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a LANGE medical book

2021
CURRENT
Medical Diagnosis
& Treatment
SIXTIETH EDITION

Edited by

Maxine A. Papadakis, MD
Professor of Medicine, Emeritus
Department of Medicine
University of California, San Francisco

Stephen J. McPhee, MD
Professor of Medicine, Emeritus
Division of General Internal Medicine
Department of Medicine
University of California, San Francisco

Associate Editor

Michael W. Rabow, MD
Professor of Medicine and Urology
Division of Palliative Medicine
Department of Medicine
University of California, San Francisco

With Associate Authors

Mc
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 Contents
Authors v 13. Blood Disorders 512
Preface xiii
Lloyd E. Damon, MD, & Charalambos Babis
1. Disease Prevention & Health Promotion 1 Andreadis, MD, MSCE

Michael Pignone, MD, MPH, & Rene Salazar, MD
2. Common Symptoms
Paul L. Nadler, MD, & Ralph Gonzales, MD, MSPH
14. Disorders of Hemostasis, Thrombosis, &
Antithrombotic Therapy 558
16
Andrew D. Leavitt, MD, Erika Leemann Price, MD,
MPH, & Tracy Minichiello, MD

3. Preoperative Evaluation & Perioperative 15. Gastrointestinal Disorders 592

Management 44
Kenneth R. McQuaid, MD
Hugo Q. Cheng, MD
16. Liver, Biliary Tract, & Pancreas
4. Geriatric Disorders 54 Disorders 693
G. Michael Harper, MD, C. Bree Johnston, Lawrence S. Friedman, MD
MD, MPH, & C. Seth Landefeld, MD
17. Breast Disorders 758
5. Palliative Care & Pain Management 70
Armando E. Giuliano, MD, FACS, FRCSEd, &
Michael 1/1/. Rabow, MD, Steven Z. Pantilat, MD, Sara A. Hurvitz, MD, FACP
Ann Cai Shah, MD, Lawrence Poree, MD, MPH, PhD,
& Scott Steiger, MD 18. Gynecologic Disorders 785

6. Dermatologic Disorders 102 Jason Woo, MD, MPH, FACOG, &

Jill Long, MD, MPH, MHS, FACOG
Kanade Shinkai, MD, PhD, & Lindy P. Fox, MD
19. Obstetrics & Obstetric Disorders 820
7. Disorders of the Eyes & Lids 173
Vanessa L. Rogers, MD, & Scott W. Roberts, MD
Jacque L. Duncan, MD, Neeti B. Parikh, MD, &
Gerami D. Seitzman, MD 20. Rheumatologic, Immunologic,
& Allergic Disorders 849
8. Ear, Nose, & Throat Disorders 210
Jinoos Yazdany, MD, MPH, Rebecca Manno, MD,
Lawrence R. Lustig, MD, & Joshua S. Schindler, MD MHS, David B. Hellmann, MD, MACP, &John B.
Imboden Jr., MD
9. Pulmonary Disorders 251
Asha N. Chesnutt, MD, Mark S. Chesnutt, MD, 21. Electrolyte & Acid-Base Disorders 909
Niall T. Prendergast, MD, & Nayan Arora, MD, &J. Ashley Jefferson, MD
Thomas J. Prendergast, MD
22. Kidney Disease 938
10. Heart Disease 334
Tonja C. Dirkx, MD, & Tyler B. Woodell, MD, MCR
Thomas M. Bashore, MD, Christopher B. Granger,
MD, Kevin P. Jackson, MD, & Manesh R. Patel, MD 23. Urologic Disorders 980
11. Systemic Hypertension 453 Mathew Sorensen, MD, MS, FACS, Thomas J. Walsh,
MD, MS, & Kevin A. Ostrowski, MD
Michael Sutters, MD, MRCP (UK)
24. Nervous System Disorders 1005
12. Blood Vessel & Lymphatic Disorders 485
Vanja C. Douglas, MD, &
Warren J. Gasper, MD, James C. lannuzzi, MD, MPH, Michael J. Aminoff, MD, DSc, FRCP
& Meshell D. Johnson, MD

iii
 iv CMDT2021 CONTENTS

25. Psychiatric Disorders 1082 39. Cancer 1654

Kristin S. Raj, MD, Nolan Williams, MD, & Sunny Wang, MD, Tiffany 0. Dea, PharmD, BCOP,
Charles DeBattista, DMH, MD Patricio A. Cornett, MD, Lawrence S. Friedman, MD,
Carling Ursem, MD, Kenneth R. McQuaid, MD, &
26. Endocrine Disorders 1138 George R. Schade, MD
Paul A. Fitzgerald, MD
40. Genetic & Genomic Disorders 1721
27. Diabetes Mellitus & Hypoglycemia 1242 Reed E. Pyeritz, MD, PhD
Umesh Moshorani, MB, BS, MRCP (UK)
41. Sports Medicine & Outpatient
Orthopedics 1730
28. Lipid Disorders 1288
Anthony Luke, MD, MPH, &C. Benjamin Mo, MD
Michael J. Blaha, MD, MPH
42. Sexual & Gender Minority Health 1765
29. Nutritional Disorders 1299
Juno Obedln-Mallver, MD, MPH, MAS,
Katherine H. Sounders, MD, &
Patricio A. Robertson, MD, Kevin L. Arc/, MD, MPH,
Leon I. lgel, MD, FACP, FTOS Kenneth H. Moyer, MD, &Madeline B. Deutsch,
MD, MPH
30. Common Problems in lnfedious
Diseases & Antimicrobial Therapy 1320 e1. Anti-lnfedive Chemotherapeutic &
Peter V. Chin-Hong, MD, & Antibiotic Agents Online*
B. Joseph Guglielmo, PharmD Katherine Gruenberg, PharmD, &
B. Joseph Guglielmo, PhormD
31. HIV Infection & AIDS 1361
Mitchell H. Katz, MD e2. Diagnostic Testing & Medical
Decision Making Online*
32. Viral & Rickettsial Infections 1403 Chuonyi Mark Lu, MD
Eva Clark. MD, PhD, & Wayne X. Shandera, MD
e3. Information Technology in Patient
33. Baderlal& Chlamydlallnfectlons 1490 Care Online*
Bryn A. Boslett, MD, & Brion S. Schwartz, MD Russ Cue/no, MD, MS

34. Spirochetal Infections 1535 e4. Integrative Medicine Online*

Susan S. Philip, MD, MPH Dorshon Mehta, MD, MPH

35. Protozoal& Helminthic Infections 1552 e5. Podiatric Disorders Online*

Philip J. Rosenthal, MD Monara Dlnl, DPM, & Charles B. Parks, DPM

36. Mycotic Infections 1593 e6. Women's Health Issues Online*

Stacey R. Rose, MD, & Richard J. Hamill, MD Brigid Dolan, MD, MEd, & Judith Walsh, MD, MPH

37. Disorders Related to Environmental e7. Appendix: Therapeutic Drug Monitoring,

Emergencies 1608 Laboratory Reference Intervals, &
Pharmacogenetic Tests Online*
Jacqueline A. Nemer, MD, FACEP, &
Marianne A. Juarez. MD Chuanyi Mark Lu, MD

Index 1787
38. Poisoning 1624
Craig Smollin, MD, & Kent R. Olson, MD

"Free access to online chapters at www.accessmedicine.com/cmdt

 Preface
Current Medical Diagnosis & Treatment 2021 (CMDT 2021) is the 60th edition of this single-source reference for
practitioners in both hospital and ambulatory settings. The book emphasizes the practical features of clinical diagnosis and
patient management in all fields of internal medicine and in specialties of interest to primary care practitioners and to
subspecialists who provide general care.
Our students have inspired us to look at issues of race and justice, which surely impact peoples health. We have therefore
reviewed the content of our work to ensure that it contains the dignity and equality that every patient deserves.

INTENDED AUDIENCE FOR CMDT

House officers, medical students, and all other health professions students will find the descriptions of diagnostic and
therapeutic modalities, with citations to the current literature, of everyday usefulness in patient care.
Internists, family physicians, hospitalists, nurse practitioners, physician assistants, and all primary care providers will
appreciate CMDT as a ready reference and refresher text. Physicians in other specialties, pharmacists, and dentists will find
the book a useful basic medical reference text. Nurses, nurse practitioners, and physician assistants will welcome the format
and scope of the book as a means of quickly referencing medical diagnosis and treatment modalities.
Patients and their family members who seek information about the nature of specific diseases and their diagnosis and
treatment may also find this book to be a valuable resource.

NEW IN THIS EDITION OF CMDT

• INNOVATIVE TABLE highlighting the “Year in Review: Key Clinical Updates in CMDT 2021,” individually listed with
page numbers and reference citations, for easy access to significant changes in this edition
• New section on SARS-CoV-2 virus and COVID-19 infection
• Extensive revision of the Viral & Rickettsial Infections chapter, including new section on acute flaccid myelitis as well
as updates on measles, mumps, and Zika virus
• 140 NEW online images in the Heart Disease, Gastrointestinal Disorders, and Cancer chapters
• Addition of the 2019 European guidelines for treating pulmonary embolism
• New table outlining agents to consider for reversing anticoagulant effect during life-threatening bleeding based on the
Anticoagulation Forum and American Society of Hematology 2019 guidelines
• Bedaquiline considered first-line medication for multidrug-resistant tuberculosis
• Lefamulin, a new commercially available medication for treating community-acquired bacterial pneumonia
• New information on the combination of emtricitabine/tenofovir alafenamide as antiretroviral treatment for preexposure
prophylaxis among men
• A two-drug regimen, dolutegravir plus lamivudine, included in the top recommended HIV antiretroviral regimens
• Recommendation from the Advisory Committee on Immunization Practices for shared clinical decision-making
regarding HPV vaccination for adults aged 26-45 years
• Substantial revision of the Sexual & Gender Minority Health chapter
• Bempedoic acid, a new FDA-approved pharmacologic option for lowering LDL cholesterol in patients who cannot toler­
ate statins
• FDA approval of various closed loop systems that adjust basal insulin delivery for diabetic patients
• Eculizumab, a newly FDA-approved medication for both myasthenia gravis and neuromyelitis optica
• FDA approval of lasmiditan, a new pharmacologic option that can safely be given to migraine sufferers with cardiovas­
cular risk factors
• The sodium-glucose linked transporter (SGLT) inhibitors slow progression of early diabetic nephropathy in addition to
their having cardioprotective effects
• The US Preventive Services Task Force recommendation for hepatitis C screening of asymptomatic adults between ages
18 and 79 years

xiii
 XIV CMDT 2021 PREFACE

• FDA approval of adjuvant trastuzumab emtansine for patients with HER2-positive breast cancer with residual disease
after standard trastuzumab-containing neoadjuvant therapy
• Data from HER2CLIMB, a phase III trial, expected to lead to FDA approval of a new therapy for breast cancer patients
with pretreated HER2-positive advanced disease
• Promising results from phase 3 clinical trials of gene therapy for hemophilia A and B
• Information on bremelanotide, a second FDA-approved medication for hypoactive sexual desire disorder in premeno­
pausal women
• Mepolizumab, newly FDA approved for the treatment of eosinophilic granulomatosis with polyangiitis

OUTSTANDING FEATURES OF CMDT

• Medical advances up to time of annual publication
• Detailed presentation of internal medicine disciplines, plus primary care topics in gynecology, obstetrics, dermatology,
ophthalmology, otolaryngology, psychiatry, neurology, toxicology, urology, geriatrics, orthopedics, womens health,
sexual and gender minority health, preventive medicine, and palliative care
• Concise format, facilitating efficient use in any practice setting
• More than 1000 diseases and disorders
• Annual update on HIV/AIDS and other newly emerging infections
• Specific disease prevention information
• Easy access to medication dosages, with trade names indexed and costs updated in each edition
• Recent references, with unique identifiers (PubMed, PMID numbers) for rapid downloading of article abstracts and, in
some instances, full-text reference articles

E-CHAPTERS, CMDT ONLINE, & AVAILABLE APPS

Seven e-chapters listed in the Table of Contents can be accessed at www.AccessMedicine.com/CMDT. These online-only
chapters (available without need for subscription) include
• Anti-Infective Chemotherapeutic & Antibiotic Agents
• Diagnostic Testing & Medical Decision Making
• Information Technology in Patient Care
• Integrative Medicine
• Podiatric Disorders
• Womens Health Issues
• Appendix: Therapeutic Drug Monitoring, Laboratory Reference Intervals, & Pharmacogenetic Tests
Institutional or individual subscriptions to AccessMedicine also have full electronic access to CMDT 2021.
Subscribers to CMDT Online receive full electronic access to CMDT 2021 as well as
• An expanded, dedicated media gallery
• Quick Medical Diagnosis & Treatment (QMDT)—a concise, bulleted version of CMDT 2021
• Guide to Diagnostic Tests—for quick reference to the selection and interpretation of commonly used diagnostic tests
• CURRENT Practice Guidelines in Primary Care—delivering concise summaries of the most relevant guidelines in
primary care
• Diagnosaurus—consisting of 1000+ differential diagnoses
CMDT 2021, QMDT, Guide to Diagnostic Tests, and Diagnosaurus are also available as individual apps for your smartphone
or tablet and can be found in the Apple App Store and Google Play.

