from areas with a high prevalence and pseudochylothorax. Terminology utilized in
of TB.66 Causes of false-positive tests (ie, elevated this setting may be confusing. Both are lipid
ADA without pleural TB) include most common- effusions and may share a similar pleural fluid
ly empyema and less commonly malignancies appearance because of a high lipid concentration.
(particularly lymphoma), other infections includ- However, they have very different pathogeneses.
ing brucellosis and Q fever, and connective tissue Chylothorax is defined by the presence of chyle in
diseases such as rheumatoid arthritis (RA).104 the pleural space due to the disruption of the
The level of pleural fluid interferon gamma may thoracic duct or one of its tributaries. A pseudo-
also efficiently distinguish tuberculous from chylothorax is most often the result of long-
nontuberculous pleural effusions. However, the standing pleural inflammation and consequent
success of ADA, driven in part by its lower cost elevated cholesterol levels.120–121 Lung entrap-
and simpler testing methods, make it the ment or trapped lung is a potential radiographic
finding with a pseudochylothorax.121 Chylotho-
preferred test compared with interferon gam-
races may be classified by etiology into those that
ma.104 Interferon gamma release assays (includ-
are traumatic (surgical or nonsurgical), tumor-
ing T-Spot, Oxford Immunotec Limited, and
related, idiopathic, or miscellaneous.121 Choles-
QuantiFERON-TB Gold In-Tube, Cellestis Limit-
terol effusions are also known as pseudochylo-
ed) have no clear advantage over ADA or
thorax or chyliform effusions. Pseudochylothorax
interferon gamma assays and are not recom-
is a lipid-rich effusion with the presence of
mended to be run on either the patient’s serum or
cholesterol crystals. A chyliform effusion is lipid
the patient’s pleural fluid to establish the
rich but without cholesterol crystals. This high
diagnosis of pleural TB.104,109 Refer to ACCP-
lipid content is not due to thoracic duct disrup-
SEEK volume XXI (question 170)72 for additional
tion.121 As noted in Table 12, I equate pseudochy-
information.
lothorax, cholesterol effusion, and chyliform
Antimicrobial resistance patterns for pleural
effusions. Refer to ACCP-SEEK volume XVII
TB broadly reflect those for pulmonary TB in the (question 120)33 for additional information.
United States. However, isolates of pleural TB are
less often resistant to at least isoniazid (6.0% vs Elevated Amylase Effusions
7.8%) and to at least one first-line TB drug (9.9%
vs 11.9%) compared with pulmonary parenchy- Table 13124,125 reviews salient features of
mal TB.65 Reliance on ADA to diagnose pleural several causes of pleural effusions with elevated
TB precludes obtaining antimicrobial sensitivity amylase levels.
patterns, a mainstay recommendation of the
CDC, and is a shortcoming of the ADA test.65,110 Hemothorax
A 6- to 9-month regimen including isoniazid and
rifampin for the entire time with the addition of Hemothorax is defined as a bloody effusion
pyrazinamide and ethambutol for the first 2 wherein the pleural fluid hematocrit is a least
months is recommended treatment of pleural 50% of the peripheral blood hematocrit. Hemo-
TB.110 Refer to ACCP-SEEK volume XXI (question thorax is divided into two main categories
153)72 for additional information. based on etiology: traumatic and nontraumatic

Table 11—Pleural Effusions Due to RA- and SLE-Induced Pleuritis
Characteristic RA SLE
Frequency ~5% of RA patients develop effusion ~40% of SLE patients develop effusion
5%–10% of SLE patients present with effusion
Clinical Arthritis several years before effusion onset Frequently with SLE exacerbation
(25% of effusions precede or simultaneous Arthritis/arthralgias preeffusion
with joint onset) Most: pleuritic chest pain
80% with effusion ¼ men Most: febrile
80% with subcutaneous nodules
20% with pleuritic chest pain
Most .35 y old
Diagnosis Suggested if: RA present and effusion present Clinical picture of SLE þ effusion þ blood
(may confuse with parapneumonic effusion) serology positive for SLE
Pleural fluid Glucose ,30 mg/dL; pH ,7.20; LDH 23 Elevated fluid antinuclear antibody not sensitive
values upper normal limit; rheumatoid factor titer or specific for SLE effusion
.1:320 and serum value
‘‘Tadpole’’-looking cell
Greenish-yellow color fluid
Chest radiograph Small- to moderate-size effusion Small effusions
25% are bilateral 50% are bilateral
Treatment Nothing specific for effusion Nonsteroidal antiinflammatory and steroid
responsive
If drug-induced: stop drug
Long-term outlook Cholesterol effusion may develop Minimal long-range impact
RA ¼ rheumatoid arthritis; SLE ¼ systemic lupus erythematosus.
(spontaneous). Traumatic hemothoraces arise Thoracic endometriosis is a cause of both

from penetrating or nonpenetrating (blunt) hemothorax and pneumothorax (potentially si-
trauma and may also be iatrogenic. Penetrating multaneously). Hemothorax and/or pneumo-
and blunt trauma are the most common causes thorax in this setting is usually seen in
of hemothorax.47 Traumatic hemothoraces are menstruating women, can recur with subse-
managed by chest tube drainage with surgical quent menses, and is called a catamenial event.
intervention considered for blood loss greater Two-thirds of these women have a pathologic
than 2 L upon chest tube drainage, a continuous diagnosis of thoracic endometriosis at surgery.
blood loss of more than 300 mL/h for 4 h (or The goal of therapy in these women is to
150 mL/h if .60 years of age), or hemodynamic minimize estrogen secretion through various
instability.47 hormonal manipulations. But medical therapy
Spontaneous hemothorax is relatively un- alone is often inadequate for the care of patients
common, with the most common cause being with pleural manifestations of thoracic endome-
triosis. Surgical intervention to remove endome-
spontaneous hemopneumothorax, primarily oc-
trial implants may be necessary.126
curring in young patients.126 This is primarily
managed by chest tube insertion to drain both
Other Exudative Effusions With Key Points
the blood and air, with surgical intervention
reserved for the more severe cases.126 Other Benign Asbestos Pleural Effusion3,127: Defini-
causes of spontaneous hemothorax include co- tion: Exudative effusion occurring in a patient
agulopathy (congenital or acquired), vascular with asbestos exposure usually within 5 to 20
(arteriovenous malformation, aneurysms, von years of exposure. This is a diagnosis of
Recklinghausen disease, Ehlers-Danlos syn- exclusion, with patients needing close evaluation
drome type IV, and various connective tissue for mesothelioma. Incidence: Approximately 3%
disorders), neoplasia of many types, and various of asbestos-exposed individuals. Etiology: Relat-
miscellaneous causes (including exostosis, endo- ed to asbestos exposure and with a direct relation
metriosis, and pulmonary sequestration).126 to the level of exposure and development of

Table 12—Chylothorax and Pseudochylothorax
Characteristic Chylothorax Pseudochylothorax
Terminology No synonyms ¼ Chyliform, ¼ cholesterol effusion

Incidence More common than chyliform, but uncommon Rare
Etiology: malignant .postoperatively
Non-Hodgkin lymphoma most common atraumatic
Postoperatively: 1%
25% of patients with LAM have this
Clinical Dyspnea: subacute, insidious Chronic effusions (usual); insidious
No fever or chest pain (noninflammatory) May be asymptomatic
Chyle is bacteriostatic; empyema rare Setting: RA, TB, empyema
Trapped lung may be present
Pathogenesis Thoracic duct rupture: crosses from right to left at T3 to T6 Usually chronic effusion: breakdown
of cellular elements/limited drainage
Pleural fluid White/opalescent Milky; satin sheen; may be turbid
values 80% lymphocytes Neutrophil predominant
Centrifuge: supernatant fails clear Cholesterol .220 mg/dL
Triglyceride .110 mg/dL (likely) Triglyceride may be .110 mg/dL
Triglyceride ,50 mg/dL (unlikely) No chylomicrons
Triglyceride 50–110: lipoprotein electrophoresis: chylomicrons? Cholesterol crystals by polarized light:
Cholesterol 65–220 mg/dL not necessary for the diagnosis
Chest radiograph Varies with level of thoracic duct disruption Variable
Diagnosis Look for underlying cause: traumatic vs atraumatic Clinical setting: suspect
Treatment Adequate nutrition Observation if not severe
Manage primary cause þ/ decortication (trapped lung)
Somatostatin, octreotide possible
Pleurodesis/surgery possible
Avoid prolonged drainage: malnutrition/immunosuppression
LAM ¼ lymphangioleiomyomatosis; RA ¼ rheumatoid arthritis.
effusion. Pleural fluid: Small- to moderate-sized Drug-Induced Pleural Disease128–130: Many

effusion that is bilateral in 10%. Exudate that is commonly used (and less commonly used) drugs
serous or serosanguineous with a pleural eosin- can promote pleural inflammation and the
ophil proportion of more than 50% in nearly half development of pleural effusions, pleural fibro-
of patients. Treatment: Effusions resolves within sis, or pleural thickening. The pathogenesis in
several months with no residual disease in most most cases is poorly understood. Although drugs
patients. Mesothelioma may develop during account for a small percentage of pleural abnor-
follow-up (5% in one series). malities, prompt recognition is important be-
cause the withdrawal of the drug leads to
Yellow Nail Syndrome122: Definition: Charac-
resolution of the pleural manifestations in many
terized by triad of yellow and thickened nails,
cases. Table 14128–130 lists the drugs that can be
lymphedema, and pleural effusion or other
related to pleural manifestations.
respiratory abnormality (including bronchiecta-
Ovarian Hyperstimulation Syndrome (OHS)131–135:
sis). Presence of any two of the triad at any time
Definition: Pleural effusions may occur as part of
may be sufficient to diagnose. Incidence: Rare. OHS, which in turn is a potential complication of the
Etiology: Poorly understood, but lymphatic duct use of human chorionic gonadotropin (hCG) hor-
abnormalities appear to play a role, with func- mone for ovulation induction therapy as part of a
tional more than structural disorder favored. fertility program. OHS is characterized by ovarian
Pleural fluid: Fluid usually bilateral with lym- enlargement and increased capillary permeability
phocyte predominance. Chylothorax in 30% of and exudation of protein-rich fluid into the perito-
patients with yellow nail syndrome. Treatment: neal cavity. Incidence: Pleural effusions occur in
Primarily supportive, with long-term prognosis ,10% of case of severe OHS cases and usually are
generally favorable. accompanied by ascites. Isolated pleural effusions

Table 13—Pleural Effusions With Elevated Amylase Levels
Esophageal
Test Acute Pancreatitis Chronic Pancreatitis Rupture Malignancy
Clinical 3%–17% with effusions Uncommon Pneumothorax seen See pleural

