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Fishman’s Pulmonary
Diseases and Disorders
Volume 1
MCGH423-FM_Vol1_pi-xxx.indd 1 16/08/22 9:32 PM

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Fishman’s Pulmonary
Diseases and Disorders
Sixth Edition
Volume 1
EDITOR-IN-CHIEF
Michael A. Grippi, MD
Pulmonary, Allergy, and Critical Care Division
Department of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, Pennsylvania
EDITORS
Danielle E. Antin-Ozerkis, MD Camille Nelson Kotton, MD
Medical Director, Yale Center for Interstitial Lung Diseases Associate Professor, Harvard Medical School
Associate Professor of Medicine Clinical Director, Transplant and Immunocompromised Host
Section of Pulmonary, Critical Care and Sleep Medicine Infectious Diseases
Yale School of Medicine Infectious Diseases Division, Massachusetts General Hospital
New Haven, Connecticut Boston, Massachusetts
Charles S. Dela Cruz, MD, PhD Allan I. Pack, MBChB, PhD

Associate Professor of Medicine John Miclot Professor of Medicine
Section of Pulmonary, Critical Care and Sleep Medicine Division of Sleep Medicine
Associate Professor of Microbial Pathogenesis Department of Medicine
Director, Center of Pulmonary Infection Research and Treatment Perelman School of Medicine at the University of Pennsylvania
Yale School of Medicine Philadelphia, Pennsylvania
New Haven, Connecticut
Robert M. Kotloff, MD
Craig and Elaine Dobbin/Nancy P. Blumenthal
Professor of Advanced Lung Disease
New York Chicago San Francisco Lisbon London Madrid Mexico City

Milan New Delhi San Juan Seoul Singapore Sydney Toronto

Copyright © 2023 by McGraw Hill LLC. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publi-
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of the publisher.
ISBN: 978-1-26-047406-0
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Library of Congress Cataloging-in-Publication Data
Names: Grippi, Michael A., editor.

Title: Fishman’s pulmonary diseases and disorders / editor-in-chief, Michael A. Grippi ; co-editors, Danielle E. Antin-Ozerkis, Charles S. Dela Cruz,
Robert M. Kotloff, Camille N. Kotton,
Allan I. Pack
Other titles: Pulmonary diseases and disorders
Description: Sixth edition. | New York : McGraw-Hill Education, [2023] | Includes bibliographical references and index. | Summary: “A presentation
of pulmonary and critical care medicine with the underlying basic and applied science upon which the clinical material is based. The book includes
relevant respiratory biology and underlying cellular and molecular mechanisms, and incorporates of a number of videos designed to complement and,
at times, accentuate information contained within the text”– Provided by publisher.
Identifiers: LCCN 2021052087 | ISBN 9781260473988 (hardcover ; set ; alk. paper) | ISBN 9781260474060 (ebook)
Subjects: MESH: Lung Diseases
Classification: LCC RC756 | NLM WF 600 | DDC 616.2/4–dc23/eng/20220510
LC record available at https://lccn.loc.gov/2021052087
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DEDICATION
DEDICATION
This book is dedicated to the many clinicians worldwide who have devoted themselves to caring for those affected by SARS-CoV-19 and to
the scientists who developed vaccines and therapeutic modalities directed against the virus.
MAG: To my wife, Barbara, and to our daughters, Kristen and Amy, for their steadfast support over the
years, and to their families—Emily, Ali, Sawyer, Sophie, Levi, and Kieran.
DAO: To my husband, Eric, and our daughters, Orly and Daya. If you are going to spend a pandemic with
anyone, you might as well laugh a lot. And to my patients, from whom I learn every day.
CDC: I would like to thank my family, friends, and all the mentors in pulmonary and critical care medicine who
helped support me throughout my career. I would also like to thank my patients, from whom I have learned
so much and who have been the motivation for my current work.
RMK: To my wife, Debbie, and my sons, Eric, Brian, and Ethan, for their unwavering love and support.
And to the memory of my parents, Jean and Leon Kotloff, for instilling in me the principles
by which I live my life and practice my profession.
CNK: Thanks to my husband, Darrell Kotton, and to our wonderful sons, David and Benjamin, for their thoughtfulness
and support, especially as we navigated our family through the peaks of the COVID-19 pandemic. And thanks to
my patients over the years, who have taught me so much about medicine, but also
about resilience, optimism, and hope.
AIP: To my very supportive wife, Frances; my long-collaborating Administrative Assistant, Daniel Barrett; my four
children, Alison, Angela, Andrew, and Allan Junior; and our 11 grandchildren.

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CHAPTER
CONTENTS
CONTENTS
000
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 15 Blood Gas Transport. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 224
Adrian Shifren / Robert A. Klocke
Preface. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix
16 Diffusion, Chemical Reactions, and Diffusing Capacity. . . . 229
Robert A. Klocke / Adrian Shifren
VOLUME 1 17 Acid–Base Balance.. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 236

Stanley Goldfarb
18 Aging of the Respiratory System.. . . . . .. . . . . . . . . . . . . . . 248
Edward J. Campbell / Corrine R. Kliment
PART 1: Perspectives
1 Milestones in the History of Pulmonary Medicine. . . . . . . . . 2 SECTION 3 Lung Immunology
Michael A. Grippi
19 Innate and Adaptive Immunity in the Lung. . . . . . . . . . . . . 262
Clemente J. Britto / Charles S. Dela Cruz
PART 2: Scientific Basis of Lung Function in 20 Macrophages and Lymphocytes in the Lung. . . . . . . . . . . . 277
Health and Disease Katrina E. Traber / Joseph P. Mizgerd / David M. Center
21 Mast Cells and Eosinophils. . . . . . . . . . .. . . . . . . . . . . . . . . 290
Edward S. Schulman / Peter H.S. Sporn / Amali E. Samarasinghe
Genetic, Cellular, and Structural Basis
SECTION 1 22 Antibody-Mediated Lung Defenses and Humoral
of Normal Lung Function
Immunodeficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
2 Functional Design of the Human Lung for Gas Exchange. . . . 22 Homer L. Twigg III
Matthias Ochs
3 The Respiratory Muscles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 SECTION 4 Lung Injury and Repair
Ghislaine Gayan-Ramirez / Daniel Langer / Marc Decramer
23 T Cell Responses in the Lung.. . . . . . . . .. . . . . . . . . . . . . . . 329
4 Molecular Regulation of Lung Development. . . . . . . . . . . . . 76 Lauren Cohn
Wellington V. Cardoso / Ying Yang / Jining Lu
24 Chemokines, Adipokines, and Growth
5 Pulmonary Surfactant and Disorders of Factors in the Lung. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 339
Surfactant Homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Marcus W. Butler / Paul McLoughlin / Michael P. Keane
Jeffrey A. Whitsett / James P. Bridges / Timothy E. Weaver
25 Redox Signaling and Oxidative Stress in Lung Diseases.. . . 356
6 Mucociliary Clearance. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . 101 Jessy Deshane / Victor J. Thannickal
Thomas W. Ferkol / John D. Dickinson / Burton F. Dickey
26 Fibroblasts in Lung Homeostasis and Disease. . . . . . . . . . . 376
7 The Genetic Basis of Respiratory Disorders. . . . . . . . . . . . . 118 Yong Zhou / Victor J. Thannickal
Micheala A. Aldred
8 Stem Cells and Respiratory Disease:
Prospects for the Future. . . . . . . . . . . . . .. . . . . . . . . . . . . . 135 PART 3: Symptoms and Signs
Konstantinos-Dionysios Alysandratos / of Respiratory Disease
Michael J. Herriges / Darrell N. Kotton
9 Personalized Pulmonary Medicine. . . . . .. . . . . . . . . . . . . . 145
SECTION 5 Clinical Approach to the Patient
Benjamin A. Raby / Kelan G. Tantisira
27 Approach to the Patient with Respiratory Symptoms. . . . . 394
Physiological Principles of Normal Michael A. Grippi / Jeffrey P. Callen
SECTION 2 Lung Function
10 Pulmonary Mechanics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 SECTION 6 Diagnostic Procedures

Allan I. Pack / Michael A. Grippi
28 Modern Approach to Thoracic Imaging Diagnosis. . . . . . . . 433
11 Control of Ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Eduardo J. Mortani Barbosa Jr. / Leonid Roshkovan
Frank J. Jacono / Atul Malhotra
29 Thoracic Ultrasonography. . . . . . . . . . . . . . . . . . . . . . . . . . . 501
12 Sleep and Circadian Rhythms. . . . . . . . . . . . . . . . . . . . . . . . 183 Andrew Weber / Fiore Mastroianni / Paul H. Mayo
Allan I. Pack
30 Physiologic and Metabolic Assessment of Pulmonary
13 The Pulmonary Circulation. . . . . . . . . . . . . . . . . . . . . . . . . . 193 Disorders Using Conventional Imaging
Robert Naeije Techniques and Positron Emission Tomography. . . . . . . . . 511
14 Ventilation, Pulmonary Blood Flow, and Ghassan El-Haddad / Søren Hess / Abass Alavi
Ventilation–Perfusion Relationships.. . . . . . . . . . . . . . . . . . 211 31 Pulmonary Function Testing. . . . . . . . . . . . . . . . . . . . . . . . . 544
Peter D. Wagner Michael A. Grippi / Gregory Tino
vii

32 Principles and Application of Cardiopulmonary 50 Bullous Lung Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
Exercise Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 Fernando J. Martinez
CONTENTS
Marco Guazzi / Alice Moroni

PART 00
51 Bronchiectasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
33 Diagnostic Bronchoscopy, Transthoracic Gregory Tino
Needle Biopsy, and Related Procedures. . . . . . . . . . . . . . . . 597
David M. DiBardino / Daniel H. Sterman / Anil Vachani
34 Interventional Pulmonology. . . . . . . . . . . . . . . . . . . . . . . . . 620 PART 5: Interstitial and Inflammatory
Daniel G. Dunlap / Andrew R. Haas / Daniel H. Sterman
Lung Diseases
35 Diagnostic Thoracic Surgical Procedures:
Thoracoscopy, VATS, RATS, and Thoracotomy. . . . . . . . . . . . 632 52 Interstitial Lung Disease: A Clinical
Robert E. Merritt Overview and General Approach. . . . . . . . . . . . . . . . . . . . . 872
Aditi Mathur / Danielle E. Antin-Ozerkis
36 Evaluation of Respiratory Impairment
and Disability.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636 53 Systemic Sarcoidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
Lisa Ruvuna / Akshay Sood Edward S. Chen
54 Idiopathic Pulmonary Fibrosis. . . . . . . . . . . . . . . . . . . . . . . 915
Tanzira Zaman / Giuliana Cerro Chiang / Paul W. Noble
PART 4: Obstructive Lung Diseases 55 Idiopathic Interstitial Pneumonias

Other Than Idiopathic Pulmonary Fibrosis. . . . . . . . . . . . . . 932
Kelly M. Hager / Ami Rubinowitz / Mridu Gulati
SECTION 7 Chronic Obstructive Pulmonary Disease
56 Hypersensitivity Pneumonitis. . . . . . . . . . . . . . . . . . . . . . . . 956
Prerna Mota / Richard I. Enelow
37 Pathology of Chronic Obstructive Pulmonary Disease:
Diagnostic Features and Differential Diagnosis. . . . . . . . . . 650 57 Radiation Pneumonitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
Joanne L. Wright / Andrew Churg James H. Laird / Kenneth B. Roberts / Roy H. Decker / Henry S. Park
38 Chronic Obstructive Pulmonary Disease: Epidemiology, 58 Pulmonary Manifestations of the Collagen
Pathophysiology, Pathogenesis. . . . . . . . . . . . . . . . . . . . . . 664 Vascular Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
Takudzwa Mkorombindo / Mark T. Dransfield Kevin P. Toole / Gregory P. Cosgrove
39 Chronic Obstructive Pulmonary 59 Pulmonary Langerhans Cell Histiocytosis.. . . . . . . . . . . . . 1006
Disease and α1-Antitrypsin Deficiency. . . . . . . . . . . . . . . . 683 Sergio Harari / Davide Elia / Joel Moss / Abdellatif Tazi
Darrell N. Kotton / Andrew A. Wilson 60 Pulmonary Lymphangioleiomyomatosis. . . . . . . . . . . . . . . . . 1015
40 Course and Treatment of Chronic Obstructive Arnold S. Kristof / Joel Moss
Pulmonary Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 61 Diffuse Cystic Lung Diseases. . . . . . . . . . . . . . . . . . . . . . . . 1030
M. Bradley Drummond / Robert A. Wise Nishant Gupta / Tami J. Bang / Kathryn A. Wikenheiser-Brokamp
41 Cigarette Smoking, Smoking Cessation, and Electronic 62 Benign Metastasizing Leiomyoma. . . . . . . . . . . . . . . . . . . 1054
Cigarettes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708 Gustavo Pacheco-Rodriguez / Olga I. Astapova /
Stephen R. Baldassarri / Stephen I. Rennard Stephen R. Hammes / Joel Moss
42 Rehabilitation in Chronic Obstructive 63 Depositional Lung Disorders:
Pulmonary Disease and Other Amyloidosis, Pulmonary Calcification,
Respiratory Disorders. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 725 and Pulmonary Ossification. . . . . . . . . . . . . . . . . . . . . . . . 1065
Andrew L. Ries / Duc M. Ha Robert J. Homer / Christopher Gange / Natalia Neparidze
SECTION 8 Asthma
PART 6: Drug-Induced Lung Diseases
43 The Biology of Asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Geoffrey L. Chupp / Matthew C. Bell / William W. Busse 64 Pulmonary Toxicity Related to
44 The Epidemiology of Asthma. . . . . . . . . . . . . . . . . . . . . . . . 750 Systemic Treatments for Cancer. . . . . . . . . . . . . . . . . . . . . 1074
Kathleen A. Lee-Sarwar / Scott T. Weiss / Augusto A. Litonjua Jennifer D. Possick / Erin DeBiasi / Lynn T. Tanoue
45 Asthma: Clinical Presentation and Management. . . . . . . . . 767 65 Drug-induced Pulmonary Disease Due to
Omar S. Usmani / Peter J. Barnes Nonchemotherapeutic Agents. . . . . . . . . . . . . . . . . . . . . . 1100
Hilary C. Cain
46 Allergic Bronchopulmonary Aspergillosis (Mycosis)
and Severe Asthma with Fungal Sensitivity. . . . . . . . . . . . . 785 66 Lung Injury Associated with Recreational Drug Use.. . . . . 1119
Geoffrey L. Chupp Timothy E. Albertson / Patrick Mangialardi /
James A. Chenoweth / Susan Murin
SECTION 9 Other Obstructive Disorders
47 Upper Airway Obstruction in Adults. . . . . . . . . . . . . . . . . . . 794 PART 7: Other Infiltrative and

Erin DeBiasi / Christine Won / Meir Kryger Airspace Disorders
48 Cystic Fibrosis. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 815
67 The Lungs in Patients with Inborn
Judith A. Voynow / Andrea Kelly / Flora K. Szabo / Thomas F. Scanlin
Errors of Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
49 Bronchiolitis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 Timothy Craig Allen
Gary R. Epler
viii

68 Alveolar Hemorrhage Syndromes. . . . . . .. . . . . . . . . . . . .
Joseph P. Lynch, III / Michael C. Fishbein / Tisha S. Wang
1144 PART 12: Occupational and
Environmental Disorders
CONTENTS
69 Aspiration-Related Pulmonary Disorders. . . . . . . . . . . . . . 1164
Paul E. Marik
70 Pulmonary Alveolar Proteinosis Syndrome. . . . . . . . . . . . 1175 SECTION 10 Occupational Disorders
Bruce C. Trapnell / Cormac McCarthy / Brenna Carey
85 Asbestos-Related Lung Disease. . . . . . . . . . . . . . . . . . . . . 1488
71 Eosinophilic Lung Diseases. . . . . . . . . . . . . . . . . . . . . . . . . 1186 William N. Rom / Jun-Chieh J. Tsay
Lauren Cohn / Carolyn L. Rochester / Brian J. Clark
86 Chronic Beryllium Disease and Hard-Metal
72 Pulmonary Arterial Hypertension. . . . . . . . . . . . . . . . . . . . 1211 Lung Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1502
Nick H. Kim / Jess Mandel / Kimberly A. Smith / Jason X.-J. Yuan Shweta Sood / Mary Elizabeth Kreider
87 Coal Workers’ Lung Diseases and Silicosis.. . . . . . . . . . . . . 1513
Robert C. Stansbury / Rahul G. Sangani / John E. Parker
PART 8: Disorders of the Pulmonary 88 Occupational Asthma, Byssinosis, and
Circulation Industrial Bronchitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1532
Shu-Yi Liao / David C. Christiani
73 Pulmonary Thromboembolic Disease. . . . . . . . . . . . . . . . . 1258
Timothy M. Fernandes / Peter F. Fedullo
74 Pulmonary Vasculitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1287 SECTION 11 Environmental Disorders
Rodrigo Cartin-Ceba / Ulrich Specks
89 Indoor and Outdoor Air Pollution. . . . . .. . . . . . . . . . . . . . 1539
75 Pulmonary Arteriovenous Malformations. . . . . . . . . . . . . 1306 Coralynn Sack / Joel D. Kaufman
Tyler J. Peck / Josanna M. Rodriguez-Lopez
90 Acute and Chronic Responses to Toxic Inhalations.. . . . . . 1559
Austin J. Jolly / David A. Schwartz
91 High-Altitude Physiology and Clinical Disorders.
PART 9: Disorders of the Pleural Space Kingman P. Strohl / Cynthia M. Beall / Nikolaus C. Netzer
. . . . . . . 1581
76 Nonmalignant Pleural Effusions. . . . . . . . . . . . . . . . . . . . . 1320 92 Diving Physiology and Dysbarism.. . . . . . . . . . . . . . . . . . . 1593

Christopher M. Kapp / David Feller-Kopman Christopher E. Winstead-Derlega / Richard E. Moon
77 Malignant Pleural Effusions. . . . . . . . . . .. . . . . . . . . . . . . 1339 93 Thermal Lung Injury and Acute Smoke Inhalation. . . . . . . 1603
Jeffrey C. Thompson / Kevin C. Ma Perenlei Enkhbaatar
78 Malignant Mesothelioma and Other
Primary Pleural Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351
Daniel H. Sterman / Edmund K. Moon / Keshav Mangalick / PART 13: Pulmonary Complications
Leslie A. Litzky
of Nonpulmonary Disorders
79 Pneumothorax.. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 1375
Rodolfo A. Estrada / Jay I. Peters / Nilam J. Soni / Philip G. Ong 94 Noninfectious Pulmonary Complications
of Hematopoietic Stem Cell and Solid
Organ Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1620
Hemang Yadav / Steve G. Peters / Robert M. Kotloff
VOLUME 2 95 Pulmonary Complications of Sickle Cell Disease. . . . . . . . 1644
Roberto F. Machado / Mark T. Gladwin
96 Pulmonary Disorders and Pregnancy. . .. . . . . . . . . . . . . . 1663
PART 10: Diseases of the Mediastinum Debasree Banerjee / Andrew T. Levinson / Jeffrey Mazer /
Ghada Bourjeily
80 Nonneoplastic Disorders of the Mediastinum. . . . . . . . . . 1398
Luis F. Tapias / Cameron D. Wright 97 Pulmonary Complications of Intra-abdominal
81 Congenital Cysts of the Mediastinum: Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1685
Hilary M. DuBrock / Sonja D. Bartolome
Bronchopulmonary Foregut Anomalies. . . . . . . . . . . . . . . 1412
Erik E. Lewis / Daniel P. McCarthy / Malcolm M. DeCamp
82 Primary Benign and Malignant Neoplasms of the
Mediastinum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423
PART 14: Sleep and Sleep Disorders
Natalie S. Lui / Joseph B. Shrager 98 Sleep Apnea Syndromes: Central and Obstructive. . . . . . . 1700
Grace W. Pien / Ilene M. Rosen / Barry G. Fields
99 Sleep-related Hypoventilation Syndromes. . . . . . . . . . . . . 1751
PART 11: Disorders of the Chest Wall, Jorge I. Mora / Richard J. Schwab
Diaphragm, and Spine 100 Changes in the Cardiorespiratory System
During Sleep. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1765
83 Nonmuscular Diseases of the Chest Wall. . . . . . . . . . . . . . 1440 Indira Gurubhagavatula / Susheel P. Patil
George E. Tzelepis / F. Dennis McCool
101 Differential Diagnosis and Evaluation
84 Effects of Neuromuscular Diseases on of Sleepiness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773
Ventilation. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 1459 Sritika Thapa / Mithu Sen / Meir Kryger
Gerard Joseph Criner / Nathaniel Marchetti
ix

PART 15: Surgical Aspects 121 The Lung Microbiome. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
John E. McGinniss / Joshua M. Diamond
2088
of Pulmonary Medicine
CONTENTS
122 Approach to Pulmonary Infection