Disease Prevention &
Health Promotion
Michael Pignone, MD, MPH1
Rene Salazar, MD
GENERAL APPROACH TO THE PATIENT
The medical interview serves several functions. It is used to
collect information to assist in diagnosis (the “history” of
the present illness), to understand patient values, to assess
and communicate prognosis, to establish a therapeutic
relationship, and to reach agreement with the patient about
further diagnostic procedures and therapeutic options. It
also serves as an opportunity to influence patient behavior,
such as in motivational discussions about smoking cessa­
tion or medication adherence. Interviewing techniques
that avoid domination by the clinician increase patient
involvement in care and patient satisfaction. Effective
clinician-patient communication and increased patient
involvement can improve health outcomes.
Patient Adherence
For many illnesses, su ccessfu l prevention and treatment
depends on difficu lt fu ndamental behavioral changes,
including altering diet, taking up exercise, giving up smok­
ing, cu tting down drinking, and adhering to medication
regimens that are often complex. Adherence is a problem in
every practice; up to 50% of patients fail to achieve full
adherence, and one-third never take their medicines. Many
patients with medical problems, even those with access
to care, do not seek appropriate care or may drop out of
care prematu rely. Adherence rates for short-term, self­
administered therapies are higher than for long-term
therapies and are inversely correlated with the number of
interventions, their complexity and cost, and the patients
perception of overmedication.
As an example, in HIV-infected patients, adherence to
antiretroviral therapy is a crucial determinant of treatment
success. Studies have unequivocally demonstrated a close
relationship between patient adherence and plasma HIV
RNA levels, CD4 cell counts, and mortality. Adherence
levels of more than 95% are needed to maintain virologic
suppression. However, studies show that over 60% of
1Dr. Pignone is a former member of the US Preventive Services
Task Force (USPSTF). The views expressed in this chapter are
his and Dr. Salazar's and not necessarily those of the USPSTF.
CMDT 2021
patients are less than 90% adherent and that adherence
tends to decrease over time.
Patient reasons for suboptimal adherence include sim­
ple forgetfulness, being away from home, being busy, and
changing daily routine. Other reasons include psychiatric
disorders (depression or substance misuse), uncertainty
about the effectiveness of treatment, lack of knowledge
about the consequences of poor adherence, regimen com­
plexity, and treatment side effects. The rising costs of medi­
cations, including generic drugs, and the increase in
patient cost-sharing burden, has made adherence even
more difficult, particularly for those with lower incomes.
Patients seem better able to take prescribed medications
than to adhere to recommendations to change their diet,
exercise habits, or alcohol intake or to perform various self-
care activities (such as monitoring blood glucose levels at
home). For short-term regimens, adherence to medications
can be improved by giving clear instructions. Writing out
advice to patients, including changes in medication, may
be helpful. Because low functional health literacy is com­
mon (almost half of English-speaking US patients are
unable to read and understand standard health education
materials), other forms of communication—such as illus­
trated simple text, videotapes, or oral instructions—may be
more effective. For non-English-speaking patients, clini­
cians and health care delivery systems can work to provide
culturally and linguistically appropriate health services.
To help improve adherence to long-term regimens, cli­
nicians can work with patients to reach agreement on the
goals for therapy, provide information about the regimen,
ensure understanding by using the “teach-back” method,
counsel about the importance of adherence and how to
organize medication-taking, reinforce self-monitoring,
provide more convenient care, prescribe a simple dosage
regimen for all medications (preferably one or two doses
daily), suggest ways to help in remembering to take doses
(time of day, mealtime, alarms) and to keep appointments,
and provide ways to simplify dosing (medication boxes).
Single-unit doses supplied in foil wrappers can increase
adherence but should be avoided for patients who have dif­
ficulty opening them. Medication boxes with compart­
ments (eg, Medisets) that are filled weekly are useful.
Microelectronic devices can provide feedback to show
 CMDT 2021 CHAPTER 1
patients whether they have taken doses as scheduled or to
notify patients within a day if doses are skipped. Reminders,
including cell phone text messages, are another effective
means of encouraging adherence. The clinician can also
enlist social support from family and friends, recruit an
adherence monitor, provide a more convenient care envi­
ronment, and provide rewards and recognition for the
patients efforts to follow the regimen. Collaborative pro­
grams in which pharmacists help ensure adherence are also
effective. Motivational interviewing techniques can be
helpful when patients are ambivalent about their therapy.
Adherence is also improved when a trusting doctor­
patient relationship has been established and when patients
actively participate in their care. Clinicians can improve
patient adherence by inquiring specifically about the behav­
iors in question. When asked, many patients admit to
incomplete adherence with medication regimens, with
advice about giving up cigarettes, or with engaging only in
“safer sex” practices. Although difficult, sufficient time must
be made available for communication of health messages.
Medication adherence can be assessed generally with a
single question: “In the past month, how often did you take
your medications as the doctor prescribed?” Other ways of
assessing medication adherence include pill counts and
refill records; monitoring serum, urine, or saliva levels of
drugs or metabolites; watching for appointment nonatten­
dance and treatment nonresponse; and assessing predict­
able drug effects, such as weight changes with diuretics or
bradycardia from beta-blockers. In some conditions, even
partial adherence, as with drug treatment of hypertension
and diabetes mellitus, improves outcomes compared with
nonadherence; in other cases, such as HIV antiretroviral
therapy or tuberculosis treatment, partial adherence may
be worse than complete nonadherence.
Guiding Principles of Care
Ethical decisions are often called for in medical practice, at
both the “micro” level of the individual patient-clinician
relationship and at the “macro” level of the allocation of
resources. Ethical principles that guide the successful
approach to diagnosis and treatment are honesty, benefi­
cence, justice, avoidance of conflict of interest, and the
pledge to do no harm. Increasingly, Western medicine
involves patients in important decisions about medical
care, eg, which colorectal screening test to obtain or which
modality of therapy for breast cancer or how far to proceed
with treatment of patients who have terminal illnesses (see
Chapter 5).
The clinician’s role does not end with diagnosis and
treatment. The importance of the empathic clinician in
helping patients and their families bear the burden of seri­
ous illness and death cannot be overemphasized. “To cure
sometimes, to relieve often, and to comfort always” is a
French saying as apt today as it was five centuries ago—as
is Francis Peabody’s admonition: “The secret of the care of
the patient is in caring for the patient.” Training to improve
mindfulness and enhance patient-centered communica­
tion increases patient satisfaction and may also improve
clinician satisfaction.
Cutler RL et al. Economic impact of medication non-adherence
by disease groups: a systematic review. BMJ Open. 2018 Jan
21;8(l):e016982. [PMID: 29358417]
Kini V et al. Interventions to improve medication adherence:
a review. JAMA. 2018 Dec 18;320(23):2461-73. [PMID:
30561486]
HEALTH MAINTENANCE & DISEASE
PREVENTION
Preventive medicine can be categorized as primary, sec­
ondary, or tertiary. Primary prevention aims to remove or
reduce disease risk factors (eg, immunization, giving up or
not starting smoking). Secondary prevention techniques
promote early detection of disease or precursor states (eg,
routine cervical Papanicolaou screening to detect carci­
noma or dysplasia of the cervix). Tertiary prevention mea­
sures are aimed at limiting the impact of established
disease (eg, partial mastectomy and radiation therapy to
remove and control localized breast cancer).
Tables 1-1 and 1-2 give leading causes of death in the
United States and estimates of deaths from preventable
causes. Recent data suggest increased mortality rates,
driven by increases in suicide and substance misuse and its
sequelae. Unintentional injuries, including deaths from
opioid-related overdoses, have become the third leading
cause of death in the United States. Non-Hispanic whites
with a high school education or less have suffered
disproportionately.
Many effective preventive services are underutilized,
and few adults receive all of the most strongly recom­
mended services. Several methods, including the use of
provider or patient reminder systems (including interac­
tive patient health records), reorganization of care environ­
ments, and possibly provision of financial incentives to
Table 1-1. Leading causes of death in the United States,
2017.
Category Estimate
All causes 2,179,857
1. Diseases of the heart 647,457
2. Malignant neoplasms 599,108
3. Unintentional injuries 169,936
4. Chronic lower respiratory 160,201
diseases
5. Cerebrovascular diseases 146,383
6. Alzheimer disease 121,404
7. Diabetes mellitus 83,564
8. Influenza and pneumonia 55,672
9. Nephritis, nephrotic syndrome, 50,633
and nephrosis
10. Intentional self-harm (suicide) 47,173
Data from National Center for Health Statistics 2019.
 DISEASE PREVENTION & HEALTH PROMOTION CMDT2021

the United States (eg, regional epidemics) highlight the need

Table 1-2. Leading preventable causes of death in the to understand the association of vaccine refusal and disease
United States, 2017. epidemiology.
Evidence suggests annual influenza vaccination is safe
Category Estimate
and effective with potential benefit in all age groups, and
Dietary risks 503,390 the Advisory Committee on Immunization Practices
High systolic blood pressure 454,346 (ACIP) recommends routine influenza vaccination for all
persons aged 6 months and older, including all adults.
Tobacco 437,706
When vaccine supply is limited, certain groups should be
High fasting plasma glucose 420,192 given priority, such as adults 50 years and older, individuals
High BMI 408,831 with chronic illness or immunosuppression, and pregnant
women. An alternative high-dose inactivated vaccine is
High LDL cholesterol 221,557
available for adults 65 years and older. Adults 65 years and
Impaired kidney function 173,378 older can receive either the standard-dose or high-dose
Air pollution 107,506 vaccine, whereas those younger than 65 years should
Alcohol use 104,536 receive a standard-dose preparation.
The ACIP recommends two doses of measles, mumps,
Drug use 104,440
and rubella (MMR) vaccine in adults at high risk for expo­
Low physical activity 70,844 sure and transmission (eg, college students, health care
Occupational risks 63,580 workers). Otherwise, one dose is recommended for adults
aged 18 years and older. Physician documentation of dis­
BMI, body mass index; LDL, low-density lipoprotein. ease is not acceptable evidence of MMR immunity.
Data from the US Burden of Disease Collaborators, 2019. Routine use of 13-valent pneumococcal conjugate
vaccine (PCV13) is recommended among adults aged 65
clinicians (though this remains controversial), can increase and older. Individuals 65 years of age or older who have
utilization of preventive services, but such methods have never received a pneumococcal vaccine should first receive
not been widely adopted. PCV13 followed by a dose of 23-valent pneumococcal
polysaccharide vaccine (PPSV23) 6-12 months later.
Borsky A et al. Few Americans receive all high-priority, appro­ Individuals who have received more than one dose of
priate clinical preventive services. Health Aff. (Millwood). PPSV23 should receive a dose of PCV13 more than 1 year
2018 Jun;37(6):925-8. [PMID: 29863918] after the last dose of PPSV23 was administered.
Heron M. Deaths: leading causes for 2017. Natl Vital Stat Rep.
The ACIP recommends routine use of a single dose of
2019 Jun 24;68(6)l-77. https://www.cdc.gov/nchs/data/nvsr/
nvsr68/nvsr68_06-508.pdf
tetanus, diphtheria, and five-component acellular pertussis
Levine DM et al. Quality and experience of outpatient care in the vaccine (Tdap) for adults aged 19-64 years to replace the
United States for adults with or without primary care. JAMA next booster dose of tetanus and diphtheria toxoids
Intern Med. 2019 Mar l;179(3):363-72. Erratum in: JAMA vaccine (Td). Due to increasing reports of pertussis in the
Intern Med. 2019 Jun 1;179(6):854. [PMID: 30688977] United States, clinicians may choose to give Tdap to per­
US Burden of Disease Collaborators. The state of US health,
sons aged 65 years and older (particularly to those who
1990-2016: burden of diseases, injuries, and risk factors
among US states. JAMA. 2018 Apr 10;319(14):1444-72.
might risk transmission to at-risk infants who are most
[PMID: 29634829] susceptible to complications, including death), despite lim­
Woolf SH et al. Life expectancy and mortality rates in the United ited published data on the safety and efficacy of the vaccine
States, 1959-2017. JAMA. 2019 Nov 26;322(20):1996-2016. in this age group.
[PMID: 31769830] Both hepatitis A vaccine and immune globulin pro­
vide protection against hepatitis A; however, administra­
PREVENTION OF INFECTIOUS DISEASES tion of immune globulin may provide a modest benefit
over vaccination in some settings. Hepatitis B vaccine
Much of the decline in the incidence and fatality rates of administered as a three-dose series is recommended for all
infectious diseases is attributable to public health children aged 0-18 years and high-risk individuals (ie,
measures—especially immunization, improved sanitation, health care workers, injection drug users, people with end­
and better nutrition. stage renal disease). Adults with diabetes are also at
Immunization remains the best means of preventing increased risk for hepatitis B infection. The ACIP recom­
many infectious diseases. Recommended immunization mends vaccination for hepatitis B in diabetic patients
schedules for children and adolescents can be found online at aged 19-59 years. The hepatitis B vaccine should also be
http://www.cdc.gov/vaccines/schedules/hcp/child-adolescent. considered in diabetic persons age 60 and older.
html, and the schedule for adults is at http://www.cdc.gov/ Human papillomavirus (HPV) virus-like particle
vaccines/schedules/hcp/adult.html (see also Chapter 30). (VLP) vaccines have demonstrated effectiveness in pre­
Substantial morbidity and mortality from vaccine-preventable venting persistent HPV infections and thus may impact
diseases, such as hepatitis A, hepatitis B, influenza, and pneu­ the rate of cervical intraepithelial neoplasia (CIN) II—III.
mococcal infections, continue to occur among adults. The ACIP recommends routine HPV vaccination for
Increases in the number of vaccine-preventable diseases in children and adults aged 9-26 years. Though routinely
 CMDT 2021 CHAPTER 1
recommended at age 11 or 12 years, vaccination can be
given starting at 9 years of age. Catch-up HPV vaccination
is recommended for all persons not adequately vaccinated
through age 26 years. Catch-up vaccination is not recom­
mended for all adults older than 26 years. Shared clinical
decision-making regarding HPV vaccination is recom­
mended for some individuals between 27 and 45 years of
age (vaccine is not licensed for adults older than 45 years).
Persons traveling to countries where infections are
endemic should take the precautions described in Chapter 30
and at https://wwwnc.cdc.gov/travel/destinations/list.
Immunization registries—confidential, population-based,
computerized information systems that collect vaccination
data about all residents of a geographic area—can be used
to increase and sustain high vaccination coverage.
The US Preventive Services Task Force (USPSTF) rec­
ommends behavioral counseling for adolescents and adults
who are sexually active and at increased risk for sexually
transmitted infections. Sexually active women aged
24 years or younger and older women who are at increased
risk for infection should be screened for chlamydia and
gonorrhea. Screening HIV-positive men or men who have
sex with men for syphilis every 3 months is associated with
improved syphilis detection.
HIV infection remains a major infectious disease prob­
lem in the world. The CDC recommends universal HIV
screening of all patients aged 13-64, and the USPSTF rec­
ommends that clinicians screen adolescents and adults
aged 15-65 years. Clinicians should integrate biomedical
and behavioral approaches for HIV prevention. In addition
to reducing sexual transmission of HIV, initiation of anti­
retroviral therapy reduces the risk for AIDS-defining
events and death among patients with less immunologi­
cally advanced disease.
Daily preexposure prophylaxis (PrEP) with the fixed-
dose combination of tenofovir disoproxil 300 mg and
emtricitabine 200 mg (Truvada) should be considered for
people who are HIV-negative but at substantial risk for
HIV infection. Studies of men who have sex with men sug­
gest that PrEP is very effective in reducing the risk of
contracting HIV. Patients taking PrEP should be encour­
aged to use other prevention strategies, such as consistent
condom use and choosing less risky sexual behaviors (eg,
oral sex), to maximally reduce their risk. Postexposure
prophylaxis (PEP) with combinations of antiretroviral
drugs is widely used after occupational and nonoccupa-
tional contact, and may reduce the risk of transmission
by approximately 80%. PEP should be initiated within
72 hours of exposure.
In immunocompromised patients, live vaccines are
contraindicated, but many killed or component vaccines
are safe and recommended. Asymptomatic HIV-infected
patients have not shown adverse consequences when given
live MMR and influenza vaccinations as well as tetanus,
hepatitis B, Haemophilus influenzae type b, and pneumo­
coccal vaccinations—all should be given. However, if
poliomyelitis immunization is required, the inactivated
poliomyelitis vaccine is indicated. In symptomatic HIV-
infected patients, live-virus vaccines, such as MMR, should
generally be avoided, but annual influenza vaccination is
safe.
Herpes zoster, caused by reactivation from previous
varicella zoster virus infection, affects many older adults
and people with immune system dysfunction. It can cause
postherpetic neuralgia, a potentially debilitating chronic
pain syndrome. The ACIP recommends the herpes zoster
subunit vaccine (HZ/su; Shingrix) be used for the preven­
tion of herpes zoster and related complications in immu­
nocompetent adults age 50 and older and in individuals
who previously received Zostavax.
Zika virus spreads to people primarily through mos­
quito bites but can also spread during sex by a person
infected with Zika to his or her partner. Although clinical
disease is usually mild, Zika virus infections in women
infected during pregnancy have been linked to fetal micro­
cephaly and loss, and newborn and infant blindness and
other neurologic problems (see Chapter 32). Pregnant
women should consider postponing travel to areas where
Zika virus transmission is ongoing.
Blackstock OJ et al. A cross-sectional online survey of HIV pre­
exposure prophylaxis adoption among primary care physicians.
J Gen Intern Med. 2017 Jan;32(l):62-70. [PMID: 27778215]
Centers for Disease Control and Prevention (CDC). HIV/AIDS,
2019. https://www.cdc.gov/hiv/basics/index.html
Centers for Disease Control and Prevention (CDC). PEP
(postexposure prophylaxis), 2018. https://www.cdc.gov/hiv/
risk/pep/index.html
Centers for Disease Control and Prevention (CDC). PrEP
(preexposure prophylaxis), 2019. https://www.cdc.gov/hiv/
basics/prep.html
Centers for Disease Control and Prevention (CDC). Recom­
mended Adult Immunization Schedules: United States, 2019.
https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html
Centers for Disease Control and Prevention (CDC). Zika virus,
2019. https://www.cdc.gov/zika/index.html
Meites E et al. Human papillomavirus vaccination for adults:
updated recommendations of the Advisory Committee on
Immunization Practices. MMWR Morb Mortal Wkly Rep.
2019 Aug 16;68(32):698-702. [PMID: 31415491]
Riddell J 4th et al. HIV preexposure prophylaxis: a review. JAMA.
2018 Mar 27;319(12):1261-8. [PMID: 29584848]
Short MD et al. Which patients should receive the herpes zoster
vaccine? JAAPA. 2019 Sep;32(9):18-20. [PMID: 31460969]
PREVENTION OF CARDIOVASCULAR DISEASE
Cardiovascular diseases (CVDs), including coronary heart
disease (CHD) and stroke, represent two of the most
important causes of morbidity and mortality in developed
countries. Several risk factors increase the risk for coronary
disease and stroke. These risk factors can be divided into
those that are modifiable (eg, lipid disorders, hypertension,
cigarette smoking) and those that are not (eg, age, sex, fam­
ily history of early coronary disease). Impressive declines
in age-specific mortality rates from heart disease and
stroke have been achieved in all age groups in North
America during the past two decades, in large part through
improvement of modifiable risk factors: reductions in ciga­
rette smoking, improvements in lipid levels, and more
aggressive detection and treatment of hypertension. This
section considers the role of screening for cardiovascular
risk and the use of effective therapies to reduce such risk.
Key recommendations for cardiovascular prevention
are shown in Table 1-3. Guidelines encourage regular
 DISEASE PREVENTION & HEALTH PROMOTION CMDT2021