Small effusion Large effusion in 25% malignancy section
Usually left side Usually left sided
PF comments Neutrophil predominant Neutrophil predominant Exudate, often with Adenocarcinoma
exudate exudate pus or positive PF cell type
culture
PF amylase Moderate Extreme Minimal Minimal
elevation, 500–10,000 Possibly .200,000
IU/L (pancreaticopleural fistula)
PF/serum ratio 10:1 .20:1 5:1 3:1
PF isoamylase Pancreatic Pancreatic Salivary Salivary
PF pH 7.30–7.39 7.28–7.39 5.50–7.00 7.05–7.40
Serum lipase Elevated Normal to minimal increase Normal Normal
Management No specific therapy; ERCP and CT scan to locate Surgical correction See pleural
resolves within 2 months fistula: surgical intervention, often required malignancy section
percutaneous drainage,
and/or somatostatin
ERCP ¼ endoscopic retrograde cholangiopancreatography; PF ¼ pleural fluid.
without additional signs of OHS are uncommon. cause or event. Traumatic pneumothoraces result
Etiology: hCG-driven ovarian enlargement with from direct or indirect trauma to the chest,
significant extravascular fluid shifts and intravas- including from diagnostic or therapeutic endeav-
cular volume depletion in part due to capillary leak ors. Traumatic pneumothoraces occurring due to
characterize OHS. hCG plays a central role in medical interventions are termed iatrogenic
precipitating OHS, but this is often in concert with pneumothoraces. SPs are subdivided into prima-
elevated levels of estradiol. Risk factors include ry and secondary. Primary SPs (PSPs) occur in
youth (,35 years of age), asthenic body build, patients without clinically obvious lung disease.
polycystic ovaries, and high serum estradiol levels. Secondary SPs (SSPs) occur in patients with
Among high-risk patients, OHS incidence ap- underlying lung disease, often COPD. Classifica-
proaches 20%. Pleural effusions usually occur from tion confusion arises because patients with PSPs
peritoneal (ascites) fluid movement intrapleurally. often demonstrate emphysemalike changes on
Once ascites fluid reaches the pleural space, CT scan and pleural porosity seen by fluorescein-
inflammatory mediators within the ascites fluid enhanced autofluorescence, both findings likely
may promote endogenous intrapleural fluid devel- contributing to the development of PSPs.137
opment. Pleural fluid: Usually an exudate with Tension pneumothorax may occur with any
protein generally .4.0 g/dL. Treatment: Primarily pneumothorax. As these patients may decom-
supportive, with possible therapeutic thoracentesis pensate quickly, emphasis must be on recogni-
used for symptomatic relief. Refer to ACCP-SEEK tion, low index of suspicion, and rapid treatment
volume XXI (question 14)72 for additional informa- with needle decompression.137–139 This chapter
tion. section will focus on spontaneous SPs and
iatrogenic pneumothoraces.
Pneumothorax
Spontaneous Pneumothorax
A pneumothorax is air within the pleural
space. Pneumothoraces are classified into spon- More than 20,000 new cases of SP occur each
taneous pneumothorax (SP) and traumatic pneu- year in the United States, with roughly 55% due
mothorax, despite some confusion created by this to PSP and 45% due to SSP. Guidelines provide
classification.136,137 SPs occur without preceding direction for the care of these patients, with the
trauma or obvious underlying precipitating most recent being published in 2010.138,140

Table 14—Drug-Induced Pleural Disease appears to be a driver to the development of the
(List Is Not Comprehensive) emphysema-like changes. SSPs are associated
Drug List
with a myriad of underlying lung diseases, with
COPD the most common, but with AIDS-related
Drug-induced lupus pleuritis pneumothoraces, particularly associated with
Procainamide Pneumocystis pneumonia, being a leading cause
Chlorpromazine
Quinidine
in urban areas. Dyspnea is a common symptom,
Isoniazid being potentially more dramatic in SSP because
Phenytoin of underlying lung disease; similarly, mortality is
Hydralazine significantly greater in SSP.136,137 As the signs
Nitrofurantoin
Chemotherapeutic agents and symptoms for SP are nonspecific; diagnosis
Bleomycin requires suspicion and confirmation with imag-
Mitomycin ing. Use of expiratory chest radiographs adds
Methotrexate
little additional information over a routine
Procarbazine
Cyclophosphamide inspiratory chest radiograph. Ultrasonography
Docetaxel (above) may play a diagnostic role.136,137
Imatinib mesylate Important in SP is the understanding of
Cardiovascular drugs
Amiodarone
recurrence rates, as this will impact treatment
Minoxidil selection. Recurrence is not a significant man-
Imidapril agement issue with iatrogenic pneumothora-
Immunomodulating/cytokines ces.136,137 PSP reported recurrence rates range
Interferons
IL-2 from 16% to 52%, with the largest SP manage-
IL-11 ment trial to date reporting 32% and 43%
Granulocyte colony-stimulating factor recurrence rates in PSP and SSP respective-
Immunoglobulin
ly.136,137,141 Most recurrences for both PSP and
Retinoids
Isotretinoin SSP occur within the first 6 months.136,137,141
All-transretinoic acid Treatment options incorporated in initial SP
Ergot derivatives management include observation, simple aspira-
Methysergide
Bromocriptine tion, and chest tube placement and offer no
Muscle relaxants recurrence prevention. Supplemental oxygen
Dantrolene sodium should be offered to most patients and increases
Tizanidine
the pleural air reabsorption rate from a baseline
Anticoagulants
Precipitate hemothorax of 1.25% per day (while on room air) by threefold
Others to fourfold.136,137
Mesalamine Choice of management should be based
Clozapine
Simvastatin
primarily upon the patient’s clinical status and
L-tryptophan less on the size of the pneumothorax.138,140 The
Acyclovir BTS guidelines define a large pneumothorax as
Metronidazole one with a .2-cm distance from the visceral to
Valproic acid
Dapsone the parietal pleural surface at the level of the
Minocycline hilum.138 Any PSP or SSP patient with significant
Itraconazole breathlessness, regardless of the size of the
pneumothorax, should undergo an invasive
intervention.138,140 Observation may be used for
patients with a small PSP without significant
Despite the time lapse between these two breathlessness.138,140 These PSP patients may be
guidelines,138,140 little has changed in the man- managed as outpatients if timely follow-up can
agement of SP. be assured.138,140 PSP patients who are asymp-
Risk factors for PSP include smoking and tomatic with a large pneumothorax may in
ectomorphic body type (tall and thin). Smoking selected circumstances be observed.138 Needle

aspiration (NA) is favored by the BTS guidelines, pleurodesis. Both of these measures promote
but this appears heavily based upon a publica- recurrence prevention.138
tion by Noppen and colleagues142 that notes a
lower hospitalization time. This reduction in time Iatrogenic Pneumothorax
was built into the simple aspiration patient group
compared with the chest tube group who all had IPs occur commonly, and their incidence is
to be hospitalized.137,138,142 The BTS guidelines likely on the rise given the increasing adoption of
note that simple NA (14–16 G) is as effective as and evolution in invasive modalities.137,139 The
chest drain placement (.20F) but that NA should expertise of the health-care profession perform-
not be repeated unless there were technical issues ing the invasive modality generally inversely
with its application. If NA fails, a small-bore correlates with IP occurrence.137 The most com-
(,14F) chest drain is recommended. Large-bore mon causes of IP in the Veterans Administration
drains are not needed for SP management.138 The patient population in the 1990s were transtho-
BTS guidelines do acknowledge that the use of racic needle biopsy (24%), subclavian vein
Seldinger-placed small-bore chest tubes, that catheterization (22%), thoracentesis (20%), trans-
may serve the purpose of initial simple aspiration bronchial biopsy (10%), pleural biopsy (8%), and
but can be left in place as needed, does play a positive pressure mechanical ventilation (7%).144
The patient’s presentation depends upon their
role based upon operator experience.138 All
underlying lung health, the inciting mechanism,
patients with SSP should be admitted to the
and other circumstances. Importantly, diagnosis
hospital, with most of these patients requiring
may be remote from the inciting event, with
insertion of a small-bore chest drain. If an air leak
diagnosis delays being reported from 8 to 96 h.
persists in an SSP patient for more than 48 h, a
Given the diversity in potential etiologies and the
surgical consultation should be considered.138
potential for delayed diagnosis, health-care pro-
Refer to ACCP-SEEK volume XV (question 4)143
viders should be suspicious for IP in any patient
for additional information.
subjected to a diagnostic or therapeutic proce-
Regarding recurrence prevention, the ACCP
dure involving the mouth, neck, chest, or
guidelines specifically suggest offering preven-
abdomen.139
tion at the time of the second occurrence of a PSP
Transthoracic needle aspiration (TTNA) and
and at the first occurrence of a SSP.140 When the intensive care setting have associated vari-
considering recurrence prevention, surgical op- ables that may predict pneumothorax risk.
tions are more effective than chemical pleurod- Greater lesion depth is consistently associated
esis, and chemical pleurodesis should only be with a greater likelihood of IP following TTNA.
offered to patients unwilling or unable to Smaller lesion size also appears to be a risk
undergo surgery.138 Graded talc, if chemical factor for TTNA-associated IP. Less consistently,
pleurodesis is pursued, is a reliable agent.137,138 the presence of or severity of emphysema in the
Up to 5 g of graded talc is recommended, but one biopsy area is reported as a risk for TTNA IP.
must recognize the rare occurrences of acute The number of needle passes and needle size
respiratory distress syndrome and empyema.138 are paradoxically not associated with TTNA-
Open thoracotomy has the lowest recurrence rate associated IP.137,139 Intensive care setting-related
(approximately 1%). Video-assisted thoracoscop- IPs have identifiable risk factors. Body weight
ic surgery with pleurectomy and pleural abra- less than 80 kg, history of AIDS, diagnosis of
sions appears better tolerated but has a higher ARDS or cardiogenic pulmonary edema at
recurrence rate (5%). The first objective in admission, central vein or pulmonary artery
providing surgery is the resection of any visible catheter insertion, and use of inotropic agents
blebs or bullae on the visceral pleura and the during the first 24 h are all associated with an
obliteration of any pleural porosities of the increased hazard ratio for IP. Mortality from an
visceral pleura. Next, adhesion between the IP in the intensive care setting is 2.6 times
visceral and parietal pleural surfaces should be greater when compared with patients without
created by any number of methods causing an IP.145

Treatment of patients suffering IPs varies. 5. Light RW, Lee YCG. Pneumothorax, chylothorax,
Recurrence is not an issue and treatment should hemothorax, fibrothorax. In: Mason RJ, Broaddus
focus on providing the least invasive means VC, Martin TR, King TE, Schraufnagel DE,
fitting the patient’s clinical circumstances. Ob- Murray JF, Nadel JA, eds. Murray and Nadel’s
servation may be a reasonable option in the Textbook of Respiratory Medicine. Philadelphia, PA:
patient who is not breathless and is otherwise Saunders Elsevier; 2010:1764–1791.
stable. Given the greater need for chest tube 6. Sahn SA. The pleura. Am Rev Respir Dis. 1988;
138(1):184–234.
placement in patients with CT scan evidence of
7. Sahn SA. Pleural diseases. Semin Respir Crit Care
underlying emphysema sustaining a TTNA IP
Med. 2010;31(6):647–779.
(27% with evidence and 9% without), initial
8. American Board of Internal Medicine website.
small-bore chest tube placement in lieu of
http://www.abim.org/default.aspx. Accessed
observation seems prudent.137,139 IP in the setting January 2, 2012.
of positive pressure mechanical ventilation raises 9. Staub NC, Wiener-Krnonish JP, Albertine KH.
the concern for a bronchopleural fistula (BPF) Transport through the pleura. Physiology of
and the development of a tension pneumothorax. normal liquid and solute exchanage in the
Chest tube placement in this setting should pleural space. In: Cretien J, Bignon J, Hirsch A,
generally be pursued.137,139 Resolution of an eds. The Pleura in Health and Disease. New York,
associated BPF with an IP occurs more rapidly NY: Marcel Dekker; 1985:169–193.
in those without underlying lung disease (100% 10. Noppen M, De Waele M, Li R, et al. Volume and
at 72 h for those without disease and 71% at 72 h cellular content of normal pleural fluid in
for those with disease).146 Refer to ACCP-SEEK humans examined by pleural lavage. Am J Respir
volume XVII (questions 54 and 154) 33 for Crit Care Med. 2000;162(3 pt 1):1023–1026.
additional information. 11. Collins TR, Sahn SA. Thoracentesis. Clinical
value, complications, technical problems and
Nothing to Disclose patient experience. Chest. 1987;91(6):817–822.
12. Accreditation Council for Graduated Medical
The author has disclosed that no relation- Education. Internal medicine program require-
ships exist with any companies/organizations ments. ACGME website. http://www.acgme.
org/acWebsite/RRC_140/140_prIndex.asp. Ac-
cessed January 7, 2011.
this chapter.
13. Havelock T, Teoh R, Laws S, Gleeson F. Pleural
procedures and thoracic ultrasound: British
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Chapter 40. Occupational and Environmental Lung
Diseases
Objectives: with dust-related interstitial lung diseases in