102 Perioperative Respiratory Considerations in the in the Immunocompetent Host.. . . . . . . . . . . . . . . . . . . . . 2099
Surgical Patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1786 Megan Rose Curtis / Tulip Ajit Jhaveri / Camille Nelson Kotton
Horace M. DeLisser / Michael A. Grippi
123 Approach to Pulmonary Infection in the
103 Acute Respiratory Failure in the Surgical Patient. . . . . . . . 1801 Immunocompromised Host. . . . . . . . . . . . . . . . . . . . . . . . 2127
Robert M. Kotloff Matthew B. Roberts / Camille Nelson Kotton
104 Thoracic Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1816 124 Microbial Virulence Factors in Pulmonary Infections. . . . . 2154
Seth A. Bellister / Bradley M. Dennis Carl D. Britto / Gregory P. Priebe / Gerald B. Pier
105 Developmental Disorders of the Lung. . . .. . . . . . . . . . . . 1824 125 Principles of Antibiotic Use and the Selection of Empiric
Himanshu Deshwal / Subha Ghosh Therapy for Pneumonia.. . . . . . . . . . . . . . . . . . . . . . . . . . . 2161
106 Lung Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843 Girish B. Nair / Michael S. Niederman
Ramsey R. Hachem
Common Syndromes in Pulmonary
SECTION 13 Infectious Diseases
PART 16: Cancer and Other Malignancies of
the Lungs 126 Viral Infections of the Lung and Respiratory Tract. .
John Treanor
. . . . . 2181
107 Genetic and Molecular Changes in Lung Cancer: 127 Aspiration, Empyema, Lung Abscesses, and Anaerobic
Prospects for a Personalized Pharmacologic Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203
Approach to Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1864 Kyle B. Enfield / Costi D. Sifri
Howard Y. Li / Jeffrey A. Kern
128 Acute Bronchitis and Community-Acquired
108 Epidemiology of Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . 1882 Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223
Lynn T. Tanoue / Charles S. Dela Cruz James M. Walter / Richard G. Wunderink
109 Lung Cancer Screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1904 129 Nosocomial Pneumonia, Including Ventilator-associated
Humberto K. Choi / Peter J. Mazzone Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2243
110 Approach to the Patient with Pulmonary Nodules. . . . . . . 1911 Andrew T. Roth / Marin H. Kollef
Moiz Salahuddin / David E. Ost
111 The Pathology of Bronchogenic Carcinoma. . . . . . . . . . . . 1929 SECTION 14 Major Pathogens in Pulmonary Infections
Leslie A. Litzky
130 Tuberculosis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2256
112 Clinical Evaluation, Diagnosis, and
Akash Gupta / Karen R. Jacobson
Staging of Lung Cancer. . . . . . . . . . . . . . . .. . . . . . . . . . . . 1950
A. Cole Burks / M. Patricia Rivera 131 Pulmonary Diseases Due to
Nontuberculous Mycobacteria. . . . . . . . . . . . . . . . . . . . . . 2278
113 Treatment of Non–Small-Cell Lung Cancer: Surgery. . . . . 1964
John S. Albin / Rocio M. Hurtado
John K. Waters / Scott I. Reznik
132 Aspergillus, Candida, and Other
114 Treatment of Non–Small-Cell Lung Cancer:
Opportunistic Pulmonary Mycoses. . . . . . . . . . . . . . . . . . . 2290
Chemotherapy and Immunotherapy. . . . . . . . . . . . . . . . . 1977
Georgios Chamilos / Dimitrios P. Kontoyiannis
Laurie L. Carr
133 Cryptococcosis and the Endemic Mycoses: Histoplasma,
115 Treatment of Non–Small-Cell Lung Cancer:
Blastomyces, and Coccidioides. . . . . . . . . . . . . . . . . . . . . . . 2319
Radiation Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1992
Marwan M. Azar / Nathan C. Bahr / Joshua Malo / Chadi A. Hage
Joseph A. Miccio / Mitchell Machtay
134 Pneumocystis Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . 2353
116 Small Cell Lung Cancer: Diagnosis,
Eliezer Zachary Nussbaum / Marwan M. Azar
Treatment, and Natural History. . . . . . . . . . . . . . . . . . . . . 2002
Jonathan E. Dowell / Benjamin J. Drapkin / David E. Gerber / 135 Protozoan Infections of the Thorax.. . . . . . . . . . . . . . . . . . 2375
David H. Johnson Louise C. Ivers / Edward T. Ryan
117 Uncommon Tumors of the Lung. . . . . . . . .. . . . . . . . . . . . 2022 136 Helminthic Diseases of the Lung.. . . . . . . . . . . . . . . . . . . . 2388
Karen Rodriguez / Gerald F. Abbott Ricardo M. La Hoz / James B. Cutrell
118 Extrapulmonary Syndromes 137 Nocardiosis and Actinomycosis.. . . . . . . . . . . . . . . . . . . . . 2401
Associated with Lung Tumors. . . . . . . . . . . . . . . . . . . . . . . 2031 Daniel N. Maxwell / Reuben J. Arasaratnam / Alejandro Restrepo /
Nicholas J. Pastis / Nichole T. Tanner / Gerard A. Silvestri Tara M. Babu
119 Lymphoproliferative Diseases Involving the Lung. . . . . . . 2045 138 Zoonotic and Environmental Bacterial Pneumonias. . . . . 2421
Venerino Poletti / Sara Piciucchi / Silvia Asioli Camille Nelson Kotton / Howard M. Heller
PART 17: Infectious Diseases of the Lungs PART 18: Respiratory Failure
SECTION 12 General Concepts 139 Respiratory Failure: An Overview. . . . . . . . . . . . . . . . . . . . 2436
Michael A. Grippi
120 Pulmonary Clearance of Infectious Agents.. . . . . . . . . . . . 2070
Theodore J. Standiford / Gary B. Huffnagle

SECTION 15 Lung Failure 147 Principles of Mechanical Ventilation. . . . . . . . . . . . . . . . . . 2573
Martin J. Tobin
CONTENTS
140 Acute Respiratory Distress Syndrome: Pathogenesis. . . . . 2447 148 Principles of Noninvasive
Asha N. Chesnutt / Michael A. Matthay Pressure-targeted Ventilation. . . . . . . . .. . . . . . . . . . . . . . 2588
141 Acute Respiratory Distress Syndrome: Clinical Features, Bernardo Selim / Janet Hilbert / Henry K. Yaggi
Management, and Outcomes. . . . . . . . . . . . . . . . . . . . . . . 2459 149 Extracorporeal Membrane Oxygenation (ECMO)
John P. Reilly / Jason D. Christie in Acute Respiratory Failure. . . . . . . . . . . . . . . . . . . . . . . . 2610
Asad Ali Usman / Jacob Gutsche
SECTION 16 Respiratory Pump Failure 150 Nutrition in Pulmonary Disease. . . . . . . . . . . . . . . . . . . . . 2634
Tachira Tavarez / David S. Seres
142 Chronic Hypercapnic Respiratory Failure: Pathogenesis
151 Diagnosis and Treatment of Pain, Agitation, and
and Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2488
Jennifer J. Dorsch / Jorge I. Mora
Delirium in the Intensive Care Unit. . . . . . . . . . . . . . . . . . . 2643
Niall T. Prendergast / Timothy D. Girard / Nathan E. Brummel
152 Ethics and Palliative Care in Critical Care Units.. . . . . . . . . 2659
Management and Therapeutic
SECTION 17 Joshua B. Kayser / Horace M. DeLisser
Interventions
143 Oxygen Therapy and Toxicity. . . . . . . . . .. . . . . . . . . . . . . 2507

Matthew Wemple / Erik R. Swenson APPENDIXES
144 Pulmonary Pharmacotherapy. . . . . . . . . .. . . . . . . . . . . . . 2523
Appendix A Terms and Symbols in Respiratory Physiology. . . . . A-2
Karen J. Tietze / Scott Manaker
Appendix B Normal Values for a Healthy 20-Year Old
145 Intubation and Upper Airway Management.. . . . . . . . . . . 2543
Joshua H. Atkins / Christopher H. Rassekh Seated Man�� A-5
146 Hemodynamic and Respiratory Monitoring in Acute

Respiratory Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2559 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I-1
Hari M. Shankar / Brian J. Anderson
xi


CONTRIBUTORS
CHAPTER 000
CONTRIBUTORS
Gerald F. Abbott, MD, FACR Danielle E. Antin-Ozerkis, MD
Department of Radiology Medical Director, Yale Center for Interstitial Lung Diseases
Division of Thoracic Imaging & Intervention Associate Professor of Medicine
Massachusetts General Hospital Section of Pulmonary, Critical Care and Sleep Medicine
Associate Professor, Harvard Medical School Yale School of Medicine
Boston, Massachusetts New Haven, Connecticut
Chapter 117 Chapter 52
Abass Alavi, MD, PhD (hon.), DSci (hon.) Reuben J. Arasaratnam, MD, MPH
Professor of Radiology and Neurology Staff Physician, Section of Infectious Diseases
Perelman School of Medicine at the University of Pennsylvania VA North Texas Health Care System
Pennsylvania University Hospital Assistant Professor of Medicine
Philadelphia, Pennsylvania Division of Infectious Diseases and Geographic Medicine
Chapter 30 UT Southwestern Medical Center
Dallas, Texas
Timothy E. Albertson, MD, MPH, PhD
Chapter 137
Chair, Internal Medicine, Distinguished Professor of Medicine
Pharmacology & Toxicology, Anesthesia & Emergency Medicine Silvia Asioli, MD
Department of Internal Medicine Team Leader of Haematopathology and Consultant
Division of Pulmonary, Critical Care and Sleep Medicine Department of Anatomic Pathology
University of California Ospedale GB Morgagni
Department of Emergency Medicine, University of California, Davis, Forlì, Italy
Sacramento Chapter 119
Veterans Administration Northern California Health Care System,
Olga I. Astapova, MD, PhD
Assistant Professor, Department of Medicine
Mather, California
Division of Endocrinology
Chapter 66
University of Rochester Medical Center
John S. Albin, MD, PhD University of Rochester School of Medicine and Dentistry
Instructor, Harvard Medical School Rochester, New York
Assistant in Medicine, Division of Infectious Diseases Chapter 62
Massachusetts General Hospital
Joshua H. Atkins, MD, PhD, FASA
Boston, Massachusetts
Associate Professor of Anesthesiology & Critical Care
Chapter 131
Department of Anesthesiology and Critical Care
Micheala A. Aldred, PhD Perelman School of Medicine at the University of Pennsylvania
Professor of Medicine Attending Physician, Co-Chair Airway Safety Committee
Catherine and Lowe Berger and Pauline L. Ford Chair of Pulmonary Director of Anesthesia for Head and Neck Surgery
Medicine Medical Director In-situ Simulation
Department of Medicine Department of Anesthesiology and Critical Care
Division of Pulmonary, Critical Care, Sleep & Occupational Medicine Hospital of the University of Pennsylvania
Indiana University School of Medicine Philadelphia, Pennsylvania
Indianapolis, Indiana Chapter 145
Chapter 7
Marwan M. Azar, MD
Timothy Craig Allen, MD, JD, FCAP Assistant Professor of Medicine/Infectious Diseases
Professor and Chair Section of Infectious Diseases
Department of Pathology Department of Internal Medicine
The University of Mississippi Medical Center Yale University School of Medicine
Jackson, Mississippi Department of Laboratory Medicine
Chapter 67 Yale University School of Medicine
Konstantinos-Dionysios Alysandratos, MD, PhD
Chapter 134
Assistant Professor of Medicine
The Pulmonary Center and Department of Medicine Tara M. Babu, MD, MSCI
Boston University School of Medicine Acting Assistant Professor
Attending Physician Department of Medicine
Department of Medicine Division of Allergy & Infectious Diseases
Boston Medical Center University of Washington
Boston, Massachusetts Seattle, Washington State
Brian J. Anderson, MD, MSCE Nathan C. Bahr, MD
Assistant Professor of Medicine Associate Professor
Department of Medicine Department of Internal Medicine
Division of Pulmonary, Allergy & Critical Care Medicine Division of Infectious Diseases
Hospital of the University of Pennsylvania University of Kansas Medical Center
Philadelphia, Pennsylvania Kansas City, Kansas
xiii

Stephen R. Baldassarri, MD, MHS Carl D. Britto, MBBS, DPhil
CONTRIBUTORS
Department of Internal Medicine Clinical Fellow in Pediatrics, Harvard Medical School

Section of Pulmonary, Critical Care, and Sleep Medicine Resident in Pediatrics, Department of Pediatrics
PART 00
Yale School of Medicine Boston Children’s Hospital

New Haven, Connecticut Boston, Massachusetts
Debasree Banerjee, MD, MS Clemente J. Britto, MD
Assistant Professor, Department of Medicine, Brown University Assistant Professor of Medicine
Director, Critical Care Consult, Rhode Island Hospital Associate Director, Yale Adult Cystic Fibrosis Program
Providence, Rhode Island Department of Internal Medicine
Chapter 96 Division of Pulmonary, Critical Care and Sleep Medicine
Yale University School of Medicine
Tami J. Bang, MD
Assistant Professor
Chapter 19
Department of Radiology, Division of Cardiothoracic Imaging
University of Colorado—Anschutz Medical Campus Nathan E. Brummel, MD, MSCI, FCCM
Aurora, Colorado Associate Professor of Medicine
Chapter 61 Department of Internal Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine
Eduardo J. Mortani Barbosa Jr., MD
The Ohio State University Columbus, Ohio
Assistant Professor of Radiology
Chapter 151
Director of Thoracic CT modality
Department of Radiology A. Cole Burks, MD
Perelman School of Medicine at the University of Pennsylvania Assistant Professor of Medicine
Philadelphia, Pennsylvania Division of Pulmonary and Critical Care Medicine
Chapter 28 University of North Carolina at Chapel Hill
Interventional Pulmonology, University of North Carolina Medical Center
Peter J. Barnes, DM, DSc, FRCP, FCCP, FMedSci, FRS
Chapel Hill, North Carolina
Professor of Thoracic Medicine
Chapter 112
National Heart & Lung Institute, Imperial College London
London, United Kingdom William W. Busse, MD
Chapter 45 Emeritus Professor of Medicine
Sonja D. Bartolome, MD
Division of Allergy, Pulmonary and Critical Care Medicine
Professor, Department of Internal Medicine, University of Texas
University of Wisconsin School of Medicine and Public Health
Southwestern Medical Center
Madison, Wisconsin
Dallas, Texas
Chapter 43
Chapter 97
Marcus W. Butler, MD, FRCPI
Cynthia M. Beall, PhD
Associate Professor
Professor, Anthropology
University College Dublin School of Medicine
Case Western Reserve University
Consultant Respiratory Physician
Cleveland, Ohio
St. Vincent’s University Hospital
Chapter 91
Dublin, Ireland
Matthew C. Bell, MD Chapter 24
Assistant Professor of Medicine and Pediatrics
Hilary C. Cain, MD, MS
Department of Pediatrics
Associate Professor of Medicine
Division of Allergy & Immunology
Section of Pulmonary, Critical Care and Sleep Medicine
University of Arkansas for Medical Sciences
Yale School of Medicine
Arkansas Children’s Hospital
Little Rock, Arkansas
Section Chief, Pulmonary Medicine
Chapter 43
VA Connecticut Healthcare System
Seth A. Bellister, MD West Haven, Connecticut
Department of Trauma and Acute Care Surgery Chapter 65
Christus Mother Frances Hospital
Jeffrey P. Callen, MD, FACP, MAAD, MACR
Tyler, Texas
Professor of Medicine (Dermatology)
Chapter 104
Chief, Division of Dermatology
Ghada Bourjeily, MD University of Louisville School of Medicine
Professor of Medicine Louisville, Kentucky
Warren Alpert Medical School of Brown University Chapter 27
Associate Chief for Academic Advancement and
Edward J. Campbell, MD
Research in Women’s Services
Heredilab, Inc.
Women’s Medicine Collaborative of Lifespan
Salt Lake City, Utah
Chapter 18
The Miriam Hospital
Providence, Rhode Island Wellington V. Cardoso, MD, PhD
Chapter 96 Professor of Medicine and Genetics & Development
Columbia Center for Human Development
James P. Bridges, PhD
Associate Professor
Columbia University Medical Center
New York, New York
National Jewish Health
Chapter 4
Denver, Colorado
Chapter 5
xiv

Brenna Carey, MS, PhD Humberto K. Choi, MD
CONTRIBUTORS
Assistant Professor of Medicine Assistant Professor of Medicine of Lerner College of Medicine of Case
Department of Pediatrics, University of Cincinnati Western Reserve University
Cincinnati Children’s Hospital Medical Center Respiratory Institute, Cleveland Clinic
Cincinnati, Ohio Cleveland, Ohio
Laurie L. Carr, MD David C. Christiani, MD, MPH, MS
Associate Professor of Medicine Elkan Blout Professor of Environmental Genetics
Division of Oncology Department of Environmental Health
National Jewish Health and University of Colorado Harvard T.H. Chan School of Public Health
Denver, Colorado Professor of Medicine
Chapter 114 Harvard Medical School
Physician, Pulmonary and Critical Care Division
Rodrigo Cartin-Ceba, MD, MSc
Professor of Medicine, Mayo Clinic College of
Medicine and Science
Consultant, Department of Medicine
Chapter 88
Division of Pulmonary Medicine, Mayo Clinic
Phoenix, Arizona Jason D. Christie, MD, MSCE
Chapter 74 Professor of Medicine and Epidemiology
Division of Pulmonary, Allergy, and Critical Care
David M. Center, MD
Gordon and Ruth Snider Professor of Pulmonary Medicine
Associate Provost for Translational Research
Professor of Medicine
Chapter 141
Boston University Geoffrey L. Chupp, MD
Chief, Pulmonary, Allergy, Sleep and Critical Care Medicine Professor of Medicine
Boston Medical Center Yale School of Medicine
Boston, Massachusetts Director, Yale Center for Asthma and Airway Disease
Chapter 20 Director, Pulmonary Function Laboratory, Yale New Haven Hospital
Georgios Chamilos, MD
Chapters 43 and 46
Department of Internal Medicine Andrew Churg, MD, PhD
School of Medicine, Stavrakia, Voutes Professor of Pathology, University of British Columbia Pathologist
University of Crete Heraklion Vancouver General Hospital
Crete, Greece Vancouver, British Columbia, Canada
Giuliana Cerro Chiang, MD Brian J. Clark, MD
Fellow in Pulmonary & Critical Care Medicine Assistant Professor, Section of Pulmonary, Critical Care and Sleep Medicine
Department of Medicine Yale School of Medicine
Cedars-Sinai Medical Center New Haven, Connecticut
Los Angeles, California VA Connecticut Healthcare System
Chapter 54 West Haven, Connecticut
Chapter 71
Edward S. Chen, MD
Assistant Professor Lauren Cohn, MD
Division of Pulmonary and Critical Care Medicine Associate Professor
Johns Hopkins University School of Medicine Department of Medicine, Section of Pulmonary,
Attending Physician, Department of Medicine Critical Care and Sleep Medicine
Division of Pulmonary and Critical Care Medicine Yale School of Medicine, New Haven, Connecticut
Johns Hopkins Hospital VA Connecticut Healthcare System
Baltimore, Maryland West Haven, Connecticut
Chapter 53 Chapters 23 and 71
James A. Chenoweth, MD, MAS Gregory P. Cosgrove, MD
Assistant Professor, Emergency Medicine Associate Professor
Department of Emergency Medicine Department of Medicine
University of California, Davis Division of Pulmonary Sciences and Critical Care Medicine
Sacramento, California University of Colorado—Anschutz Medical Campus
Veterans Administration Northern Denver, Colorado
Department of Medicine California Health Care System Chapter 58
Mather, California
Gerard Joseph Criner, MD
Chapter 66
Chair and Professor of Thoracic Medicine and Surgery
Asha N. Chesnutt, MD Department of Thoracic Medicine and Surgery
The Oregon Clinic Lewis Katz School of Medicine at Temple University
Pulmonary, Critical Care & Sleep Medicine Philadelphia, Pennsylvania
Portland, Oregon Chapter 84
Chapter 140
Megan Rose Curtis, MD, MS
Research Fellow, Harvard Medical School
Associate Physician, Division of Infectious Diseases,
Brigham and Women’s Hospital
Chapter 122
xv

James B. Cutrell, MD Himanshu Deshwal, MD
CONTRIBUTORS
Associate Professor of Internal Medicine Fellow in Pulmonary Disease and Critical Care Medicine
Program Director, Infectious Diseases Fellowship Program Division of Pulmonary, Critical Care, and Sleep Medicine
Director, Antimicrobial Stewardship, Clements University Hospital and New York University Grossman School of Medicine
UTSW Health Systems New York, New York
Department of Internal Medicine Chapter 105
Division of Infectious Diseases and Geographic Medicine
Joshua M. Diamond, MD, MSCE
University of Texas Southwestern Medical Center
Dallas, Texas
Chapter 136
Division of Pulmonary, Allergy and Critical Care Medicine
Erin DeBiasi, MD University of Pennsylvania
Assistant Professor of Medicine Philadelphia, Pennsylvania
Department of Internal Medicine Chapter 121
Section of Pulmonary,
David M. DiBardino, MD
Critical Care, and Sleep Medicine
Assistant Professor of Clinical Medicine
Section of Interventional Pulmonology
Division of Pulmonary, Allergy and Critical Care
Chapters 47 and 64
Malcolm M. DeCamp, MD, FACS Philadelphia, Pennsylvania
Professor and Chair, Division of Cardiothoracic Surgery Chapter 33
University of Wisconsin Hospitals and Clinics
Burton F. Dickey, MD
Madison, Wisconsin
Clifton Howe Distinguished Professor of Pulmonary Medicine
Chapter 81
University of Texas MD Anderson Cancer Center
Roy H. Decker, MD, PhD Houston, Texas
Professor, Department of Therapeutic Radiology Chapter 6
John D. Dickinson, MD, PhD
Radiation Oncologist
Yale New Haven Hospital
Department of Internal Medicine
Chapter 57
University of Nebraska Medical Center
Marc Decramer, MD, PhD Omaha, Nebraska
Emeritus Professor of Medicine Chapter 6
University of Leuven
Jennifer J. Dorsch, MD
Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE)
Department of Chronic Diseases and Metabolism (CHROMETA),
KU-Leuven
Division of Sleep Medicine,
Leuven, Belgium
The Hospital of the University of Pennsylvania
Chapter 3
Associate Director, Sleep Non-Invasive Ventilation Program
Charles S. Dela Cruz, MD, PhD Philadelphia, Pennsylvania
Associate Professor of Medicine Chapter 142
Section of Pulmonary, Critical Care and Sleep Medicine
Jonathan E. Dowell, MD
Associate Professor of Microbial Pathogenesis
Professor of Internal Medicine
Director, Center of Pulmonary Infection Research and Treatment
Division of Hematology/Oncology
UT Southwestern
Dallas, Texas
Chapters 19 and 108
Chapter 116
Horace M. DeLisser, MD
Mark T. Dransfield, MD
Professor of Medicine, Endowed Chair in Pulmonary Disease
Division of Pulmonary, Allergy, and Critical Care Medicine
Associate Dean for Diversity and Inclusion
Lung Health Center
University of Alabama at Birmingham
Birmingham VA Medical Center
Chapters 105 and 152
Birmingham, Alabama
Bradley M. Dennis, MD Chapter 38
Associate Professor of Surgery
Benjamin J. Drapkin, MD, PhD
Division of Acute Care Surgery,
Assistant Professor of Internal Medicine
Vanderbilt University School of Medicine
Trauma Medical Director, Vanderbilt University Medical Center
UT Southwestern
Associate Chief of Staff, Vanderbilt University Hospital
Dallas, Texas
Nashville, Tennessee
Chapter 116
Chapter 104
M. Bradley Drummond, MD, MHS
Jessy Deshane, PhD
Associate Professor
Division of Pulmonary Diseases and Critical Care Medicine
University of North Carolina at Chapel Hill
Division of Pulmonary Allergy and Critical Care Medicine
Attending Physician
University of North Carolina at Chapel Hill Medical Center
Birmingham, Alabama
Chapel Hill, North Carolina
Chapter 25
Chapter 40
xvi