Table 1-3. Expert recommendations for cardiovascular risk prevention methods: US Preventive Services Task Force
(USPSTF).1

Prevention Method Recommendation/[Year Issued]

Screening for Recommends one-time screening for AAA by ultrasonography in men aged 65-75 years who have ever smoked. (B)
abdominal aortic Selectively offer screening for AAA in men aged 65-75 years who have never smoked. (C)
aneurysm (AAA) Current evidence is insufficient to assess the balance of benefits and harms of screening for AAA in women aged
65-75 years who have ever smoked or have a family history of AAA. (1)
Recommends against routine screening for AAA in women who have never smoked and have no family history of
AAA. (D)
[2019]
Aspirin use Recommends initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and
colorectal cancer (CRC) in adults aged 50-59 years who have a 10% or greater 10-year CVD risk, are not at increased
risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least
10 years. (B)
The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60-69 years
who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are not at increased risk for
bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least
10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential
harms may choose to initiate low-dose aspirin. (C)
The current evidence is insufficient to assess the balance of benefits and harms of initiating aspirin use for the
primary prevention of CVD and CRC in adults younger than 50 years or older than age 70. (I)
[2016]
Blood pressure The USPSTF recommends screening for high blood pressure in adults aged 18 years or older. The USPSTF
screening recommends obtaining measurements outside of the clinical setting for diagnostic confirmation before starting
treatment. (A)
[2015]
Serum lipid screening The USPSTF recommends that adults without a history of CVD use a low- to moderate-dose statin for the prevention
and use of statins of CVD events and mortality when all of the following criteria are met: (1) they are aged 40-75 years; (2) they have
for prevention one or more CVD risk factors (ie, dyslipidemia, diabetes mellitus, hypertension, or smoking); and (3) they have a
calculated 10-year risk of a cardiovascular event of 10% or greater.
Identification of dyslipidemia and calculation of 10-year CVD event risk requires universal lipids screening in adults
aged 40-75 years. See the "Clinical Considerations" section of the USPSTF recommendations1 for more information
on lipids screening and the assessment of cardiovascular risk. (B)
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of initiat­
ing statin use for the primary prevention of CVD events and mortality in adults aged 76 years and older without a
history of heart attack or stroke. (I)
[2016]
Counseling about Recommends offering or referring adults who are overweight or obese and have additional CVD risk factors to inten­
healthful diet and sive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention. (B)
physical activity for [2014]
CVD prevention Recommends that primary care professionals individualize the decision to offer or refer adults without obesity who
do not have hypertension, dyslipidemia, abnormal blood glucose levels, or diabetes to behavioral counseling to
promote a healthful diet and physical activity. (C)
[2017]
Screening for Recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged
diabetes mellitus 40-70 years who are overweight or obese. Clinicians should offer or refer patients with abnormal blood glucose
to intensive behavioral counseling interventions to promote a healthful diet and physical activity. (B)
[2015]
Screening for smoking Recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide
and counseling to behavioral interventionsand US Food and Drug Administration (FDA)-approved pharmacotherapy for cessation
promote cessation to adults who use tobacco. (A)
[2015]

1US Preventive Services Task Force recommendations available at http://www.uspreventiveservicestaskforce.org/BrowseRec/lndex/browse-

recommendations.
Recommendation A: The USPSTF strongly recommends that clinicians routinely provide the service to eligible patients. (The USPSTF found
good evidence that the service improves important health outcomes and concludes that benefits substantially outweigh harms.)
Recommendation B: The USPSTF recommends that clinicians routinely provide the service to eligible patients. (The USPSTF found at least
fair evidence that the service improves important health outcomes and concludes that benefits substantially outweigh harms.)
Recommendation C: The USPSTF makes no recommendation for or against routine provision of the service.
Recommendation D: The USPSTF recommends against routinely p roviding the service to asymp tomatic p atients. (The USPSTF found at
least fair evidence that the service is ineffective or that harms outweigh benefits.)
Recommendation I: The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing the service.
 CMDT 2021 CHAPTER 1
assessment of global cardiovascular risk in adults
40-79 years of age without known CVD, using standard
cardiovascular risk factors. The role of nontraditional risk
factors for improving risk estimation remains unclear.
Lin JS et al. Nontraditional risk factors in cardiovascular disease
risk assessment: a systematic evidence report for the US
Preventive Services Task Force [Internet]. Rockville, MD:
Agency for Healthcare Research and Quality (US); 2018 Jul.
https://www.ncbi.nlm.nih.gov/books/NBK525925/ [PMID:
30234933]
Wall HK et al. Vital signs: prevalence of key cardiovascular
disease risk factors for Million Hearts 2022—United States,
2011-2016. MMWR Morb Mortal Wkly Rep. 2018 Sep 7;
67(35):983-91. [PMID: 30188885]
Yadlowsky S et al. Clinical implications of revised pooled cohort
equations for estimating atherosclerotic cardiovascular
disease risk. Ann Intern Med. 2018 Jul 3; 169( 1 ):20—9. [PMID:
29868850]
Abdominal Aortic Aneurysm
One-time screening for abdominal aortic aneurysm (AAA)
by ultrasonography is recommended by the USPSTF
(B recommendation) in men aged 65-75 years who have
ever smoked. One-time screening for AAA is associated
with a relative reduction in odds of AAA-related mortality
over 12-15 years (odds ratio [OR] 0.65 [95% confidence
interval [CI] 0.57-0.74]) and a similar reduction in AAA-
related ruptures (OR 0.62 [95% CI 0.55-0.70]). Women
who have never smoked and who have no family history
of AAA do not appear to benefit from such screening (D
recommendation); the current evidence for women who
have ever smoked or who have a family history of AAA is
insufficient to assess the balance of risks versus benefits (I
recommendation) (Table 1-3).
Guirguis-Blake JM et al. Primary care screening for abdominal
aortic aneurysm: updated evidence report and systematic
review for the US Preventive Services Task Force. JAMA. 2019
Dec 10;322(22):2219-38. [PMID: 31821436]
US Preventive Services Task Force, Owens DK et al. Screening
for abdominal aortic aneurysm: US Preventive Services Task
Force Recommendation Statement. JAMA. 2019 Dec
10;322(22):2211—8. [PMID: 31821437]
Ying AJ et al. Abdominal aortic aneurysm screening: a system­
atic review and meta-analysis of efficacy and cost. Ann Vase
Surg. 2019 Jan;54:298-303.e3. [PMID: 30081169]
Cigarette Smoking
Cigarette smoking remains the most important cause of
preventable morbidity and early mortality. In 2015, there
were an estimated 6.4 million premature deaths in the
world attributable to smoking and tobacco use; smoking is
the second leading cause of disability-adjusted life-years
lost. Cigarettes are responsible for one in every five deaths
in the United States, or over 480,000 deaths annually.
Annual cost of smoking-related health care is approxi­
mately $130 billion in the United States, with another $150
billion in productivity losses. Fortunately, US smoking
rates have been declining; in 2015,15.1% of US adults were
smokers, and by 2018, 13.7% were smokers. Global direct
health care costs from smoking in 2012 were estimated at
$422 billion, with total costs of over $1.4 trillion.
Over 41,000 deaths per year in the United States are
attributable to environmental tobacco smoke.
Smoking cessation reduces the risks of death and of
myocardial infarction in people with coronary artery
disease; reduces the rate of death and acute myocardial
infarction in patients who have undergone percutaneous
coronary revascularization; lessens the risk of stroke; and is
associated with improvement of chronic obstructive pul­
monary disease symptoms. On average, women smokers
who quit smoking by age 35 add about 3 years to their life
expectancy, and men add more than 2 years to theirs.
Smoking cessation can increase life expectancy even for
those who stop after the age of 65.
Although tobacco use constitutes the most serious
common medical problem, it is undertreated. Almost 40%
of smokers attempt to quit each year, but only 4% are suc­
cessful. Persons whose clinicians advise them to quit are
1.6 times as likely to attempt quitting. Over 70% of smokers
see a physician each year, but only 20% of them receive any
medical quitting advice or assistance.
Factors associated with successful cessation include
having a rule against smoking in the home, being older,
and having greater education. Several effective clinical
interventions are available to promote smoking cessation,
including counseling, pharmacotherapy, and combinations
of the two.
Helpful counseling strategies are shown in Table 1-4.
Additionally, a system should be implemented to identify
smokers, and advice to quit should be tailored to the
patients level of readiness to change. All patients trying to
quit should be offered pharmacotherapy (Table 1-5) except
those with medical contraindications, women who are
pregnant or breast-feeding, and adolescents. Weight gain
occurs in most patients (80%) following smoking cessa­
tion. Average weight gain is 2 kg, but for some (10-15%),
major weight gain—over 13 kg—may occur. Planning for
the possibility of weight gain, and means of mitigating it,
may help with maintenance of cessation.
Several pharmacologic therapies shown to be effective
in promoting cessation are summarized in Table 1-5. Nico­
tine replacement therapy doubles the chance of successful
quitting. The nicotine patch, gum, and lozenges are avail­
able over the counter and nicotine nasal spray and inhalers
by prescription. The sustained-release antidepressant drug
bupropion (150-300 mg/day orally) is an effective smoking
cessation agent and is associated with minimal weight gain,
although seizures are a contraindication. It acts by boosting
brain levels of dopamine and norepinephrine, mimicking
the effect of nicotine. Varenicline, a partial nicotinic acetyl -
choline-receptor agonist, has been shown to improve ces­
sation rates; however, its adverse effects, particularly its
effects on mood, are not completely understood and war­
rant careful consideration. No single pharmacotherapy is
clearly more effective than others, so patient preferences
and data on adverse effects should be taken into account in
selecting a treatment. Combination therapy is more effec­
tive than a single pharmacologic modality. The efficacy of
 DISEASE PREVENTION & HEALTH PROMOTION CMDT2021

Table 1-4. Inquiries to help in support of smoking cessation.