Recognize differences between impairment and disability. Chapter 18 (Pneumoconioses) while adding
Appreciate general concepts in assessing individuals additional information regarding occupationally
with suspected occupational or environmental condi-
induced airway diseases and several other
tions, noting the importance of a detailed occupational
and environmental history. conditions. Inhalation of organic or low-
Recognize the complexity of assessing occupational lung molecular-weight chemical antigens is reviewed
disease in terms of addressing exposure and handling in Chapter 42 (Hypersensitivity Pneumonitis).
administrative aspects involved, such as writing work
restrictions.
Perhaps one of the more challenging aspects
Define work-related asthma and understand the concep- of assessing the patient with the potential for
tual framework for the differences between work- occupational or environmental lung disease is
exacerbated asthma and occupational asthma. that few of these illnesses actually involve classic
Know classification of sensitizer-induced asthma, includ-
ing examples of high-molecular-weight and low-, findings that distinguish it from conditions that
molecular-weight antigens. do not involve an environmental source. There-
Recognize work-related asthma without latency (reactive fore, it is imperative that the pulmonary clinician
airways dysfunction syndrome).
Understand essential concepts of diagnosing and treat-
include occupational and environmental sources
ing a variety of work-related pulmonary conditions. of disease routinely as part of the differential
Review illnesses associated with acute toxic inhalations. diagnosis. To complicate matters, the diagnosis of
work-related pulmonary conditions may involve
Key words: disability; impairment ratings; occupational substances that affect multiple organ systems
asthma; occupational lung disease; work restrictions; work- concurrently, such as causing airway disease and
er’s compensation
pulmonary parenchymal abnormalities. Expo-
Synopsis: sures may involve synergistic effects (eg, smok-
ing tobacco with inhalation of asbestiform fibers)
Occupational and environmental lung diseases encompass
respiratory system dysfunction caused by or exacerbated by and often follow a dose-response pattern (inha-
contact with antigens or irritants that are inhaled, resulting lation of compounds at higher doses cause more
in acute or chronic illness. There is a wide spectrum of pathology); but they may involve individual
conditions included in this category of pulmonary dysfunc-
variation resulting in only select individuals
tion, and assessment and management of administrative
issues surrounding occupational and environmental lung experiencing symptoms in an area in which
disease is often one of the more challenging aspects of multiple people encounter the same exposure.
caring for individuals encountering illnesses or injuries Once a diagnosis of occupational lung disease is
associated with workplace exposures. Although occupa-
tional asthma is often the condition most commonly
confirmed, addressing administrative issues that
associated with environmental respiratory illness inhala- inevitably arise when one hypothesizes or draws
tional exposures may involve a variety or mixture of a causal relationship between an environmental
compounds including toxic substances, metal fumes, or
or occupational exposure and a physical impair-
organic antigens.
ment may be time-consuming and confusing for
the provider. This occurs not only due to lack of
familiarity with the nuances involved in restrict-
Introduction ing an individual from continued environmental
exposure but also the complexity and variety of
This chapter supplements information provided compensation systems that exist for the purpose
in Chapter 3 (Asthma) and also describes the of reimbursement medical expenses, income, and
overarching concepts for evaluating patients retraining issues should that individual be

unable to perform their regular work duties due specifically identifying an environmental source
to an illness or injury encountered at work or an for the dysfunction. The most important part of
impairment that precludes them from continuing investigating a suspected occupational illness is
their prior job duties. taking a detailed history. Although the physical
examination, chest radiography, and spirometry
Defining Impairment and Disability may add important information for many condi-
tions (these aspects of evaluation are outlined
Impairment has been defined by the World elsewhere in this textbook), the clinical history is
Health Organization as ‘‘any loss or abnormality a particularly powerful tool in assessing the
of psychological, physiological or anatomic nature of extrinsic disease. Obtaining prior
structure or function.’’1 Therefore, an abnormal- records of the patient from multiple sources
ity in expiratory airflow measured upon spiro- may be useful in identifying similar symptoms
metric testing would be considered an impair- encountered by the patient in the past in similar
ment as would the presence of emphysema on a work conditions may offer testing results that can
chest radiograph, or thoracic splinting due to be utilized as baseline markers of disease or may
pleuritic chest pain. Disability, meanwhile, refers point out a temporal association between expo-
to ‘‘an alteration of an individual’s capacity to sure and chronic diseases development. The
meet personal, social, or occupational demands detailed history from the patient must not only
because of an impairment.’’2 It is important to include information regarding current symptoms
identify specific impairments while performing a and health history such as comorbidities, symp-
diagnostic assessment of an individual with tom onset, medication use, or current or prior
respiratory disease. However, not all impair- tobacco abuse, but must also involve a detailed
ments result in a disability. For example, if a work history. Occupational history taking is often
welder who is a current smoker experiences an time-consuming but often may result in identifi-
upper respiratory infection and complains of cation of clues to confirm or refute certain
cough symptoms, spirometry may be performed occupationally related illnesses. Although the
as part of a diagnostic evaluation, which might job title is important, more critical are the specific
reveal air flow limitation (that likely resulted workplace exposures and maneuvers that oc-
from tobacco abuse). Mild airflow obstruction curred during employment. Was the individual
does represent impairment; however, if the in direct contact with the substance (or was the
individual is experiencing no functional limita- substance just known to be in the structure in
tion and is able to perform his/her usual job which they worked)? Did the patient use
duties, no disability is present. Conversely, personal respiratory protection or were engineer-
an individual who has become sensitized to ing controls such as local exhaust ventilation in
isocyanate-related compounds (resulting in dra- place? Listing specific workplace exposures is
matic bronchospasm with exposure to even often helpful and may be supplemented by
minute amounts of the offending agent) may obtaining Material Safety Data Sheets (MSDSs)
have relatively minor impairment in terms of for any potential substance encountered in the
specific respiratory symptoms or even normal workplace. An MSDS is a document that contains
baseline spirometry but the individual would be information on the potential health effects of
considered to have disability if the essential exposure to chemicals or other potentially dan-
functions of his/her normal occupation involves gerous substances. It also provides recommen-
frequent or predictable exposure to isocyanates. dations for ensuring safe handling of hazardous
chemical products and contains hazard evalua-
Clinical Approach to the Patient tions on the use, storage, and emergency proce-
dures related to that material. The MSDS
It is important to emphasize that making a contains much more information about the
clear diagnosis of a specific condition, including specific product in question than what is listed
the degree of impairment and the nature of the on the label and is intended to outline specific
abnormality, is vital prior to assuming or product hazards, how to use the product safely,
670 Chapter 40. Occupational and Environmental Lung Diseases (Cowl)

what to expect if the recommendations are not Table 1—Classification of Occupational Respiratory Tract
Disease
followed, what to do if accidents occur, how to
recognize symptoms of overexposure, and what Industrial Bronchitis/Rhinitis
to do if such incidents occur. Employers must Airway diseases
make sure that all controlled products have an Work-related asthma
Work-exacerbated asthma
up-to-date (less than 3 years old) MSDS when
Occupational asthma
they enter the workplace. Since the MSDS must Endotoxin/grain dust inhalation
be readily available to workers who are exposed Byssinosis
to the controlled product (for businesses em- Acute toxic inhalations
ploying more than approximately 15 employees, Metal fume fever
Polymer fume fever
depending on the locality), any treating medical Toxic pneumonitis (bronchiolitis obliterans)
provider or the patient should be able to obtain Combustible/smoke inhalation
this information from the employer. In addition, Pneumoconioses
Asbestosis
the history should include whether or not the Silicosis
patient participated in prior military service or Coal-worker’s pneumoconiosis (Black Lung)
is/was involved in any secondary jobs or hobbies Hypersensitivity pneumonitis (extrinsic allergic alveolitis)
Occupational infections
that involve(d) significant environmental expo- Occupational neoplasms
sure. Not only should information be garnered
from the patient but, with the patient’s permis-
sion, data regarding the nature of the specific conceptualize a framework for considering each
exposures involved for the occupation in ques- condition in the differential diagnosis of pulmo-
tion should also be obtained from a representa- nary patients.
tive of the employer in order to more thoroughly
ascertain all of the variables involved in the care Managing Work Restrictions
of the individual. A patient’s refusal to allow
dialogue with the employer should introduce The provider’s ability to manage workplace
suspicion as to the possible underlying agenda of restrictions is particularly challenging for patients
the patient, or make secondary gain issues a who are experiencing respiratory system impair-
possibility. The medical provider should always ment. This is due to a variety of factors, including
attempt to obtain as much information as the frequent presence of multifactorial etiologies
possible in order to make a more precise and for the symptoms, confounding factors such as
accurate determination as to the need for active tobacco abuse, frequent inability to identify
workplace restrictions and how best to safely a specific inciting factor that is causing the
return an individual to work. respiratory symptoms, inexperience by the
healthcare provider in writing workplace restric-
Classification of Occupational Lung tions, and significant time commitment to modify
Disease work restrictions as the course of the respiratory
condition changes. Once all available data re-
The complex nature of the presentation and garding the patient’s exposures and specific
variety of occupational- and environmental- workplace requirements have been obtained and
induced conditions that result in respiratory reviewed and the diagnostic assessment has been
system impairment has resulted in classifying completed, the treating provider may then decide
these disorders using several paradigms. This to restrict the individual from certain physical
includes dividing conditions into disease catego- maneuvers or from certain types of exposures. It
ries (Table 1) by pathophysiology or, in the case is important to recognize that simply taking the
of some illnesses such as occupational asthma, by individual out of work altogether is often not
whether or not the condition was caused by or necessary. In many cases, the employer is willing
just exacerbated by the inciting environmental and able to accommodate workplace restrictions
exposure. Classifying these disorders helps to by modifying the specific requirements of the

position, changing the location of where the sation systems vary among states, among em-
individual performs their work duties, or allow- ployers, and even among occupations within a
ing adjustment of productivity measures in order specific business. There is a variety of jurisdic-
to keep the patient active in the workplace. Taking tions for each type of compensation system, each
time to speak to a representative of the employer with specific plan language and definitions.
may often identify return-to-work options avail- Workers’ compensation refers to a no-fault
able that are not otherwise intuitively obvious. If insurance that provides compensation of medical
the employer is able to keep the patient active in care for employees who are injured in the course
gainful employment during his/her recovery and of employment in exchange for mandatory
treatment period, the individual will continue to relinquishment of the employee’s right to sue
receive full income and continue to accrue fringe his or her employer for the tort of negligence.3–4
benefits. While employers may ultimately not be Short-term and long-term disability plans are
able to accommodate some respiratory-related often available to workers employed by larger
work restrictions, the health-care provider should companies, but many self-employed individuals
at least offer the option for the employer to make or employees of small businesses do not have
that determination prior to completely restricting disability benefits and are not required to be
the individual from working in any capacity. covered under workers’ compensation in many
Work restrictions should center on limiting jurisdictions. Social Security Disability Insurance
specific physical exertions or, in conjunction with is available in the United States to qualified
specific dialogue with the employer, certain individuals with impairments that preclude them
environments (eg, excessive smoke, dust, chem- from performing gainful employment for at least
ical fumes). However, if the respiratory condition 1 year or that will result in death.5 The Family
in question involves severe impairment or a Medical Leave Act allows eligible employees to
situation in which exposure to specific inciting take off up to 12 work weeks in any 12-month
compounds is required as an essential function of period for the birth or adoption of a child, to care
the job, then the individual should be completely for a family member, or for the employee’s own
restricted from his/her prior work environment. serious health condition. The Americans with
This should also be accompanied by discussion Disabilities Act of 1990 (ADA) prohibits private
with the employer as to the general nature of the employers, state and local governments, employ-
condition (details of which need to be handled ment agencies, and labor unions from discrimi-
with care due to privacy concerns) and input nating against qualified individuals with
regarding prognosis and long-range planning of disabilities in job application procedures, hiring,
returning the patient to work if that appears to be firing, advancement, compensation, job training,
feasible at some point in the future. Ultimately, if and other terms, conditions, and privileges of
the patient is unable to have his/her work employment. The ADA covers employers with 15
restrictions accommodated or if the condition or more employees. An individual with a
involves severe impairment resulting in total disability is defined as a person who has a
disability, the patient may ultimately require physical or mental impairment that substantially
retraining in a different occupation or require limits one or more major life activities; has a
plans for long-term care if he/she is unable to record of such an impairment; or is regarded as
serve in any form of gainful employment because having such an impairment. A qualified em-
of underlying illness. ployee or applicant with a disability is an
individual who, with or without reasonable
Types of Compensation and Laws accommodation, can perform the essential func-
Applicable to Injured or Ill With tions of the job in question. An employer is
Respiratory Impairment required to make a reasonable accommodation to
the known disability of a qualified applicant or
There are a number of different compensation employee if it would not impose an ‘‘undue
systems available to workers who encounter hardship’’ on the operation of the employer’s
impairment of the respiratory system. Compen- business. Reasonable accommodations are ad-