Hilary M. DuBrock, MD David Feller-Kopman, MD
CONTRIBUTORS
Assistant Professor, Department of Internal Medicine Professor of Medicine, Department of Medicine, Geisel School of Medicine
Mayo Clinic Chief, Pulmonary and Critical Care Medicine,
Rochester, Minnesota Dartmouth Hitchcock Medical Center
Chapter 97 Lebanon, New Hampshire
Chapter 76
Daniel G. Dunlap, MD
Assistant Professor of Medicine Thomas W. Ferkol, MD
Division of Pulmonary, Allergy, and Critical Care Medicine Alexis F. Hartmann M.D. Professor of Pediatrics
University of Pittsburgh Department of Pediatrics
Pittsburgh, Pennsylvania Professor, Department of Cell Biology and Physiology
Chapter 34 Washington University School of Medicine
St. Louis Children’s Hospital
Ghassan El-Haddad, MD
St. Louis, Missouri
Section Head, Radionuclide Therapy Program
Chapter 6
Associate Member, Interventional Radiology
Associate Member, Cancer Physiology Timothy M. Fernandes, MD, MPH
H. Lee Moffitt Cancer Center and Research Institute Associate Clinical Professor of Medicine
Associate Professor of Radiology and Oncologic Sciences University of California, San Diego School of Medicine
University of South Florida Division of Pulmonary, Critical Care and Sleep Medicine
Tampa, Florida La Jolla, California
Davide Elia, MD Barry G. Fields, MD, MSEd
Unità di Pneumologia e Terapia Semi-Intensiva Respiratoria Associate Professor of Medicine
Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine
Ospedale San Giuseppe, MultiMedica IRCCS Emory University School of Medicine
Milano, Italy Sleep Physician, Sleep Medicine Center, Atlanta VA Health Care System
Chapter 59 Atlanta, Georgia
Chapter 98
Richard I. Enelow, MD
Professor of Medicine, and of Microbiology and Immunology Michael C. Fishbein, MD
Geisel School of Medicine at Dartmouth Distinguished Professor of Pathology and Medicine
Dartmouth-Hitchcock Medical Center Department of Pathology and Laboratory Medicine
Lebanon, New Hampshire David Geffen School of Medicine at UCLA
Chapter 56 Ronald Reagan Medical Center
Los Angeles, California
Kyle B. Enfield, MD, MS
Chapter 68
Section Chief, Critical Care Christopher Gange, MD
Department of Medicine Assistant Professor, Radiology and Biomedical Imaging
Division of Pulmonary and Critical Care Medicine Yale University School of Medicine
University of Virginia School of Medicine Thoracic Radiologist
Associate Chief Medical Officer for Critical Care UVA Health Yale New Haven Hospital
Charlottesville, Virginia New Haven, Connecticut
Perenlei Enkhbaatar, MD, PhD, FAHA David E. Gerber, MD
Professor, Department of Anesthesiology David Bruton, Jr. Professorship in Clinical Cancer Research
Director, Translational Intensive Care Unit Departments of Internal Medicine and Population and Data Sciences
Charles Robert Allen Professor in Anesthesiology Division of Hematology/Oncology
The University of Texas Medical Branch UT Southwestern
Galveston, Texas Dallas, Texas
Gary R. Epler, MD Ghislaine Gayan-Ramirez, PhD
Clinical Associate Professor Professor at University of Leuven
Harvard Medical School Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE)
Pulmonary and Critical Care Medicine Department of Chronic Diseases and Metabolism (CHROMETA),
Brigham and Women’s Hospital KU-Leuven
Boston, Massachusetts Leuven, Belgium
Rodolfo A. Estrada, MD Subha Ghosh, MD, MBA
Assistant Professor of Medicine Assistant Professor, Lerner College of Medicine of Case
Division of Pulmonary and Critical Care Western Reserve University
UT Health San Antonio/University of Texas Health Science Staff Physician
Center San Antonio Imaging Institute, Section of Thoracic Imaging
San Antonio, Texas Cleveland Clinic Foundation
Chapter 79 Cleveland, Ohio
Chapter 105
Peter F. Fedullo, MD
Clinical Professor of Medicine Timothy D. Girard, MD, MSCI, ATSF
University of California San Diego Health Associate Professor of Critical Care Medicine
Division of Pulmonary, Critical Care, and Sleep Medicine Department of Critical Care Medicine
San Diego, California University of Pittsburgh
Chapter 73 Pittsburgh, Pennsylvania
Chapter 151
xvii

Mark T. Gladwin, MD Ramsey R. Hachem, MD
CONTRIBUTORS
Vice President for Medical Affairs, UM Baltimore Professor of Medicine

John Z. and Akiko K. Bowers Distinguished Professor and Division of Pulmonary and Critical Care Medicine
Dean, University of Maryland School of Medicine Department of Medicine
Baltimore, Maryland Washington University in St. Louis
Chapter 95 Medical Director of Lung Transplantation
Barnes-Jewish Hospital
Stanley Goldfarb, MD
St. Louis, Missouri
Former Associate Dean for Curriculum
Chapter 106
Philadelphia, Pennsylvania Chadi A. Hage, MD, ATSF
Chapter 17 Professor of Medicine
University of Pittsburgh
Michael A. Grippi, MD Pulmonary, Allergy, and Critical Care Medicine
Pulmonary, Allergy, and Critical Care Division McGowan Institute for Regenerative Medicine
Department of Medicine Medical Director, Lung Transplant
Perelman School of Medicine at the University of Pennsylvania University of Pittsburgh Medical Center
Philadelphia, Pennsylvania Pittsburgh, Pennsylvania
Chapters 1, 10, 27, 31, 102, and 139 Chapter 133
Marco Guazzi, MD, PhD
Kelly M. Hager, MD, MPH
Professor of Cardiology,
Fellow, Yale Occupational and Environmental Medicine
University of Milano School of Medicine
Department of Medicine, Yale University School of Medicine
Head of Cardiology Division
San Paolo University Hospital
Chapter 55
Milano, Italy
Chapter 32 Stephen R. Hammes, MD, PhD
Professor and Chief, Division of Endocrinology
Mridu Gulati, MD, MPH Department of Medicine
Associate Professor University of Rochester School of Medicine and Dentistry
Departments of Internal Medicine Rochester, New York
Section of Pulmonary, Critical Care and Sleep Medicine Chapter 62
New Haven, Connecticut Sergio Harari, MD
Chapter 55 Professor of Internal Medicine
University of Milan
Akash Gupta, MD Unità di Pneumologia e Terapia Semi-Intensiva Respiratoria
Instructor, Harvard Medical School Servizio di Fisiopatologia Respiratoria ed Emodinamica Polmonare
Assistant in Medicine, Department of Medicine Ospedale San Giuseppe, MultiMedica IRCCS
Division of Infectious Diseases Department of Medical Sciences, San Giuseppe Hospital
Massachusetts General Hospital MultiMedica IRCCS
Boston, Massachusetts Department of Clinical Sciences and Community Health
Chapter 130 Università degli Studi di Milano
Nishant Gupta, MD, MS Milan, Italy
Associate Professor Chapter 59
Division of Pulmonary, Critical Care and Sleep Medicine
Howard M. Heller, MD, MPH
University of Cincinnati
Assistant Professor of Medicine, Harvard Medical School
Cincinnati, Ohio
Infectious Disease Division, Massachusetts General Hospital
Chapter 61
Indira Gurubhagavatula, MD, MPH, FAASM Chapter 138
Associate Professor of Medicine, Division of Sleep Medicine
Michael J. Herriges, PhD
Post-doctoral Fellow
Corporal Michael Crescenz VA Medical Center
Center for Regenerative Medicine (CReM) of Boston
University and Boston Medical Center
Chapter 100
Jacob Gutsche, MD Chapter 8
Associate Professor Søren Hess, MD
Department of Anesthesiology and Critical Care
Chief Physician, Head of Section (Nuclear Medicine & PET)
Department of Radiology and Nuclear Medicine
Hospital South West Jutland
Chapter 149
Esbjerg, Denmark
Duc M. Ha, MD, MAS Clinical Associate Professor, Head of Research (Imaging)
Assistant Professor of Medicine Research Unit for Radiology and Nuclear Medicine
Department of Medicine Department of Regional Health Research, Faculty of Health Sciences
University of Colorado Anschutz Medical Campus University of Southern Denmark
Staff Physician, Section of Pulmonary and Critical Care Odense, Denmark
Rocky Mountain Regional Veterans Affairs Medical Center Chair, Danish Society of Clinical Physiology and Nuclear Medicine
Aurora, Colorado Aarup, Denmark
Andrew R. Haas, MD, PhD Janet Hilbert, MD
Associate Professor of Medicine Associate Professor of Clinical Medicine
Director, Section of Interventional Pulmonary and Thoracic Oncology Medical Director of Yale Noninvasive Ventilation Program
Pulmonary, Allergy, and Critical Care Division Division of Pulmonary and Critical Care Medicine
Perelman School of Medicine at the University of Pennsylvania Yale University
Philadelphia, Pennsylvania New Haven, Connecticut
xviii

Robert J. Homer, MD, PhD Joel D. Kaufman, MD, MPH
CONTRIBUTORS
Professor of Pathology Professor
Yale University School of Medicine Departments of Environmental & Occupational Health Sciences
New Haven, Connecticut University of Washington
Chapter 63 Medicine, and Epidemiology
Seattle, Washington
Gary B. Huffnagle
Chapter 89
Department of Molecular Cell and Developmental Biology Joshua B. Kayser, MD, MPH, MBE, FCCM
Division of Pulmonary and Critical Care Medicine Professor of Clinical Medicine and Medical Ethics & Health Policy
University of Michigan Medical Center Department of Medicine
Ann Arbor, Michigan Department of Medical Ethics & Health Policy
Chapter 120 Perelman School of Medicine University of Pennsylvania
Rocio M. Hurtado, MD
Chapter 152
Assistant Professor of Medicine, Harvard Medical School
Director, Mycobacterial Center, Division of Infectious Diseases Michael P. Keane, MD, FRCP, FRCPI
Massachusetts General Hospital Professor of Medicine
Boston, Massachusetts Dean and Head of School of Medicine
Chapter 131 University College Dublin
Consultant Respiratory Physician
Louise C. Ivers, MD, MPH
Professor of Medicine, Professor of Global Health and Social Medicine,
Dublin, Ireland
Harvard Medical School
Chapter 24
Director, Center for Global Health, Massachusetts General Hospital
Boston, Massachusetts Andrea Kelly, MD MSCE
Chapter 135 Attending Physician, Division of Endocrinology and Diabetes
Children’s Hospital of Philadelphia
Karen R. Jacobson, MD, MPH
Professor of Pediatrics
Section of Infectious Diseases
Boston University School of Medicine and Boston Medical Center
Chapter 48
Chapter 130 Jeffrey A. Kern, MD
Frank J. Jacono, MD
Virginia Hubbell Chair in Pulmonary and Critical Care and Tenured
University of Colorado, Denver
Chief, Oncology Division
Case Western Reserve University School of Medicine
Vice-Chair, Department of Medicine
Division Chief, Pulmonary, Critical Care & Sleep Medicine
University Hospitals Cleveland Medical Center
Denver, Colorado
Cleveland VA Medical Center, VA Northeast Ohio Health System
Chapter 107
Cleveland, Ohio
Chapter 11 Nick H. Kim, MD
Tulip Ajit Jhaveri, MBBS
Section Chief, Pulmonary Vascular Medicine
Assistant Professor of Medicine, University of Mississippi
Medical Director, Pulmonary Thromboendarterectomy Program
School of Medicine
Pulmonary, Critical Care, and Sleep Medicine
Attending Physician, Division of Infectious Diseases,
University of California San Diego
University of Mississippi Medical Center
La Jolla, California
Jackson, Mississippi
Chapter 72
Chapter 122
Corrine R. Kliment, MD, PhD
David H. Johnson, MD
Assistant Professor
R. Ellwood Jones, M.D. Distinguished Professorship in Clinical Education
Division of Pulmonary, Allergy and Critical Care Medicine
UT Southwestern
University of Pittsburgh Medical Center
Dallas, Texas
Pittsburgh, Pennsylvania
Chapter 116
Chapter 18
Austin J. Jolly
Robert A. Klocke, MD
MD/PhD Student, Department of Medicine
Emeritus Professor of Chairperson
University of Colorado Anschutz Medical Campus
Aurora, Colorado
Jacobs School of Medicine and Biomedical Sciences
Chapter 90
University at Buffalo
Christopher M. Kapp, MD Buffalo, New York
Clinical Instructor of Medicine, Department of Medicine, Chapters 15 and 16
University of Illinois at Chicago College of Medicine
Marin H. Kollef, MD
Interventional Pulmonologist and Pulmonary Critical Care Medicine
Director, Critical Care Research
Physician, Department of Medicine, University of Illinois Hospital
Director, Respiratory Care Services Barnes-Jewish Hospital
Chicago, Illinois
Virginia E. and Sam J. Golman Chair in Respiratory
Chapter 76
Intensive Care Medicine
Division of Pulmonary and Critical Care Medicine
Washington University School of Medicine
St. Louis, Missouri
Chapter 129
xix

Dimitrios P. Kontoyiannis, MD, ScD, FACP, FIDSA Daniel Langer, PT, PhD
CONTRIBUTORS
Frances King Black Endowed Professor, Infectious Diseases Professor of Rehabilitation Sciences and Physiotherapy
Deputy Head Department of Rehabilitation Sciences
Division of Internal Medicine Research Group for Cardiovascular and Respiratory Rehabilitation
The University of Texas MD Anderson Cancer Center KU-Leuven
Adj Professor Baylor College of Medicine Respiratory Rehabilitation and Respiratory Division
Adj Professor University of Houston University Hospital Leuven
Houston, Texas Leuven, Belgium
Robert M. Kotloff, MD Kathleen A. Lee-Sarwar, MD, MS
Craig and Elaine Dobbin/Nancy P. Blumenthal Instructor, Harvard Medical School
Professor of Advanced Lung Disease Physician, Department of Medicine, Brigham and Women’s Hospital
Perelman School of Medicine at the University of Pennsylvania Boston, Massachusetts
Philadelphia, Pennsylvania Chapter 44
Chapters 94 and 103
Andrew T. Levinson, MD, MPH
Darrell N. Kotton, MD Associate Professor of Medicine, Clinician Educator
David C. Seldin Professor of Medicine Program Director, Critical Care Medicine Fellowship
The Pulmonary Center and Department of Medicine Warren Alpert Medical School of Brown University
Boston University School of Medicine Department of Medicine
Director, Center for Regenerative Medicine (CReM) of Boston Miriam Hospital and Rhode Island Hospital
University and Boston Medical Center Providence, Rhode Island
Attending Physician Chapter 96
Erik E. Lewis, MD
Boston Medical Center
Fellow, Division of Cardiothoracic Surgery, University of Wisconsin
Hospitals and Clinics
Chapters 8 and 39
Madison, Wisconsin
Mary Elizabeth Kreider, MD, MSCE Chapter 81
Professor of Clinical Medicine
Howard Y. Li, MD
Vice Chief for Education and Faculty Development
Associate Professor
Fellowship Program Director
Director, ILD Program
Division of Pulmonary Disease and Critical Care Medicine
Virginia Commonwealth University
Director, Lung Cancer Screening
Medical Service
Chapter 86
Section of Pulmonary and Critical Care Medicine
Arnold S. Kristof, MDCM, FRCPC Hunter Holmes McGuire Veterans Affairs Medical Center
Associate Professor of Medicine Richmond, Virginia
Meakins-Christie Laboratories and Translational Research in Respiratory Chapter 107
Diseases Program
Shu-Yi Liao, MD, MPH, MS, ScD
Research Institute of the McGill University Health Centre
Departments of Critical Care and Medicine, McGill University
Montreal, Quebec
Chapter 60
Meir Kryger, MD, FRCPC Department of Medicine
Professor, Pulmonary, Critical Care, and Sleep Medicine University of Colorado Anschutz Medical Campus
Yale School of Medicine Physician
New Haven, Connecticut Department of Medicine
Chapters 47 and 101 Division of Environmental & Occupational Health Sciences
Ricardo M. La Hoz, MD
Denver, Colorado
Director, Solid Organ Transplant Infectious Diseases
Chapter 88
Associate Professor of Internal Medicine
Department of Internal Medicine Augusto A. Litonjua, MD, MPH
Division of Infectious Diseases and Geographic Medicine Professor of Pediatrics and Medicine
University of Texas Southwestern Medical Center Department of Pediatrics and Department of Medicine
Dallas, Texas University of Rochester School of Medicine and Dentistry
Chapter 136 Division Chief of Pediatric Pulmonary Medicine
Physician, Department of Pediatrics, Golisano Children’s Hospital
James H. Laird, MD
Department of Medicine, Strong Memorial Hospital, University of
Resident Physician
Rochester Medical Center
Department of Therapeutic Radiology
Rochester, New York
Chapter 44
Resident Physician
Yale New Haven Hospital Leslie A. Litzky, MD
New Haven, Connecticut Professor, Pathology and Laboratory Medicine
Chapter 57 Perelman School of Medicine at the University of Pennsylvania
Chief of Surgical and Medical Pathology
Subspecialty Director, Thoracic Pathology
Hospital of the University of Pennsylvania
Chapters 78 and 111
xx

Jining Lu, PhD Keshav Mangalick, MD
CONTRIBUTORS
Program Director Resident Physician, Department of Medicine
Division of Lung Diseases New York University Grossman School of Medicine
National Heart, Lung, and Blood Institute Resident Physician, Department of Medicine
National Institutes of Health New York University Langone Health
Bethesda, Maryland New York, New York
Natalie S. Lui, MD Patrick Mangialardi, DO
Assistant Professor of Cardiothoracic Surgery Senior Fellow, Pulmonary, Critical Care and Sleep Medicine
Stanford University School of Medicine/Stanford Cancer Institute Department of Internal Medicine
Stanford, California Division of Pulmonary, Critical Care and Sleep Medicine
Chapter 82 University of California, Davis, Sacramento
Veterans Administration Northern California Health Care System
Joseph P. Lynch, III, MD, FCCP, FERS
Holt and Jo Hickman Endowed Chair of Advanced Lung Disease and
Mather, California
Lung Transplantation
Chapter 66
Distinguished Professor of Clinical Medicine
Division of Pulmonary and Critical Care Medicine, Nathaniel Marchetti, DO
Clinical Immunology, and Allergy Professor of Thoracic Medicine and Surgery
David Geffen School of Medicine at UCLA Department of Thoracic Medicine and Surgery
Los Angeles, California Lewis Katz School of Medicine at Temple University
Chapter 68 Philadelphia, Pennsylvania
Chapter 84
Kevin C. Ma, MD
Assistant Professor of Clinical Medicine Paul E. Marik, MD, FCCP, FCCM
Section of Interventional Pulmonology and Thoracic Oncology Professor, Pulmonary and Critical Care Medicine
Division of Pulmonary, Allergy, and Critical Care Department of Internal Medicine
Perelman School of Medicine at the University of Pennsylvania Eastern Virginia Medical School
Philadelphia, Pennsylvania Norfolk, Virginia
Roberto F. Machado, MD Fernando J. Martinez, MD, MS
Dr. Calvin H. English Professor of Medicine Chief, Division of Pulmonary and Critical Care Medine
Chief, Division of Pulmonary, Critical Care, Sleep, and Joan and Sanford Weill Department of Medicine
Occupational Medicine Weill Cornell Medicine
Department of Medicine NY Presbyterian Hospital
Indiana University New York, New York
Indianapolis, Indiana Chapter 50
Chapter 95 Fiore Mastroianni, MD
Mitchell Machtay, MD Attending Intensivist and Pulmonologist
Professor of Radiation Oncology Department of Intensive Care and Pulmonary Medicine
Department of Radiation Oncology Mather Hospital
Penn State University College of Medicine and Cancer Institute Northwell Health
Hershey, Pennsylvania Port Jefferson, New York
Atul Malhotra, MD Aditi Mathur, MD
Peter C. Farrell Presidential Chair and Tenured Professor of Medicine Attending Pulmonary Physician
University of California San Diego Summit Health, Department of Pulmonary, Critical Care & Sleep Medicine
Division of Pulmonary, Critical Care & Sleep Medicine Hackensack University Medical Center
La Jolla, California Montclair, New Jersey
Joshua Malo, MD Michael A. Matthay, MD
Associate Professor of Medicine, Clinical Scholar Professor, Departments of Medicine and Anesthesia
Associate Director, Internal Medicine Residency Senior Associate Cardiovascular Research Institute
Program—Tucson Campus University of California San Francisco
Tucson, Arizona Associate Director, Critical Care Medicine
Chapter 133 University of California, San Francisco Medical Center
San Francisco, California
Scott Manaker, MD, PhD Chapter 140
University of Pennsylvania Daniel N. Maxwell, MD
Hospital of the University of Pennsylvania Fellow of Infectious Disease and Critical Care, UT Southwestern
Philadelphia, Pennsylvania Fellow of Infectious Disease and Critical Care
Chapter 144 Parkland Hospital, Clements Hospital, North Texas VA Hospital
Dallas, Texas
Jess Mandel, MD, MACP, ATSF Chapter 137
Kenneth M. Moser Professor of Medicine
Chief, Division of Pulmonary, Critical Care, and Sleep Medicine Paul H. Mayo, MD, FAACP
Vice-Chair for Education, Department of Internal Medicine Professor of Clinical Medicine at the Donald and
UC San Diego School of Medicine Barbara Zucker School of Medicine at Hofstra/Northwell
La Jolla, California Academic Director of Critical Care
Chapter 72 Division of Pulmonary, Critical Care, and Sleep Medicine
Northwell Health
New Hyde Park, New York
Chapter 29
xxi