Component Helpful Clinician Statements and Inquiries

Communicate your caring and concern
Encourage the patient to talk about the
quitting process
Provide basic information about smoking
(eg, its addictive nature) and successful
quitting (eg, nature and time course of
withdrawal)
Encourage the patient to make a quit attempt
"1 am concerned about the effects of smoking on your health...
• and want you to know that 1 am willing to help you to quit."
• and so how do you feel about quitting?"
• do you have any fears or ambivalent feelings about quitting?"
"Tell me...
• why do you want to quit smoking?"
• when you tried quitting smoking in the past, what sort of difficulties did you
encounter?"
• were you able to succeed at all, even for a while?"
• what concerns or worries do you have about quitting now?"
"Did you know that...
• the nicotine in cigarette smoke is highly addictive?"
• within a day of stopping, you will notice nicotine withdrawal symptoms, such as
irritability and craving?"
• after you quit, any smoking (even a single puff) makes it likely that you will fully
relapse into smoking again?"
"1 want you to reassure you that...
• as your clinician, 1 believe you are going to be able to quit."
• there are now available many effective smoking cessation treatments."
• more than half the people who have ever smoked have now successfully quit."

e-cigarettes in smoking cessation has not been well evalu­

ated, and some users may find them addictive. Recent
reports of “vaping-related” lung disease should prompt
additional caution in the use of unregulated nicotine deliv­
ery devices for smoking cessation (see Chapter 9).
Clinicians should not show disapproval of patients who
fail to stop smoking or who are not ready to make a quit
attempt. Thoughtful advice that emphasizes the benefits of
cessation and recognizes common barriers to success can
increase motivation to quit and quit rates. An upcoming
medical procedure or intercurrent illness or hospitalization
may motivate even the most addicted smoker to quit.
Individualized or group counseling is very cost effec­
tive, even more so than treating hypertension. Smoking
cessation counseling by telephone (“quitlines”) and text
messaging-based interventions have both proved effective.
An additional strategy is to recommend that any smoking
take place outdoors to limit the effects of passive smoke on
housemates and coworkers. This can lead to smoking
reduction and quitting.
Public policies, including higher cigarette taxes and
more restrictive public smoking laws, have also been
shown to encourage cessation, as have financial incentives
directed to patients.
Anonymous. Drugs for smoking cessation. Med Lett Drugs
Ther. 2019 Jul 15;61(1576): 105-10. [PMID: 31381546]
Centers for Disease Control and Prevention (CDC). Current
cigarette smoking among adults in the United States in 2017.2019
November 18. https://www.cdc.gov/tobacco/data_statistics/
fact_sheets/adult_data/cig_smoking/index.htm
Goodchild M et al. Global economic cost of smoking-attributable
diseases. Tob Control. 2018 Jan;27(l):58-64. [PMID:
28138063]
Hollands GJ et al. Interventions to increase adherence to medi­
cations for tobacco dependence. Cochrane Database Syst Rev.
2019 Aug 16;8:CD009164. [PMID: 31425618]
Ma J et al. Smoking-attributable mortality by state in 2014, U.S.
Am J Prev Med. 2018 May;54(5):661-70. [PMID: 29551325]
Tibuakuu M et al. National trends in cessation counseling,
prescription medication use, and associated costs among US
adult cigarette smokers. JAMA Netw Open. 2019 May 3;
2(5):el94585. [PMID: 31125108]
Lipid Disorders
Higher low-density lipoprotein (LDL) cholesterol concen­
trations and lower high-density lipoprotein (HDL) levels are
associated with an increased risk of CHD (see Chapter 28).
Measurement of total and high-density lipoprotein choles­
terol levels can help assess the degree of CHD risk. The best
age to start screening is controversial, as is its frequency.
Cholesterol-lowering therapy reduces the relative risk of
CHD events, with the degree of reduction proportional to
the reduction in LDL cholesterol achieved, at least at LDL
levels greater than 100 mg/dL. The absolute benefits of
screening for—and treating—abnormal lipid levels depend
on the presence and level of other cardiovascular risk fac­
tors, including hypertension, diabetes mellitus, smoking,
age, and sex. If other risk factors are present, atherosclerotic
CVD risk is higher and the potential benefits of therapy are
greater. Patients with known CVD are at higher risk and
have larger benefits from reduction in LDL cholesterol. The
optimal risk threshold for initiating statins for primary pre­
vention remains somewhat controversial, although most
guidelines now suggest statin therapy when the 10-year
atherosclerotic cardiovascular risk is greater than 10%.
Evidence for the effectiveness of statin-type drugs is
better than for the other classes of lipid-lowering agents
 CMDT 2021 CHAPTER 1

Table 1-5. Medications for tobacco dependence and smoking cessation.

Cost3
Drug Some Formulations Usual Adult Dosage1,2 30 days

Nicotine Replacement Therapies (NRTs]

Nicotine transdermal patch4 - generic 7,14,21 mg/24 hr patches 1 patch/day5 $54.90
(NicoDerm CQ)
Nicotine polacrilex gum4 - generic 2,4 mg/pieces 8-24 pieces/day5,6,7 $70.40
(Nicorette gum)
Nicotine polacrilex lozenge4,8 - generic 2,4 mg/lozenges 8-20 lozenges/day5,6,9 $81.47
(Nicorette Lozenge)

Nicotine oral inhaler - Nicotrol 10 mg cartridges10 4-16 cartridges/day5 $524.87

Nicotine nasal spray - Nicotrol NS 200 sprays/10 mL bottles (0.5 mg/spray) 2 sprays 8-40x/day (max 10 sprays/hr)4 $551.11
(4-bottle
package)
Dopaminergic-Noradrenergic Reuptake Inhibitor
Bupropion SR - generic 100,150,200 mg SR tablets11 150 mg orally once daily x 3 days, then $116.00
150 mg orally twice daily
Nicotinic Receptor Partial Agonist
Varenicline tartrate - Chantix 0.5,1 mg tablets 0.5 mg orally once daily x 3 days, then $568.80
0.5 mg twice daily on days 4-7, then
1 mg twice daily

SR, sustained-release.
1 Dosage reductions may be needed for liver or kidney impairment.

2Patients should receive a minimum of 3-6 months of effective therap y. In general, the dosage of NRTs can be tap ered at the end of

treatment; bup rop ion SR and varenicline can usually be stop p ed without a gradual dosage reduction, but some clinicians recommend
a taper.
3Cost for 30 days treatment.

4Available over-the-counter for persons >18 years old.

5See expanded table for dosage titration instructions, available at: medicalletter.org/TML-article-1576c.

6Eating or drinking within 15 minutes of using a gum or lozenge should be avoided.

7 A second piece of gum can be used within 1 hour. Continuously chewing one piece after another is not recommended.

8Also available in a mini-lozenge.

9Maximum of 5 lozenges in 6 hours or 20 lozenges/day. Use of more than 1 lozenge at a time or continuously using one after another is

not recommended.
10Each cartridge delivers 4 mg of nicotine.

11Only the generic 150-mg SR tablets are FDA-approved as a smoking cessation aid.

Modified, with permission, from Drugs for smoking cessation. Med L ett Drugs Ther. 2019 Jul 15;61 (1576): 105-10. http://www.medicalletter
•org.