justments or modifications provided by an Causes of Occupational Asthma
employer to enable people with disabilities to
enjoy equal employment opportunities. Accom- More than 450 compounds have been associ-
modations vary depending upon the needs of the ated with development of asthma symptoms.14
individual applicant or employee. Not all people Table 2 contains several categories and examples
with disabilities (or even all people with the same of these products. These compounds are com-
disability) will require the same accommodation. monly classified into high-molecular-weight an-
tigens (.5,000 Da) and low-molecular-weight
Clinical Conditions Associated With antigens (,5,000 Da). High-molecular-weight
Occupational Etiologies compounds are typically organic molecules
comprised of plant or animal matter such as pelt
Occupational Asthma or urinary proteins, insect proteins, or extractable
plant proteins. Other high-molecular-weight
This condition involves variable airflow limita- compounds that may incite asthma include
tion caused by dusts, allergens, gases, vapors, or biologic enzymes, natural rubber latex, and
fumes inhaled in an occupational environment. certain gums. Examples of low-molecular-weight
The prevalence of new cases of occupational antigens include isocyanates; anhydrides; certain
asthma reported in North America is estimated at wood dusts such as plicatic acid in Western red
9% to 15% (somewhere between 1:6 to 1:10 of new cedar; soldering fluxes; certain fixatives such as
onset cases of asthma).6–8 Since occupationally formaldehyde or glutaraldehyde; and pharma-
related asthma will present in the same manner ceutical products such as antibiotics, piperazine,
as asthma unrelated to workplace exposures, the or psyllium.
chest physician must maintain a high index of
suspicion for this condition; otherwise, only the
Clinical Features of Occupational Asthma
symptoms will likely be treated, and the inciting
History: The presence of new-onset asthmatic
antigen causing the condition will never be
symptoms in any individual with a prior history
identified. The diagnosis and management of of asthma, particularly if the symptoms have
occupational asthma was outlined in a detailed begun after entering the workplace, should
consensus statement by the American College of trigger the chest physician to consider an
Chest Physicians in 2008.9 The report divided all occupational source.15 The presence of a tempo-
forms of work-related asthma into situations in ral association with symptom escalation follow-
which the individual with preexisting asthma ing exposure and reduction in symptoms upon
experienced clinical decline (work-exacerbated removal from work makes occupational asthma
asthma) and asthma that was incited de novo more likely. Upper respiratory symptoms such as
because of an occupational exposure (occupational allergic rhinitis frequently precede the develop-
asthma). Work-related asthma can be classified into ment of lower respiratory tract symptoms.
the more prevalent form of asthma with latency, in Physical Examination: Although in many cases
which workers develop symptoms after a period of the lung examination will be normal in workers,
exposure involving weeks to months, and the less particularly after removal from potential expo-
common asthma without latency (also known as sures, the presence of wheezing during respira-
irritant-induced asthma), in which symptoms tory efforts is suggestive but not confirmatory for
develop within hours of exposure. The latter airflow limitation.
condition is reviewed later in this chapter and Skin and Immunologic Testing: Use of allergy
has also been associated with the term ‘‘reactive skin testing may be helpful in identifying certain
airway dysfunction syndrome.’’10,11 Risk factors for allergens or sensitization to any of a variety of
developing occupational asthma include a family specific extracts suspected to be exacerbating
or personal history of atopy, smoking, and certain respiratory symptoms. In addition, specific IgE
genetic factors involving major histocompatibility antibodies to extracts of products containing
complex class II proteins. either high-molecular-weight or low-molecular-

Table 2—Examples of Select Agents Associated With Occupational Asthma
Skin Test Specific IgE

Agent Industry or Occupation Reaction Antibodies
Isocyanates
Toluene diisocyanate Polyurethane foam manufacturing, paint application, plastics CD CD
Diphenylmethane Core production in foundries, paint application þ
Anhydrides
Trimellitic anhydride Plastics, epoxy resins þ þ
Phthalic anhydride Plastics, epoxy resins þ þ
Amines
Ethanolamines Soldering, paint application, machining metal products CD
Other chemicals
Formaldehyde Hospital personnel, laboratory technicians, chemical production
Metals
Nickel Metal plating þ CD
Cobalt Hard metal manufacturing þ CD
Chromium salts Leather tanning CD þ
Vanadium Hard metal manufacturing CD
Zinc Metal plating CD
Platinum salts Platinum refining þ
Vegetable and wood products
Grain Grain processing þ
Wheat/rye flour Baking, food processing þ þ
Castor beans Castor oil production þ
Raw tobacco Tobacco production þ þ
Coffee beans Coffee production, processing þ þ
Western red cedar Logging, lumber processing, home building, cabinet production þ þ
Colophony (pine resin) Electronics manufacturing CD þ
Gum acacia Printing þ
Animals
Pigeons Pigeon breeding þ
Chickens Poultry production and processing þ þ
Crabs Crab production and processing þ CD
Oysters Oyster production and processing þ þ
Mice Animal handling, laboratory technicians þ CD
Guinea pigs Animal handling, veterinarians, laboratory technicians þ þ
Enzymes
Papain Meat packaging and processing þ þ
Trypsin Pharmaceutical processing þ þ
Pepsin Pharmaceutical industry þ þ
Microorganisms/fungi
Bacillis subtilis Detergent manufacturing þ þ
Plus (þ) ¼ positive skin testing associated with exposure, but not in all individuals exposed; minus () ¼ no positive skin tests or
specific IgE antibodies in individuals tested; CD ¼ conflicting data (some reports show positive testing while others do not).
Information adapted from van Kampen et al12 and Chan-Yeung et al.13
weight compounds bound to serum proteins may testing measurements obtained before and after
be detected by the radioallergosorbent test or work shifts are frequently helpful in collating
enzyme-linked immunosorbent assay. A positive objective data required to establish a workplace
result does not necessarily confirm a causal relationship to the patient’s asthma. Use of a
relationship to developing occupational asthma peak flow meter can also be useful as an
but does suggest sensitization to the compound inexpensive method for obtaining objective expi-
when the test is positive and increases the ratory air flow measurements several times
probability of a work-related condition. during the day, including measurements during
Pulmonary Function Testing: The details of this the work shift. However, all tests of pulmonary
testing have been outlined in Chapter 6 (Pulmo- function are heavily effort dependent and data
nary Function Testing). Pulmonary function from these studies should be used cautiously and

should meet quality and reproducibility stan- a febrile reaction noted in workers in the cotton
dards to avoid manipulation of data by patients and hemp industries. Originally coined ‘‘Monday
seeking secondary gain. morning fever’’ because workers developed chest
Bronchoprovocation Testing: Nonspecific agents tightness and fever upon return to work after
such as histamine or methacholine to assess being off for several days, after which symptoms
bronchial reactivity are used frequently in assess- improved, byssinosis seemed to involve workers
ing the patient suspected of having occupational with more direct contact with cotton processing.
asthma. Patients without a positive challenge are Workers with jobs that involve ginning, carding,
less likely to have asthma and other etiologies of or cleaning machinery that processes cotton all
their respiratory symptoms should be identified. seemed to be at higher risk for developing
Specific bronchoprovocation using a particular disease. Degrees of respiratory impairment seem
agent suspected of causing asthma can also be to hinge on total concentration of dust exposure
performed in certain centers with whole body and length of employment in the industry.
chambers that allow for improved simulation of Workers with byssinosis encounter airflow
ambient air in the workplace. There are two main obstruction on spirometry that seems to improve
patterns of bronchoconstriction seen after exposure over time with similar exposure. The mechanism
to a sensitizing antigen, including an immediate by which this tolerance develops remains un-
response (10–15 min after challenge) and a late known. The exact mechanism by which the
response (peaking at 5–8 h after initial challenge). respiratory system is affected is controversial
However, a combination of both early and late but seems to involve a lipopolysaccharide (endo-
responses, a prolonged response appearing as late toxin) generated by microbial contaminants of the
as 1 day after the initial challenge, and nocturnal cotton plant. Other theories have centered on a
asthma symptoms that resolve over several days portion of the cotton bract itself while yet other
after the challenge have all been reported. studies have suggested that histamine or a similar
derivative is present in cotton dust extracts.
Management of Occupational Asthma Treatment involves recognition of the expo-
sure and removal of the individual from the
If it can be established that the patient has offending agent. Workers with chronic symptoms
indeed developed asthma from a workplace are often treated empirically for asthma.
exposure, the essential treatment goals are to
remove the individual from the inciting agent Chronic Beryllium Disease (Berylliosis)
and minimize or eliminate symptoms utilizing a
medication regimen with the least toxicity to the Beryllium is a very lightweight metal that
patient. Using targeted work restrictions or was used commercially in combination with
addition of engineering controls or respiratory alloys of aluminum, copper, nickel, and cobalt
protection as outlined above, the worker often before being used in the form of beryllium oxide
may be returned to perform the essential tasks in the fluorescent lamp industry and later in the
required in their occupation while minimizing nuclear industry. The prevalence of berylliosis
continued exposure to the offending agent. peaked in the 1940s; implementation of strict
Although as many as half of the recognized industrial hygiene regulations has resulted in
cases of work-related asthma will resolve com- very few cases since that time, barring lapses in
pletely over time with removal from exposure, following safety protocols or mishaps in the
many individuals will require pharmacologic physical plant where beryllium is used.
management in a sequentially increasing fashion The disease itself is considered a granuloma-
as outlined in Chapter 3 (Asthma). tous disorder in which the respiratory system is
primarily affected. Histologically, it seems to
Byssinosis emulate sarcoidosis but there are a few distinct
differences clinically. This includes a greater
This condition involves development of prevalence of hilar adenopathy, hypercalcemia,
bronchitic symptoms, dyspnea, and occasionally osteoporotic changes, and CNS involvement in

sarcoidosis that is absent or rare in berylliosis. environment that contains hard metal and
Patients with berylliosis often present with supportive therapies for individuals who devel-
nonspecific findings such as exertional dyspnea op asthma.
and nonproductive cough. Radiography may
initially be nondiagnostic, and spirometry is Toxic Inhalations
often normal in early stages or may have an
isolated reduction in diffusing capacity as its Because the respiratory system is in constant
only hallmark. Over time, the symptoms advance contact with the external environment, inhalation
and radiographic changes parallel those seen in of gases, fumes, aerosols, vapors, and smoke has
chronic interstitial lung disease. the potential for causing immediate and long-
In terms of treatment, because use of cortico- term pathology in the human. Several attributes
steroids often is the cornerstone of management, of toxic inhalants ultimately determine the
it is important to obtain a tissue biopsy in degree of injury to the upper and lower
individuals with an occupational history and respiratory tract (Table 3). These include particle
clinical picture consistent with this condition. size, concentration of the agent, water solubility
Beryllium proliferation testing should be per- of the compound, duration of exposure, location
formed and is available at several specialized of the inhalation (whether or not it was in a
laboratories around the country, but use of serum confined space or if ventilation was present), and
testing or bronchoalveolar lavage cell testing for the physical properties of the inhaled substance
proliferative responses is also available at several itself (eg, whether or not a gas was heavier than
laboratories and represents a valid alternative if air).16 Particles of greater size (.10 lm) tend to
histologic sampling is not possible or is unsafe. be filtered by the upper pharyngeal anatomy,
Therapy with corticosteroids has not been whereas very small particles (,5 lm) tend to
standardized, much like treatment of other bypass the usual respiratory tract filtering mech-
conditions involving interstitial pulmonary lung anisms and deposit into the lower respiratory
disease. tract, where the risk for chronic disease becomes
greater. Water solubility of the inhaled com-
Hard-Metal Lung Diseases pound is also important to understand since
particles with high water solubility tend to react
Hard metal refers to an alloy composed of more readily with the moist mucosal structures
tungsten carbide and cobalt with varying com- of the upper airway (nasopharynx and orophar-
binations of other metals such as vanadium, ynx) and eyes rather than the lower airway.
titanium, nickel, chromium, and molybdenum Inhalation of water-soluble compounds tends to
added. After a process of heating, it forms an
alloy with nearly the hardness of diamond. In Table 3—Factors Determining the Pathogenicity of Inhaled
fact, hard metal is used frequently as a compo- Toxic Substances
nent of drill bits and cutting tools and in the
Physical properties of inhaled substance
aerospace industry because of these attributes. Water solubility
Individuals exposed to hard metal have been Particle size
reported to experience asthma from inhalation of Concentration of inhaled gas or vapor
Duration of exposure
metallic particles composed of tungsten and Characteristics of site of exposure (eg, confined space,
cobalt and pulmonary parenchymal conditions ventilation present, etc.)
similar to interstitial pulmonary fibrosis; occa- Nature of inhalant (eg, heavier than air)
sionally they will present radiographically with Host factors
Age
changes that appear much like that of hypersen- Physical stature
sitivity pneumonitis (extrinsic allergic alveolitis). Smoking history
Carcinogenicity of cobalt-containing compounds Medical comorbidities
Presence or absence of personal respiratory protection
has been questioned, but only animal studies
(eg, respirator mask use)
have shown any evidence for neoplasia. Treat- Genetic susceptibility to respiratory illness
ment centers on removal from the ambient