Jeffrey Mazer, MD Edmund K. Moon, MD
CONTRIBUTORS
Director of Pulmonary and Critical Care Medical Director

Lovelace Medical Group Cell & Gene Therapy
Albuquerque, New Mexico Oncology R&D
Chapter 96 Collegeville, Pennsylvania
Chapter 78
Peter J. Mazzone, MD, MPH
Section Head, Thoracic Oncology Richard E. Moon, MD, FACP, FCCP
Respiratory Institute Professor of Anesthesiology
Cleveland Clinic Professor of Medicine
Cleveland, Ohio Duke University Medical Center
Chapter 109 Durham, North Carolina
Cormac McCarthy, MD, PhD Chapter 92
Associate Professor of Medicine Jorge I. Mora, MD
School of Medicine, University College Dublin Associate Professor of Clinical Medicine
Consultant Respiratory Physician, St. Vincent’s University Hospital Perelman School of Medicine at the University of Pennsylvania
Dublin, Ireland Associate Chief for Clinical Affairs and
Chapter 70 Medical Director Division of Sleep Medicine
Daniel P. McCarthy, MD, MBA, MEM Hospital of the University of Pennsylvania
Assistant Professor, Division of Cardiothoracic Surgery Director, Sleep Non-Invasive Ventilation Program
University of Wisconsin Hospitals and Clinics Philadelphia, Pennsylvania
Madison, Wisconsin Chapter 99
Chapter 81 Alice Moroni, MD
F. Dennis McCool, MD Resident in Cardiology
Professor of Medicine, Warren Alpert Medical School of Brown University University of Milano school of Medicine
Division of Pulmonary Critical Care and Sleep Medicine Milano, Italy
Rhode Island Hospital Chapter 32
Providence, Rhode Island Joel Moss, MD, PhD
Chapter 83 Senior Investigator, Pulmonary Branch
John E. McGinniss, MD National Heart, Lung, and Blood Institute, National Institutes of Health
Assistant Professor of Medicine Clinical Center, National Institutes of Health
Department of Medicine Bethesda, Maryland
Division of Pulmonary, Allergy, and Critical Care Medicine Chapters 59, 60, and 62
Hospital of the University of Pennsylvania Prerna Mota, MD
Philadelphia, Pennsylvania Assistant Professor of Medicine
Chapter 121 Geisel School of Medicine at Dartmouth
Paul McLoughlin, MB, BCh, MRCPI, PhD Dartmouth-Hitchcock Medical Center
Professor of Physiology Lebanon, New Hampshire
University College Dublin Chapter 56
School of Medicine
Susan Murin, MD, MBA
Conway Institute of Biomedical and Biomolecular Research
Professor and Associate Dean
Dublin, Ireland
Division of Pulmonary, Critical Care and Sleep Medicine
Chapter 24
University of California
Robert E. Merritt, MD, FACS Davis, Sacramento
Professor of Surgery Department of Medicine
Director, Division of Thoracic Surgery Veterans Administration Northern California Health Care System
Medical Director of Inpatient Services Mather, California
The James Comprehensive Cancer Center Chapter 66
The Ohio State University Wexner Medical Center
Columbus, Ohio
Robert Naeije, MD, PhD
Professor of Physiology
Chapter 35
Department of Physiology
Joseph A. Miccio, MD Erasme Campus of the Free University of Brussels
Assistant Professor of Radiation Oncology Brussels, Belgium
Department of Radiation Oncology Chapter 13
Penn State University College of Medicine and Cancer Institute
Hershey, Pennsylvania Girish B. Nair, MD, MS, FACP, FCCP
Chapter 115 Division of Pulmonary and Critical Care
Beaumont Health
Joseph P. Mizgerd, ScD Associate Professor of Medicine
Jerome S. Brody, MD, Professor of Pulmonary Medicine OUWB School of Medicine
Professor of Medicine, Microbiology, and Biochemistry Royal Oak, Michigan
Director, Pulmonary Center Chapter 125
Pulmonary Center, Boston University School of Medicine
Boston, Massachusetts Camille Nelson Kotton, MD
Chapter 20 Associate Professor, Harvard Medical School
Clinical Director, Transplant and Immunocompromised Host
Takudzwa Mkorombindo, MD Infectious Diseases
Division of Pulmonary, Allergy, and Critical Care Medicine Infectious Diseases Division, Massachusetts General Hospital
Lung Health Center Boston, Massachusetts
University of Alabama at Birmingham Chapters 123 and 138
Birmingham VA Medical Center
Birmingham, Alabama
Chapter 38
xxii

Natalia Neparidze, MD Henry S. Park, MD, MPH
CONTRIBUTORS
Associate Professor Assistant Professor, Department of Therapeutic Radiology
Research DART Leader, Multiple Myeloma and Gammopathies Program Yale School of Medicine
Section of Hematology Radiation Oncologist
Department of Internal Medicine and Yale Cancer Center Yale New Haven Hospital
Yale University School of Medicine New Haven, Connecticut
New Haven, Connecticut Chapter 57
Chapter 63
John E. Parker, MD
Nikolaus C. Netzer, MD, PhD Professor of Pulmonary Critical Care and Sleep Medicine
Prof. Prof.(Hon)/Director Hermann Buhl Institute for Hypoxia and Sleep Department of Medicine
Medicine Research West Virginia University
University Innsbruck Morgantown, West Virginia
Innsbruck, Austria Chapter 87
Scientific Medical Director, Terra X Cube
Nicholas J. Pastis, MD
Institute of Mountain Emergency Medicine
Eurac Research
Director of Interventional Pulmonology
Bozen, Italy
Interventional Pulmonology Fellowship Program Director
Chapter 91
The Ohio State University Wexner Medical Center
Michael S. Niederman, MD, MACP, FCCP, FCCM, FERS Columbus, Ohio
Professor of Clinical Medicine Chapter 118
Susheel P. Patil, MD, PhD
New York Presbyterian/Weill Cornell Medical Center
Clinical Associate Professor of Medicine
Weill Cornell Medical College
Pulmonary, Critical Care, and Sleep Medicine
New York, New York
University Hospitals Cleveland Medical Center
Chapter 125
Cleveland, Ohio
Paul W. Noble, MD Chapter 100
Professor of Medicine and Chair, Department of Medicine
Tyler J. Peck, MD
Vera and Paul Guerin Family Distinguished Chair in Pulmonary Medicine
Instructor of Medicine, Harvard Medical School
Medical Director, Women’s Guild Lung Institute
Physician, Division of Pulmonary, Critical Care, and Sleep Medicine
Cedars-Sinai Medical Center
Beth Israel Deaconess Medical Center
Chapter 54
Chapter 75
Eliezer Zachary Nussbaum
Jay I. Peters, MD
Fellow in infectious diseases
Professor of Medicine, Division of Pulmonary and Critical Care
Department of infectious disease
UT Health San Antonio/University of Texas Health Science Center San
Antonio and the South Texas Veterans Health Care System
San Antonio, Texas
Chapter 134
Chapter 79
Matthias Ochs, MD
Steve G. Peters, MD
Professor and Chair, Institute of Functional Anatomy, Charité—
Universitätsmedizin Berlin, Germany
Division of Pulmonary/Critical Care Medicine
Chapter 2
Mayo Clinic
Philip G. Ong, MD Rochester, Minnesota
Associate Professor of Medicine, Division of Pulmonary and Critical Care Chapter 94
UT Health San Antonio/University of Texas Health Science Center San Antonio
Sara Piciucchi, MD
San Antonio, Texas
Team Leader of Thoracic Radiology and Consultant
Chapter 79
Department of Radiology
David E. Ost, MD, MPH Ospedale GB Morgagni
Professor of Medicine, Department of Pulmonary Medicine Forlì, Italy
The University of Texas MD Anderson Cancer Center Chapter 119
Houston, Texas
Grace W. Pien, MD, MSCE
Chapter 110
Program Director, Sleep Medicine Fellowship Program
Gustavo Pacheco-Rodriguez, PhD Assistant Professor of Medicine
Staff Scientist, Pulmonary Branch Pulmonary and Critical Care Division
National Heart, Lung, and Blood Institute Johns Hopkins School of Medicine
National Institutes of Health Baltimore, Maryland
Bethesda, Maryland Chapter 98
Chapter 62
Gerald B. Pier, PhD
Allan I. Pack, MBChB, PhD Professor of Medicine (Microbiology and Immunology)
John Miclot Professor of Medicine Department of Medicine, Harvard Medical School
Division of Sleep Medicine Senior Investigator, Department of Medicine
Department of Medicine Brigham and Women’s Hospital
Perelman School of Medicine at the University of Pennsylvania Boston, Massachusetts
Chapters 10 and 12
xxiii

Venerino Poletti, MD Alejandro Restrepo, MD
CONTRIBUTORS
Professor of Pulmonary Medicine, Dipartimento di Medicina Clinical Assistant Professor

Specialistica e Sperimentale (DIMES) Department of Medicine
Università di Bologna UTMB Health
Bologna, Italy League City, Texas
Honorary Professor of Pulmonary Medicine Chapter 137
Department of Clinical Medicine
Scott I. Reznik, MD
Aarhus University Hospital
Associate Professor
Aarhus, Denmark
Department of Cardiovascular and Thoracic Surgery
Head & Professor, Department of Pulmonology, Ospedale GB Morgagni
University of Texas Southwestern Medical Center
Forlì, Italy
Dallas, Texas
Chapter 119
Chapter 113
Jennifer D. Possick, MD
Andrew L. Ries, MD, MPH
Professor of Medicine and Public Health
Associate Vice Chancellor for Health Sciences Academic Affairs
Section of Pulmonary,
University of California, San Diego
Critical Care, and Sleep Medicine
San Diego, California
Chapter 42
Director, Winchester Center for Lung Disease
Yale-New Haven Hospital M. Patricia Rivera, MD
New Haven, Connecticut C. Jane Davis & C. Robert Davis Distinguished
Chapter 64 Professor in Pulmonary Medicine
Chief, Division of Pulmonary and Critical Care Medicine
Niall T. Prendergast, MD
University of Rochester
Research Fellow, Division of Pulmonary,
Associate Director of DEI, Wilmot Cancer Center
Allergy, and Critical Care Medicine
University of Rochester Medical Center
Attending Physician, Department of Medicine
Rochester, New York
University of Pittsburgh Medical Center
Chapter 112
Pittsburgh, Pennsylvania Kenneth B. Roberts, MD
Chapter 151 Professor, Department of Therapeutic Radiology
Yale University School of Medicine
Gregory P. Priebe, MD
Attending Physician, Department of Radiation Oncology
Associate Professor of Anaesthesia, Harvard Medical School
Yale-New Haven Health System
Senior Associate in Critical Care Medicine
Department of Anesthesiology, Critical Care and Pain Medicine
Chapter 57
Associate in Pediatrics
Department of Pediatrics, Division of Infectious Diseases Matthew B. Roberts, MBBS, MPH&TM, FRACP
Boston Children’s Hospital Infectious Diseases Physician, Infectious Diseases Unit
Boston, Massachusetts Royal Adelaide Hospital
Chapter 124 Adelaide, South Australia
Chapter 123
Benjamin A. Raby, MD, CM, MPH
Professor of Pediatrics Carolyn L. Rochester, MD
Division of Pulmonary Medicine Professor, Section of Pulmonary, Critical Care and Sleep Medicine
Boston Children’s Hospital Yale School of Medicine
Harvard Medical School New Haven, Connecticut
Boston, Massachusetts VA Connecticut Healthcare System
Chapter 9 West Haven, Connecticut
Chapter 71
Christopher H. Rassekh, MD, FACS
Professor of Clinical Otorhinolaryngology: Head and Neck Surgery Karen Rodriguez, MD
Department of Otorhinolaryngology: Head and Neck Surgery Department of Radiology
Perelman School of Medicine at the University of Pennsylvania Division of Thoracic Imaging & Intervention
Attending Physician, Co-Chair Airway Safety Committee Massachusetts General Hospital
Director of Risk Reduction, Professional Practice, and Instructor, Harvard Medical School
Salivary Gland Center Boston, Massachusetts
Department of Otorhinolaryngology: Head and Neck Surgery Chapter 117
Josanna M. Rodriguez-Lopez, MD
Instructor of Medicine, Harvard Medical School
Chapter 145
Physician, Division of Pulmonary and Critical Care Medicine
John P. Reilly, MD, MSCE Massachusetts General Hospital
Assistant Professor of Medicine Boston, Massachusetts
Division of Pulmonary, Allergy, and Critical Care Chapter 75
William N. Rom, MD, MPH
Sol and Judith Bergstein Professor, Emeritus
Chapter 141
Stephen I. Rennard, MD NYU Grossman School of Medicine
Internal Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy Research Scientist
University of Nebraska Medical Center NYU School of Global Public Health
Omaha, Nebraska New York, New York
xxiv

Ilene M. Rosen, MD, MSCE Thomas F. Scanlin, MD
CONTRIBUTORS
Assistant Dean for Graduate Medical Education Chief, Division of Pediatric Pulmonary Medicine and
Vice Chair for Education, Department of Medicine The Cystic Fibrosis Center
Associate Professor of Medicine Professor, Department of Pediatrics,
Division of Sleep Medicine Rutgers, Robert Wood Johnson Medical School
Perelman School of Medicine at the University of Pennsylvania New Brunswick, New Jersey
Chapter 98
Edward S. Schulman, MD
Leonid Roshkovan, MD Professor of Medicine
Department of Radiology Division of Pulmonary, Critical Care and Sleep Medicine
Hospital of the University of Pennsylvania Director, Allergy and Asthma Research Center
Perelman School of Medicine at the University of Pennsylvania Drexel University College of Medicine
Philadelphia, Pennsylvania Philadelphia, Pennsylvania
Andrew T. Roth, MD Richard J. Schwab, MD
Fellow Professor of Medicine
Department of Medicine Perelman School of Medicine at the University of Pennsylvania
Division of Pulmonary and Critical Care Medicine Chief, Division of Sleep Medicine
Washington University School of Medicine The Hospital of the University of Pennsylvania
St. Louis, Missouri Philadelphia, Pennsylvania
Ami Rubinowitz, MD David A. Schwartz, MD
Associate Professor of Radiology & Biomedical Imaging Distinguished Professor of Medicine and Immunology
Yale School of Medicine Anschutz Medical Campus
Thoracic Imaging Section University of Colorado Denver
Yale-New Haven Hospital Aurora, Colorado
New Haven, Connecticut Chapter 90
Chapter 55
Bernardo Selim, MD
Lisa Ruvuna, MD Associate Professor of Medicine
Fellow, Division of Pulmonary Sciences and Critical Care Medicine Medical Director of Respiratory Care Unit
University of Colorado Anschutz Medical Campus Division of Pulmonary and Critical Care Medicine
University of Colorado School of Medicine Mayo Clinic
Denver, Colorado Rochester, Minnesota
Edward T. Ryan, MD Mithu Sen, MD, FRCPC, DABSM, ABIM, FCCP, FCCM, FAASM
Professor of Medicine, Harvard Medical School Professor of Medicine, University of Western Ontario
Professor of Immunology and Infectious Diseases Schulich School of Medicine & Dentistry
Harvard T.H. Chan School of Public Health Department of Medicine
Director, Global Infectious Diseases, Massachusetts General Hospital Division of Respirology, Critical Care, & Sleep Medicine
Boston, Massachusetts London, Canada
Coralynn Sack, MD, MPH David S. Seres, MD
Assistant Professor Professor of Medicine in the Institute of Human Nutrition
Departments of Medicine and Environmental & Director of Medical Nutrition
Occupational Health Sciences Associate Clinical Ethicist
University of Washington Department of Medicine
Seattle, Washington Columbia University Irving Medical Center
Chapter 89 New York, New York
Chapter 150
Moiz Salahuddin, MD
Interventional Pulmonary fellow, Interventional Pulmonology Hari M. Shankar, MD
MD Anderson Cancer Center Assistant Professor of Clinical Medicine
Houston, Texas Department of Medicine
Chapter 110 Division of Pulmonary, Allergy & Critical Care Medicine
Amali E. Samarasinghe, MS, PhD
Plough Foundation Endowed Chair of Excellence
Chapter 146
Director of the Pediatric Asthma Research Center
Associate Professor, Department of Pediatrics, Division of Pulmonology Adrian Shifren, MBBCh, FCCP
University of Tennessee Health Science Center Associate Professor of Medicine
Le Bonheur Children’s Hospital Washington University School of Medicine
Children’s Foundation Research Institute St. Louis, Missouri
Memphis, Tennessee Chapters 15 and 16
Chapter 21
Joseph B. Shrager, MD
Rahul G. Sangani, MD Professor of Cardiothoracic Surgery
Associate Professor, Section of Pulmonary, Critical Care and Sleep Medicine Chief, Division of Thoracic Surgery
West Virginia University Department of Medicine Director, Thoracic Oncology CCP
Morgantown, West Virginia Stanford University School of Medicine/Stanford Cancer Institute
Chapter 87 Stanford, California
Chapter 82
xxv

Costi D. Sifri, MD Daniel H. Sterman, MD, FCCP, ATSF, DAABIP
CONTRIBUTORS
Becton, Dickinson and Company Endowed Chair of Infectious Diseases Thomas & Suzanne Murphy Professor of Pulmonary &
and International Health Division of Infectious Diseases and International Critical Care Medicine
Health Department of Medicine, University of Virginia School of Medicine Departments of Medicine and Cardiothoracic Surgery
Attending Physician and Director, Hospital Epidemiology/Infection Director, Division of Pulmonary, Critical Care & Sleep Medicine
Prevention & Control UVA Health Director, Multidisciplinary Pulmonary Oncology Program
Charlottesville, Virginia Principal Investigator, NYU Pulmonary Oncology
Chapter 127 Research Team (NYU PORT)
NYU Grossman School of Medicine/NYU Langone Health
Gerard A. Silvestri, MD, MS
New York, New York
Hillenbrand Professor of Thoracic Oncology
Chapters 33, 34, and 78
Senior Vice-Chair of Faculty Development
Department of Medicine Kingman P. Strohl, MD
Medical University of South Carolina Professor, Medicine and Physiology & Biophysics
Charleston, South Carolina Case Western Reserve University
Chapter 118 Cleveland, Ohio
Chapter 91
Kimberly A. Smith, PhD
Research Associate Erik R. Swenson, MD
Department of Pediatrics Professor of Medicine and Physiology
Northwestern University Division of Pulmonary, Critical Care and Sleep Medicine
Chicago, Illinois University of Washington School of Medicine
Chapter 72 Attending Physician
Pulmonary, Critical Care and Sleep Medicine
Nilam J. Soni, MD
VA Puget Sound Health Care System
Professor of Medicine, Academic Hospitalist
Seattle, Washington
UT Health San Antonio/University of Texas Health Science Center San
Chapter 143
Antonio and the South Texas Veterans Health Care System
San Antonio, Texas Flora K. Szabo, MD, PhD
Chapter 79 Assistant Professor of Pediatrics
Akshay Sood, MD, MPH
Division of Gastroenterology, Hepatology and Nutrition
Professor, Department of Internal Medicine
Children’s Hospital of Richmond, VCU
University of New Mexico School of Medicine
Richmond, Virginia
Albuquerque, New Mexico
Chapter 48
Chapter 36
Nichole T. Tanner, MD, MSCR
Shweta Sood, MD, MS
Co-Director, Hollings Lung Cancer Screening Program
Medical Director of Perelman Harron Lung Center
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine
Medical University of South Carolina
The Perelman School of Medicine at the University of Pennsylvania
Core Investigator
Health Equity and Rural Outreach Innovation Center (HEROIC)
Chapter 86
Ralph H. Johnson Veterans Affairs Hospital
Ulrich Specks, MD Charleston, South Carolina
Professor of Medicine, Mayo Clinic College of Medicine and Science Chapter 118
Consultant, Department of Medicine
Lynn T. Tanoue, MD, MBA
Professor of Medicine and Vice-Chair for Clinical Affairs
Mayo Clinic
Rochester, Minnesota
Chapter 74
Director, Lung Screening and Nodule Program
Peter H.S. Sporn, MD Yale Cancer Center, Yale New Haven Hospital
Professor of Medicine New Haven, Connecticut
Cell and Developmental Biology, and Medical Education Chapters 64 and 108
Northwestern University Feinberg School of Medicine
Kelan G. Tantisira, MD, MPH
Chicago, Illinois
Professor of Pediatrics
Chapter 21
Chief, Department of Pediatrics
Theodore J. Standiford, MD Division of Pediatric Respiratory Medicine
Professor of Medicine University of California San Diego and Rady Children’s Hospital
Chief, Division of Pulmonary and Critical Care Medicine San Diego, California
University of Michigan Medical Center Chapter 9
Ann Arbor, Michigan
Luis F. Tapias, MD
Chapter 120
Assistant Professor of Surgery
Robert C. Stansbury, MD Mayo Clinic College of Medicine and Science
Associate Professor Thoracic Surgeon, Mayo Clinic
Department of Medicine Rochester, Minnesota
Section of Pulmonary, Critical Care and Sleep Medicine Chapter 80
West Virginia University
Tachira Tavarez, MD, MSc
Morgantown, West Virginia
Clinical Associate, Neurosciences Critical Care
Chapter 87
NIH T32 Post-Doctoral Research Fellow in Critical Care
Departments of Neurology, Anesthesiology & Critical Care Medicine
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Chapter 150
xxvi