or dietary changes specifically for improving lipid levels.
Multiple large, randomized, placebo-controlled trials
have demonstrated important reductions in total mortal­
ity, major coronary events, and strokes with lowering
levels of LDL cholesterol by statin therapy for patients
with known CVD. Statins also reduce cardiovascular
events for patients with diabetes mellitus. For patients
with no previous history of cardiovascular events or dia­
betes, meta-analyses have shown important reductions of
cardiovascular events.
Newer antilipidemic monoclonal antibody agents (eg,
evolocumab and alirocumab) lower LDL cholesterol by
50-60% by binding proprotein convertase subtilisin kexin
type 9 (PCSK9), which decreases the degradation of LDL
receptors. PCSK9 inhibitors also decrease Lp(a) levels. These
newer agents are very expensive so are often used mainly in
high-risk patients when statin therapy does not reduce the
LDL cholesterol sufficiently at maximally tolerated doses
or when patients are intolerant of statins. So far, few side
effects have been reported with PCSK9 inhibitor use.
Guidelines for statin and PCSK9 therapy are discussed
in Chapter 28.
Navarese EP et al. Association between baseline LDL-C level and
total and cardiovascular mortality after LDL-C lowering: a
systematic review and meta-analysis. JAMA. 2018 Apr
17;319(15):1566-79. [PMID: 29677301]
Pagidipati NJ et al. Comparison of recommended eligibility for
primary prevention statin therapy based on the US Preventive
Services Task Force Recommendations vs the ACC/AHA
Guidelines. JAMA. 2017 Apr 18;317(15):1563-7. [PMID:
28418481]
 DISEASE PREVENTION & HEALTH PROMOTION
US Preventive Services Task Force. Statin use for the primary
prevention of cardiovascular disease in adults: US Preventive
Services Task Force Recommendation Statement. JAMA.
2016 Nov 15;316( 19): 1997-2007. [PMID: 27838723]
Hypertension
Over 67 million adults in the United States have hyperten­
sion, representing 29% of the adult US population (see
Chapter 11). Hypertension in nearly half of these adults is
not controlled (ie, less than 140/90 mm Hg). Among those
whose hypertension is not well controlled, nearly 40% are
not aware of their elevated blood pressure; almost 16% are
aware but not being treated; and 45% are being treated but
the hypertension is not controlled. In every adult age group,
higher values of systolic and diastolic blood pressure carry
greater risks of stroke and heart failure. Systolic blood pres­
sure is a better predictor of morbid events than diastolic
blood pressure. Home monitoring is better correlated with
target organ damage than clinic-based values. Clinicians
can apply specific blood pressure criteria, such as those of
the Joint National Committee or American Heart Associa­
tion guidelines, along with consideration of the patients
cardiovascular risk and personal values, to decide at what
levels treatment should be considered in individual cases.
Primary prevention of hypertension can be accom­
plished by strategies aimed at both the general population
and special high-risk populations. The latter include per­
sons with high-normal blood pressure or a family history
of hypertension, blacks, and individuals with various
behavioral risk factors, such as physical inactivity; exces­
sive consumption of salt, alcohol, or calories; and deficient
intake of potassium. Effective interventions for primary
prevention of hypertension include reduced sodium and
alcohol consumption, weight loss, and regular exercise.
Potassium supplementation lowers blood pressure mod­
estly, and a diet high in fresh fruits and vegetables and low
in fat, red meats, and sugar-containing beverages also
reduces blood pressure. Interventions of unproven efficacy
include pill supplementation of potassium, calcium, mag­
nesium, fish oil, or fiber; macronutrient alteration; and
stress management.
Improved identification and treatment of hypertension
is a major cause of the recent decline in stroke deaths as
well as the reduction in incidence of heart failure-related
hospitalizations. Because hypertension is usually asymp­
tomatic, screening is strongly recommended to identify
patients for treatment. Elevated office readings should be
confirmed with repeated measurements, ideally from
ambulatory monitoring or home measurements. Despite
strong recommendations in favor of screening and treat­
ment, hypertension control remains suboptimal. An inter­
vention that included both patient and provider education
was more effective than provider education alone in
achieving control of hypertension, suggesting the benefits
of patient participation; another trial found that home
monitoring combined with telephone-based nurse support
was more effective than home monitoring alone for blood
pressure control. Pharmacologic management of hyperten­
sion is discussed in Chapter 11.
CMDT2021
Bundy JD et al. Comparison of the 2017 ACC/AH A Hyperten­
sion Guideline with earlier guidelines on estimated reduc­
tions in cardiovascular disease. Curr Hypertens Rep. 2019
Aug 31;21(10):76. [PMID: 31473837]
Fryar CD et al. Hypertension prevalence and control among
adults: United States, 2015-2016. NCHS Data Brief. 2017
Oct;(289):l-8. [PMID: 29155682]
Weiss J et al. Benefits and harms of intensive blood pressure
treatment in adults aged 60 years or older: a systematic review
and meta-analysis. Ann Intern Med. 2017 Mar 21;166(6):
419-29. [PMID: 28114673]
Whelton PK et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/
ASH/ASPC/NMA/PCNA guideline for the prevention, detec­
tion, evaluation, and management of high blood pressure in
adults: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice
Guidelines. Hypertension. 2018 Jun;71(6):1269-324. [PMID:
29133354]
Chemoprevention
Regular use of low-dose aspirin (81-325 mg) can reduce
cardiovascular events but increases gastrointestinal bleed­
ing. Aspirin may also reduce the risk of death from several
common types of cancer (colorectal, esophageal, gastric,
breast, prostate, and possibly lung). The potential benefits
of aspirin may exceed the possible adverse effects among
middle-aged adults who are at increased cardiovascular
risk, which can be defined as a 10-year risk of greater than
10%, and who do not have an increased risk of bleeding. A
newer trial in older healthy adults did not find clear benefit
from aspirin for reduction of cardiovascular events and
saw an increase in all-cause mortality with aspirin. There­
fore, aspirin should not be routinely initiated in healthy
adults over age 70.
Nonsteroidal anti-inflammatory drugs may reduce the
incidence of colorectal adenomas and polyps but may also
increase heart disease and gastrointestinal bleeding, and
thus are not recommended for colon cancer prevention in
average-risk patients.
Antioxidant vitamin (vitamin E, vitamin C, and
beta-carotene) supplementation produced no significant
reductions in the 5-year incidence of—or mortality from—
vascular disease, cancer, or other major outcomes in high-
risk individuals with coronary artery disease, other
occlusive arterial disease, or diabetes mellitus.
Gaziano JM. Aspirin for primary prevention: clinical consider­
ations in 2019. JAMA. 2019 Jan 22;321(3):253-55. [PMID:
30667488]
Huang WY et al. Frequency of intracranial hemorrhage with low-
dose aspirin in individuals without symptomatic cardiovascular
disease: a systematic review and meta-analysis. JAMA Neurol.
2019 May 13. [Epub ahead of print] [PMID: 31081871]
McNeil JJ et al; ASPREE Investigator Group. Effect of aspirin on
cardiovascular events and bleeding in the healthy elderly.
N Engl J Med. 2018 Oct 18;379( 16): 1509-18. [PMID: 30221597]
Patrono C et al. Role of aspirin in primary prevention of cardio­
vascular disease. Nat Rev Cardiol. 2019 Nov;16(ll):675-86.
[PMID: 31243390]
Zheng SL et al. Association of aspirin use for primary prevention
with cardiovascular events and bleeding events: a systematic
review and meta-analysis. JAMA. 2019 Jan 22;321 (3):277-87.
[PMID: 30667501]
 1 CMDT 2021 CHAPTER 1
PREVENTION OF OSTEOPOROSIS
See Chapter 26.
Osteoporosis, characterized by low bone mineral den­
sity, is common and associated with an increased risk of
fracture. The lifetime risk of an osteoporotic fracture is
approximately 50% for women and 30% for men. Osteopo­
rotic fractures can cause significant pain and disability. As
such, research has focused on means of preventing osteo­
porosis and related fractures. Primary prevention strategies
include calcium supplementation, vitamin D supplementa­
tion, and exercise programs. The effectiveness of calcium
and vitamin D for fracture prevention remain controver­
sial, particularly in noninstitutionalized individuals.
Screening for osteoporosis on the basis of low bone
mineral density is recommended for women over age 65,
based on indirect evidence that screening can identify
women with low bone mineral density and that treatment
of women with low bone density with bisphosphonates is
effective in reducing fractures. However, real-world adher­
ence to pharmacologic therapy for osteoporosis is low:
one-third to one-half of patients do not take their medica­
tion as directed. Screening for osteoporosis is also recom­
mended in younger women who are at increased risk. The
effectiveness of screening in men has not been established.
Concern has been raised that bisphosphonates may
increase the risk of certain uncommon atypical types of
femoral fractures and rare osteonecrosis of the jaw, making
consideration of the benefits and risks of therapy impor­
tant when considering osteoporosis screening.
US Preventive Services Task Force. Screening for osteoporosis to
prevent fractures: US Preventive Services Task Force recom­
mendation statement. JAMA. 2018 Jun 26;319(24):2521-31.
[PMID: 29946735]
US Preventive Services Task Force. Vitamin D, calcium, or com­
bined supplementation for the primary prevention of frac­
tures in community-dwelling adults: US Preventive Services
Task Force recommendation statement. JAMA. 2018 Apr
17;319(15):1592-9. [PMID: 29677309]
Yedavally-Yellayi S et al. Update on osteoporosis. Prim Care.
2019 Mar;46(l):175-90. [PMID: 30704657]
PREVENTION OF PHYSICAL INACTIVITY
Lack of sufficient physical activity is the second most
important contributor to preventable deaths, trailing only
tobacco use. The US Department of Health and Human
Services and the CDC recommend that adults (including
older adults) engage in 150 minutes of moderate-intensity
(such as brisk walking) or 75 minutes of vigorous-intensity
(such as jogging or running) aerobic activity or an equiva­
lent mix of moderate- and vigorous-intensity aerobic activ­
ity each week. In addition to activity recommendations, the
CDC recommends activities to strengthen all major muscle
groups (abdomen, arms, back, chest, hips, legs, and shoul­
ders) at least twice a week.
Patients who engage in regular moderate to vigorous
exercise have a lower risk of myocardial infarction, stroke,
hypertension, hyperlipidemia, type 2 diabetes mellitus,
diverticular disease, and osteoporosis. Evidence supports
the recommended guidelines of 30 minutes of moderate
physical activity on most days of the week in both the pri­
mary and secondary prevention of CHD.
In longitudinal cohort studies, individuals who report
higher levels of leisure-time physical activity are less likely
to gain weight. Conversely, individuals who are overweight
are less likely to stay active. However, at least 60 minutes of
daily moderate-intensity physical activity may be necessary
to maximize weight loss and prevent significant weight
regain. Moreover, adequate levels of physical activity
appear to be important for the prevention of weight gain
and the development of obesity. Physical activity also
appears to have an independent effect on health-related
outcomes, such as development of type 2 diabetes mellitus
in patients with impaired glucose tolerance when com­
pared with body weight, suggesting that adequate levels of
activity may counteract the negative influence of body
weight on health outcomes. Compared to individuals with­
out CVD, those with CVD may benefit from physical activ­
ity to a greater extent.
Physical activity can be incorporated into any person’s
daily routine. For example, the clinician can advise a
patient to take the stairs instead of the elevator, to walk or
bike instead of driving, to do housework or yard work, to
get off the bus one or two stops earlier and walk the rest of
the way, to park at the far end of the parking lot, or to walk
during the lunch hour. The basic message should be the
more the better, and anything is better than nothing.
To be more effective in counseling about exercise, clini­
cians can also incorporate motivational interviewing tech­
niques, adopt a whole-practice approach (eg, use practice
nurses to assist), and establish linkages with community
agencies. Clinicians can incorporate the “5 As” approach:
1. Ask (identify those who can benefit).
2. Assess (current activity level).
3. Advise (individualize plan).
4. Assist (provide a written exercise prescription and sup­
port material).
5. Arrange (appropriate referral and follow-up).
Such interventions have a moderate effect on self­
reported physical activity and cardiorespiratory fitness,
even if they do not always help patients achieve a predeter­
mined level of physical activity. In their counseling, clini­
cians should advise patients about both the benefits and
risks of exercise, prescribe an exercise program appropriate
for each patient, and provide advice to help prevent injuries
and cardiovascular complications.
Although primary care providers regularly ask patients
about physical activity and advise them with verbal coun­
seling, few providers provide written prescriptions or per­
form fitness assessments. Tailored interventions may
potentially help increase physical activity in individuals.
Exercise counseling with a prescription, eg, for walking at
either a hard intensity or a moderate intensity with a high
frequency, can produce significant long-term improve­
ments in cardiorespiratory fitness. To be effective, exercise
prescriptions must include recommendations on type, fre­
quency, intensity, time, and progression of exercise and
 DISEASE PREVENTION & HEALTH PROMOTION
must follow disease-specific guidelines. Several factors
influence physical activity behavior, including personal,
social (eg, family and work), and environmental (eg, access
to exercise facilities and well-lit parks) factors. Walkable
neighborhoods around workplaces support physical activ­
ity such as walking and bicycling. A community-based
volunteer intervention resulted in increased walking activ­
ity among older women, who were at elevated risk for both
inactivity and adverse health outcomes.
Broad-based interventions targeting various factors are
often the most successful, and interventions to promote
physical activity are more effective when health agencies
work with community partners, such as schools, businesses,
and health care organizations. Enhanced community
awareness through mass media campaigns, school-based
strategies, and policy approaches are proven strategies to
increase physical activity.
Giroir BP et al. Physical activity guidelines for health and pros­
perity in the United States [Viewpoint]. JAMA. 2018 Nov
20;320(19): 1971-2. [PMID: 30418473]
Jeong SW et al. Mortality reduction with physical activity in
patients with and without cardiovascular disease. Eur Heart J.
2019 Nov 14;40(43):3547-55. [PMID: 31504416]
Kennedy AB et al. Tools clinicians can use to help get patients
active. Curr Sports Med Rep. 2018 Aug;17(8):271-6. [PMID:
30095547]
Piercy KL et al. The physical activity guidelines for Americans.
JAMA. 2018 Nov 20;320(19):2020-8. [PMID: 30418471]
PREVENTION OF OVERWEIGHT & OBESITY
Obesity is now a true epidemic and public health crisis that
both clinicians and patients must face. Normal body
weight is defined as a body mass index (BMI), calculated as
the weight in kilograms divided by the height in meters
squared, of less than 25; overweight is defined as a BMI =
25.0-29.9, and obesity as a BMI greater than 30. BMI is
often miscategorized as overweight, when it is in fact in the
obese range.
Risk assessment of the overweight and obese patient
begins with determination of BMI, waist circumference for
those with a BMI of 35 or less, presence of comorbid condi­
tions, and a fasting blood glucose and lipid panel. Obesity
is clearly associated with type 2 diabetes mellitus, hyper­
tension, hyperlipidemia, cancer, osteoarthritis, cardiovas­
cular disease, obstructive sleep apnea, and asthma.
Obesity is associated with a higher all-cause mortality