result in immediate irritation and reactivity of the some anecdotal usefulness, but most treatment
conjunctival surfaces, nasal passages, and oro- includes use of short-acting bronchodilators and
pharynx. These include compounds such as humidified supplemental oxygen.
ammonia, sulfur dioxide, and chlorine. Less
water-soluble agents such as nitrogen dioxide Sulfur Dioxide
(which is the compound prevalent in ‘‘silo filler’s
disease’’) or phosgene (often inhaled as a gaseous This is a heavier-than-air, highly water-
byproduct in the welding industry) often do not soluble gas with the potential for significant
cause acute symptoms but instead react with upper respiratory irritation. It is produced as a
structures in the lower respiratory tract, resulting byproduct of coal and petroleum combustion
in delayed but severe pulmonary parenchymal (the main pollutant in ‘‘acid rain’’), is used as a
abnormalities. As with most occupational and food preservative, and is released in mass
environmental exposures, removal from the quantity into the atmosphere during volcanic
inciting agent and providing supportive care is eruptions. The sulfur molecule reacts with water
the mainstay of therapy. and forms sulfuric acid, causing a coagulation
necrosis reaction to any underlying exposed
Ammonia surface. Exposure to sulfur dioxide may result
in both upper and lower respiratory tract injury,
Ammonia is a highly water-soluble com- depending on the concentration and duration of
pound that has been deemed to be the most exposure. With large enough exposures, lower
commonly encountered hazardous substance respiratory tract injury may include noncardio-
due to accidental release. It is common in genic pulmonary edema, alveolar hemorrhage,
household cleaners and can be used as a and death. Treatment is with supportive mea-
chemical coolant for refrigeration, a fertilizer, sures such as maintaining a patent airway, using
and a fixative in photocopier toners. Since nebulized bronchodilators, providing supple-
ammonia is a water-soluble compound, it will mental humidified oxygen, and removing the
affect the upper airways immediately, and the individual from the exposure.
victim should have all exposed surfaces irrigated
with copious amounts of water. Airway preser- Oxides of Nitrogen (NO2)
vation is paramount since laryngeal edema
frequently ensues after large ammonia expo- Although the most common exposures are
sures. due to industrial releases including mining,
acetylene welding, and production of explosives,
Chlorine and Hydrochloric Acid Compounds oxides of nitrogen (most commonly nitrogen
dioxide) have also been associated with inhaled
Chlorine derivatives are most commonly exposures by farmers inside silos, where the
encountered near water purification or cleaning compound is released as a byproduct of decom-
efforts. Examples include swimming pools and posing silage (silo filler’s disease). Because these
water-treatment facilities as well as use in home compounds are of relatively low water solubility,
cleaning. These compounds have intermediate initial clinical effects are mild if at all present.
water solubility and cause irritant effects of the There is a delayed reaction with the lower
upper airway but may affect the lower airway as respiratory tract, where, several hours after the
well. The effects center on its direct toxic initial exposure, patients develop severe pulmo-
sequelae, including irritant bronchospasm of the nary edema resembling ARDS because of in-
airway, denudation of airway epithelium, and creased capillary permeability due to damage of
ulcerative tracheobronchitis in large exposures. the airway epithelium. Treatment after removal
Treatment is similar to other inhalational expo- and restriction from the inciting exposure should
sures for which the patient is to be removed from include very close monitoring of the individual’s
the source of the inhalation. Nebulized sodium clinical status, with a low threshold for airway
bicarbonate has been used experimentally with patency preservation and supportive therapy.

Metal Fume Fever (Polymer Fume Fever) whose products or services may be discussed in
this chapter.
These systemic illnesses, encountered from
inhaled toxic effects of certain metals, cause Annotated References
cytokine release and typically involve a self-
limited course of dry throat; a metallic taste in the
oropharynx; and development of shaking chills,
Impairment vs Disability
fever, and myalgias beginning 4 to 8 h after
1. World Health Organization. International Classifica-
exposure, all of which resolve spontaneously
within 48 h. Fluorocarbon polymers used for tion of Impairments, Disabilities, and Handicaps. Gene-
nonstick coatings on cookware (polytetrafluoro- va, Switzerland: World Health Organization; 1980.
ethylene or Teflon), when heated to very high Original report that provides definitions and classifica-
temperatures or during industrial applications, tions for disability determination.
may result in a similar systemic illness beginning 2. Rondinelli RD, ed. Guides to the Evaluation of
4 to 8 h after exposure and characterized by dry Permanent Impairment. 6th ed. Chicago, IL: Amer-
throat, atypical chest pain, conjunctivitis, and ican Medical Association; 2011.
fever that spontaneously resolves within 1 day. A textbook used as the ‘‘bible’’ of impairment rating
determination for workers’ compensation programs in
Pulmonary Mycotoxicosis (Organic Dust Toxic many states.
Syndrome)
Compensation Programs Available to Injured
Inhalation of organic dusts, such as following Workers
exposure to hay or corn silage, spoiled animal feed,
or confinement facilities for swine or cattle, can 3. Guyton GP. A brief history of workers’ compen-
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tightness that begins 4 to 8 h after initial exposure challenges, and anecdotes over time.
and resolves within 48 h. Treatment is removal 4. Gerdes DA. Workers’ compensation, an overview
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This is another excellent primer for the practitioner
Thermal Lung Injury and Acute Smoke interested in further information on how workers’
Inhalation compensation benefits are designed to work.
5. US Department of Labor. www.socialsecurity.gov.
Fires and concurrent explosions account for
Accessed March 12, 2012.
the majority of cases of acute toxic inhalation
This is the website from the Department of Labor that
from smoke accompanied by thermal injury.
outlines every aspect of Social Security Disability
Heat, toxic gases, and low ambient oxygen levels
Insurance for eligible workers.
account for the high mortality rate associated
with structural fires. A variety of toxic chemicals
are released during active combustion of wood
Occupational Asthma Frequency, Diagnosis,
and plastics, some of the most virulent being a and Management
combination of hydrogen cyanide and carbon
monoxide. The combination of these compounds 6. Balmes J, Becklake M, Blanc P, et al. American
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Nothing to Disclose Among other items, prevalence of occupational asthma
is discussed.
The author has disclosed that no relation- 7. Chan-Yeung M, Malo JL. Occupational asthma. N
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Albeit somewhat dated, it remains a relevant and 586. This article concisely addresses some of the
comprehensive review. controversy that initially surrounded this condition.
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dysfunction syndrome. Chest. 1996;109(6):1618– al history taking in the scheme of broad management.
1626.
Older but comprehensive article that ties together the Acute Toxic Inhalations
concept that reactive airways dysfunction syndrome is
a form of irritant-induced asthma. 16. Miller K, Chang A. Acute inhalation injury. Emerg
11. Bardana EJ. Reactive airways dysfunction syn- Med Clinics North Am. 2003;21(2):533–557.
drome (RADS): guidelines for diagnosis and Very good review of the approach to acute toxic
treatment and insight into likely prognosis. inhalations, including examples of the compounds
Ann Allergy Asthma Immunol. 1999;83(6 Pt 2):583– discussed in this chapter.

Notes

Chapter 41. Altitude Physiology and Illness, Diving
Medicine, and Hyperbaric Oxygen Therapy
Objectives: Basic Concepts in Altitude Physiology

Review atmospheric composition and the basics of
altitude physiology including gas laws. The Atmosphere and Gas Laws
Understand symptoms and clinical approach to high-
altitude illnesses.
Appreciate issues with air travel for special populations The earth’s atmosphere is a harsh environ-
with cardiopulmonary conditions. ment. Approximately 78% of the atmosphere is
Discuss basic concepts of diving medicine including made up of nitrogen, followed by 21% oxygen
contraindications, risks, and untoward events.
Recognize early effects of drowning or near drowning. and small fractions of CO2 and other trace
Know the accepted indications and general principles of elements or compounds. The atmosphere is
hyperbaric oxygen therapy. made up of several layers, including the tropo-
sphere (up to 30,000 ft), the stratosphere (from
about 30,000 to 60,000 ft [9,144 to 18,288 m]), the
Key words: altitude physiology; atmosphere; diving med-
icine; drowning; gas laws; hyperbaric oxygen therapy; mesosphere (up to 50–60 km above the surface),
hypoxia; mountain illness the thermosphere (95–120 km), and the exo-
sphere (.600 km), which includes deep space.
The troposphere is the layer in which most
Synopsis:
weather phenomena take place. The tropopause,
From the depths of the oceans to the outer reaches of the earth’s
located between the troposphere and strato-
atmosphere, we are bathed in a pressure environment. The
principles of physiology are useful in describing observed sphere, is the point at which the rate in which
changes at depth or altitude and include laws that explain the the atmospheric cooling as one ascends (referred
behavior of gases. The atmosphere is divided into several to as the lapse rate) abruptly changes and
layers, including the troposphere, where weather exists.
Hypobaric hypoxia exists at high altitudes in which the temperature stabilizes as the air becomes almost
pressure exerted by the atmosphere is so low that tissue completely dry. The Armstrong line, present at
hypoxia results because of lack of alveolar driving pressure. about 65,000 ft (19,812 m) above sea level
Several conditions are associated with respiratory abnormal-
depending on the latitude being considered,
ities at terrestrial altitude, including acute mountain illness,
high-altitude pulmonary edema, and high-altitude cerebral defines the point where atmospheric pressure is
edema. Because of decreased pressure at altitude, special so low that nitrogen will dissolve out of solution
consideration should be provided for individuals with (‘‘blood boils’’). The von Karman line, located at
preexisting cardiopulmonary disease. Thousands of people
participate in diving activities each year, making important to
about 62 mi (100 km) above the earth’s surface, is
understand the basic concepts of diving physiology and some a point where aerodynamic flight is no longer
of the unique pulmonary risks encountered while diving. possible.
Hyperbaric oxygen therapy provides an increased partial
There are several gas laws that govern many of
pressure of oxygen to poorly vascularized tissues in patients
with difficult-to-heal vascular wounds and radiation-induced the findings in altitude physiology. Among those is
tissue breakdown and has also been useful in managing acute the Dalton law, which states that the total pressure
sequelae of arterial gas embolisms or histotoxic hypoxia from exerted by the mixture of nonreactive gases is equal
carbon monoxide inhalation. As with other procedural
interventions in medicine, there are also contraindications to
to the sum of the partial pressures of individual
hyperbaric oxygen that should be carefully managed. gases. This accounts for the fact that the fraction of
oxygen in the atmosphere remains at 21% whether
at the earth’s surface or an extreme altitude. The
difference when one ascends to altitude is the
driving pressure of gas into the alveoli. Boyle’s Law
accounts for the inversely proportional relationship