Abdellatif Tazi, MD, PhD John Treanor, MD
CONTRIBUTORS
Professor of Pulmonology, Medical School, Université Paris Cité, Emeritus Professor of Medicine
INSERM UMR 976 University of Rochester Medical Center
Human Immunology Pathophysiology and Immunotherapy Rochester, New York
Head of Respiratory Department, National Reference Center for Chapter 126
Histiocytoses
Jun-Chieh J. Tsay, MD, MSc
St. Louis Hospital, AP-HP
Assistant Professor, Department of Medicine
Paris, France
Chapter 59
NYU Grossman School of Medicine
Victor J. Thannickal, MD Department of Medicine
Professor and Harry B. Greenberg Chair VA New York Harbor Healthcare System
John W. Deming Department of Medicine New York, New York
Tulane University School of Medicine Chapter 85
New Orleans, Louisiana
Homer L. Twigg III, MD
Chapters 25 and 26
Sritika Thapa, MD Department of Medicine
Clinical Instructor, Pulmonary, Critical Care, and Sleep Medicine Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine
Yale School of Medicine Indiana University
New Haven, Connecticut Indianapolis, Indiana
Chapter 101 Chapters 22 and 63
Jeffrey C. Thompson, MD, MTR George E. Tzelepis, MD
Assistant Professor of Medicine Professor of Medicine
Section of Interventional Pulmonology and Thoracic Oncology National and Kapodistrian University of Athens Medical School
Division of Pulmonary, Allergy, and Critical Care Athens, Greece
Perelman School of Medicine at the University of Pennsylvania Chapter 83
Asad Ali Usman, MD, MPH
Chapter 77
Instructor of Anesthesiology and Critical Care
Gregory Tino, MD University of Pennsylvania
Associate Professor of Medicine Hospital of the University of Pennsylvania
Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania
Chief, Department of Medicine Chapter 149
Penn Presbyterian Medical Center
Omar S. Usmani, MBBS, PhD, FHEA, FRCP, FERS
Professor of Respiratory Medicine
Chapters 31 and 51
National Heart and Lung Institute, Imperial College London
Karen J. Tietze, PharmD Royal Brompton Hospital and St. Mary’s Hospital London
Professor of Clinical Pharmacy London, United Kingdom
Department of Pharmacy Practice Chapter 45
Philadelphia College of Pharmacy
Anil Vachani, MD, MS
St. Joseph’s University
Associate Professor of Clinical Medicine
Section of Interventional Pulmonology
Chapter 144
Division of Pulmonary, Allergy and Critical Care
Martin J. Tobin, MD Perelman School of Medicine at the University of Pennsylvania
Professor of Medicine Philadelphia, Pennsylvania
Division of Pulmonary and Critical Care Medicine Chapter 33
Loyola University of Chicago Stritch School of Medicine and
Judith A. Voynow, MD
Hines VA Hospital
Edwin L. Kendig Jr. Professor of Pediatric Pulmonary Medicine
Chicago, Illinois
Chapter 147
Virginia Commonwealth University School of Medicine
Kevin P. Toole Children’s Hospital of Richmond at VCU
College of Science Richmond, Virginia
University of Notre Dame Chapter 48
Notre Dame, Indiana
Peter D. Wagner, MD
Chapter 58
Emeritus Distinguished Professor of Medicine and Bioengineering
Katrina E. Traber, MD, PhD Department of Medicine, University of California San Diego
Assistant Professor of Medicine La Jolla, California
Boston University Chapter 14
Pulmonary, Allergy, Sleep and Critical Care Medicine
James M. Walter, MD
Assistant Professor
Chapter 20
Bruce C. Trapnell, MD Northwestern University Feinberg School of Medicine
Professor, Departments of Medicine and Pediatrics, Chicago, Illinois
University of Cincinnati Chapter 128
Attending Physician, Department of Medicine University of Cincinnati
Tisha S. Wang, MD
Medical Center
Professor of Clinical Medicine
Attending Physician, Department of Pediatrics, Cincinnati Children’s
UCLA Department of Medicine
Hospital Medical Center
UCLA Division of Pulmonary, Critical Care, and Sleep Medicine
Cincinnati, Ohio
Ronald Reagan Medical Center
Chapter 70
Chapter 68
xxvii

John K. Waters, MD Robert A. Wise, MD
CONTRIBUTORS
Assistant Professor Professor of Medicine

Department of Cardiovascular and Thoracic Surgery Johns Hopkins University School of Medicine
University of Texas Southwestern Medical Center Attending Physician
Dallas, Texas Johns Hopkins Hospital
Chapter 113 Johns Hopkins Bayview Medical Center
Baltimore, Maryland
Timothy E. Weaver, PhD
Chapter 40
Professor of Pediatrics (retired)
Division of Pulmonary Biology Christine Won, MD, MS
Cincinnati Children’s Hospital Medical Center Associate Professor of Medicine
Department of Pediatrics Section of Pulmonary, Critical Care and Sleep Medicine
University of Cincinnati College of Medicine Yale University School of Medicine
Trout Run, Pennsylvania Chapter 47
Chapter 5
Cameron D. Wright, MD
Andrew Weber, MD Professor of Surgery, Harvard Medical School
Attending Intensivist and Pulmonologist Thoracic Surgeon, Massachusetts General Hospital
Department of Intensive Care and Pulmonary Medicine Boston, Massachusetts
Mather Hospital Chapter 80
Northwell Health
Joanne L. Wright, MD, FRCP(C)
Port Jefferson, New York
Professor of Pathology, University of British Columbia
Chapter 29
Pathologist, St. Paul’s Hospital
Scott T. Weiss, MD, MS Vancouver, British Columbia, Canada
Professor of Medicine, Harvard Medical School Chapter 37
Physician, Department of Medicine, Brigham and Women’s Hospital
Richard G. Wunderink, MD
rofessor of Medicine
P
Chapter 44
Matthew Wemple, MD Division of Pulmonary and Critical Care
Clinical Associate Professor of Medicine Northwestern University Feinberg School of Medicine
Division of Pulmonary, Critical Care and Sleep Medicine Medical Director, Medical Intensive Care Unit,
University of Washington School of Medicine Northwestern Memorial Hospital
Intensivist, Medical Director, MICU Chicago, Illinois
Pulmonary, Critical Care and Sleep Medicine Chapter 128
VA Puget Sound Health Care System
Hemang Yadav, MBBS
Seattle, Washington
Chapter 143
Jeffrey A. Whitsett, MD Mayo Clinic
Kindervelt Professor of Pediatrics Rochester, Minnesota
Co-Director, Perinatal Institute Chapter 94
Chief, Division of Neonatology and Pulmonary Biology
Henry K. Yaggi, MD, MPH, BA
Cincinnati Children’s Hospital Medical Center
Professor of Internal Medicine
University of Cincinnati College of Medicine
Vice Chief of Research in Pulmonary, Critical Care & Sleep Medicine
Cincinnati, Ohio
Associate Director of Yale Pulmonary Critical Care Fellowship Program
Chapter 5
Director of Yale Centers for Sleep Medicine
Kathryn A. Wikenheiser-Brokamp, MD, PhD Division of Pulmonary and Critical Care Medicine
Professor, Department of Pathology & Laboratory Medicine Yale University
Cincinnati Children’s Hospital Medical Center and University of Cincinnati New Haven, Connecticut
Cincinnati, Ohio Chapter 148
Chapter 61
Ying Yang, PhD
Andrew A. Wilson, MD Columbia Center for Human Development
Associate Professor of Medicine Department of Medicine
The Pulmonary Center and Department of Medicine Columbia University Medical Center
Boston University School of Medicine New York, New York
Director, The Alpha-1 Center of Boston University and Chapter 4
Jason X.-J. Yuan, MD, PhD
Attending Physician
Professor and Director, Department of Medicine
University of California, San Diego
La Jolla, California
Chapter 72
Chapter 39
Tanzira Zaman, MD
Christopher E. Winstead-Derlega, MD
Assistant Professor of Medicine, Department of Medicine
Undersea & Hyperbaric Fellow
Medical Director, Interstitial Lung Disease Program
Department of Emergency Medicine
Cedars-Sinai Medical Center
The Outer Banks Hospital
Nags Head, North Carolina
Chapter 54
Chapter 92
Yong Zhou, PhD
Associate Professor
Birmingham, Alabama
Chapter 26
xxviii

CHAPTER
PREFACE
PREFACE
000
This, the 6th edition of Fishman’s Pulmonary Diseases and Disorders, impact that the pandemic has had on all aspects of society, including
represents a major update of the prior edition. The book continues health care, has been extraordinary. The fact that this edition was
to incorporate broad and authoritative discussions of topics relevant orchestrated during a time when those most engaged in its prepara-
to pulmonary physicians and those interested in sleep medicine and tion were also heavily involved in caring for patients with corona-
associated disorders; it also includes core topics of importance to the virus-related respiratory disease is noteworthy. The dedication of
practice of critical care medicine. As in previous editions, the 6th the scientists and clinicians globally who contributed to the volume
relies heavily upon expert presentations of many basic science areas during this time is duly recognized and greatly appreciated. In fact,
that, in the Editors’ opinions, constitute an important substrate for the 6th edition is the result of contributions from 328 authors from
clinically based discussions. The clinical sections of the book have many countries around the world, reflecting expertise that is truly
been extensively revamped and expanded. global in nature; 141 are new to the publication.
Notable content additions include important information on Illustrations remain a pivotal component of the book, with nearly
the respiratory effects of vaping, more detailed discussion of the 2500 included in the book and online on AccessMedicine.com.
idiopathic interstitial pneumonitides, an expanded presentation Preparation of this edition required the work of many. The Editors
on the imaging and work-up of lung nodules, consideration of wish to express their sincere gratitude to the clinicians and scientists
immunotherapy in the treatment of lung cancer, information on who contributed content. They are among the leading authorities on
COVID-19–related lung disease and its management, and com- the topics on which they have written. The Editorial group itself in-
prehensive discussion of noninvasive ventilation, including its cludes three new members. Each has stepped up to the challenge and
use in ambulatory and ICU settings. In addition, new chapters on has invested considerable time and energy in helping to prepare the
cystic lung disease, lung cancer screening, the lung microbiome, work. On a personal note, I’d like to express my sincere gratitude to
developmental lung disorders, nocardiosis and actinomycosis, and all my Editor colleagues who collaborated in the book’s development.
application of ECMO have been included. The work is extensively Finally, the Editors wish to thank key individuals on the McGraw-
referenced, with more than 22,000 citations. Hill staff who played important roles during the project, includ-
Remarkably, all the material presented was prepared during an ing Jason Malley, Executive Editor, Medical Publishing; Christie
unprecedented global pandemic caused by the coronavirus, SARS- Naglieri, Senior Project Development Editor; and Leah Carton,
CoV-2. At the time of the 6th edition’s publication, more than 6.3 Associate Editor.
million deaths due to COVID-19 had been reported worldwide. The Michael A. Grippi, M.D.
xxix


PART 1
Perspectives
1 Milestones in the History of Pulmonary Medicine. . . . . . . . . 2
MCGH423-Ch001_p001-020.indd 1 10/08/22 5:27 PM

CHAPTER 1 The first is the Hippocratic corpus, a collection of about 70 works
PART 1
that includes case reports, textbooks, lectures, and notebooks. The

collection contains a description of Cheyne–Stokes respiration and
Milestones in the History the use of Hippocratic succussion for the diagnosis of fluid and air
in the pleural space. The second is a collection of aphorisms—a
of Pulmonary Medicine* compilation of brief generalizations related to medicine. The third,

which is more likely attributable to Pythagoras (c. 530 bc) than
Hippocrates (who lived about a century later), is the Hippocratic
Perspectives
Michael A. Grippi oath, which not only represents the spirit of the physician of ancient
Greece, but which has endured to modern times as a reflection of
Clinical, scientific, and technologic aspects of medicine have the physician’s code of ethics.
evolved over more than 2000 years, and the study of lung function Another Greek, Aristotle, not only had an enduring influence on
and pulmonary diseases has been an integral part of its growth and the intellect of humankind in his own time, but also for two millen-
development. About 3 centuries ago, progress toward scientific nia thereafter. Not until the 17th century were Aristotle’s doctrine of
medicine accelerated markedly, and it has continued to gain speed the four elements (earth, air, fire, and water) and that of Hippocrates
ever since. In the 17th century, research and experimentation began (blood, phlegm, yellow bile, and black bile) laid to rest, thereby
to tilt clinical medicine toward the exact sciences; by the 18th cen- clearing the way for modern scientific medicine.
tury, pathology had become an integral part of clinical medicine, Soon after Aristotle, in about 300 bc, an extraordinary medical
and clinical–pathologic correlations succeeded empiricism, dog- school was founded at Alexandria in Egypt. One of the first teachers
matism, and metaphysics. The age of the great clinicians dawned at the school, Erasistratus, postulated that the “pneuma,” or spirit
in Europe in the early 19th century, when autopsies became legal essential for life, is generated from interplay between air and blood.
and socially acceptable, and when physicians who cared for patients About four centuries after Erasistratus, Galen (Fig. 1-2) drew upon
actually performed the autopsies. the medical, philosophic, and anatomic knowledge of his day to fash-
The road to our current understanding and practice of pul- ion a remarkable physiologic schema.3,4 His construct was largely tele-
monary medicine and science has been somewhat convoluted.1–3 ologic. Unfortunately, it was so convincing that even though it was ulti-
However, it is possible to retrace the scientific trail by examining mately proved to be fanciful, it sufficed to retard scientific progress for
iconic figures and addressing milestones (Table 1-1). This chapter a millennium and a half. Galen was a talented individual who was well
traces the course of scientific pulmonary medicine over the last two educated, well read, and well positioned in society to popularize his
millennia. By necessity, what follows constitutes a limited overview beliefs. Moreover, his concepts fit well into the tenets of Christianity,
of selected aspects of the history of the field, including alveolar–cap- which was then in its ascendency; to controvert his authority was
illary gas exchange, lung volumes, mechanics of breathing, control tantamount to blasphemy. Among his long-lasting, albeit erroneous,
of breathing, ventilation–perfusion relationships, and scientific postulates were the following: invisible pores in the ventricular septum
advancements impacting clinical medicine, including chest imag- that enabled the bulk of the blood to flow from the right ventricle to
ing, lung transplantation, bronchoscopic techniques, and advances the left ventricle, thereby bypassing the lungs; a diminutive pulmonary
in critical care. Indeed, much of the content of the book addresses circulation that served only to nourish the lungs; and two-way traffic
the many advances in respiratory disorders achieved over the last in the pulmonary veins that enabled inspired air and “effluent waste
50 years. vapors” to go their respective ways (Fig. 1-3).
Voices raised in protest to Galen’s theories were without last-
ALVEOLAR–CAPILLARY GAS EXCHANGE ing effect. In the 13th century, Ibn al-Nafis, writing in his Canon
In reflecting on the history of the science and thinkers largely of Avicenna, objected that blood does not traverse the ventricular
responsible for our current understanding of the central role of the septum from right to left, as Galen had proposed. However, this
lungs in gas exchange, the following are considered: the ancient insight attracted little attention. Three hundred years later, Vesalius
Greeks, William Harvey and the Oxford physiologists, the “phlo- voiced similar misgivings. In the 16th century, Michael Servetus, a
giston theory,” theories of blood gas diffusion and “secretion” of polymath trained in theology, geography, and anatomy, pictured the
oxygen, and the physical chemistry of blood gas transport. pulmonary circulation as the vehicle by which the “inhaled spirit”
could be distributed throughout the body. In his theologic treatise,
■ Ancient Greek Medicine Christianismi Restitutio, he pointed out that blood could not traverse
the septum between the right and left ventricles, and that the lumen
The beginnings of scientific medicine can be traced to ancient
of the pulmonary artery was too large for a nutrient vessel. He
Greece in the sixth century bc. At that time, natural philosophers
became a hunted heretic, wanted for execution by both the Catholic
speculated that air, or an essential ingredient in air, was inspired to
Church and Calvin. He was warned by Calvin to stay out of Geneva.
generate a “vital essence” for distribution throughout the body.
Both Servetus and Calvin then behaved predictably: Servetus showed
Hippocrates, the “father of medicine,” is as much a symbol of the
up at a church where Calvin was preaching, and Calvin had him
Greek physician of the fifth and fourth centuries bc as the name of
captured and burned at the stake. In 1559, Realdus Columbus of
a real figure (Fig. 1-1). As an individual, he exemplified the caring
Cremona, a pupil of Vesalius, rediscovered the pulmonary circula-
physician who kept accurate records, made cautious inferences, and
tion, as did Andreas Caesalpinus in 1571. Despite these challenging
relied more on nature, rest, and diet than on drugs for treatment.
observations, Galen’s schema was to last for more than another half
His name has been immortalized by affixing it to three major com-
century—until the physiologic experiments of William Harvey.
ponents of Greek medicine, even though none appears to be the
work of a single individual. ■ William Harvey and the Oxford Physiologists
William Harvey’s (Fig. 1-4) discovery of the circulation of the
*This chapter is a revision of the original chapter written by Alfred P. blood5 was preceded by anatomic observations on the valves in sys-
Fishman. temic veins made by his mentor, Fabricus ab Aquapedente. Harvey’s
MCGH423-Ch001_p001-020.indd 2 10/08/22 5:27 PM

TABLE 1-1 Landmark Figures in the Evolution of Modern Pulmonary Medicine
CHAPTER 1
Alveolar–Capillary Gas Exchange Mechanics of Breathing
Ancient Greek Medicine John Hutchinson (1811–1861)
Hippocrates of Cos (c. 460–359 bc) Karl Ludwig (1816–1895)
Aristotle (384–322 bc) Franciscus Cornelius Donders (1818–1889)
Erasistratus of Chios (c. 300–250 bc) Fritz Rohrer (1888–1926)
Galen of Pergamon (ad 129–99) Wallace Osgood Fenn (1893–1971)
Control of Breathing
Milestones in the History of Pulmonary Medicine

Ibn al-Nafis (c. 1210–1288)
Leonardo da Vinci (1452–1519) The Central Respiratory Centers
Miguel Servetus (1511–1553) Thomas Lumsden (1874–1953)
Andreas Vesalius of Brussels (1514–1564) Hans Winterstein (1878–1963)
Realdus Columbus of Cremona (1516–1559) Merkel Henry Jacobs (1884–1970)
Andreas Caesalpinus of Pisa (1519–1603) The Peripheral Chemoreceptors
William Harvey and the Oxford Physiologists Ewald Hering (1834–1918)
Galileo Galilei (1564–1642) Joseph Breuer (1842–1925)
William Harvey (1578–1657) Cornelius Heymans (1892–1968)
Giovanni Alfonso Borelli (1608–1679) Scientific Basis of Clinical Medicine
Marcello Malpighi (1628–1694) Pathologic Anatomy
Robert Boyle (1627–1691) Gioranni Battista Morgagni (1682–1771)
Richard Lower (1631–1691) Leopold Auenbrugger (1727–1809)
Robert Hooke (1635–1703) Jean Nicolas Corvisart (1755–1821)
John Mayow (1640–1679) René Théophile Hyacinthe Laënnec (1781–1826)
Phlogiston: The Rise and Fall Microbiology
Georg Ernst Stahl (1660–1734) Robert Koch (1843–1910)
John Black (1728–1799) Physiology of the Pulmonary Circulation
Joseph Priestley (1733–1804) Claude Bernard (1813–1878)
Carl Wilhelm Scheele (1742–1782) Auguste Chauveau (1827–1917)
Respiration and Metabolism Étienne Jules Marey (1830–1904)
Antoine Laurent Lavoisier (1743–1794) Dickinson W. Richards (1895–1973)
John Dalton (1766–1844) André Frederic Cournand (1895–1988)
Julius Robert von Mayer (1814–1878) Werner Forssmann (1904–1979)
Carl von Voit (1831–1908) Thoracic Imaging
Nathan Zuntz (1847–1920) Wilhelm Conrad Roentgen (1845–1923)
The Blood Gases Godfrey N. Hounsfield (1919–2004)
Joseph Black (1728–1799) Bronchoscopy
John Dalton (1766–1844) Gustav Killian (1860–1921)
Heinrich Gustav Magnus (1802–1870) Chevalier Jackson (1865–1958)
Felix Hoppe-Seyler (1825–1895) Shigeto Ikeda (1925–2001)
Paul Bert (1833–1886) Lung Transplantation
Christian Bohr (1855–1911) Vladimir P. Demikhov (1916–1998)
John Scott Haldane (1860–1936) James D. Hardy (1918–2003)
August Krogh (1874–1949) Joel D. Cooper
Diffusion or Secretion of Oxygen
Joseph Barcroft (1872–1947)
Marie Krogh (1874–1943)
The Physical–Chemical Synthesis
Lawrence J. Henderson (1878–1942)
small book, De Motu Cordis, published in 1628, not only corrected use of the microscope, he could not picture how the pulmonary
a self-perpetuating error in Galenical teaching, but also marked the arteries made connections with the pulmonary veins. Galileo
birth of modern physiology. The time, however, was not yet ripe invented the compound microscope in 1610. In 1661, using the
to relate the function of the heart to the physiology of breathing. compound microscope, Marcello Malpighi reported that alveoli
To his dying day, Harvey clung to the idea that the main function were covered by capillaries and that blood and air were kept separate
of breathing was to cool the heart. Moreover, since he made no by the continuous alveolar–capillary barrier.
MCGH423-Ch001_p001-020.indd 3 10/08/22 5:27 PM

PART 1
Perspectives
Figure 1-1 The Hippocrates of Ostia.