rate. Data suggest an increase among those with grades 2
and 3 obesity (BMI more than 35); however, the impact on
all-cause mortality among overweight (BMI 25-30) and
grade 1 obesity (BMI 30-35) is questionable. Persons with
a BMI of 40 or higher have death rates from cancers that
are 52% higher for men and 62% higher for women than
the rates in men and women of normal weight.
Prevention of overweight and obesity involves both
increasing physical activity and dietary modification to
reduce caloric intake. Adequate levels of physical activity
appear to be important for the prevention of weight gain
and the development of obesity. Physical activity programs
consistent with public health recommendations may
CMDT 2021
promote modest weight loss (~2 kg); however, the amount
of weight loss for any one individual is highly variable.
Clinicians can help guide patients to develop personal­
ized eating plans to reduce energy intake, particularly by
recognizing the contributions of fat, concentrated carbohy­
drates, and large portion sizes (see Chapter 29). Patients
typically underestimate caloric content, especially when
consuming food away from home. Providing patients with
caloric and nutritional information may help address the
current obesity epidemic. To prevent the long-term chronic
disease sequelae of overweight and obesity, clinicians must
work with patients to modify other risk factors, eg, by
smoking cessation (see previous section on cigarette smok­
ing) and strict blood pressure and glycemic control (see
Chapters 11 and 27).
Lifestyle modification, including diet, physical activity,
and behavior therapy, has been shown to induce clinically
significant weight loss. Other treatment options for obesity
include pharmacotherapy and surgery (see Chapter 29).
Counseling interventions or pharmacotherapy can produce
modest (3-5 kg) sustained weight loss over 6-12 months.
Counseling appears to be most effective when intensive
and combined with behavioral therapy. Pharmacotherapy
appears safe in the short term; long-term safety is still not
established.
Commercial weight loss programs are effective in pro­
moting weight loss and weight loss management. A ran­
domized controlled trial of over 400 overweight or obese
women demonstrated the effectiveness of a free prepared
meal and incentivized structured weight loss program
compared with usual care.
Weight loss strategies using dietary, physical activity, or
behavioral interventions can produce significant improve­
ments in weight among persons with prediabetes and a
significant decrease in diabetes incidence. Lifestyle inter­
ventions including diet combined with physical activity are
effective in achieving weight loss and reducing cardiometa-
bolic risk factors among patients with severe obesity.
Bariatric surgical procedures, eg, adjustable gastric
band, sleeve gastrectomy, and Roux-en-Y gastric bypass,
are reserved for patients with morbid obesity whose BMI
exceeds 40, or for less severely obese patients (with BMIs
between 35 and 40) with high-risk comorbid conditions
such as life-threatening cardiopulmonary problems (eg,
severe sleep apnea, Pickwickian syndrome, and obesity-
related cardiomyopathy) or severe diabetes mellitus. In
selected patients, surgery can produce substantial weight
loss (10-159 kg) over 1-5 years, with rare but sometimes
severe complications. Nutritional deficiencies are one com­
plication of bariatric surgical procedures and close moni­
toring of a patients metabolic and nutritional status is
essential.
Finally, clinicians seem to share a general perception
that almost no one succeeds in long-term maintenance of
weight loss. However, research demonstrates that approxi­
mately 20% of overweight individuals are successful at long­
term weight loss (defined as losing 10% or more of initial
body weight and maintaining the loss for 1 year or longer).
Clinicians must work to identify and provide the best
prevention and treatment strategies for patients who are
 CMDT 2021 CHAPTER 1
overweight and obese. Clinician advice on weight loss can
have a significant impact on patient attempts to adjust
weight-related behaviors. Unfortunately, many clinicians
are poorly prepared to address obesity. Clinicians are more
likely to give advice as BMI increases, missing opportuni­
ties to discuss weight with overweight patients. Clinician
bias and lack of training in behavior-change strategies
impair the care of obese patients. Strategies to address
these issues should be incorporated into innovative treat­
ment and care-delivery strategies (see Chapter 29).
Ryan DH et al. Guideline recommendations for obesity manage­
ment. Med Clin North Am. 2018 Jan;102(l):49-63. [PMID:
29156187]
Walsh K et al. Health advice and education given to overweight
patients by primary care doctors and nurses: a scoping
literature review. Prev Med Rep. 2019 Jan 25;14:100812.
[PMID: 30805277]
CANCER PREVENTION
Primary Prevention
Cancer mortality rates continue to decrease in the United
States; part of this decrease results from reductions in
tobacco use, since cigarette smoking is the most important
preventable cause of cancer. Primary prevention of skin
cancer consists of restricting exposure to ultraviolet light
by wearing appropriate clothing, and use of sunscreens.
Persons who engage in regular physical exercise and avoid
obesity have lower rates of breast and colon cancer. Preven­
tion of occupationally induced cancers involves minimiz­
ing exposure to carcinogenic substances, such as asbestos,
ionizing radiation, and benzene compounds. Chemopre­
vention has been widely studied for primary cancer pre­
vention (see earlier Chemoprevention section and Chapter
39). Use of tamoxifen, raloxifene, and aromatase inhibitors
for breast cancer prevention is discussed in Chapters 17
and 39. Hepatitis B vaccination can prevent hepatocellular
carcinoma (HCC), and screening and vaccination pro­
grams may be cost effective and useful in preventing HCC
in high-risk groups, such as Asians and Pacific Islanders.
Screening and treatment of hepatitis C is another strategy
to prevent HCC (see Chapter 16). The use of HPV vaccine
to prevent cervical and possibly anal cancer is discussed
earlier in this chapter. HPV vaccines may also have a role
in the prevention of HPV-related head and neck cancers.
The USPSTF recommends genetic counseling and, if indi­
cated after counseling, genetic testing for women whose
family or personal history is associated with an increased
risk of harmful mutations in the BRCA 1/2 gene. Guide­
lines for optimal cancer screening in adults over the age of
75 are unsettled; thus, an individualized approach that
considers differences in disease risk rather than chrono­
logical age alone is recommended.
US Preventive Services Task Force; Owens DK et al. Risk assess­
ment, genetic counseling, and genetic testing for BRCA-
related cancer: US Preventive Services Task Force
Recommendation Statement. JAMA. 2019 Aug 20;322(7):
652-65. [PMID: 31429903]
Wernli KJ et al. Screening for skin cancer in adults: updated
evidence report and systematic review for the US Preventive
Services Task Force. JAMA. 2016 Jul 26;316(4):436-47.
[PMID: 27458949]
Screening & Early Detection
Screening prevents death from cancers of the breast, colon,
and cervix. Current cancer screening recommendations
from the USPSTF are available online at https://www.
uspreventiveservicestaskforce.org/BrowseRec/Index/
browse-recommendations. Despite an increase in rates of
screening for breast, cervical, and colon cancer over the last
decade, overall screening for these cancers is suboptimal.
Interventions effective in promoting recommended cancer
screening include group education, one-on-one education,
patient reminders, reduction of structural barriers, reduc­
tion of out-of-pocket costs, and provider assessment and
feedback.
Though breast cancer mortality is generally reduced
with mammography screening, evidence from randomized
trials suggests that screening mammography has both ben­
efits and downsides. Clinicians should discuss the risks and
benefits with each patient and consider individual patient
preferences when deciding when to begin screening (see
Chapters 17 and e6).
Digital mammography is more sensitive in women with
dense breasts and in younger women; however, studies
exploring outcomes are lacking. MRI is not currently rec­
ommended for general screening, and its impact on breast
cancer mortality is uncertain; nevertheless, the American
Cancer Society recommends it for women at high risk
(20-25% or more), including those with a strong family
history of breast or ovarian cancer. Screening with both
MRI and mammography might be superior to mammogra­
phy alone in ruling out cancerous lesions in women with
an inherited predisposition to breast cancer. Digital breast
tomosynthesis (three-dimensional mammography) inte­
grated with digital mammography increases cancer detec­
tion rates compared to digital mammography alone;
however, the extent of improved detection and impact on
assessment outcomes need further exploration.
All current recommendations call for cervical and
colorectal cancer screening. Screening for testicular can­
cers among asymptomatic adolescent or adult males is not
recommended by the USPSTF. Prostate cancer screening
remains controversial, since no completed trials have
answered the question of whether early detection and
treatment after screen detection produce sufficient benefits
to outweigh harms of treatment. For men between the ages
of 55 and 69, the decision to screen should be individual­
ized and include a discussion of its risks and benefits with
a clinician. The USPSTF recommends against PSA-based
prostate cancer screening for men older than age 70 years
(grade D recommendation).
Annual or biennial fecal occult blood testing reduces
mortality from colorectal cancer. Fecal immunochemical
tests (FIT) are superior to guaiac-based fecal occult blood
tests (gFOBT) in detecting advanced adenomatous polyps
and colorectal cancer, and patients are more likely to favor
 DISEASE PREVENTION & HEALTH PROMOTION
FIT over gFOBT. Randomized trials using sigmoidoscopy
as the screening method found 20-30% reductions in mor­
tality from colorectal cancer. Colonoscopy has also been
advocated as a screening examination. It is more accurate
than flexible sigmoidoscopy for detecting cancer and pol­
yps, but its value in reducing colon cancer mortality has
not been studied directly. CT coIonography (virtual colo­
noscopy) is a noninvasive option in screening for colorectal
cancer. It has been shown to have a high safety profile and
performance similar to colonoscopy.
The USPSTF recommends screening for cervical cancer
in women aged 21-65 years with a Papanicolaou smear
(cytology) every 3 years or, for women aged 30-65 years
who desire longer intervals, screening with cytology and
HPV testing every 5 years. The USPSTF recommends
against screening in women younger than 21 years of age
and average-risk women over 65 with adequate negative
prior screenings. Receipt of HPV vaccination has no
impact on screening intervals.
Women whose cervical specimen HPV tests are positive
but cytology results are otherwise negative should repeat
co-testing in 12 months (option 1) or undergo HPV-
genotype-specific testing for types 16 or 16/18 (option 2).
Colposcopy is recommended in women who test positive
for types 16 or 16/18. Women with atypical squamous cells
of undetermined significance (ASCUS) on cytology and a
negative HPV test result should continue routine screening
as per age-specific guidelines.
In a randomized, controlled trial, transvaginal ultra­
sound combined with serum cancer antigen 125 (CA-125)
as screening tools to detect ovarian cancer did not reduce
mortality. Furthermore, complications were associated with
diagnostic evaluations to follow up false-positive screening
test results. Thus, screening for ovarian cancer with trans­
vaginal ultrasound and CA-125 is not recommended.
The USPSTF recommends offering annual lung cancer
screening with low-dose CT to current smokers aged 55 to
80 years with a 30-pack-year smoking history or to smokers
who quit within the past 15 years. Screening should stop
once a person has not smoked for 15 years or a health prob­
lem that significantly limits life expectancy has developed.
Screening should not be viewed as an alternative to smok­
ing cessation but rather as a complementary approach.
Geneve N et al. Colorectal cancer screening. Prim Care. 2019
Mar;46(l):135-48. [PMID: 30704654]
Li T et al. Digital breast tomosynthesis (3D mammography) for
breast cancer screening and for assessment of screen-recalled
findings: review of the evidence. Expert Rev Anticancer Ther.
2018 Aug;18(8):785-91. [PMID: 29847744]
Qaseem A et al. Screening for breast cancer in average-risk
women: a guidance statement from the American College of
Physicians. Ann Intern Med. 2019 Apr 16;170(8):547-60.
[PMID: 30959525]
Qaseem A et al. Screening for colorectal cancer in asymptomatic
average-risk adults: a guidance statement from the American
College of Physicians. Ann Intern Med. 2019 Nov 5;171 (9):
643-54. [PMID: 31683290]
US Preventive Services Task Force; Grossman DC et al. Screening
for ovarian cancer: US Preventive Services Task Force recom­
mendation statement. JAMA. 2018 Feb 13;319(6):588-94.
[PMID: 29450531]
CMDT 2021 3
US Preventive Services Task Force; Grossman DC et al. Screening
for prostate cancer: US Preventive Services Task Force recom­
mendation statement. JAMA. 2018 May 8;319(18):1901-13.
Erratum in: JAMA. 2018 Jun 19;319(23):2443. [PMID: 29801017]
US Preventive Services Task Force; Curry SJ et al. Screening for
cervical cancer: US Preventive Services Task Force recommen­
dation statement. JAMA. 2018 Aug 21;320(7):674-86. [PMID:
30140884]
PREVENTION OF INJURIES & VIOLENCE
Injuries remain the most important cause of loss of poten­
tial years of life before age 65. Homicide and motor vehicle
accidents are a major cause of injury-related deaths among
young adults, and accidental falls are the most common
cause of injury-related death in older adults. Approxi­
mately one-third of all injury deaths include a diagnosis of
traumatic brain injury, which has been associated with an
increased risk of suicide.
Although motor vehicle accident deaths per miles driven
have declined in the United States, there has been an increase
in motor vehicle accidents related to distracted driving (using
a cell phone, texting, eating). Evidence also suggests that
motorists’ use of sleeping medications (such as zolpidem)
almost doubles the risk of motor vehicle accidents. Clinicians
should discuss this risk when selecting a sleeping medication.
For 16- and 17-year-old drivers, the risk of fatal crashes
increases with the number of passengers.
Men ages 16-35 are at especially high risk for serious
injury and death from accidents and violence, with blacks
and Latinos at greatest risk. Deaths from firearms have
reached epidemic levels in the United States. Having a gun
in the home increases the likelihood of homicide nearly
threefold and of suicide fivefold. Educating clinicians to
recognize and treat depression as well as restricting access
to lethal methods have been found to reduce suicide rates.
In addition, clinicians should try to educate their patients
about always wearing seat belts and safety helmets, about the
risks of using cellular telephones or texting while driving and
of drinking and driving—or of using other intoxicants
(including marijuana) or long-acting benzodiazepines and
then driving—and about the risks of having guns in the home.
Clinicians have a critical role in the detection, preven­
tion, and management of intimate partner violence (see
Chapter e6). The USPSTF recommends screening women
of childbearing age for intimate partner violence and pro­
viding or referring women to intervention services when
needed. Inclusion of a single question in the medical
history—“At any time, has a partner ever hit you, kicked
you, or otherwise physically hurt you?”—can increase
identification of this common problem. Assessment for
abuse and offering of referrals to community resources cre­
ate the potential to interrupt and prevent recurrence of
domestic violence and associated trauma. Clinicians
should take an active role in following up with patients
whenever possible, since intimate partner violence screen­
ing with passive referrals to services may not be adequate.
Evaluation of services available to patients after identifica­
tion of intimate partner violence should be a priority.
Physical and psychological abuse, exploitation, and
neglect of older adults are serious, underrecognized
 CMDT 2021 CHAPTER 1