between the absolute pressure and volume of a gas in what is referred to as ‘‘the death zone’’ as
if the temperature is kept constant within a closed climbers approach the summit.
system. This explains the fact that gases expand at There are several physiologic responses to
altitude where pressures are low and accounts for hypobaric hypoxia that occur over several days
issues with abdominal distention, barotrauma, in order to achieve acclimatization. Initially, tidal
aerodontalgia (dental pain from air expansion in volume and breathing frequency are increased,
an abscess cavity) in certain susceptible individuals resulting in a reduction in PCO2, an increased in
as one travels to high elevations, and why one must alveolar PO2, and a net increase in oxygen
ascend slowly from water depths because of the content. The increased ventilatory drive results
risk of expanding gas in the lung or other anatomic in a respiratory alkalosis, which, in turn stimu-
cavities. Charles’ Law refers to the fact that when a lates a partially compensated metabolic acidosis.
given mass of a gas is heated at constant pressure, Additional physiologic responses to altitude
the volume of a given mass of a gas is directly include increases in heart rate and cardiac
proportional to its absolute temperature. This output, increased pulmonary artery pressures,
explains why air, when heated in a hot air balloon, reduction in ventilation/perfusion mismatching,
expands and creates thrust to lift a payload. and increased vasodilation that equates to better
oxygen delivery to the brain to offset localized
The Concept of Atmospheric Pressure vasoconstriction induced by hypoxemia. After a
period of 10 days to 2 weeks, reduced oxygen
A standard atmosphere (ATA) is actually a tension at altitude stimulates production of
set of models that define values for atmospheric erythropoietin, which then generates increased
temperature, density, pressure, and other prop- red blood cell mass and consequently improved
erties over a wide range of altitudes. It is used as oxygen delivery to the tissues.
a reference value to describe the average pressure
(weight) exerted by the atmosphere at varying Clinical Illness Related to High
levels, typically set at a 760-mm Hg column of Altitude
mercury at 08C (328F) at sea level, and at 1
standard gravity 32.174 ft/sec2. Other units of Acute Mountain Illness (AMS)
measure to describe 1 ATA include 29.92 in Hg;
14.69 psi; and 1,013.3 millibars or 101.33 kPa. AMS comprises the majority of cases of
Although in basic respiratory physiology courses altitude-related illness, occurring within hours
the atmospheric pressure is set at a constant, to days after relatively rapid exposure to altitude
when one considers physiology at altitude, the greater than 8,000 ft (2,440 m). Although hypoxia-
alveolar gas exchange equation reflects the induced vasodilation of the cerebral vessels
significant reductions in alveolar driving pres- seems to be the primary etiology for symptom
sures as one ascends into the atmosphere. generation, the precise mechanism is yet un-
Conversely, as one dives into the ocean depths, known. The most common symptoms include
atmospheric pressure increases. At 33 ft (10 m) of headache, generalized fatigue, anorexia, malaise,
water depth, the total pressure experienced is 2 nausea, vomiting, and insomnia. These symp-
ATA (a total of one equivalent atmosphere of toms may be magnified with strenuous physical
depth plus the weight of one atmosphere at sea activity such as climbing, hiking, or skiing;
level). Therefore, at 66 ft (20 m) of water depth, alcohol consumption; and use of sedating med-
there would be a total of 3 ATA absolute. As one ications that include tranquilizers to initiate
ascends, atmospheric pressure decreases. For sleep. Sleep-related disordered breathing seems
example, at the summit of Mount Everest to worsen at altitude, likely because of increased
(altitude 29,029 ft [8,848 m]) the barometric central apneic events due to hypoxia. Prevention
pressure drops from 760 mm Hg at sea level to rather than early treatment seems to be the best
just 250 mm Hg once the summit is reached. The strategy for dealing with what may be rather
pressure at that altitude is so low that hypoxia profound and functionally limiting symptoms. If
may become critical, resulting in many fatalities hiking or climbing, adhering to a plan of slow
682 Chapter 41. Altitude Physiology & Illness, Diving Medicine, and Hyperbaric Oxygen Therapy (Cowl)
ascents and sleeping at an altitude that is only and phosphodiesterase inhibitors that promote
slightly greater than or at a similar altitude to the pulmonary vasodilation. All treatment strategies
previous night seems to attenuate most symp- should include descent from altitude as soon as
toms. Emphasis should be placed on adequate safely possible.
oral hydration, adequate rest, and maintaining
adequate body temperature. Chronic Mountain Sickness (Monge Disease)
Pharmacologic management to prevent AMS
typically involves use of acetazolamide (125 mg This has been observed in several cohorts of
po bid beginning 24 h prior to ascent) that individuals who reside at high altitude, is more
triggers alkalinization of the urine with bicar- common in males, and is thought to be secondary
bonate excretion and subsequent increase in to erythropoietin-induced stimulation of red
respiratory ventilation. Those with a sulfa allergy blood cells released in response to hypoxemia
should not take acetazolamide. An alternative that results in profound polycythemia. Hemo-
drug is dexamethasone, but abrupt cessation of globin concentrations in the range of 21 to 23
the drug may result in symptom recurrence. g/dL and hematocrits in the range of 75% to 80%
Treatment of AMS should be early and include have been reported. Once again, symptoms seem
descending to lower altitudes, use of supplemen- to involve headaches, dizziness, lethargy, insom-
tal oxygen, and adequate oral hydration. nia, memory problems, cognitive dysfunction,
fluid retention, and paresthesias. Treatment may
High-Altitude Cerebral Edema include symptom control using supplemental
oxygen, phlebotomy for the polycythemia, and
This severe and potentially fatal manifestation acetazolamide, as well as travel to sea level,
of high-altitude exploration or recreation is which is considered the gold standard in treating
actually considered an extension of AMS, occur- chronic mountain sickness.
ring within hours or several days of initial arrival
at altitude. In addition to severe headache, the Issues Associated With
patient also may experience ataxia, confusion, Cardiopulmonary Patients and Travel
hallucinations, stupor, or coma. Immediate de- to Altitude
scent in conjunction with other treatment modal-
ities such as supplemental oxygen and The average age and overall volume of the
glucocorticoids is of key importance. If descent traveling population continues to escalate each
is not possible, use of a portable hyperbaric year. Worldwide, more than 1 billion passenger
chamber should be implemented if available. embarkments are recorded. Individuals have
access to travel to remote destinations by air over
High-Altitude Pulmonary Edema thousands of miles to places of terrestrial altitudes
that were never thought possible even within the
This form of altitude illness has actually last decade. In fact, plans are being finalized
accounted for more fatalities than any other form currently for medical requirements related to
of altitude-related condition. Part of this may have civilian suborbital space flight. Cruise altitude in
to do with its relatively late presentation several most commercial airline flights range from 10,000
days after arrival at altitude. The exact mechanism ft (3,000 m) to 40,000 ft (12,200 m). By federal
of high-altitude pulmonary edema remains some- regulation, airline cabins must be pressurized to
what uncertain but seems to center on involvement maintain a simulated altitude of no greater than
of pulmonary hypertension and pulmonary edema 8,000 ft (2,438 m) other than in emergent
through the release of cytokines and other inflam- situations. At most cabin altitudes, the general
matory mediators. The symptoms classically re- flying population notices no symptoms but will
volve around a nonproductive cough, fatigue, and subconsciously increase tidal volume and/or
dyspnea, and later, mental status changes, lethargy, breathing frequency slightly. However, travelers
and coma. Medications used for prophylaxis with cardiopulmonary limitation may develop
include nifedipine, dexamethasone, salmeterol, clinically significant hypoxia resulting in dyspnea

and necessitating initiation of supplemental oxy- cardiac limitation is suspected. Outside of gen-
gen or increasing flow rates of baseline supple- eral fitness, physical evaluation of the potential
mental oxygen utilized. There are a variety of diver should be focused on upper respiratory
options to the traveler needing supplemental tract disease that would preclude the individual
oxygen, including bottled oxygen that must be from performing pressure equalization maneu-
provided (for a fee) by the airline, or via a battery- vers while ascending or descending, BMI (obese
powered portable oxygen concentrator that may individuals are at higher risk for experiencing
be brought on board the aircraft by the passenger. decompression illness, or the bends, because
Passengers will need a prescription or written nitrogen is a lipid-soluble gas), mental health
statement from their physician describing the history (anxiety or cognitive issues could limit
indication for use of supplemental oxygen in the ability to understand instructions before and
order to pass security. The American College of during critical portions of diving activities), and
Chest Physicians has released a primer on caring excessive use of alcohol or use of certain sedating
for passengers with a variety of health conditions medications because of effects of certain drugs at
who are traveling to altitude (http://www. depth. Asthma and diabetes mellitus are com-
accpstorage.org/newOrganization/patients/ mon conditions considered as being relative
TravelingwithOxygen.pdf). Specific indications contraindications to diving, but individuals with
for supplemental oxygen are provided in the these conditions generally can be considered
document. acceptable diving candidates if the conditions
are well controlled and the risk for anxiety or
Diving Medicine acute hypoglycemic reactions is low for each of
these conditions, respectively.
It is estimated that there are more than 2 In contrast to recreational diving, commercial
million active divers in the United States, divers are subject to more rigorous medical
including participants in commercial diving and screening and surveillance under the auspices of
recreational enthusiasts. The variety of types of several regulating agencies. These examinations
diving available to the sports diver is outlined in focus not only on cardiovascular fitness but also
Table 1. According to published estimates, musculoskeletal conditioning that could limit
slightly more than 1,000 diving-related injuries mobility or ability to perform certain maneuvers.
occur annually, with a significant proportion Deep dives are associated with the risk for
being fatalities. Most deaths were reported as osteonecrosis from dysbarisms, and neurologic
secondary to drowning, followed by air embo- screening (with use of MRI as indicated) is an
lism, cardiovascular-related causes, and decom- important component of surveillance in this
pression illness. cohort because of risk for development of plaques
of the brain and spinal cord. Individuals with a
Medical Clearance and Surveillance seizure disorder should not participate in any
form of compressed gas diving. Because of the
Because general fitness is required to partic-
risk for development of air outside of the alveoli
ipate in safe diving, individuals proposing to
(pulmonary overpressure), a variety of pulmonary
snorkel dive should be screened for cardiovas-
conditions are also considered contraindications
cular risks similarly to the sedentary patient
for diving, including chronic symptomatic asth-
initiating a new fitness program. Most diving
ma; COPD; history of spontaneous pneumothorax
organizations require completion of a medical
and/or pulmonary scars, cysts, or blebs; and
questionnaire form to identify potential health-
pulmonary fibrosis.
related contraindications prior to pursuing self-
contained underwater breathing apparatus
Medical Issues Encountered in Diving Medicine
(scuba) training. Diving candidates should be
assessed for general fitness and a stress ECG or Barotraumas, both ear/sinus and pulmonary,
similar functional cardiovascular study should comprise the most common medical condition
be considered if aerobic deconditioning or encountered by divers. When an individual is
Table 1—Types of Sport Diving
Type Breathing Equipment Advantages Disadvantages Comments
Breath- Snorkel Freedom Depth limited by breath- Probably the largest