This damaged bust is believed to repre-
sent Hippocrates as perceived in antiq-
uity. It was found in a family tomb in
excavations near Ostia. (Reproduced with
permission from Dr. Dickinson W. Richards.)
Figure 1-3 Galen’s scheme of the circulation. The diagram shows the
source and distribution of the three types of spirits. The validity of this
scheme depended on invisible pores in the ventricular septum, two-
way traffic in the pulmonary vein, and selective permeability of the
mitral valve for sooty wastes but not for spirit-containing blood. Vena
Figure 1-2 Galen of Pergamon as depicted in medieval times. No arterialis, pulmonary vein; arteria venalis, pulmonary artery. (Modified
authentic reproduction exists of Galen in ancient times. (Reproduced with permission from Singer C. A Short History of Scientific Ideas to 1900.
with permission from Galen’s Therapeutica, published in Venice in 1500.) London: Oxford University Press; 1959.)
MCGH423-Ch001_p001-020.indd 4 10/08/22 5:28 PM

CHAPTER 1
Figure 1-4 William Harvey (1578–1657). This portrait of William
Harvey is part of a family group in which William Harvey and his five
brothers are gathered around their father, William Harvey.
Harvey’s description in 1628 of the circulation of the blood had

three major consequences for pulmonary medicine: (1) it oriented Figure 1-5 Robert Boyle (1627–1691). This engraving, from an
pulmonary medicine toward the basic sciences and away from phi- original painting by Johann Kerseboom, hangs in the Royal Society,
losophy and empiricism; (2) it demolished the Galenic concept of London. Boyle’s invention of a pneumatic air pump and his publications
the movement of the blood; and (3) it set the stage for an upcoming concerning “the spring of air and its effect” stimulated considerable
generation of physiologists at Oxford University to explore breath- research on the physical properties of air and its role in respiration
ing in chemical and physical terms. and combustion. He strongly influenced Hooke, Lower, and Mayow
The physiologists working at Oxford in the 1660s were greatly at Oxford.
impressed by Harvey’s disciplined approach to scientific inquiry.
Many were medical practitioners who conducted research as a the fiery phlogiston escaped. The phlogiston theory was sufficiently
sideline. Four, in particular, began the systematic study of air and its malleable to accommodate almost every new discovery that could
constituents, thereby laying the foundations for contemporary respi- have overthrown it, including the rediscovery of carbon dioxide in
ratory physiology and medicine: Robert Boyle (Fig. 1-5), Robert 1754 by John Black, and the independent discoveries of oxygen by
Hooke, Richard Lower, and John Mayow. Priestley and Scheele. Although the respiratory gases had been dis-
In 1660, Robert Boyle proved by means of his air pump that air is covered by the end of the 18th century and many of their properties
necessary for life. In 1667, Robert Hooke showed that insufflation of characterized, the discoveries were misapplied to support, rather
the lungs with air while breathing movements were arrested could than destroy, the phlogiston theory. The phlogiston theory was
keep an open-chest animal alive; that is, that movement of the lungs finally undone by the experiments of Lavoisier.
was not essential for life. Richard Lower, the first to practice blood
transfusion, took advantage of Hooke’s continuously inflated lung ■ Respiration and Metabolism
preparation in the dog to observe that dark venous blood becomes
From the time of Hippocrates until early in the 20th century, debate
bright red as it traverses lungs insufflated with air. In 1674, Mayow
had continued about the site of heat production in the body. In
interpreted the change in the color of blood from venous to arte-
1777, Lavoisier suggested that air was composed of one respirable
rial as due to the uptake of “nitroaerial particles” (later to be called
gas (which he later named “oxygine”) and another (nitrogen) that
“oxygen”) from the air.
remained unchanged in the course of respiration. Between 1782 and
1784, Lavoisier and Laplace concluded, on the basis of calorimetric
■ Phlogiston: the Rise and Fall experiments on guinea pigs, that “respiration is therefore a combus-
Unfortunately, the discoveries and insights of the Oxford physiolo- tion, admittedly very slow, but otherwise exactly similar to that of
gists went largely unnoticed during the century that followed, over- charcoal” (Fig. 1-6). The similarity between respiration and com-
shadowed by the “phlogiston theory” of combustion. The theory, bustion had previously been recognized by the Oxford physiologists,
advanced by Stahl, postulated that all combustible materials were especially Mayow.6 By 1783, Lavoisier was accumulating evidence
composed of two ingredients: phlogiston, a principle that trans- against the phlogiston theory and began to replace it with an entirely
formed into fire when heated, and an ash that was left behind after new system of chemistry.
MCGH423-Ch001_p001-020.indd 5 10/08/22 5:28 PM

PART 1
Perspectives
Figure 1-6 Scene from the labo-

ratory of Antoine Laurent Lavoisier
(1743–1794). His wife is acting as his
assistant, and Sequin is the subject.
Studies such as this led to the con-
clusion that respiration and combus-
tion are similar processes.
As noted previously, the ancients pictured the heart as the heat before Priestley had obtained oxygen by heating mercuric oxide,
generator. Lavoisier favored the lungs. Others held that combus- Scheele discovered oxygen independently because of his interest in
tion occurred in the blood. Although Spallanzani had shown in the fire, and he designated oxygen as “fire air.”
18th century that isolated tissues take up oxygen and evolve carbon In 1662, Van Helmont, a Capuchin friar and talented chemist, as
dioxide, the idea that combustion occurred in the tissues was slow to well as a mystic with a drive to quantify, discovered carbon dioxide,
gain acceptance. However, the hypothesis gained strength through coined the word gas, and called carbon dioxide “wild gas” (“gas
the work of Pflüger in 1878. He measured oxygen consumption sylvestre”). In 1755, Joseph Black rediscovered carbon dioxide. He
and carbon dioxide production in dogs and calculated respiratory showed that calcium carbonate (limestone) and magnesium car-
quotients. His research substantiated a concept that had been enun- bonate (magnesia alba) lost weight on heating, releasing “fixed air”
ciated, but not named, by Lavoisier.7 (CO2) in the process. This fixed air extinguished both flame and
Once the idea that oxidation occurred in the tissues had become life. Lavoisier knew of the observations of Black and of Priestley
generally accepted, investigators delved into the processes involved
in utilization of foodstuffs by the tissues, energetics, growth, and
repair. Carl von Voit and Max von Pettenkofer, using a respiration
chamber, drew upon chemical balances and respiratory quotients in
humans to distinguish the nature of the foodstuffs being burned and
to show that the amounts of fat, protein, and carbohydrate burned
varied with the mechanical work done by the subject. Between
1842 and 1845, Julius Robert von Mayer formulated the law of
conservation of energy. Subsequently, Max Rubner showed that the
law applied to the living body, and Herman von Helmholtz showed
that its relevance to metabolism could be demonstrated experi-
mentally. Application of these principles at the bedside was greatly
facilitated by the development of a portable metabolic apparatus by
Nathan Zuntz. Pioneering bedside studies of metabolic states were
conducted by a succession of distinguished investigators, including
Magnus-Levy, Graham Lusk, F. G. Benedict, and Eugene F. DuBois.
■ The Blood Gases

The Oxford physiologists set the stage for the discovery of the blood
gases. Using his vacuum pump, Robert Boyle extracted “air” from
blood. John Mayow came close to discovering oxygen by showing
that only a portion of air was necessary for life—the “nitroaerial
spirits”—which were removed both by respiration and fire (combus-
tion). One of his famous experiments entailed enclosing a mouse
and a lighted lamp in an airtight container; the lamp went out first
and then the mouse died. However, Mayow did not realize that the Figure 1-7 Joseph Priestley (1733–1804), the discoverer of oxy-
“nitroaerial spirits” could be isolated as a gas.6 gen. This figure shows a silver medal struck in his honor in 1783. A
One hundred years after Mayow, Joseph Priestley (Fig. 1-7) Presbyterian minister, he was radical in his religious and political
exposed a mouse to the gas released from heated mercuric oxide and beliefs, inventive in science, and conservative in the interpretation of
found that the gas supported life better than air did; he also noticed his findings. (Reproduced with permission from Fishman AP, Richards DW.
that a flame burned more vigorously in this gas than in air. Priestley Circulation of the Blood: Men and Ideas. New York, NY: Oxford University
was not alone in his preoccupation with flame. In 1773, about a year Press; 1964.)
MCGH423-Ch001_p001-020.indd 6 10/08/22 5:28 PM

he pictured the curve as hyperbolic. Christian Bohr (Fig. 1-8)
subsequently identified its s-shaped contour, and in 1904, together
CHAPTER 1
with Hasselbach and August Krogh, showed that increasing carbon
dioxide tension in blood drives out oxygen, that is, the “Bohr effect.”
Shortly thereafter, the influence of various factors, for example,
temperature and electrolytes, on the affinity of oxygen for hemoglo-
bin (and, consequently, on the position of the oxygen dissociation
curve) was explored in detail by Barcroft and associates. In 1914,
Christiansen, Douglas, and Haldane reported that an increase in
the oxygen tension of the blood drives out carbon dioxide, that is,

the “Haldane effect.” In 1967, a new dimension was added to the
understanding of the position and configuration of the oxygen
dissociation curve by the demonstration that diphosphoglycerate,
a chemical constituent of red cells, regulates the release of oxygen
from oxyhemoglobin.
■ Diffusion or Secretion of Oxygen

Bohr is a central figure as an investigator and mentor in respiratory
physiology.8 In 1904, he raised a troublesome issue that was not
easily resolved, primarily because of limitations in methodology at
the time. He postulated that even though diffusion could account
for oxygen uptake at rest, it could not suffice during strenuous
exercise, particularly at altitude. He held that oxygen secretion had
Figure 1-8 Christian Bohr (1855–1911). At work in his laboratory, to be involved.9 He clung to this misconception during his lifetime,
Bohr (far right) and his associates systematically explored the interplay a conviction supported by two major lines of evidence. The first was
between the respiratory gases and hemoglobin that led to the dis- indirect: Oxygen secretion by the swim bladder of fish showed by
covery of the “Bohr effect.” (Reproduced with permission from Fishman extrapolation that active transport of oxygen in the lungs was pos-
AP, Richards DW. Circulation of the Blood: Men and Ideas. New York, NY: sible. The second was based on observations made during Bohr’s
Oxford University Press; 1964.) expedition to Pike’s Peak in 1912, during which it was erroneously
demonstrated that with exercise at altitude, arterial oxygen tension
and Scheele. He decided in 1778 that the gas obtained from heat- exceeded alveolar oxygen tension.
ing mercuric oxide was not “fixed air” or “common air,” but “highly However, even before the report from high altitude, Bohr’s former
respirable air” (oxygen). assistant, August Krogh, and his wife, Marie Krogh (Fig. 1-9) had
The story of hemoglobin, the essential element in the transport marshaled new evidence to show that “the absorption of oxygen
of the respiratory gases by the blood, begins with Hoppe-Seyler, and the elimination of carbon dioxide in the lungs takes place by
who, between 1866 and 1871, crystallized hemoglobin, explored its diffusion and diffusion alone.” The final blow to the secretion theory
chemical properties, and assigned it a proper role in the transport was delivered by Marie Krogh.10 Based on the single-breath carbon
of oxygen by the blood. At the turn of the 19th century, Dalton monoxide method for determining diffusing capacity that she and
reported his experiments with the respiratory gases, which led to her husband had developed in 1910,11 she was able to account for
the development of his atomic theory. In 1872, taking advantage oxygen uptake in the lungs by diffusion alone, even during strenu-
of Dalton’s law, Paul Bert published the first oxygen dissociation ous exercise under conditions of low oxygen tension. Refinements
curve, that is, oxygen content at different barometric pressures; in the carbon monoxide method by Roughton and others extended
Figure 1-9 August and Marie Krogh

in 1922, at the time of their first visit
to the United States so that August
Krogh could deliver the Silliman
Lecture at Yale. They demonstrated
that diffusion, without secretion,
could account for the transfer of O2
and CO2 across the alveolar–capillary
membranes of the lungs. (Reproduced
with permission of their daughter,
Dr. Bodil Schmidt-Nielsen.)
MCGH423-Ch001_p001-020.indd 7 10/08/22 5:28 PM

PART 1
Perspectives
Figure 1-10 Two founders of contemporary respiratory physiology

in 1936. Sir Joseph Barcroft (1872–1947) (left) proved, in experiments
on himself, that diffusion was the mechanism for gas exchange in
the lungs and pioneered current understanding of the respiratory
functions of the blood. Lawrence J. Henderson (1878–1942) (right)
provided a mathematical analysis of blood as a physiochemical system
and stimulated research on the complex interplay involved in respira-
tory gas exchange during exercise. (Reproduced with permission from Figure 1-11 John Hutchinson’s illustration of a subject about to
Fishman AP, Richards DW. Circulation of the Blood: Men and Ideas. New undergo measurements of lung volumes. (Reproduced with permission
York, NY: Oxford University Press; 1964.) from Hutchinson J. On the capacity of the lungs, and on the respiratory
functions, with a view of establishing a precise and easy method of detect-
ing disease by the spirometer. Med Chir Trans. 1846;29:137–252.)
its clinical applicability and provided further evidence against the
secretion theory.12 Despite these observations, Haldane would not
let go. Throughout his life, despite mounting evidence to the con- further by discovering carbonic anhydrase in the red cell and
trary, he adhered to the idea that oxygen was secreted by the alveolar addressing transient phenomena related to transport of respiratory
membrane. gases and carbon monoxide in blood.
The issue was finally settled by Joseph Barcroft (Fig. 1-10). Using
a chamber to reproduce the circumstances of hypoxia and strenuous LUNG VOLUMES
exercise assessed during the Pike’s Peak expedition, he found that Although Humphrey Davy had determined his own lung volume
under all conditions, the oxygen saturation of arterial blood was using hydrogen as the test gas in 1800,13 it was not until the 1840s
less than that of arterial blood exposed to a sample of alveolar gas that John Hutchinson laid the groundwork for modern pulmonary
obtained at the same time. He subsequently confirmed these results function testing. He devised a spirometer and used it to determine
by experiments done at high altitude at Cerro de Pasco (1921–1922). the subdivisions of the lung in a large number of healthy subjects,
relating the measurements to height and age (Fig. 1-11). The many
■ The Physical–Chemical Synthesis refinements since then are too numerous for mention in this chap-
Lawrence J. Henderson undertook the herculean task of depicting ter. A big step forward was the invention of the body plethysmo-
the reactions of oxygen and carbon dioxide in blood, not as cause graph many years later, which made possible the determination of
and effect, but as interplay among physiochemical variables and the thoracic gas volume and airway resistance.
functions (Fig. 1-10). His theoretical considerations and practi-
cal applications in the Fatigue Laboratory at Harvard University MECHANICS OF BREATHING
were greatly abetted by close collaboration with Van Slyke, Wu, The ancients wondered how air moved into and out of the lungs; as
and McLean at the Rockefeller Institute in New York, who were far back as the time of Erasistratus, the diaphragm was recognized
exploring the exchanges of blood constituents between red cells and as involved in breathing. Galen was aware that the lungs fill the chest
plasma. In 1828, Henderson presented his synthesis in the form of a cavity and are moved by the actions of the thorax, and that the large
d’Ocagne nomogram that displayed changes in the various elements airways enlarge and lengthen during inspiration. He marveled at
that entered into the exchange of the respiratory gases between the long course of the nerves to the diaphragm and the innervation
alveolar gas and blood: plasma; the red cell; hemoglobin; and chlo- of the intercostal muscles. After Galen, interest in the mechanics of
ride, bicarbonate, and hydrogen ions. He presented nomograms not breathing waned except for sporadic observations and experiments
only for the normal subject at rest and during exercises, but also for by anatomists, notably Leonardo da Vinci and Andreas Vesalius.
individuals with anemia, nephritis, diabetic coma, and other major Interest in respiratory mechanics resumed in the 16th century,
clinical entities. Henderson dealt with steady-state observations. largely as a result of progress in physics and mathematics, as exem-
Roughton and associates enlarged the physiochemical horizons plified in the works of Borelli and Galileo.
MCGH423-Ch001_p001-020.indd 8 10/08/22 5:28 PM

■ Airway Resistance
A giant step forward occurred in 1916 when Rohrer, as part of
CHAPTER 1
his doctoral dissertation, presented a conceptual framework for
determining flow and resistance in airways. His equations were
based on precise anatomic measurements of airway dimensions
in a human cadaver, coupled with aerodynamic principles. During
the following decade, he and his coworkers, Neergaard and Wirz,
applied Poiseuille’s law for laminar flow and his equations to the
determination of airway resistance. Use of Fleisch’s pneumotacho-
graph, coupled with periodic interruptions of airflow, permitted

measurement of alveolar pressure. Clinically useful measurements
Figure 1-12 Mayow’s model of the chest and lungs. The bellows of alveolar pressure became available in 1956 with the introduction
encloses a bladder, the neck of which opens to the outside. A glass by DuBois and associates of the whole-body plethysmograph, which
window on the upper side makes it possible to observe the bladder they coupled with the application of Boyle’s law.
during inflation and deflation. (Reproduced with permission from Mayow
J: Medico-Physical Works, Crum A, Brown, Dobbin L [trans]. Edinburgh, ■ Synthesis of Mechanics
Alembic Club, Reprints, no 17, 1957. [Translated from Tractatus quinque
During the decade between 1915 and 1926, Rohrer and his col-
medico-physics, 1674.])
leagues provided a remarkably comprehensive synthesis of respira-
tory mechanics that included a description of the static pressure–
■ The Respiratory Muscles volume characteristics of the respiratory system and the work of
breathing; they also developed the principle of optimal frequencies
Mayow, one of the Oxford physiologists, drew heavily on the work
of breathing to minimize respiratory work. Together with von
of colleagues, including Boyle and Hooke, to develop considerable
Neergaard and Wirz, Rohrer developed and tested, experimentally,
insight into the mechanics of breathing. He also built the first
concepts involving pressures, flows, and volumes. The full signifi-
model on record of the chest as a bellows, which contained a blad-
cance of Rohrer’s work was not appreciated until the publications
der within it (Fig. 1-12). He understood that air moved into the
by Fenn and his group at the University of Rochester, starting in the
lungs as the chest expanded because of the pressure and elasticity
1940s. The contributions of W. O. Fenn, H. Rahn, and A. B. Otis to
of ambient air; he also appreciated that the chest expands because
our present understanding of the mechanics of breathing are sig-
of the action of the intercostal muscles (internal and external),
nificant, and there is little doubt that this group shaped much of the
that the diaphragm is the primary muscle of inspiration, and that
contemporary thinking of respiratory physiologists and pulmonary
normal expiration is passive. After Mayow, little research was
physicians.14–17
done on the role of the respiratory muscles in breathing until
the mid-19th century, when Donders distinguished between the
CONTROL OF BREATHING
respective roles played by the inspiratory muscles and elastic
forces. The control of breathing is a complex process that depends on the
integrity of the entire respiratory system—lungs, airways, circula-
■ Elastic Properties of Lungs and Chest Wall tion, and control systems.18 Two dominant control systems exist.
One is in the central nervous system; the other is outside the brain.
Until the 20th century, observations on the elastic properties of the
Control mechanisms in the central nervous system are influenced
lungs and chest wall in humans were fragmentary. Access to the
by the state of wakefulness or alertness and are subject to voluntary
pleural space was the major limiting factor. With few e xceptions—
control. These mechanisms are also influenced reflexively by a vari-
notably Neergaard and Wirz, who used pleural pressures to deter-
ety of peripheral receptors.
mine elastic recoil in normal human subjects, and Christie, who
recorded pleural pressures to demonstrate loss of pulmonary elas-
■ Localization of the Central Respiratory Centers
ticity in emphysematous patients—measurements in humans were
largely confined either to therapeutic interventions, for example, In 1812, Legallois, apparently intrigued by the gasping movements
induction of a pneumothorax or aspiration of pleural fluid, or of the head after decapitation, identified an area in the medulla that
experiments done at autopsy. The number of observations on the was essential for life. In 1923, Lumsden systematically explored the
mechanical properties of the lungs increased dramatically when it effects of serial sectioning of the brain stem on respiration, mark-
was shown by Buytendijk, in 1949, and again by Dornhurst and ing the beginning of the era of contemporary research on rhythmic
Leathart, in 1952, that esophageal pressures provided an accurate breathing. He designated an area in the caudal pons responsible for
measure of pleural pressures. a sustained inspiratory drive as the “apneustic center,” and an area in
The role of alveolar surface tension in determining the elastic the rostral and lateral portions of the pons that presumably inhibited
forces in the lungs began to be widely appreciated in the late 1950s, the apneustic drive as the “pneumotaxic center”; sectioning of the
although the stage had been set long before. In 1812, Laplace had vagi exaggerated the inhibition of the apneustic drive by the pneu-
published the law of surface tension. The implication of this law motaxic center. Sixteen years later, Pitts et al.,19 using stereotactic
for the lungs was appreciated initially in 1929 when Neergaard stimulation of the cat medulla, identified inspiratory and expiratory
compared pressure–volume curves of lungs filled with air with centers and proposed a theory that could account for both rhythmic
those filled with fluid. He concluded that unopposed surface ten- breathing and apneusis.
sions would favor alveolar collapse. Then, between 1954 and 1960, a
remarkable outpouring of papers from different laboratories showed ■ Chemical Stimulation of the Respiratory Centers
that a unique surfactant lined the alveoli, and that this material was The chemical stimuli to breathing have been known for more than a
absent in premature infants with hyaline membrane disease (and century. In 1885, Miescher-Ruesch showed in humans that ventila-
alveolar collapse); these papers prompted extensive research on the tion at rest is primarily regulated by carbon dioxide. Between 1887
chemical and physical properties of surfactant and on its sites of and 1901, cross-perfusion experiments by Leon Fredericq under-
formation and removal. scored the role of carbon dioxide. However, it was not until 1905
MCGH423-Ch001_p001-020.indd 9 10/08/22 5:28 PM