problems; they may occur in up to 10% of elders. Risk fac­
tors for elder abuse include a culture of violence in the
family; a demented, debilitated, or depressed and socially
isolated victim; and a perpetrator profile of mental illness,
alcohol or drug abuse, or emotional and/or financial
dependence on the victim. Clues to elder mistreatment
include the patient’s ill-kempt appearance, recurrent
urgent-care visits, missed appointments, suspicious physi­
cal findings, and implausible explanations for injuries.
Feltner C et al. Screening for intimate partner violence, elder
abuse, and abuse of vulnerable adults: evidence report and
systematic review for the US Preventive Services Task Force.
JAMA. 2018 Oct 23;320(16):1688—701. [PMID: 30357304]
Jin J. JAMA Patient Page. Screening for intimate partner vio­
lence, elder abuse, and abuse of vulnerable adults. JAMA.
2018 Oct 23;320(16):1718. [PMID: 30357300]
Lutgendorf MA. Intimate partner violence and women's health.
Obstet Gynecol. 2019 Sep;134(3):470-80. [PMID: 31403968]
PREVENTION OF SUBSTANCE USE DISORDER:
ALCOHOL & ILLICIT DRUGS
Unhealthy alcohol use is a major public health problem in
the United States, where approximately 51% of adults
18 years and older are current regular drinkers (at least 12
drinks in the past year). The 2015-2020 US Dietary Guide­
lines for Americans recommends that if alcohol is con­
sumed, it should be consumed in moderation—up to one
drink per day for women and two drinks per day for men—
and only by adults of legal drinking age. The spectrum of
alcohol use disorders includes alcohol dependence, harm­
ful pattern use of alcohol, and entities such as alcohol
intoxication, alcohol withdrawal, and several alcohol-
induced mental disorders. The ICD-11 includes a new
category: hazardous alcohol use. Categorized as a risk fac­
tor, hazardous alcohol use is a pattern of alcohol use that
appreciably increases the risk of physical or mental health
harmful consequence to the user.
Underdiagnosis and undertreatment of alcohol misuse
is substantial, both because of patient denial and lack of
detection of clinical clues.
As with cigarette use, clinician identification and
counseling about unhealthy alcohol use are essential. The
USPSTF recommends screening adults aged 18 years and
older for unhealthy alcohol use.
The Alcohol Use Disorder Identification Test (AUDIT)
consists of questions on the quantity and frequency of alco­
hol consumption, on alcohol dependence symptoms, and
on alcohol-related problems (Table 1-6). The AUDIT
questionnaire is a cost-effective and efficient diagnostic

Table 1-6. Screening for alcohol abuse using the Alcohol Use Disorder Identification Test (AUDIT).
(Scores for response categories are given in parentheses. Scores range from 0 to 40, with a cutoff score of 5 or more indicating
hazardous drinking, harmful drinking, or alcohol dependence.)
1. How often do you have a drink containing alcohol?
(0) Never (1) Monthly or less (2) Two to four times a month (3) Two or three times a week (4) Four or more times a week
2. How many drinks containing alcohol do you have on a typical day when you are drinking?
(0)1 or 2 (1)3 or 4 (2) 5 or 6 (3) 7 to 9 (4) 10 or more
3. How often do you have six or more drinks on one occasion?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
4. How often during the past year have you found that you were not able to stop drinking once you had started?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
5. How often during the past year have you failed to do what was normally expected of you because of drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
6. How often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking session?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
7. How often during the past year have you had a feeling of guilt or remorse after drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
8. How often during the past year have you been unable to remember what happened the night before because you had been
drinking?
(0) Never (1) Less than monthly (2) Monthly (3) Weekly (4) Daily or almost daily
9. Have you or has someone else been injured as a result of your drinking?
(0) No (2) Yes, but not in the past year (4) Yes, during the past year
10. Has a relative or friend or a doctor or other health worker been concerned about your drinking or suggested you cut down?
(0) No (2) Yes, but not in the past year (4) Yes, during the past year

Adapted, with permission, from BaborTF, Higgins-Biddle JC, Saunders JB, Montiero MG. AUDIT. The Alcohol Use Disorders Identification Test.
Guidelines for Use in Primary Health Care, 2nd ed. Geneva, Switzerland: World Health Organization; 2001.
 DISEASE PREVENTION & HEALTH PROMOTION
tool for routine screening of alcohol use disorders in pri­
mary care settings. Brief advice and counseling without
regular follow-up and reinforcement cannot sustain sig­
nificant long-term reductions in unhealthy drinking
behaviors.
Time restraints may prevent clinicians from using the
full AUDIT to screen patients, but single-question screen­
ing tests for unhealthy alcohol use may help increase the
frequency of subsequent AUDIT screening in primary care
settings. The National Institute on Alcohol Abuse and
Alcoholism recommends the following single-question
screening test (validated in primary care settings): “How
many times in the past year have you had X or more drinks
in a day?” (X is 5 for men and 4 for women, and a response
of more than 1 time is considered positive.)
Clinicians should provide those who screen positive for
hazardous or risky drinking with brief behavioral counsel­
ing interventions to reduce alcohol misuse. Use of screen­
ing procedures and brief intervention methods (see
Chapter 25) can produce a 10-30% reduction in long-term
alcohol use and alcohol-related problems.
Several pharmacologic agents are effective in reducing
alcohol consumption. In acute alcohol detoxification, long-
acting benzodiazepines are preferred because they can be
given on a fixed schedule or through “front-loading” or
“symptom-triggered” regimens. Adjuvant sympatholytic
medications can be used to treat hyperadrenergic symp­
toms that persist despite adequate sedation. Three drugs
are FDA approved for treatment of alcohol dependence:
disulfiram (500 mg orally daily), naltrexone (50 mg orally
daily), and acamprosate (666 mg orally three times daily).
Prescription and nonprescription opioid-based drug
abuse, misuse, and overdose has reached epidemic propor­
tions in the United States. Deaths due to opioid overdose
have dramatically increased. Opioid risk mitigation strate­
gies include use of risk assessment tools, treatment agree­
ments (contracts), and urine drug testing. Additional
strategies include establishing and strengthening prescrip­
tion drug monitoring programs, regulating pain manage­
ment facilities, and establishing dosage thresholds requiring
consultation with pain specialists. Medication-assisted
treatment, the use of medications with counseling and
behavioral therapy, is effective in the prevention of opioid
overdose and substance abuse disorders. Methadone,
buprenorphine, and naltrexone are FDA approved for use
in medication-assisted treatment. Buprenorphine has
potential as a medication to ameliorate the symptoms and
CMDT 2021 5
signs of withdrawal from opioids and is effective in reduc­
ing concomitant cocaine and opioid abuse. The risk of
overdose is lower with buprenorphine than methadone,
and it is preferred for patients at high risk for methadone
toxicity (see Chapter 5). The FDA supports greater access
to naloxone and is currently exploring options to make
naloxone more available to treat opioid overdose. (See
Chapter 5.)
Use of illegal drugs—including cocaine, methamphet­
amine, and so-called designer drugs—either sporadically
or episodically remains an important problem. Lifetime
prevalence of drug abuse is approximately 8% and is gener­
ally greater among men, young and unmarried individuals,
Native Americans, and those of lower socioeconomic sta­
tus. As with alcohol, drug abuse disorders often coexist
with personality, anxiety, and other substance abuse disor­
ders. Abuse of anabolic-androgenic steroids has been asso­
ciated with use of other illicit drugs, alcohol, and cigarettes
and with violence and criminal behavior.
Clinical aspects of substance abuse are discussed in
Chapter 25.
Hepner KA et al. Rates and impact of adherence to recom­
mended care for unhealthy alcohol use. J Gen Intern Med.
2019 Feb;34(2):256-63. [PMID: 30484101]
Kaner EF et al. Effectiveness of brief alcohol interventions in
primary care populations. Cochrane Database Syst Rev. 2018
Feb 24;2:CD004148. [PMID: 29476653]
Pace CA et al. Addressing unhealthy substance use in primary
care. Med Clin North Am. 2018 Jul;102(4):567-86. [PMID:
29933816]
Peglow SL et al. Preventing opioid overdose in the clinic and
hospital: analgesia and opioid antagonists. Med Clin North
Am. 2018 Jul;102(4):621-34. [PMID: 29933819]
Saunders JB et al. Alcohol use disorders in ICD-11: past, present,
and future. Alcohol Clin Exp Res. 2019 Aug;43(8):1617-31.
[PMID: 31194891]
Substance Abuse and Mental Health Services Administration
(SAMHSA). Medication-Assisted Treatment (MAT), https://
www.samhsa.gov/medication-assisted-treatment
US Food and Drug Administration. FDA approves first generic
naloxone nasal spray to treat opioid overdose. 2019 Apr 19.
https://www.fda.gov/news-events/press-announcements/
fda-approves-first-generic-naloxone-nasal-spray-treat-
opioid-overdose
US Preventive Services Task Force, Curry SJ et al. Screening and
behavioral counseling interventions to reduce unhealthy
alcohol use in adolescents and adults: US Preventive Services
Task Force Recommendation Statement. JAMA. 2018 Nov
13;320(18):1899-909. [PMID: 30422199]
 CMDT 2021
Common Symptoms
Paul L. Nadler, MD
Ralph Gonzales, MD, MSPH
COUGH
ESSENTIAL INQUIRIES
► Age, tobacco use, e-cigarette vaping, cannabis use,
occupational history, environmental exposures,
and duration of cough.
► Dyspnea (at rest or with exertion).
► Vital signs (heart rate, respiratory rate, body
temperature).
► Chest examination.
► Chest radiography when unexplained cough lasts
more than 3-6 weeks.
General Considerations
Cough is the most common symptom for which patients
seek medical attention. Cough adversely affects personal
and work-related interactions, disrupts sleep, and often
causes discomfort of the throat and chest wall. Most people
seeking medical attention for acute cough desire symptom
relief; few are worried about serious illness. Cough results
from stimulation of mechanical or chemical afferent nerve
receptors in the bronchial tree. Effective cough depends on
an intact afferent-efferent reflex arc, adequate expiratory
and chest wall muscle strength, and normal mucociliary
production and clearance.
Clinical Findings
A. Symptoms
Distinguishing acute (less than 3 weeks), persistent
(3-8 weeks), and chronic (more than 8 weeks) cough ill­
ness syndromes is a useful first step in evaluation. Postin-
fectious cough lasting 3-8 weeks has also been referred to
as subacute cough to distinguish this common, distinct
clinical entity from acute and chronic cough.
1. Acute cough—In healthy adults, most acute cough
syndromes are due to viral respiratory tract infections.
Additional features of infection such as fever, nasal conges­
tion, and sore throat help confirm this diagnosis. Dyspnea
(at rest or with exertion) may reflect a more serious condi­
tion, and further evaluation should include assessment of
oxygenation (pulse oximetry or arterial blood gas measure­
ment), airflow (peak flow or spirometry), and pulmonary
parenchymal disease (chest radiography). The timing and
character of the cough are not very useful in establishing
the cause of acute cough syndromes, although cough­
variant asthma should be considered in adults with promi­
nent nocturnal cough, and persistent cough with phlegm
increases the likelihood of chronic obstructive pulmonary
disease (COPD). The presence of posttussive emesis or
inspiratory whoop in adults modestly increases the likeli­
hood of pertussis, and the absence of paroxysmal cough
and the presence of fever decrease its likelihood. Uncom­
mon causes of acute cough should be suspected in those
with heart disease (heart failure [HF]) or hay fever (allergic
rhinitis) and those with occupational risk factors (such as
farmworkers).
2. Persistent and chronic cough—Cough due to acute
respiratory tract infection resolves within 3 weeks in the
vast majority (more than 90%) of patients. Pertussis should
be considered in adolescents and adults who have persis­
tent or severe cough lasting more than 3 weeks, who have
not recently been boosted with Tdap, and who have been
exposed to a person with confirmed pertussis. It should
also be considered in selected geographic areas where its
prevalence approaches 20% (although its exact prevalence
is difficult to ascertain due to the limited sensitivity of
diagnostic tests).
When angiotensin-converting enzyme (ACE) inhibitor
therapy, acute respiratory tract infection, and chest radio­
graph abnormalities are absent, most cases of persistent
and chronic cough are due to (or exacerbated by) postna­
sal drip (upper airway cough syndrome), asthma, or gas­
troesophageal reflux disease (GERD), or some combination
of these three entities. Approximately 10% of cases are
caused by nonasthmatic eosinophilic bronchitis. A history
of nasal or sinus congestion, wheezing, or heartburn
should direct subsequent evaluation and treatment,
though these conditions frequently cause persistent cough
 COMMON SYMPTOMS CMDT 2021 7