holding hold time number of participants
Scuba Regulator and tank; open Extends bottom time Inefficient use of air The majority of
circuita supplyb recreational scuba
diving
Enriched-air Regulator and tank; open Reduced chances of Increased chances of Less fatigue
nitrox circuit decompression sickness oxygen toxicity
Rebreather Closed circuitc Prolongs underwater Many hours of training; Equipment costs about
times increased hazards $5,000–$10,000
Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College of
a
Open circuit: After inhaling compressed gas from the SCUBA tanks via the regulator, the diver exhales each breath into
the water.
b
Efficiency: This is a very inefficient use of the gas supply because 79% of the contents of the tank is the inert gas
nitrogen. Each inhalation contains 21% oxygen, whereas there is 16% oxygen in the exhaled gas. Consequently, only 5% of the
air in the scuba tank is used for the body’s respiration and ventilation needs, whereas 95% is exhaled into the water.
c
Closed circuit: The gas supply recycles through breathing bags while CO2 is absorbed in the rebreather circuit. Oxygen is
added (usually via sensor controls) at a rate sufficient to meet the diver’s oxygen requirements.
unable to clear unequal gas pressure present signs and symptoms while respiration and heart
between the nasopharynx and middle ear cavities rate are maintained. Symptoms typically occur
because of occlusion of the eustachian tube or sinus during ascent or within minutes after surfacing. A
ostia when encountering pressure changes while small percentage of divers with arterial gas
ascending or descending (recall Boyle’s Law that embolisms suffer deadly injuries with cardiopul-
describes gas expansion with ascent and contrac- monary arrest, despite rapid recompression ef-
tion with descent), it results in pain and may forts.
develop into rupture of the vascular structures of Decompression sickness (DCS) describes the
the middle ear or even perforation of the tympanic phenomenon of nitrogen or other inert physio-
membrane. If the inner ear is exposed to cold water logic gases in the bloodstream coming out of
at depth after tympanic membrane rupture, the solution when ambient pressure is reduced
diver may experience disorientating vertigo, par- rapidly. This may occur if a diver ascends too
ticularly if tympanic rupture is unilateral (referred rapidly or if an aviator or astronaut is exposed to
to as alternobaric vertigo), and resulting uncontrol- low ambient pressure compared with sea level.
lable panic. Persistent symptoms of pain, vertigo, Musculoskeletal pain (type I DCS) is the most
dizziness, nausea, or auditory acuity loss warrant common manifestation of DCS, with symptoms
immediate medical attention because of the risk for occurring within 6 h after the dive is completed.
rupture of the round or oral window of the inner ear Neurologic sequelae (type II DCS) may involve
or other structures. paresthesias or sensory deficits with or without
Pulmonary overpressure syndromes are less associated weakness or paralysis. Rarely, indi-
common but quite serious. Breath holding during viduals may experience a form of pulmonary
descent or ascent can result in alveolar rupture, DCS with substernal pain, cough, and dyspnea as
lung collapse, mediastinal emphysema, and/or well as extreme malaise; this is known to divers
pneumothorax. Arterial gas embolisms occur as ‘‘the chokes.’’ Application of 100% oxygen is
when expanding extra-alveolar gas is forced into the treatment of choice for most cases of DCS,
a pressure gradient into torn septal vessels, after with definitive therapy using hyperbaric oxygen
which it is ejected into the systemic circulation as recompression.
particles or bubbles, eventually lodging in the There is a variety of other potential medical
cerebral, peripheral, or pulmonary circulation. conditions associated with indirect effects of
Most arterial gas embolisms involve neurologic pressure. These are outlined in Table 2.

Table 2—Additional Problems Associated With Indirect Effects of Pressure
Condition Etiology Symptoms Management Prevention
Nitrogen narcosis, Narcotic effects from Confusion, irrational Ascent; the dive buddy Adhere to safe depth
ie, ‘‘rapture of breathing this gas actions, stupor, needs to control the limits (,130 ft [40
the deep’’ under pressure. Each syncope. Victim may victim’s ascent to m]). Use helium for
50 ft (15 m) of descent panic and ascend in avoid complications. deep dives.
is roughly equivalent an uncontrolled Symptom resolve
to the effects from fashion. immediately with
drinking one martini. Complications ascent.
include arterial gas
embolisms, DCS,
and/or drowning.
Oxygen toxicity, ie, Breathing oxygen under Anxiety, tunnel vision, Ascent; breathe gas Adhere to strict depth
‘‘oxygen hit’’ increased pressure. tinnitus, muscle with lower oxygen limits when diving
Seizure threshold is a twitching, and content, eg, air with pure oxygen (33
function of depth, seizures. instead of pure ft [10 m] for 30 min)
duration, activity, and oxygen or nitrox and table limits with
the environment, eg, mixtures. nitrox mixtures.
cold water, poor
visibility, currents.
CO2 toxicity Increased carbon dioxide Headache, increased Ventilate by breathing Strict adherence to
from problems with respiratory rate, fresh air. Terminate safety and setup
carbon dioxide feelings of dive if rebreather protocols when
absorber or work in suffocation, syncope. (with carbon dioxide using rebreather
unventilated spaces Burns in mouth from absorber) equipment equipment. Ensure
(tunnel and caisson soda lime. is used. adequate ventilation
workers). when working in
closed spaces.
Carbon monoxide Contamination of air Headache, confusion, Surface, breathe pure Ensure gas supply is
poisoning supply with exhaust collapse, syncope, oxygen, hyperbaric free of
fumes from internal coma, and death. oxygen. contamination.
combustion engines.
High-pressure Diving deeper than 650 Tremors, Ascent. Add small amounts of
nervous system ft (198 m) with incoordination, nitrogen to the
syndrome helium-oxygen syncope. breathing gas.
mixtures.
Reprinted with permission from ACCP Pulmonary Medicine Board Review. 25th ed. Northbrook, IL: American College
of Chest Physicians; 2009.
Hyperbaric Oxygen Therapy at 2 ATA absolute while breathing 100% oxygen

increases plasma and tissue oxygen tension 10-
The concept of placing an individual into a
fold, blood oxygen content by 125%, and oxygen
chamber and applying increased ambient pres-
sure while breathing 100% oxygen intermittently diffusion through tissue fluids by a factor of
has been utilized for decades to treat a variety of three. Side effects include barotrauma as dis-
illnesses. Treatments involve approximately 2- to cussed earlier in this chapter. Oxygen toxicity
3-h compression sessions over multiple days. causing seizures is an uncommon but real side
Treatments are performed in monoplace cham- effect mitigated in most programs by use of air
bers in which a single patient breaths ambient breaks in which the patient breathes room air
area provided or larger multiplace chambers in rather than 100% oxygen periodically. Other
which several patients undergo treatment con- effects of hyperbaric therapy include vasocon-
currently while breathing pure oxygen through a striction to minimize posttraumatic edema, pro-
face hood or other delivery device. moting wound healing by enabling host factors
Hyperbaric oxygen therapy involves hyper- such as fibroblast activity, angiogenesis, leuko-
oxygenation and mechanical effects of pressuri- cyte oxidative killing, and bone remodeling,
zation. Exposure to a hyperbaric environment microbiological effects such as bacteriostasis,
cessation of toxin production, toxin inactivation, whose products or services may be discussed in
and gas washout for management of DCS and this chapter.
carbon monoxide poisoning.
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Chapter 42. Hypersensitivity Pneumonitis (Extrinsic
Allergic Alveolitis)
Objectives: fresh air from the ventilation system within the structure
itself.
Define hypersensitivity pneumonitis and describe exam-
ples of environmental sources of antigens associated
with this condition.
Recognize the complexity of the epidemiology of the
disease and associated risk factors. Introduction
Outline a clinical approach for recognizing the clinical
presentation of this condition, including classification of Chapter 40 covered general concepts in evaluating
severity of illness and radiographic and histologic
features used to ascertain a diagnosis. and recognizing occupational and environmental
Discuss treatment strategies for hypersensitivity pneu- lung disease, including various forms of systemic
monitis. toxic inhalations and airway illnesses associated
Describe clinical syndromes often confused with hyper- with organic dusts and inhalation of metals. This
sensitivity pneumonitis but that are considered distinct
entities. chapter focuses on one form of environmental
Review clinical syndromes associated with certain exposure that involves inhalation of organic or low-
indoor air environments. molecular-weight chemical antigens, which may
lead to chronic and, in some cases, permanent
Key words: allergic alveolitis; farmer’s lung; hypersensitiv- fibrotic parenchymal changes. Conditions such as
ity pneumonitis; indoor air quality; inhalation fever; organic silo-filler’s disease, ornithosis, and organic dust
dust inhalation; pigeon breeder’s disease
toxic syndrome are discussed, illnesses that have
Synopsis:
been reviewed in Chapter 40 as well. In addition,
this chapter covers clinical syndromes due to
Ambient air may contain a variety of irritants, allergens, or
toxins that result in dysfunction of the respiratory system.
indoor air quality issues.
Hypersensitivity pneumonitis involves inhalation of partic- Hypersensitivity pneumonitis (also known as
ulate matter, typically organic materials that serve as an extrinsic allergic alveolitis) is a respiratory
antigenic stimulus of an immunologic sensitivity reaction condition characterized by inhalation of any of
that develops in the alveoli, terminal bronchioles, and
interstitium. There is a higher prevalence of nonsmokers a plethora of organic dusts or low-molecular-
who develop this illness, and manifestations of hypersen- weight chemicals bound as haptens, resulting in
sitivity pneumonitis may be acute, subacute, or chronic. an inflammatory reaction that may cause acute
Radiographic findings are often variable but tend to and/or chronic sequelae including irreversible
demonstrate poorly defined nodular opacities with varia-
tions of ground-glass densities or consolidation most fibrotic changes involving the pulmonary inter-
prominent in the lower lobes. Chronic forms typically stitium (Fig 1). Not all who are exposed to
involve diffuse linear and nodular opacities with an organic dusts develop this condition. One of the
upper-lobe predominance. Laboratory findings include
more perplexing aspects of hypersensitivity
peripheral blood leukocytosis with a predominance of
neutrophils and an absence of eosinophils. Bronchoalveolar pneumonitis is the fact that among similar
lavage sampling often reveals lymphocytosis with a low groups of individuals affected by similar expo-
CD4:CD8 ratio. Management centers on removal from the sures, there will be a spectrum of disease severity
presumed source of inhalation, and judicious use of
that hinges on multiple variables such as
corticosteroids. There are several other syndromes with
similar features that may cause confusion and are more differing exposure intensity, frequency of expo-
clearly outlined in this chapter. Finally, nonspecific upper sure, duration of inhalation, season of the year
respiratory symptoms and headaches have been reported (worse in cold, damp climates for forms of the
from certain cohorts affected by building-related illnesses.
illness encountered in agricultural environ-
Most of these cases have no identifiable etiology, but seem to
involve poor indoor air quality resulting from specific ments), and certain host factors such as possible
contaminants and more commonly, lack of recirculating genetic factors that have yet to be discovered.

Figure 1. Histopathologic specimens from individuals with hypersensitivity pneumonitis (also known as extrinsic allergic
alveolitis) may show several different patterns, even within specimens taken concurrently.
Nonsmokers seem to be more susceptible to with published etiologies of hypersensitivity

developing hypersensitivity pneumonitis than pneumonitis, associated antigen sources and
those who are current smokers. likely microbial candidates that initiate the
inflammatory process. The thermophilic actino-
Clinical Approach to the Patient mycetes are ubiquitous, unicellular organisms
The clinical features of hypersensitivity pneu- resembling fungi but are, in reality, bacterial
monitis are outlined by classification type in species. They grow in the warm water of air
Table 1. The illness may present with acute, conditioner condensers and have been isolated in
subacute, or chronic features that are associated damp hay or grass, soil, manure, and grain
with exposure to a variety of products that often compost. These organisms have been attributed
have ‘‘colorful’’ descriptions that center on the to disease development that has been coined
nature of the occupation or environment in riding school lung (from hay in horse stalls),
which the presumed antigen is encountered. bagassosis (decomposing pressed sugarcane, or
For example, the terms farmer’s lung, bird bagasse), tractor lung (from organisms inside the
fancier’s disease, suberosis (inhalation of moldy filtering system of enclosed agricultural equip-
cork), and potato riddler’s lung (from moldy hay ment cabs), and mushroom worker’s disease
surrounding potatoes being harvested) all refer (from moldy compost associated with harvesting
to the same general disease entity, but involve and processing mushrooms for consumption).
different inciting antigens. A variety of lists exist Some reports classify only acute and chronic
690 Chapter 42. Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis) (Cowl)