to 1909 that Haldane, Priestley, and Douglas paved the way to the ■ The Reflex Regulation of Breathing
modern understanding of the role of carbon dioxide under a vari- A considerable and diverse number of peripheral receptors can
ety of experimental conditions.20 In their experiments on humans, influence breathing reflexively by supplying information to respi-
PART 1
they relied heavily on the Haldane gas analyzer and an alveolar gas ratory centers located in the brain. These include pain receptors,
sampler of their own invention. However, their experiments did not stretch receptors in the muscles and distensible thoracic structures,
distinguish clearly between CO2 and H+ in the stimulation of the and organs and chemoreceptors in major systemic arteries.
respiratory centers. Winterstein, and later Gesell,21 advanced the
idea that the chemical regulation of respiration is determined by
the concentration of hydrogen ions within the respiratory centers. ■ Mechanoreceptors
The Winterstein theories22 provide a good example of the evo- Until the work of Hering and his student, Breuer, little was known
Perspectives
lution of ideas prompted by new discoveries and inventions. The about the role of afferent impulses to the central control mecha-
original theory in 1911 attributed increments in ventilation caused nisms in the control of breathing, other than the fact that electrical
by hypoxic or hypercapnic inspired mixtures to a single mecha- stimulation of the vagus nerves influenced respiration.24 In 1868,
nism, that is, acidification of arterial blood by either carbonic acid Hering and Breuer reported that inflation of the lungs stopped
or lactic acid. In 1921, Jacobs’ demonstration of the rapid diffusion respiration in expiration and promoted expiration, and that, con-
of carbon dioxide into starfish eggs implicated acidity within the versely, a decrease in lung volume ended expiration and promoted
respiratory centers,23 as well as arterial blood acidity, as the sites of inspiration. They inferred that inflation mechanically stimulated
stimulation. To account for the stimulation of breathing by hypoxia nerve endings in the lungs and that the resulting impulses ascending
(the peripheral chemoreceptors had not yet been discovered), he the vagi were inhibitory to inspiration.
invoked the release of asphyxiating substances (Erstickungsstoffen)
within the respiratory centers themselves. A third theory, postulated ■ Peripheral Chemoreceptors
in 1949, attempted to incorporate the discovery of the peripheral In 1841, Volkmann suggested the existence of chemoreceptors in the
chemoreceptors, and it finally gave way in 1955 to his fourth theory, systemic circulation that were sensitive to blood-borne stimulants
which explained the effects of acid or hypoxia on both the central to respiration. In 1927, J. F. Heymans and C. Heymans first showed
and peripheral chemoreceptors. that the aortic bodies served this function, and in 1930, C. Heymans
A major consequence of Winterstein’s research was an impetus to and Bouckaert demonstrated the peripheral chemoreceptive func-
subsequent exploration of the chemical control of breathing. These tion of the carotid bodies. These were physiologic observations that
studies led to the identification of central chemoreceptors, distinct tallied well with the observations of F. De Castro, a student and
from mechanoreceptors, on the ventral surface of the medulla, and later a colleague of Ramón y Cajal, who was sufficiently impressed
clarification of the role of hydrogen ion activity as the central stimu- by the histologic structure, location, and rich innervation of the
lus to breathing. The studies also prompted a search for a unifying carotid body to propose that it might be stimulated by blood-borne
theory for the chemical control of breathing. substances (Fig. 1-13).25
Figure 1-13 Drawing by De Castro

showing the structure of the chemore-
ceptor. The glomus cells (e) present an
ample cytoplasmic surface for contact
with the perfusing blood delivered by
the capillary (c); sensory nerve fiber (f)
with sheath of myelin; Schwann cells
(a) surround the unmyelinated fibers
which form the terminal menisci; cell
membrane (b). (Reproduced with per-
mission from De Castro F: Sur la structure
de la synapse dans les chemocepteurs:
leur mécanisme d’Excitation et R™ le
dans la circulation sanguine locale. Acta
Physiol Scand. 1951;22(1):14–43.)
10
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CHAPTER 1
Figure 1-15 Rene T.H. Laënnec (1781–1826). (Drawn from life in
1825 by Charles James Blasius Williams (1805–1889) and reproduced in
his autobiography, Memoirs of Life and Work, London: Smith, Elder & Co;
1884.)
Figure 1-14 Giovanni Battista Morgagni (1682–1771). The five vol-
and doctrinal systems to pathology as its scientific foundation.
umes of his De Sedibus contain the clinical and pathologic descriptions
Eminent physicians, such as Bichat, Bayle, and Corvisart in France,
of approximately 700 cases. (Reproduced with permission from the
and William and John Hunter and Baillie in England, were turning to
Library of the College of Physicians of Philadelphia.)
anatomic findings at autopsy to understand the signs and symptoms
of their patients. Percussion had been rediscovered by Corvisart.
Although Auenbrugger had reported in Latin his “new invention” in
VENTILATION–PERFUSION RELATIONSHIPS
1761, the idea had not caught on until Corvisart—eminent clinician
In 1946, William Dock attributed the apical localization of tubercu- and teacher and personal physician to Napoleon—published a trans-
losis to hypoperfusion of well-ventilated alveoli in the lung apices lation in French in 1808. Corvisart’s approach to medicine strongly
in the upright position.26 Shortly thereafter, ventilation–blood flow influenced Laënnec. Laënnec applied the stethoscope and Corvisart’s
relationships were described in quantitative terms in papers by two “sounding of the chest” to study individual patients with diseases
separate groups: Rahn and Fenn27 and Riley and Cournand.28–30 of the lungs and heart throughout their clinical course, along with
anatomical examination at autopsy. This was no simple matter. Since
SCIENTIFIC BASIS OF CLINICAL PULMONARY MEDICINE there were no pathologists in those days, the physician not only had
Five remarkable figures serve to illustrate different stages in the to provide continuous care during the patient’s lifetime, but he also
evolution of the scientific basis of pulmonary medicine: Morgagni, had to arrange for, and perform, the autopsy; he then had to gather
Laënnec, Koch, Cournand, and Richards. They represent key scien- all that he had seen and learned and prepare it for publication.
tists in the areas of pathologic anatomy, microbiology, and physiology. In 1819, two years after the invention of the stethoscope, Laënnec
published his famous monograph, De l’Auscultation médiate, which
■ Pathologic Anatomy drew lessons from carefully documented cases that were studied
Morgagni and Laënnec, almost a century apart, made major contri- throughout their clinical course and at autopsy. In this work,
butions to the field of pathologic anatomy. Morgagni (Fig. 1-14), who Laënnec built upon the monumental tome of Morgagni, who, a
lived in the 18th century and was a student of Valsalva, veered away generation before, had related the clinical features of the diseases he
from the undisciplined case reports of his predecessors. Instead, he described to the morbid anatomy, but who had not been able to take
adopted a logical system for relating findings at autopsy to their clini- the next step of relating the clinical course of individual patients to
cal manifestations. At age 79, he published a compilation of his life- the anatomic findings after death.
long experience in his famous work, De Sedibus et Causis Morborum Laënnec’s monograph contains descriptions of physical signs,
per Anatomen Indagatis. De Sedibus includes about 700 cases. The clinical–pathologic correlations for tuberculosis, pneumonia, bron-
clinical–pathologic correlations in this work benefited greatly from chiectasis, emphysema, and cancer of the lung, and instructions for
the fact that Morgagni was both a seasoned clinician and a patholo- the treatment of these conditions. The descriptions of tuberculosis
gist. One of the compilation’s five books is devoted to diseases of the were an outstanding contribution to the field and were reported
thorax. Among his descriptions were those of a tubercle undergoing prior to Koch’s discovery of the causative agent.
liquefaction and the hepatization stage of pneumonia.
René Théophile Laënnec is, perhaps, best known for inventing the ■ Microbiology
stethoscope in 1816 (Fig. 1-15).31,32 At that time, clinical medicine in Tuberculosis provides a remarkably illuminating example of the
Europe, especially in France, was turning from metaphysical concepts impact of a novel basic science on clinical medicine.33–35 The disease
11
MCGH423-Ch001_p001-020.indd 11 10/08/22 5:28 PM

can be traced back to the ancients, who were familiar with the
diverse clinical syndromes that we now take for granted as due to
tuberculosis; however, they had no way to relate them to a common
PART 1
etiologic agent. A synthesis by Morton in 1685 of all that was then

known about tuberculosis focused on cavitary lesions, emaciation
(“consumption”), and the tubercle, but it was shrouded in Galenic
humors. An understanding of the disease accelerated in the 18th
century when clinicians, such as William Cullen, began to sort out
the various syndromes relating to phthisis, including hemoptysis,
empyema, catarrh, and asthma.
Perspectives
The tempo of discovery increased dramatically in the 19th

century after the French Revolution. During the Napoleonic era,
distinguished Parisian clinicians, including Bichat, Bayle, Louis,
Broussais, and Laënnec, reported clinical–pathologic correlations
of tuberculosis. (Notably, both Bayle and Laënnec died of tuber-
culosis.) However, little advance was made in understanding the
pathogenesis of tuberculosis until Villemin, who, impressed by the
analogy between glanders and syphilis on the one hand, and tuber-
culosis on the other, and the fact that two of the three diseases had
been shown to be infectious in origin, undertook experiments dem-
onstrating that tuberculosis was an infectious disease that could be
transmitted from humans to animals, and from animals to animals.
Koch
In 1876, Koch was a general practitioner in the German township
of Wollestein in the province of Posen, where he was responsible for
the health care of 4000 inhabitants (Fig. 1-16). Between obstetrical
deliveries and satisfying the medical and surgical needs of patients
of all ages, he managed to conduct research on the microbial causes
of communicable diseases. His laboratory was homemade—based
in either the barn or his living room; his major instrument was a
microscope used to examine bacteriologic and tissue specimens. In
pursuing his research, he kept in mind the dictum of Jacob Henle,
one of his teachers in medical school, who counseled that, “before Figure 1-16 Robert Koch (1843–1910), announcing his discovery
microscopic organisms can be regarded as the cause of contagion in of the tubercle bacillus as the cause of tuberculosis, Berlin, March 28,
man, they must be found constantly in the contagious material, they 1882. (Reproduced with permission from Knight D: Robert Koch: Founder
must be isolated from it and their strength tested.” This lesson was to of Bacteriology. New York, NY: Franklin Watts, Inc; 1961.)
become the keynote of the future “Koch postulates.”
In 1876, Koch, the busy medical practitioner, sent a letter to
Professor Ferdinand Cohn, director of the Botanical Institute in produce transparent solid media, coupled with Koch’s invention of
Breslau, indicating that he had discovered “the process of develop- new staining methods, paved the way for him to tackle the microbial
ment of bacillus anthracis” and requesting permission to present his cause of tuberculosis.
findings to Professor Cohn, “the foremost authority on bacteria.” Koch’s scientific approach, which has been immortalized as
Koch had discovered the spores of anthrax bacilli. Cohn arranged “Koch postulates,” consisted of four essential steps: (1) To prove
for him to present his results before a room full of formidable, that a microbe is the cause of a disease, it must be present in all
distinguished scientists, including Julius Cohnheim, Carl Weigert, cases of the disease. (Koch showed this for the tubercle bacil-
Moritz Traube, Ludwig Lichtheim, and Leopold Auerbach. Koch’s lus using methylene blue and a counter stain.) (2) The microbe
demonstration of the complete life history of the anthrax bacillus, must be grown outside of the body in pure culture. (Koch devised
including sporulation, was entirely convincing to these scientists. blood-serum jelly as a culture medium for the slow-growing
After the meeting, Cohnheim, upon his return home, announced tubercle bacillus.) (3) The pure culture must be capable of caus-
to his colleagues, “This man has made a splendid discovery which ing the disease in healthy animals. (Koch proved this initially by
is all the more astonishing because Koch has had no scientific inoculation and, subsequently, by allowing animals to breathe con-
connections and has worked entirely on his own initiative and has taminated air.) (4) The same microbe must then be isolated from
produced something absolutely complete. There is nothing more the inoculated (infected) animal and grown outside of the body in
to be done. I consider this the greatest discovery in the field of pure culture.
bacteriology.” Koch’s discovery of the tubercle bacillus and its modes of trans-
During the next 2 years, Koch described novel procedures for mission revolutionized the treatment of tuberculosis. Before the dis-
the examination, preservation, and photography of bacteria and covery, tubercular patients were treated in sanitaria, which offered
demonstrated the role of microorganisms in traumatic infections, fresh air and altitude. Those who ran the sanitaria did not know that
while continuing his dual existence as a country doctor and an tuberculosis was a contagious disease: Sanitation was unregulated,
independent investigator. In 1880, Cohn and Cohnheim arranged and neither sterilization nor fumigation was practiced; diagnostic
for him to move to Berlin as a member of the Imperial Sanitary capabilities were limited. Koch’s discovery of the tubercle bacillus
Commission. The move freed more time for research. By 1881, he revolutionized therapy. For the rest of his life, while pursuing the
made another breakthrough—the pour-plate method for isolat- causes of other diseases around the world—rinderpest in South
ing pure cultures. The opportunity that this technique afforded to Africa, Texas fever, tropical malaria, blackwater fever, and bubonic
12
MCGH423-Ch001_p001-020.indd 12 10/08/22 5:28 PM

CHAPTER 1
Figure 1-17 André Frederic
Cournand (1895–1988) and
Dickinson W. Richards (1895–
1973). After Forssman’s report of
the uneventful catheterization of
his own right heart, Cournand
and Richards pioneered the use
of cardiac catheterization for
the study of the normal and the
abnormal pulmonary circulation
and the standardization of pul-
monary function tests.
plague in Bombay—Koch maintained his interest in tuberculosis. The interposition of the pulmonary circulation between the
This interest, however, led him into a major mistake—advocacy of right and left sides of the heart is a prerequisite for gas exchange.
tuberculin as a vaccine instead of as a diagnostic test. In 1905, he was However, it also serves a variety of other functions, for example, a
awarded the Nobel Prize. On April 7, 1910, the year of his death, he mechanical role, as a filter for particulate matter in blood returning
delivered a final address on the epidemiology of tuberculosis before to the heart, and a metabolic role, effecting the synthesis, uptake,
the Berlin Academy of Sciences. and breakdown of biologic compounds. Extensive studies have been
■ Physiology of the Pulmonary Circulation

Starting with William Harvey,5 studies of the pulmonary circulation
have gone hand in hand with advances in pulmonary physiology and
medicine. For many years, research on the pulmonary circulation
was confined to animal experimentation. A giant step forward was
made with the introduction of cardiac catheterization in humans.
Accurate measurement of pulmonary blood flow is a sine qua
non for assessing pulmonary and cardiac performance in health and
disease. The use of nitrous oxide in humans by Krogh and Lindhard
was an important beginning in this direction, but not until mixed
venous blood could be sampled for application of the Fick principle
could reliable determinations of pulmonary blood flow be made.
Claude Bernard in 1846, and Chauveau and Marey in 1861,
had catheterized the right side of the heart in animal experiments.
Whether this technique could be used safely in humans was not
known until 1929, when Werner Forssmann, a young surgeon in
Germany, introduced a ureteral catheter into his own right atrium.
In the 1940s, Cournand, Richards, and their colleagues resorted to
right heart catheterization to obtain mixed venous blood for the
determination of cardiac output by application of the Fick principle
(Fig. 1-17). The technique opened the way not only to the accurate
determination of cardiac output, but also to exploration of the heart
and lungs in a wide variety of clinical disorders.
Until 1946, when von Euler and Liljestrand reported the effects
of hypoxia and hypercapnia on the pulmonary circulation in an
open-chest preparation of an anesthetized cat (Fig. 1-18),36 there Figure 1-18 Effects of the blood gases on pulmonary arterial pres-
was little understanding of the regulation of the pulmonary circula- sure in the open-chest cat, artificial respiration. LA, left atrial pressure;
tion. However, these studies, coupled with the proposition of local PA, pulmonary arterial pressure; lower trace, systemic arterial blood
control of the pulmonary circulation by local concentrations of pressure. Numbers along the baseline represent the administration of
the respiratory gases, paved the way to understanding pulmonary test gases: 1, O2 (from air); 2, 6.5% CO2 in O2; 3, O2; 4, 18.7% CO2 in CO2;
hypertension and the behavior of the pulmonary circulation in nor- 5, O2; 6, 10.5% O2 in N2; 7, O2. (Reproduced with permission from Von Euler
mal individuals at rest, after birth, during exercise, and at altitude, US, Liljestrand, G: Observations on the pulmonary arterial blood pressure
and in individuals with heart or lung disease. in the cat. Acta Physiol Scand. 1946;12(4):301–320.)
13
MCGH423-Ch001_p001-020.indd 13 10/08/22 5:28 PM

conducted in recent decades on the nonrespiratory functions of the
lungs. From these studies has emerged considerable understanding
of the diverse functions served by the branching pulmonary circu-
PART 1
lation and its components, including the endothelium and smooth

muscle and their interplay.
TECHNOLOGIC ADVANCES THROUGH

THE EARLY 20TH CENTURY
The road to contemporary pulmonary medicine could be just as
easily traced by using technologic advances as landmarks, instead
Perspectives
of people and discoveries. For example, the introduction of the

manometer for pressure recording, the use of chambers to simulate
high altitude, the development of accurate blood gas analyzers,
and the application of sophisticated optical systems for viewing the
lumens of the airways and the inside of the chest cavity are all nota-
ble milestones. However, probably no better example exists than the
discovery of radiographs and the application of this discovery to the
diagnosis, prevention, and management of pulmonary tuberculosis.
Wilhelm Conrad Roentgen discovered radiographs in 1895 while
experimenting with cathode ray tubes in his physics laboratory at the
University of Wurzburg. Although others before him had seen radio-
graphs as early as 1890, Roentgen was apparently the first to grasp the
full significance of the discovery, and his publication, quite unpreten-
tious, immediately attracted worldwide attention because of its pros-
Figure 1-19 The first clinical CT scan, obtained in 1971. The grainy
pects for the study of anatomic structures and pathologic changes.
image shows a brain tumor in a frontal lobe (left side of image).
Within 2 years after Roentgen’s discovery, fluoroscopy of the chest
Advances in image quality over the last four decades have been dra-
had been introduced into clinical practice, and its value in the early
matic. (Reproduced with permission from impactscan.org.)
detection of tuberculosis and the diagnosis of pleural effusions was
appreciated. In 1901, an atlas of chest radiographs was published,
and the use of chest radiography increased greatly with each sub-
sequent improvement in hot cathode radiograph tubes and inten-
sifying screens. The radiographic evaluation of tuberculosis was
superior to physical examination for diagnosis and characterization
of the disease. By 1910, all patients admitted to sanatoriums had a
chest radiographic examination, and by 1917 tuberculosis was clas-
sified according to radiographic findings.
MAJOR DEVELOPMENTS SINCE THE MID-20TH CENTURY

Many notable developments have occurred over the last 60 years in
pulmonary medicine and the related field of critical care. Measured
against the metric of having a broad and deep impact on clinical
care, several are particularly noteworthy: advances in thoracic imag-
ing, lung transplantation, bronchoscopy and interventional bron-
choscopic techniques, and advances in management of the critically
ill, including those infected with COVID-19 (SARS-CoV-2).
■ Advances in Thoracic Imaging

Following Roentgen’s discovery of the x-ray at the turn of the 20th
century, another major diagnostic leap forward in pulmonary medi-
cine occurred with development of computerized tomography (CT)
in the 1960s.37–39 In 1967, the first experimental CT scan was gener-
ated, with computer reconstruction of an image of a mouse taking
9 days to complete. The first human application was a head CT
that demonstrated a brain tumor (Fig. 1-19). In 1973, Dr. Godfrey
Hounsfield published a description of CT scanning in the British
Journal of Medicine. Along with Dr. Allan Cormack, Hounsfield
(Fig. 1-20) was awarded a Nobel Prize in 1979.
Application of CT to lung imaging arose in the mid-1970s; high-
resolution techniques were developed in the 1980s. Multi-slice CT
scanning now permits rapid acquisition of high-resolution images
from which multiplanar reconstructions can be derived (Fig. 1-21). Figure 1-20 Dr. Godfrey Hounsfield, inventor of computerized
Elegant characterization and classification of a variety of interstitial tomography (CT). Along with Dr. Allan Cormack, Hounsfield was
and airway diseases is now possible using CT. In addition, when awarded a Nobel Prize in 1979. (Reproduced with permission from Visible
coupled with intravenous contrast injection (CT angiography), Proofs, National Library of Medicine, National Institutes of Health.)
14
MCGH423-Ch001_p001-020.indd 14 10/08/22 5:28 PM

Another random document with
no related content on Scribd:
find them, he at last went down into the cellars, and
soon perceived whereabout they lay: he stepped up to
the place, and, on a sudden, made his appearance
over the edge of the tun. The Monks were prodigiously
alarmed at this unexpected appearance of the Abbot;
and there was none among them but who would have
gladly compromised the affair, by giving up his
remaining share of the entertainment, and submitting
to instant dismission. But the Abbot, contrary to all
hope, put on a mild and chearful look: he kindly
expostulated with the Monks on their having made a
secret of the affair to him; expressed to them the great
pleasure it would have been for him to be one of their
party; and added, that he should still be very glad to be
admitted to partake of the entertainment. The Monks
answered, by all means: the Abbot thereupon leaped
into the tun; sat down among them; partook of their
excellent wine and well-seasoned dishes with the
greatest freedom, in just the same manner as it is said
the late Sir James Lowther would of the dinner of his
servants in his own kitchen; and, in short, spent an
hour or two with them in the tun, in the most agreeable
and convivial manner.
At last, the Abbot thought proper to withdraw; and as
soon as he had taken his leave, some of the Monks
began to admire his extraordinary condescension;
while the others were not without fears that it
foreboded some misfortune. Indeed, the latter were in
the right; for the Reader must not think that the Abbot
had acted in the manner above-described, out of any
sudden temptation he had felt at the sight of the jollity
of the Friars, or of the dainties that composed their
entertainment: by no means; his design had only been,
by thus making himself guilty along with them, to be
the better able to shew them afterwards the way to
repentance, and thereby derive good from evil. In fact,
the next day, a chapter having been summoned, the
Abbot desired the Prior to fill his place, while himself
took his feat among the rest of the Monks. Soon after
the Chapter was met, he stepped forward into the
middle of the Assembly, accused himself of the sin he
had committed the day before, and requested that
discipline might be inflicted upon him. The Prior
objected much to a discipline being inflicted on the
Abbot; but the latter having insisted, his request was
complied with. The other Monks were at first greatly
astonished; but seeing no possibility of keeping back
on that occasion, they stepped into the middle of the
Chapter, and likewise confessed their sin; when the
Abbot, by means of a proper person he had selected
for that purpose, got a lusty discipline to be inflicted
upon every one of his late fellow-banqueters.
[59] Which signifies, to sip, or to swallow.
[60] He who drinks three times before the others.
C H A P. X.
Strictness of certain Superiors of Convents, in

exerting their power of flagellation. The same
is abused by several of them.
THE Reader has seen, in the preceding Chapter, that

the punishment of flagellation was extended to
almost every possible offence Monks could commit;
and the duration of the flagellations was, moreover,
left pretty much to the discretion of the Abbot,
whether in consequence of the generality of the
terms used in the Statutes, or through some express
provision made for that purpose. In the ancient
Constitutions of the Monastery of Cluny, for instance,
which St. Udalric has collected in one volume,
several kinds of offence are mentioned, for the
punishment of which it is expressly said, that the
Offender shall be lashed as long as the Abbot shall
think meet.
That Abbots and Priors have at all times well
known how to exert those discretionary and
flagellatory powers we mention, there is no manner
of doubt. On this occasion, the two following stories
may be related.
The first is that of the discipline which the Prior of a
certain Monastery, who lived in the times of Charles
Martel (A. 750) inflicted on some Carpenters who
were employed by him in the service of the Convent,
and who having too carelessly marked the proper
size of a certain piece of timber, with their string
rubbed with chalk, made afterwards a mistake in
sawing it. The fact, as it is recited in the life of St.
Pardulph, is as follows.
‘One Liframnus, the then Prior of the Monastery,
resolved to build a few wooden steps, in the Chapel
of St. Albinus the Martyr. After the Carpenters had
measured the place on which those steps were to be
raised, he took them to the wood, where they
accordingly cut a beam, which they loaded upon a
Cart, and conveyed to the Convent; but when they
attempted to settle it upon the proper spot, it was
found to be eighteen inches too short. The Prior,
amazed at such a gross mistake, fell into a passion,
and ordered disciplines to be inflicted upon the
Carpenters[61].’
The other fact I mean to relate, to prove the great
strictness of certain Ecclesiastical Superiors in
exerting their power of flagellation, is contained in the
Book written by Thomas de Chantpré. ‘There was
(that Author says) in the Church of Rheims, a very
able Dean, an Englishman by birth (genere
Anglicano), who, as I have been informed by several
persons who knew him, used stoutly to correct his
brother Canons for their faults. It happened in his
time, that the venerable Albert, Bishop of Liege, and
Brother to the Duke of Brabant, was driven out of
Germany by the Emperor Henry, and treacherously
slain by a few Soldiers of that Emperor, near the City
of Rheims. On the day appointed to celebrate his
funeral, the venerable Rothard, who, though he was
still Archdeacon of Rheims, had lately been elected
Bishop of Châlons in Champagne, made his
appearance, accompanied by a number of noble
persons, without being clothed in his Canonical
gown. After the ceremony was concluded, the Dean
called all the Canons together, and among them the
above Bishop. As soon as they were seated, the
Dean said to the Prelate, You have not, as far as I
know, resigned yet your Canonship, or
Archdeaconship? The latter made answer, he had
not. Well then, said the Dean, come and make
satisfaction to the Church, and prepare your back for
a discipline in the presence of the Brothers, for your
having been at the choir without the nuptial robe. The
Bishop-elect made no objection: he rose from his
seat, stripped himself, and received a most vigorous
discipline from the Dean: this done, he put on again
his clothes, and, before the whole congregation, said
to the Dean in a most graceful manner, I give thanks
to God, and to his blessed Mother, the Patroness of
the Church of Rheims, that I leave it under the
government of such a person as you[62].’
Indeed so far have a number of Abbots, or
Superiors of Convents, been from suffering their
power of flagellation to lay dormant and useless, that
they, on the contrary, have abused it to a great
degree. Ovisiesius cautioned them, in very early
days, against being guilty of such a fault. Nay, certain
Heads of Monasteries have gone such lengths in that
respect, that Cesarius, Bishop of Arles, was obliged
to remind them, that, ‘if they inflicted flagellations
continued too long upon Offenders, so that they died
in consequence thereof, they were guilty of
homicide.’
Among those Abbots who have distinguished
themselves by their severity, St. Romuald may be
mentioned, who, as we are informed in his Life
written by Cardinal Damianus, was once exposed to
a calumny of the blackest kind, from a Monk whom
he used to scourge with great severity: nay, that holy
Man’s Monks, as we are also informed by Cardinal
Damianus, in one instance rose against him, flogged
him without mercy, and drove him out of the Convent.
This Saint, besides, had before been frequently
lashed by the Devil[63].
FOOTNOTES:
[61] ... Tum Præpositus multum scandalizans, &

iracundiæ furore succensus, eisdem Carpentariis
disciplinam corporis imponi jussit.
Aulus Gellius, in his Noctes Atticæ, relates a fact
which bears much resemblance to the above; though,
indeed, much greater Men were concerned in it, than
the Prior of a Convent, and Carpenters: the one was a
Roman Consul, and the other, the Engineer of a Town,
allied to the Republick.
The name of the Consul in question was P. Crassus,
who must not, however, be mistaken for the celebrated
M. Crassus, the partner in power with Pompey and
Cæsar; though both lived in the same times. This
Consul P. Crassus, having been intrusted with the
conduct of the war that was then carrying on in Asia,
laid siege to the Town of Leucas; and wanting a strong
beam of oak to make a battering-ram, he recollected
he had lately seen at Elæa, a Town allied to the
Romans, just such a piece of timber as he wished to
have: he therefore wrote to the Magistrates of that
place, to request them to send it to him. The
Magistrates accordingly directed their Engineer to
convey the beam to Crassus; but as there was another
in the yards belonging to the Town, which, the
Engineer thought, would be fitter for the use Crassus
wanted to put it to, he made choice of the latter, and
conveyed it to the Roman camp. However, the
Engineer had been mistaken in his calculations, and
the beam unfortunately proved too small; which the
Consul did no sooner perceive, and that his orders had
been neglected, than, like the above-mentioned Prior,
he fell into a passion, and ordered the Engineer to be
stript, and soundly lashed.
Some apology, however, may be made in favour of
the action of the Roman Consul. As himself observed
upon the spot, the whole business of war would be at
an end, if those whose duty it is to obey, were
permitted to canvass the orders which they receive,
and to set aside what part they please: besides that an
allowance should be made for Men of a military life,
and who are invested with military command; and
some little indulgence, I think, ought to be shewn them,
when they happen to inflict flagellations somewhat
cavalierly. But as to the above holy Prior, who had
made so many vows of obedience, humility,
forbearance, and the like, it is not, indeed, quite so
easy a talk to excuse him: I shall not, therefore,
undertake it; and I will content myself with observing,
how advantageous it would have been both for the
above Engineer and Carpenters, in the perplexing
situations in which they were respectively placed, to
have possessed a power of the same kind as that
which the Golden Legend (or perhaps some other
Book of equal merit) supposes Jesus Christ to have
exerted on a similar occasion. Joseph, as it is related,
who had the care of the infant Jesus trusted to him,
tried to bring him up to his own trade of a Carpenter;
and one day, finding that the Boy had sawed a piece of
wood shorter than the measure he had prescribed, he
ran up to him, full of anger, with a stick raised in his
hand, in order to chastise him; but the arch apprentice,
who was beginning to be conscious of his power of
working miracles, on a sudden exerted it, and
lengthened the piece of wood to its proper size.
[62] ... Nec mora, vestes exuit Electus, & Decani
validissimam disciplinam accepit: quâ acceptâ,
vestibus reindutus, Decano cum maximâ oris gratiâ
coram omnibus dixit; gratias ago Deo, & Patronæ
Remensis Ecclesiæ ejus piissimæ genitrici, quod te
talem in regimine relinquo. Lib. II. Cap. XXXIX. Num.
20.
[63] The arbitrary power of inflicting flagellations,
possessed by Abbots, ought, one should think, to
insure them in a high degree the veneration of their
Monks; yet, from the manner in which St. Romuald is
above said to have been used by those under his
government, we may conclude the case is otherwise.
A farther proof of the great freedom with which
Monks use their Abbots, is to be derived from what
Mons. Richelet says, in his well-known Dictionary of
the French language, that Monks never trouble their
heads about waiting for their Abbot, when he comes
too late to dinner. Mons. Richelet informs us of this fact
under the word Abbé, when he explains the origin of
the French common saying, on l’attend comme les
Moines font l’Abbé (they wait for him, as Monks do for
their Abbot), which is said jocularly of a person who is
not at all waited for: this saying is derived, the above
Gentleman observes, from the remarkable expedition
with which Monks sit down to their dinner, as soon as
the bell strikes, without caring whether the Abbot is
come or not.
This singular piece of neglect on the part of Monks,
towards a person invested with such formidable
prerogatives as those abovementioned, may be
accounted for, different ways. In the first place, since
Monks are so celebrated for their love of good dinners,
and even entertain such high notions of the value of a
plentiful table, as to have rated the hardship of living
upon bread and water, at that of receiving a hundred
lashes a day, we may naturally suppose, that, when
their mess is served upon the table, their attention is
so agreeably engaged by the presence of that object,
that they presently run to it, wholly regardless of any
trifling flagellation that may afterward be the
consequence of such expedition.
The same neglectful conduct of Monks towards their
Abbot, though he is possessed of such a despotic
power over them, may also be explained in another
manner: for, the subject is deep, and being considered
in a political light, may admit a number of different
interpretations. In general, it may be observed, that
Monks may easily form close combinations among
themselves against their Abbots; that as the latter live
together with them, within the walls of the same
Monasteries, they have it in their power to play them a
thousand tricks; and that these considerations are very
apt to induce Abbots to make a mild use of their
authority, at least with respect to the greater part of
their Monks.
Indeed this latter explanation agrees pretty well with
several facts. It has frequently happened, for instance,
that Abbots who have used their Monks with cruelty,
have been made away with, in some way or other,
within the walls of their Monasteries. The Abbé Boileau
informs us in his Book, that St. Romuald was much
maltreated, and at last expelled by his Monks; which,
no doubt, was owing to the flagellations he inflicted
upon them; flagellations which the Abbé also
mentions, though he does not assign the causes of
them, whether it was because they did not wait for him
at dinner, or for some other reason, but the truth and
severity of which we shall the more readily believe, if
we consider that the Saint, upon a certain occasion, as
will be related hereafter, flagellated even his own
Father. Nay, it is not quite unlikely that those
flagellations which the Saint used to imagine he
received from the hands of the Devil, were the effects
of the revenge of his Monks; till at last they openly
revolted against him, and turned him out of the
Monastery.
Since we are upon the subject of St. Romuald, it will
not be amiss to add, that the flagellations which he
received both from the Devil, and from his Monks,
were however nothing in comparison with the danger
to which he was once exposed, on account of his very
sanctity.
The Saint, as is related in the History of his Life, was
once settled in a certain Convent in Catalonia, and
was in great reputation for his virtue in the
neighbourhood. The report having been spread that
the holy Man was going to leave the Country, the
People began to be afraid that they should thereby be
deprived of the possession of his relicks, to which they
thought they had a fair title, on account of the length of
time he had resided among them; and they formed the
ingenious scheme of murdering him, in order to secure
to themselves the possession of his body; but the
Saint, having received timely information of the plot,
thought proper to decline the honour that was intended
for him, and made his escape.
C H A P. XI.
Disciplines of the same wholesome kind have

been prescribed for Novices, and such
persons as are intended to embrace the
Ecclesiastical Life.
THE framers of Rules and Statutes of religious

Orders have also extended their attention to the
young Men and Novices brought up in Convents; and
have ordered flagellations to be inflicted upon them,
for the improvement of their morals. In the Rule
framed by the holy Fathers Serapion, Macarius, and
Paphnutius, which is to be found in the Collection of
Holstenius, it is ordered, ‘That if any Novice is found
guilty of theft, he shall be lashed with rods, and never
admitted to the degree of Clerk.’
St. Pacom, in that Rule which was dictated to him
by an Angel, expresses himself in the following
terms: ‘Let those Boys who are regardless of the evil
consequences of sin, and are so imprudent as not to
mind the judgments of Heaven, in case admonitions
prove useless, be whipped till they have the fear of
God.’
In the Rule of St. Benedict, Art. LXX. flagellations
are prescribed as excellent methods of improving the
minds of such Boys as are brought up to the
Ecclesiastic life; and are more particularly
recommended to be used till they are fifteen years of
age.
St. Isidorus, archbishop of Seville, observes, that
Boys ought not to be excommunicated for their sins,
but that this awful mode of correction ought to be
supplied, with them, by flagellations.
At the same time, lest those who were to inspect
the conduct of the Novices, should suffer themselves
to be influenced by passion, in the flagellations they
were directed to inflict, an express provision was
made in the Rule of St. Benedict, that such Teachers
as should be guilty of the above fault, should
themselves receive a sound flogging[64].
FOOTNOTES:
[64] A certain modern Latin Author, whose name I

have forgot, has written a Treatise on the antiquity of
the practice so much recommended above, of
whipping boys at School. Had I been so happy as to
have seen his Book, I would have been enabled to
make, in this place, learned remarks on the subject;
but as I have not had that advantage, I find myself
unable to make any, and can only refer the Reader to
the discovery of Uncle Thomas, as well as to the few
other critical annotations that are contained in p. 76,
77, 78, of this Work.
I could have likewise wished much to be able to add
the names of some of those illustrious Characters who
have distinguished themselves in the practice of
flagellating School-boys, to those of the respectable
Thwackum, and the plagosus Orbilius, mentioned in
the above place; but though the History of great
Schools, in this and other Countries, supplies numbers
of such names, yet I have not been able to discover
any of sufficient eminence to deserve a place in this
Book; except indeed that of the great Doctor Tempête,
who is mentioned by Rabelais as a celebrated
flagellator of School-boys in the College of Montaigu,
in Paris, and which I therefore insert in this place.
Neither should we neglect to mention here, the
name of Buchanan, his pupil having afterwards been a
King; and the more so, as he used, it seems, to make
the flagellations bestowed by him on his royal disciple
(the Anointed of the Lord) the subject of his jokes with
the Ladies at Court[65].
The justice which is due to the Reverend Fathers
Jesuits, also requires that we should, in a Book like
this, give an account of the laudable regularity with
which they used to inflict flagellations upon the young
Men who pursued their studies in their Schools, as well
as upon such Strangers as were occasionally
recommended to them for that purpose. Among the
different facts which may serve to prove both the spirit
of justice that has constantly directed the actions of the
Society, and the punctuality of their flagellations, the
following is not the least remarkable.
It was, the Reader ought to know, an established
custom in their Schools, to give prizes every year to
such Scholars as had made the best Latin verses upon
proposed subjects. One year it happened that the
subject which had been fixed upon, was the Society of
the Jesuits itself; and a Scholar took that opportunity,
only by quibbling on the names of the two principal
Schools belonging to the Fathers, to give them a smart
stroke of satire. The name of the one of these two
Schools, was the School of the Bow (le Collège de
l’Arc), which was situated at Dôle, in Franche-Comté;
and the other happened to be called, the School of the
Arrow (la Flêche), it being situated near the Town of
that name in Anjou, and was originally a Royal
mansion which was given by the Crown to the Society,
in the reign of King Henry the Fourth. The import of the
distich made by the School-boy (or perhaps by
somebody else for him) was this: “Dôle gave the Bow
to the Fathers, mother France gave them the Arrow;
who shall give them the String which they have
deserved?” The following are the Latin verses
themselves, which indeed are very beautiful.
Arcum Dôla dedit Patribus, dedit alma Sagittam
Gallia; quis funem quem meruere dabit?
The Reverend Fathers, struck with the merit of these
lines, and, at the same time, unwilling to suffer a bon-
mot made at their expence, and that was so likely to
be circulated, to go unpunished, delivered the prize to
the boy, and ordered him to be flagellated immediately
after.
The celebrated Fathers of St. Lazare, in Paris,
whose School was otherwise named the “Seminary of
the good Boys” (des bons enfans) have no less
recommended themselves by the regularity of the
disciplines they inflicted, than the Reverend Fathers
Jesuits. They were even superior to the latter, in
regard to those recommendatory flagellations
mentioned above, which were administered to such
persons as were, by some means or other, induced to
deliver letters to the Fathers for that purpose. Being
situated in the metropolis, the Seminary carried on, a
very extensive business in that way. Fathers or
Mothers who had undutiful Sons, Tutors who had
unruly Pupils, Uncles who were intrusted with the
education of ungovernable Nephews, Masters who
had wickedly-inclined Apprentices, whom they durst
not themselves undertake to correct, applied to the
Fathers of St. Lazare, and by properly seeing them,
had their wishes gratified. Indeed the Fathers had
found means to secure their doors with such good
bolts, they were so well stocked with the necessary
implements or giving disciplines, and had such a
numerous crew of stout Cuistres to inflict them, that
they never failed to execute any job they had engaged
to perform, and without minding either age, courage, or
strength, were at all times ready to undertake the most
difficult flagellations. So regular was the trade carried
on, by the good Fathers in that branch of Business,
that letters of the above kind directed to them, were
literally notes of hand payable on sight; and provided
such notes did but come to hand, whoever the bearer
might be, the Fathers were sure to have them
discharged with punctuality.
This kind of business, as it was carried on, for a
number of years, frequently gave rise to accidents, or
mistakes, of rather a ludicrous kind. Young men who
had letters to carry to the House of St. Lazare, the
contents of which they did not mistrust, would often
undesignedly charge other persons to carry the same
for them, either on account of their going to that part of
the town, or for some other reason of a like kind: and
the unfortunate bearer, who suspected no harm, had
no sooner delivered the dangerous letter with which he
had suffered himself to be intrusted, than he was
collared, and rewarded for his good-nature by a severe
and unexpected flagellation.
Ladies, it is likewise said, who had been forsaken, or
otherwise ungenteelly used, by their Admirers, when
every other means of revenge failed, would also recur
to the ministry of the Fathers of St. Lazare. Either by
making interest with other persons, or using some
artfully-contrived scheme, the provoked Fair-one
endeavoured to have the Gentleman who caused her
grief, inveigled into the House of the Seminary: at the
same time she took care to have a letter to
recommend him, sent there from some unknown
quarter, with proper fees in it; for that was a point that
must not be neglected: and when the Gentleman came
afterwards to speak with the Fathers, he was no
sooner found by them, either from the nature of the
business he said he came upon, or other marks, to be
the person mentioned in the letter they had before
received, than they shewed him into an adjoining-
room, where this treacherous and deceitful Lover was
immediately seized, mastered, and every thing in short
was performed that was requisite to procure ample
satisfaction to the fair injured Lady.
It is also said (for a number of stories are related on
that subject, and the Seminary of St. Lazare was
become for a while an object of terror to all Paris) that
schemes of the most abusive kind were in latter times
carried on, through the connivance which the Fathers
began to shew at the knavery of certain persons: and
this indeed seems to be a well-ascertained part of the
story. Abuses of the same kind as those which once
prevailed in the Mad-houses established in this
country, were at last practised in the Seminary. Men
possessed of estates which some near relations
wanted to enjoy, or whom it was the interest of other
persons to keep for a while out of the way, were
inveigled into the House of St. Lazare, where they
were detained, and large sums paid monthly for their
board. Though they might be full-grown persons, they
were boldly charged with having been naughty, or
such-like grievous guilt; and the Fathers, in order to
shew that they meant to act a perfectly honest part in
the affair, ordered them to be flagellated with more
than common regularity.
Nor was it of any service for the unfortunate
boarders to expostulate with the Fathers, to insist that
it was unlawful to detain them by force in a strange
house, and use them in the manner they were used,
that they had important affairs which they must go and
settle, that they were no boys, after all, or to offer other
equally pertinent arguments: the Fathers continued to
be well paid; they cared for no more; and all the
complainants got by raising objections like these, were
cold negative answers, and fresh flagellations. Abuses
of the kind we mention, came at last to the knowledge
of the Government, which interposed its authority, and
the Seminary was abolished.
[65] King James the First.—See Dr. Berkenhout’s
Biographia Literaria.

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Fishman's Pulmonary Diseases and

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Charles S. Dela Cruz, MD, PhD Allan I. Pack, MBChB, PhD

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Names: Grippi, Michael A., editor.

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VOLUME 1 17 Acid–Base Balance.. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 236

10 Pulmonary Mechanics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 SECTION 6 Diagnostic Procedures

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Marco Guazzi / Alice Moroni

PART 4: Obstructive Lung Diseases 55 Idiopathic Interstitial Pneumonias

SECTION 9 Other Obstructive Disorders

47 Upper Airway Obstruction in Adults. . . . . . . . . . . . . . . . . . . 794 PART 7: Other Infiltrative and

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76 Nonmalignant Pleural Effusions. . . . . . . . . . . . . . . . . . . . . 1320 92 Diving Physiology and Dysbarism.. . . . . . . . . . . . . . . . . . . 1593

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122 Approach to Pulmonary Infection

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143 Oxygen Therapy and Toxicity. . . . . . . . . .. . . . . . . . . . . . . 2507

146 Hemodynamic and Respiratory Monitoring in Acute

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Department of Internal Medicine Clinical Fellow in Pediatrics, Harvard Medical School

Yale School of Medicine Boston Children’s Hospital

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Vice President for Medical Affairs, UM Baltimore Professor of Medicine

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Director of Pulmonary and Critical Care Medical Director

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Professor of Pulmonary Medicine, Dipartimento di Medicina Clinical Assistant Professor

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Assistant Professor Professor of Medicine

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1 Milestones in the History of Pulmonary Medicine. . . . . . . . . 2

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that includes case reports, textbooks, lectures, and notebooks. The