Table 1—Clinical Features of Individuals With Suspected confirm the diagnosis of hypersensitivity
pneumonitis. Therefore, the most appropriate
Acute Hypersensitivity Pneumonitis
approach is to maintain a high clinical suspicion,
Transient fever, myalgias, arthralgias, shortness of to obtain a detailed occupational and environmen-
breath, cough, and hypoxemia that develops several tal history (as outlined in Chapter 40), and to bolster
hours after exposure and resolves in 1 to 3 days
the pretest probability of each diagnostic modality
spontaneously
Peripheral blood leukocytosis with neurtrophilia and in a sequential fashion by using a combination of
lymphopenia (usually no eosinophils) characteristic symptoms, physical examination
Increased neutrophils and hypercellularity on BAL
findings, radiographic changes, spirometric mea-
Chest radiographs show diffuse, poorly formed
nodular densities associated with ground-glass change
surements, and immunologic test results. Clinical-
and in some cases, consolidation located in the lower ly, if a patient presents with recurrent bouts of a
lobes and sparing the apex flulike illness or demonstrates evolving interstitial
Nonspecific serum markers of inflammation (eg,
lung disease, it is critical to obtain a detailed
erythrocyte sedimentation rate and C-reative protein)
may be elevated occupational, avocational, and environmental
Pulmonary function testing is nonspecific but work history. Laboratory data may show a mild
restriction is most common. Obstruction or a mixed elevation in white blood cell count with left shift.
pattern has also been described.
Immediate- or delayed-type skin tests to detect Eosinophilia is unusual. IgE levels remain normal
sensitization are not helpful (extracts produce but IgG levels occasionally increase. The chest
reactions that do not confirm sensitization nor do they radiograph findings may be normal and do not rule
sort out sensitized from nonsensitized patients)
out the disease. A fine reticulonodular pattern
Chronic Hypersensitivity Pneumonitis
Gradual progressive development of cough, shortness (often referred to as alveolar mottling) is frequently
of breath, fatigue, weight loss (and patients may not identified. Symptoms experienced by the patient
report a prior history of past acute exacerbations) are often worse than what appears on the chest
Symptoms present from months to years
Lack of fever, but crackles may be present radiograph, as opposed to acute respiratory infec-
Decreased CD4:CD8 ratio on BAL tions with Mycoplasma pneumonia in which the chest
Diffuse linear and nodular opacification involving the
radiograph appears more concerning than the
upper lobes and generally sparing the bases
Multiple small centrilobular nodules noted throughout
benign symptoms described by the patient. CT
the lung fields on CT scan imaging that do not appear imaging has been used as a more sensitive and
to be connected to the bronchovascular bundle as in specific modality in making a diagnosis (Fig 2).
sarcoidosis. May see fibrotic changes similar to High-resolution images are associated with poorly
pulmonary fibrosis.
Lung biopsy is suggested in selected cases defined centrilobular micronodules, widespread
ground-glass opacities, mosaic attenuation on
inspiratory images, and air trapping on expiratory
forms of hypersensitivity pneumonitis, hypothe- CT scan images.
sizing that subacute forms of the illness simply
are an intermediate point in the spectrum of Treatment of Hypersensitivity
disease, attributable to less intense but more Pneumonitis
prolonged exposure to the inciting agent. Much
Because removal from the offending antigen is
like chronic hypersensitivity pneumonitis, the
the mainstay of effective therapy, the detailed
subacute form involves gradual worsening of
history again becomes vital to the overall manage-
cough, shortness of breath, fatigue, and weight ment of this group of patients. Workplace restric-
loss; symptoms seem to be much less specific and tions often must be implemented but also have to be
are not clearly apparent in their association with balanced with an understanding of the environ-
a specific inhalation. It is difficult to assess, but ment in which the patient works. For example, a
recognizing this entity is important in order to self-employed farmer, even with significant disease
avoid progression to irreversible forms of the burden, may not be willing to evacuate the farm but
disease. may willingly comply with efforts to clean affected
Unfortunately, there is no single clinical feature, equipment, use engineering controls such as local
radiographic image, or laboratory test that can exhaust ventilation, or implement personal respi-

decline. Some of these patients have undergone
successful lung transplant.
Syndromes Commonly Confused With

Several conditions may be confused with
hypersensitivity pneumonitis because of the
similarities in agricultural references or in the
name of the entity itself. These include silo filler’s
disease (see Chapter 40), which refers to an acute
toxic inhalation of oxides of nitrogen; organic
dust toxic syndrome (see Chapter 40), which
involves inhalation of bacterial endotoxins or
spores that reach the terminal airways and may
Figure 2. Diffuse micronodular opacities and mosaic provoke an intense inflammatory reaction; and
attenuation characterize acute hypersensitivity pneumonitis
ornithosis (not related to pigeon breeder ’s
as exemplified in this representative CT scan image.
disease), which describes an infectious pulmo-
ratory protection to decrease the risk of disease nary condition in which inhaled contaminated
progression. Even with removal of the individual bird droppings causes an acute flulike illness
from the site of the antigen, or removal of the typically associated with Chlamydia psittaci.
antigen from contact with the patient (eg, pigeon
breeder’s disease), some antigens may remain Clinical Conditions Associated With
present for up to 3 years or more even after efforts Indoor Air Quality Issues
to clean up the site of direct exposure; moreover,
some patients will continue to experience symp- Building-Related Illness
toms even after being removed from the exposure
site. In most cases, identification and removal of the Since most North Americans spend the vast
patient from the inciting antigen may be enough to portion of their time indoors, including more
completely resolve all pulmonary issues if the than half of the entire workforce that now works
intervention is successful before radiographic or in offices or commercial buildings, the quality of
other clinical sequelae ensue. air inspired while working in these indoor
For patients with persistent symptoms associ- environments has come under public scrutiny.
ated with progressive disease, systemic cortico- These illnesses may be best classified into
steroids are typically used for treatment. epidemiologic cases in which a specific disorder
However, there are no published data supporting is identified as causing patient symptoms (eg, a
a specific treatment regimen (40 to 60 mg of faulty humidifier, a documented respiratory tract
prednisolone or prednisone is commonly used infection) and situations in which a nonspecific
over a 1- to 2-week period, then tapered thereafter disorder is present (referred to as sick building
as tolerated), there is no evidence to support use of syndrome). The latter situation has been associ-
corticosteroids as a way to completely cure the ated with poor air circulation of fresh air intake
illness. Individuals with chronic hypersensitivity in about half of all cases, while slightly more than
pneumonitis appearing radiographically as cellu- one-third were determined to be exacerbated by
lar nonspecific interstitial pneumonitis pattern of contaminants such as excess carbon dioxide with
pulmonary fibrosis typically respond favorably to levels .1,000 parts per million or off-gassing of
treatment with corticosteroids, while those with chemicals used as preservatives in furniture or
fibrotic-appearing nonspecific interstitial pneu- carpeting such as formaldehyde; for approxi-
monitis pattern of pulmonary fibrosis or other mately 1 in 10 cases no cause could be identified.
patterns of interstitial lung disease do not seem to In most reported cases of building-related
respond to therapy, and experience a gradual illness, multiple workers present with dry eyes,

nasal congestion, fatigue, dry skin, and head- nitis. J Thorac Imaging. 2002;17(4):261–272.
aches. The World Health Organization has Nice review of complexity of making a diagnosis.
defined sick building syndrome as an excess of Lacasse Y, Selman M, Costabel U, et al. Clinical
work-related irritations of the skin and mucous diagnosis of hypersensitivity pneumonitis. Am J Resp
membranes, along with other symptoms such as Crit Care Med. 2003;168(8):952–958.
headache, fatigue, and concentration difficulties, Members of expert panel assess validity of a clinical
at a prevalence greater than what would be prediction rule for the diagnosis.
expected at baseline across a working clerical
Pathology
population with a clear temporal association
with workplace symptoms, barring any evidence Barrios RJ. Hypersensitivity pneumonitis: histopa-
for nonoccupational causes. thology. Arch Pathol Lab Med. 2008;132(2):199-203.
Nothing to Disclose Churg A, Muller NL, Flint J, et al. Chronic hypersen-

sitivity pneumonitis. Am J Surg Pathol. 2006;30(2):201–
The author has disclosed that no relation- 208.
ships exist with any companies/organizations Takemura T, Akashi T, Ohtani Y, et al. Pathology of
whose products or services may be discussed in hypersensitivity pneumonitis. Curr Opin Pulm Med.
this chapter. 2008;14(5):440–454.
Discussion of pathologic features of the disease.
Reviews Pathogenesis
Woda BA. Hypersensitivity pneumonitis: an immu-
Costabel U, Bonella F, Guzman J. Chronic hypersensi-
nopathology review. Arch Pathol Lab Med. 2008;132(2):
tivity pneumonitis. Clin Chest Med. 2012;33(1):151-163.
204–205.
Current review of chronic manifestations of this illness.
Hirschmann JV, Pipavath SNJ, Godwin JD. Hypersensi- Building-Related Illness
tivity pneumonitis: a historical, clinical, and radiologic Alberts WM. Building-related illness. J Respir Dis.
review. Radiographics. 2009;29(7):1921–1938. 1994;15:899-910.
Detailed review of all aspects of hypersensitivity pneumonitis.
Brooks SM, Spaul W, McCluskey JD. The spectrum of
Ismail T, McSherry C, Boyd G. Extrinsic allergic building-related airways disorders. Chest. 2005;128(3):
alveolitis. Respirology. 2006;11(3):262-268. 1720-1727.
General review of this condition. Burge PS. Sick building syndrome. Occup Environ
Madison JM. Hypersensitivity pneumonitis: clinical Med. 2004;61(2):185–190.
perspectives. Arch Pathol Lab Med. 2008;312(2):195-198. Capman JA, Terr AI, Jacobs RL, et al. Toxic mold:
Concise, but comprehensive review. phantom risk versus science. Ann Allergy Asthma
Immunol. 2003;91(3):222–232.
Diagnosis of Hypersensitivity Pneumonitis
Jones TF, Craig AS, Hoy D, et al. Mass psychogenic
Dangman KH, Cole SR, Hodgson MJ, et al. The illness attributed to toxic exposure at a high school
hypersensitivity pneumonitis diagnostic index: use of [comment in: Wessely S. Responding to mass psycho-
non-invasive testing to diagnose hypersensitivity genic illness. N Engl J Med. 2000;342(22):129–130]. N
pneumonitis in metalworkers. Am J Ind Med. 2002; Engl J Med. 2000;342(2):96–100.
42(2):150–162. Report and discussion of a nonspecific building-related
Use of symptom score/index format in a cohort of metal disorder with excellent discussion of the psychiologic
workers. symptoms in a psychogenic disorder.
Glazer CS, Rose CS, Lynch DA. Clinical and radio- Menzies D, Bourbeau J. Building-related illnesses. N
graphic manifestations of; hypersensitivity pneumo- Engl J Med. 1997;337(21):1524-1530.

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ACCP Pulmonary

Printed in the United States of America

Chapter 2. Pulmonary Vascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Chapter 4. Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Chapter 5. Cardiopulmonary Exercise Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Chapter 6. Pulmonary Function Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Chapter 7. Ethics in Pulmonary and Critical Care Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Chapter 8. Other Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Chapter 9. Thoracic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Chapter 10. Bronchoscopy and Interventional Pulmonology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Chapter 11. Pulmonary Complications of Cardiothoracic Surgery and Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Chapter 12. Sleep Science and Polysomnography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Chapter 13. Sleep-Related Breathing Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Chapter 14. Other Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Chapter 15. Epidemiology and Statistics for the Boards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Chapter 16. Fungal Infections in Pulmonary Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Chapter 17. Drug-Induced Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Chapter 18. Pneumoconiosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Chapter 19. Acid-Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

ACCP Pulmonary Medicine Board Review: 26th Edition iii

Chapter 21. Community-Acquired Pneumonia: Advances in Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

Chapter 22. Hospital-Acquired and Ventilator-Associated Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

Chapter 23. Hypoxemic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339

Chapter 24. Mechanical Ventilatory Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Chapter 25. Hypercapnic Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Chapter 26. Respiratory Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Chapter 27. Unusual and Uncommon Pulmonary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Chapter 28. Mediastinal and Other Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Chapter 29. Lung Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

Chapter 30. Women’s Issues in Pulmonary Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

Chapter 31. Eosinophilic Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Chapter 32. Tuberculosis and Other Mycobacterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Chapter 35. Pulmonary Vasculitis and Alveolar Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595

Chapter 36. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Chapter 38. Pathology of Diffuse Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635

Chapter 39. Pleural Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641

Chapter 42. Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689

ACCP Pulmonary Medicine Board Review: 26th Edition v

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