in the absence of typical symptoms. Dyspnea at rest or

with exertion is not commonly reported among patients Table 2-1. Positive and negative likelihood ratios for
with persistent cough; dyspnea requires assessment for history, physical examination, and laboratory findings
chronic lung disease, HF, anemia, pulmonary embolism, in the diagnosis of pneumonia.
or pulmonary hypertension.
Positive Negative
Bronchogenic carcinoma is suspected when cough is
Likelihood Likelihood
accompanied by unexplained weight loss, hemoptysis, and Finding Ratio Ratio
fevers with night sweats, particularly in persons with sig­
nificant tobacco or occupational exposures (asbestos, Medical history
radon, diesel exhaust, and metals). Persistent and chronic Fever 1.7-2.1 0.6-0.7
cough accompanied by excessive mucus secretions Chills 1.3-1.7 0.7-0.9
increases the likelihood of COPD, particularly among
Physical examination
smokers, or of bronchiectasis if accompanied by a history
of recurrent or complicated pneumonia; chest radiographs Tachypnea (RR > 25 1.5-3.4 0.8
are helpful in diagnosis. Chronic cough with dry eyes may breaths/min)
represent Sjogren syndrome. A chronic dry cough may be Tachycardia (> 100 beats/ 1.6-2.3 0.5-0.7
the first symptom of idiopathic pulmonary fibrosis. min in two studies or
> 120 beats/min in one
study)
B. Physical Examination
Hyperthermia (> 37.8°C) 1.4-4.4 0.6-0.8
Examination can direct subsequent diagnostic testing for
Chest examination
acute cough. Pneumonia is suspected when acute cough is
accompanied by vital sign abnormalities (tachycardia, Dullness to percussion 2.2-4.3 0.8-0.9
tachypnea, fever). Findings suggestive of airspace consoli­ Decreased breath sounds 2.3-2.5 0.6-0.8
dation (crackles, decreased breath sounds, fremitus,
Crackles 1.6-2.7 0.6-0.9
egophony) are significant predictors of community-
acquired pneumonia but are present in a minority of cases. Rhonchi 1.4-1.5 0.8-0.9
Purulent sputum is associated with bacterial infections in Egophony 2.0-8.6 0.8-1.0
patients with structural lung disease (eg, COPD, cystic Laboratory findings
fibrosis), but it is a poor predictor of pneumonia in the
Leukocytosis (> 11 x 109/L 1.9-3.7 0.3-0.6
otherwise healthy adult. Wheezing and rhonchi are fre­
in one study or > 10.4 x
quent findings in adults with acute bronchitis and do not
109/L in another study)
indicate consolidation or adult-onset asthma in most cases.
Examination of patients with persistent cough should RR, respiratory rate.
look for evidence of chronic sinusitis, contributing to post­
nasal drip syndrome or asthma. Chest and cardiac signs
may help distinguish COPD from HF. In patients with [CI], 0.93-0.97) and a specificity of 0.90 (95% CI, 0.86-0.94).
cough and dyspnea, a normal match test (ability to blow Chest radiography had a pooled sensitivity of 0.77 (95% CI,
out a match from 25 cm away) and maximum laryngeal 0.73-0.80) and a specificity of 0.91 (95% CI, 0.87-0.94). In
height greater than 4 cm (measured from the sternal notch patients with dyspnea, pulse oximetry and peak flow help
to the cricoid cartilage at end expiration) substantially exclude hypoxemia or obstructive airway disease. How­
decrease the likelihood of COPD. Similarly, normal jugular ever, a normal pulse oximetry value (eg, greater than 93%)
venous pressure and no hepatojugular reflux decrease the does not rule out a significant alveolar-arterial (A-a) gra­
likelihood of biventricular HF. dient when patients have effective respiratory compensa­
tion. During documented outbreaks, clinical diagnosis of
C. Diagnostic Studies influenza has a positive predictive value of -70%; this
usually obviates the need for rapid diagnostic tests. No
1. Acute cough—Chest radiography should be considered
evidence exists to assess whether the initial evaluation of
for any adult with acute cough whose vital signs are abnor­
cough in immunocompromised patients should differ
mal or whose chest examination suggests pneumonia. The
from immunocompetent patients, but expert recommen­
relationship between specific clinical findings and the
dations suggest that tuberculosis be considered in HIV-
probability of pneumonia is shown in Table 2-1. A large,
infected patients in areas with a high prevalence of
multicenter randomized clinical trial found that elevated
tuberculosis regardless of radiographic findings.
serum C-reactive protein (levels greater than 30 mg/dL)
improves diagnostic accuracy of clinical prediction rules 2. Persistent and chronic cough—Chest radiography is
for pneumonia in adults with acute cough; procalcitonin indicated when ACE inhibitor therapy-related and postin-
added no clinically relevant information. A meta-analysis fectious cough are excluded. If pertussis is suspected, poly­
found that lung ultrasonography had better accuracy merase chain reaction testing should be performed on a
than chest radiography for the diagnosis of adult nasopharyngeal swab or nasal wash specimen—although
community-acquired pneumonia. Lung ultrasonography the ability to detect pertussis decreases as the duration of
had a pooled sensitivity of 0.95 (95% confidence interval cough increases. When the chest film is normal, postnasal
 CMDT 2021 CHAPTER 2
Table 2-2. Empiric therapy or definitive testing for
persistent cough.
Suspected Step 1 (Empiric Step 2 (Definitive
Condition Therapy) Testing)
Postnasal drip Therapy for allergy or Sinus CT scan;
chronic sinusitis ENT referral
Asthma Beta-2-agonist Spirometry; consider
methacholine
challenge if normal
GERD Lifestyle and diet mod­ Esophageal pH
ifications with or monitoring
without proton
pump inhibitors
ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease.
drip, asthma, or GERD are the most likely causes. The
presence of typical symptoms of these conditions directs
further evaluation or empiric therapy, though typical
symptoms are often absent. Definitive tests for determin­
ing the presence of each are available (Table 2-2).
However, empiric treatment with a maximum-strength
regimen for postnasal drip, asthma, or GERD for
2-4 weeks is one recommended approach since docu­
menting the presence of postnasal drip, asthma, or GERD
does not mean they are the cause of the cough. Alterna­
tive approaches to identifying patients who have asthma
with its corticosteroid-responsive cough include examin­
ing induced sputum for increased eosinophil counts
(greater than 3%) or providing an empiric trial of predni­
sone, 30 mg daily orally for 2 weeks. Spirometry may help
identify large airway obstruction in patients who have
persistent cough and wheezing and who are not respond­
ing to asthma treatment. When empiric treatment trials are
not successful, additional evaluation with pH manometry,
endoscopy, barium swallow, sinus CT, or high-resolution
chest CT may identify the cause.
Differential Diagnosis
A. Acute Cough
Acute cough may be a symptom of acute respiratory tract
infection, asthma, allergic rhinitis, HF, and ACE inhibitor
therapy, as well as many less common causes.
B. Persistent and Chronic Cough
Causes of persistent cough include environmental expo­
sures (cigarette smoke, air pollution), occupational expo­
sures, pertussis, postnasal drip, asthma (including
cough-variant asthma), GERD, COPD, chronic aspiration,
bronchiectasis, eosinophilic bronchitis, tuberculosis or
other chronic infection, interstitial lung disease, and bron­
chogenic carcinoma. COPD is a common cause of persis­
tent cough among patients older than 50 years. Persistent
cough may also be due to somatic cough syndrome (previ­
ously called “psychogenic cough”) or tic cough (previously
called “habit cough”).
Treatment
A. Acute Cough
Treatment of acute cough should target the underlying
etiology of the illness, the cough reflex itself, and any addi­
tional factors that exacerbate the cough. Cough duration is
typically 1-3 weeks, yet patients frequently expect cough to
last fewer than 10 days. Limited studies on the use of dex­
tromethorphan suggest a minor or modest benefit.
When influenza is diagnosed (including H1N1 influ­
enza), oral oseltamivir or zanamivir or intravenous pera-
mivir are equally effective (1 less day of illness) when
initiated within 30-48 hours of illness onset; treatment is
recommended regardless of illness duration when patients
have severe, complicated, or progressive influenza and in
patients requiring hospitalization. In Chlamydophila- or
Mycoplasma-documented infection or outbreaks, first-line
antibiotics include erythromycin or doxycycline. Antibiot­
ics do not improve cough severity or duration in patients
with uncomplicated acute bronchitis. In patients with
bronchitis and wheezing, inhaled beta-2-agonist therapy
reduces severity and duration of cough. In patients with
acute cough, treating the accompanying postnasal drip
(with antihistamines, decongestants, saline nasal irrigation,
or nasal corticosteroids) can be helpful. A Cochrane review
(n = 163) found codeine to be no more effective than pla­
cebo in reducing cough symptoms.
B. Persistent and Chronic Cough
Evaluation and management of persistent cough often
require multiple visits and therapeutic trials, which fre­
quently lead to frustration, anger, and anxiety. When per­
tussis infection is suspected early in its course, treatment
with a macrolide antibiotic (see Chapter 33) is appropriate
to reduce organism shedding and transmission. When
pertussis has lasted more than 7-10 days, antibiotic treat­
ment does not affect the duration of cough, which can last
up to 6 months. Early identification, revaccination with
Tdap, and treatment of adult patients who work or live with
persons at high risk for complications from pertussis (preg­
nant women, infants [particularly younger than 1 year],
and immunosuppressed individuals) are encouraged.
Table 2-2 outlines empiric treatments for persistent
cough. There is no evidence to guide how long to continue
treatment for persistent cough due to postnasal drip,
asthma, or GERD. Studies have not found a consistent
benefit of inhaled corticosteroid therapy in adults with
persistent cough. Eight weeks of thrice-weekly azithromy­
cin did not improve cough in patients without asthma.
When empiric treatment trials fail, consider other
causes of chronic cough such as obstructive sleep apnea,
tonsillar or uvular enlargement, and environmental fungi.
The small percentage of patients with idiopathic chronic
cough should be managed in consultation with an otolar­
yngologist or a pulmonologist; consider a high-resolution
CT scan of the lungs. Treatment options include nebu­
lized lidocaine therapy and morphine sulfate, 5-10 mg
orally twice daily. Sensory dysfunction of the laryngeal
branches of the vagus nerve may contribute to persistent
 COMMON SYMPTOMS
cough syndromes and may help explain the effectiveness of
gabapentin in patients with chronic cough. Speech pathol­
ogy therapy combined with pregabalin has some benefit in
chronic refractory cough. In patients with reflex cough
syndrome, therapy aimed at shifting the patients atten-
tional focus from internal stimuli to external focal points
can be helpful. Proton pump inhibitors are not effective on
their own; most benefit appears to come from lifestyle
modifications and weight reduction.
When to Refer
• Failure to control persistent or chronic cough following
empiric treatment trials.
• Patients with recurrent symptoms should be referred to an
otolaryngologist, pulmonologist, or gastroenterologist.
When to Admit
• Patient at high risk for tuberculosis for whom compli­
ance with respiratory precautions is uncertain.
• Need for urgent bronchoscopy, such as suspected for­
eign body.
• Smoke or toxic fume inhalational injury.
• Gas exchanged is impaired by cough.
• Patients at high risk for barotrauma (eg, recent
pneumothorax).
Hill AT et al; CHEST Expert Cough Panel. Adult outpatients
with acute cough due to suspected pneumonia or influenza:
CHEST Guideline and Expert Panel Report. Chest. 2019 Jan;
155(l):155-67. [PMID: 30296418]
Moore A et al; CHEST Expert Cough Panel. Clinically diagnosing
pertussis-associated cough in adults and children: CHEST
Guideline and Expert Panel Report. Chest. 2019 Jan; 155(1):
147-54. [PMID: 30321509]
Sinharay R et al. Respiratory and cardiovascular responses to
walking down a traffic-polluted road compared with walking
in a traffic-free area in participants aged 60 years and older
with chronic lung or heart disease and age-matched healthy
controls: a randomised, crossover study. Lancet. 2018 Jan 27;
391(10118):339-49. [PMID: 29221643]
Smith SM et al. Antibiotics for acute bronchitis. Cochrane
Database SystRev. 2017 Jun 19;6:CD000245. [PMID: 28626858]
DYSPNEA
ESSENTIAL INQUIRIES
► Fever, cough, and chest pain.
► Vital sign measurements; pulse oximetry.
► Cardiac and chest examination.
► Chest radiography and arterial blood gas mea­
surement in selected patients.
General Considerations
Dyspnea is a subjective experience or perception of uncom­
fortable breathing. There is a lack of empiric evidence on
CMDT 2021 9
the prevalence, etiology, and prognosis of dyspnea in gen­
eral practice. The relationship between level of dyspnea
and the severity of underlying disease varies widely among
individuals. Dyspnea can result from conditions that
increase the mechanical effort of breathing (eg, asthma,
COPD, restrictive lung disease, respiratory muscle weak­
ness), conditions that produce compensatory tachypnea
(eg, hypoxemia, acidosis), primary pulmonary vasculopa­
thy (pulmonary hypertension), or psychogenic conditions.
The following factors play a role in how and when dyspnea
presents in patients: rate of onset, previous dyspnea, medi­
cations, comorbidities, psychological profile, and severity
of underlying disorder.
Clinical Findings
A. Symptoms
The duration, severity, and periodicity of dyspnea influence
the tempo of the clinical evaluation. Rapid onset or severe
dyspnea in the absence of other clinical features should
raise concern for pneumothorax, pulmonary embolism, or
increased left ventricular end-diastolic pressure (LVEDP).
Spontaneous pneumothorax is usually accompanied by
chest pain and occurs most often in thin, young males and
in those with underlying lung disease. Pulmonary embo­
lism should always be suspected when a patient with new
dyspnea reports a recent history (previous 4 weeks) of
prolonged immobilization or surgery, estrogen therapy, or
other risk factors for deep venous thrombosis (DVT) (eg,
previous history of thromboembolism, cancer, obesity,
lower extremity trauma) and when the cause of dyspnea is
not apparent. Silent myocardial infarction, which occurs
more frequently in diabetic persons and women, can result
in increased LVEDP, acute HF, and dyspnea.
Accompanying symptoms provide important clues to
causes of dyspnea. When cough and fever are present, pul­
monary disease (particularly infection) is the primary
concern; myocarditis, pericarditis, and septic emboli can
present in this manner. Chest pain should be further char­
acterized as acute or chronic, pleuritic or exertional.
Although acute pleuritic chest pain is the rule in acute
pericarditis and pneumothorax, most patients with pleu­
ritic chest pain in the outpatient clinic have pleurisy due to
acute viral respiratory tract infection. Periodic chest pain
that precedes the onset of dyspnea suggests myocardial
ischemia or pulmonary embolism. When associated with
wheezing, most cases of dyspnea are due to acute bronchi­
tis; however, other causes include new-onset asthma, for­
eign body, and vocal cord dysfunction. Interstitial lung
disease and pulmonary hypertension should be considered
in patients with symptoms (or history) of connective tissue
disease. Pulmonary lymphangitis carcinomatosis should be
considered if a patient has a malignancy, especially breast,
lung, or gastric cancer.
When a patient reports prominent dyspnea with mild
or no accompanying features, consider noncardiopulmo-
nary causes of impaired oxygen delivery (anemia, methe­
moglobinemia, cyanide ingestion, carbon monoxide
poisoning), metabolic acidosis, panic disorder, neuromus­
cular disorders, and chronic pulmonary embolism.
 1 CMDT 2021 CHAPTER 2
Platypnea-orthodeoxia syndrome is characterized by
dyspnea and hypoxemia on sitting or standing that
improves in the recumbent position. It may be caused by
an intracardiac shunt, pulmonary vascular shunt (includ­
ing hepatopulmonary syndrome), or ventilation-perfusion
mismatch. Hyperthyroidism can cause dyspnea from
increased ventilatory drive, respiratory muscle weakness,
or pulmonary hypertension.
B. Physical Examination
A focused physical examination should include evaluation
of the head and neck, chest, heart, and lower extremities.
Visual inspection of the patient can suggest obstructive
airway disease (pursed-lip breathing, use of accessory
respiratory muscles, barrel-shaped chest), pneumothorax
(asymmetric excursion), or metabolic acidosis (Kussmaul
respirations). Patients with impending upper airway
obstruction (eg, epiglottitis, foreign body) or severe asthma
exacerbation sometimes assume a tripod position. Focal
wheezing raises the suspicion for a foreign body or other
bronchial obstruction. Maximum laryngeal height (the
distance between the top of the thyroid cartilage and the
suprasternal notch at end expiration) is a measure of
hyperinflation. Obstructive airway disease is virtually non­
existent when a nonsmoking patient younger than age
45 years has a maximum laryngeal height greater than 4 cm.
Factors increasing the likelihood of obstructive airway
disease include patient history of more than 40 pack-years
smoking (adjusted likelihood ratio [LRJ + 11.6; LR- 0.9),
patient age 45 years or older (LR+ 1.4; LR- 0.5), and maxi­
mum laryngeal height greater than or equal to 4 cm (LR+
3.6; LR- 0.7). With all three of these factors present, the
LR+ rises to 58.5 and the LR- falls to 0.3.
Absent breath sounds suggest a pneumothorax. An
accentuated pulmonic component of the second heart
sound (loud P2) is a sign of pulmonary hypertension and
pulmonary embolism.
Clinical predictors of increased LVEDP in dyspneic
patients with no prior history of HF include tachycardia,
systolic hypotension, jugular venous distention, hepato­
jugular reflux, bibasilar crackles, third heart sound, lower
extremity edema, and chest film findings of pulmonary
vascular redistribution or cardiomegaly. When none is
present, there is a very low probability (less than 10%) of
increased LVEDP, but when two or more are present, there
is a very high probability (greater than 90%) of increased
LVEDP.
C. Diagnostic Studies
Causes of dyspnea that can be managed without chest radi­
ography are few: ingestions causing lactic acidosis, anemia,
methemoglobinemia, and carbon monoxide poisoning.
The diagnosis of pneumonia should be confirmed by chest
radiography in most patients, and elevated blood levels of
procalcitonin or C-reactive protein can support the diag­
nosis of pneumonia in equivocal cases or in the presence of
interstitial lung disease. Conversely, a low procalcitonin
can help exclude pneumonia in dyspneic patients present­
ing with HF.
Chest radiography is fairly sensitive and specific for
new-onset HF (represented by redistribution of pulmonary
venous circulation) and can help guide treatment of
patients with other cardiac diseases. NT-proBNP can assist
in the diagnosis of HF.
Lung ultrasonography is superior to chest radiography
in detecting pulmonary edema due to acute decompen­
sated HF among adult patients presenting with dyspnea
and in the diagnosis of pneumonia in patients admitted to
an acute geriatric ward. End-expiratory chest radiography
enhances detection of small pneumothoraces.
A normal chest radiograph has substantial diagnostic
value. When there is no physical examination evidence of
COPD or HF and the chest radiograph is normal, the
major remaining causes of dyspnea include pulmonary
embolism, Pneumocystis jirovecii infection (the initial
radiograph may be normal in up to 25%), upper airway
obstruction, foreign body, anemia, and metabolic acidosis.
If a patient has tachycardia and hypoxemia but a normal
chest radiograph and electrocardiogram (ECG), then tests
to exclude pulmonary emboli, anemia, or metabolic acido­
sis are warranted. High-resolution chest CT is particularly
useful in the evaluation of interstitial and alveolar lung
disease. Helical (“spiral”) CT is useful to diagnose pulmo­
nary embolism since the images are high resolution and
require only one breathhold by the patient, but to minimize
unnecessary testing and radiation exposure, the clinician
should first consider a clinical decision rule (with or with­
out D-dimer testing) to estimate the pretest probability of
a pulmonary embolism. It is appropriate to forego CT
scanning in patients with very low probability of pulmo­
nary embolus when other causes of dyspnea are more likely
(see Chapter 9).
Laboratory findings suggesting increased LVEDP
include elevated serum B-type natriuretic peptide (BNP or
NT-proBNP) levels. BNP has been shown to reliably diag­
nose severe dyspnea caused by HF and to differentiate it
from dyspnea due to other conditions.
Arterial blood gas measurement may be considered if
clinical examination and routine diagnostic testing are
equivocal. With two notable exceptions (carbon monoxide
poisoning and cyanide toxicity), arterial blood gas mea­
surement distinguishes increased mechanical effort causes
of dyspnea (respiratory acidosis with or without hypox­
emia) from compensatory tachypnea (respiratory alkalosis
with or without hypoxemia or metabolic acidosis) and
from psychogenic dyspnea (respiratory alkalosis). An
observational study, however, found that arterial blood gas
measurement had little value in determining the cause of
dyspnea in patients presenting to the emergency depart­
ment. Carbon monoxide and cyanide impair oxygen deliv­
ery with minimal alterations in Po2; percent
carboxyhemoglobin identifies carbon monoxide toxicity.
Cyanide poisoning should be considered in a patient with
profound lactic acidosis following exposure to burning
vinyl (such as a theater fire or industrial accident). Sus­
pected carbon monoxide poisoning or methemoglobin­
emia can also be confirmed with venous carboxyhemoglobin
or methemoglobin levels. Venous blood gas testing is also
an option for assessing respiratory and acid-base status by
 COMMON SYMPTOMS
measuring venous pH and Pco2 but is unable to provide
information on oxygenation status. To correlate with arte­
rial blood gas values, venous pH is typically 0.03-0.05 units
lower, and venous Pco2 is typically 4-5 mm Hg higher than
arterial samples.
Because arterial blood gas testing is impractical in most
outpatient settings, pulse oximetry has assumed a central
role in the office evaluation of dyspnea. Oxygen saturation
values above 96% almost always correspond with a Po2
greater than 70 mm Hg, whereas values less than 94% may
represent clinically significant hypoxemia. Important
exceptions to this rule include carbon monoxide toxicity,
which leads to a normal oxygen saturation (due to the
similar wavelengths of oxyhemoglobin and carboxyhemo­
globin), and methemoglobinemia, which results in an
oxygen saturation of about 85% that fails to increase with
supplemental oxygen. A delirious or obtunded patient with
obstructive lung disease warrants immediate measurement
of arterial blood gases to exclude hypercapnia and the need
for intubation, regardless of the oxygen saturation. If a
patient reports dyspnea with exertion, but resting oximetry
is normal, assessment of desaturation with ambulation (eg,
a brisk walk around the clinic) can be useful for confirming
impaired gas exchange.
A study found that for adults without known cardiac or
pulmonary disease reporting dyspnea on exertion, spirom­
etry, NT-proBNP, and CT imaging were the most informa­
tive tests.
Episodic dyspnea can be challenging if an evaluation
cannot be performed during symptoms. Life-threatening
causes include recurrent pulmonary embolism, myocardial
ischemia, and reactive airway disease. When associated
with audible wheezing, vocal cord dysfunction should be
considered, particularly in a young woman who does not
respond to asthma therapy. Spirometry is very helpful in
further classifying patients with obstructive airway disease
but is rarely needed in the initial or emergent evaluation of
patients with acute dyspnea.
Differential Diagnosis
Urgent and emergent conditions causing acute dyspnea
include pneumonia, COPD, asthma, pneumothorax, pul­
monary embolism, cardiac disease (eg, HF, acute myocar­
dial infarction, valvular dysfunction, arrhythmia,
intracardiac shunt), pleural effusion, diffuse alveolar hem­
orrhage, metabolic acidosis, cyanide toxicity, methemoglo­
binemia, and carbon monoxide poisoning. The etiology of
dyspnea secondary to e-cigarette vaping is being actively
studied. Chronic dyspnea may be caused by interstitial
lung disease, pulmonary hypertension, or pulmonary
alveolar proteinosis.
Treatment
The treatment of urgent or emergent causes of dyspnea
should aim to relieve the underlying cause. Pending diag­
nosis, patients with hypoxemia should be immediately
provided supplemental oxygen unless significant hyper­
capnia is present or strongly suspected pending arterial
blood gas measurement. Dyspnea frequently occurs in
CMDT 2021 21
patients nearing the end of life. Opioid therapy, anxiolytics,
and corticosteroids can provide substantial relief indepen­
dent of the severity of hypoxemia. However, inhaled opi­
oids are not effective. Oxygen therapy is most beneficial to
patients with significant hypoxemia (Pao2 less than 55 mm
Hg) (see Chapter 5). In patients with severe COPD and
hypoxemia, oxygen therapy improves exercise perfor­
mance and mortality. Pulmonary rehabilitation programs
are another therapeutic option for patients with moderate
to severe COPD or interstitial pulmonary fibrosis. Nonin-
vasive ventilation may be considered for patients with
dyspnea caused by an acute COPD exacerbation, but the
efficacy of this treatment is still uncertain.
When to Refer
• Following acute stabilization, patients with advanced
COPD should be referred to a pulmonologist, and
patients with HF or valvular heart disease should be
referred to a cardiologist.
• Cyanide toxicity or carbon monoxide poisoning should
be managed in conjunction with a toxicologist.
• Lung transplantation can be considered for patients
with advanced interstitial lung disease.
When to Admit
• Impaired gas exchange from any cause or high risk of
pulmonary embolism pending definitive diagnosis.
• Suspected cyanide toxicity or carbon monoxide
poisoning.
Freund Y et al; PROPER Investigator Group. Effect of the Pul­
monary Embolism Rule-Out Criteria on subsequent throm­
boembolic events among low-risk emergency department
patients: the PROPER randomized clinical trial. JAMA. 2018
Feb 13;319(6):559-66. [PMID: 29450523]
Layden JE et al. Pulmonary illness related to e-cigarette use in
Illinois and Wisconsin—preliminary report. N Engl J Med.
2020 Mar 5;382(10):903-16. [PMID: 31491072]
Maw AM et al. Diagnostic accuracy of point-of-care lung
ultrasonography and chest radiography in adults with
symptoms suggestive of acute decompensated heart failure: a
systematic review and meta-analysis. JAMA Netw Open. 2019
Mar l;2(3):el90703. [PMID: 30874784]
Sendama W et al. Decision-making with D-dimer in the diagnosis
of pulmonary embolism. Am J Med. 2018 Dec 131(12):
1438-43. [PMID: 30125536]
HEMOPTYSIS
ESSENTIAL INQUIRIES
► Fever, cough, and other symptoms of lower respi­
ratory tract infection.
► Smoking history.
► Nasopharyngeal or gastrointestinal bleeding.
► Chest radiography and complete blood count
(and, in some cases, INR).
 CMDT 2021 CHAPTER 2
General Considerations
Hemoptysis is the expectoration of blood that originates
below the vocal cords. It is commonly classified as trivial,
mild, or massive—the latter defined as more than 200-600 mL
(about 1-2 cups) in 24 hours. Massive hemoptysis can be
usefully defined as any amount that is hemodynamically
significant or threatens ventilation. Its in-hospital mortal­
ity was 6.5% in one study. The initial goal of management
of massive hemoptysis is therapeutic, not diagnostic.
The causes of hemoptysis can be classified anatomically.
Blood may arise from the trachea due to malignant inva­
sion, and from the airways in COPD, bronchiectasis, bron­
chial Dieulafoy disease, and bronchogenic carcinoma; from
the pulmonary vasculature in left ventricular failure, mitral
stenosis, pulmonary embolism, pulmonary arterial hyper­
tension, and arteriovenous malformations; or from the
pulmonary parenchyma in pneumonia, fungal infections,
inhalation of crack cocaine, or granulomatosis with poly­
angiitis. Diffuse alveolar hemorrhage—manifested by alve­
olar infiltrates on chest radiography—is due to small vessel
bleeding usually caused by autoimmune or hematologic
disorders, or rarely precipitated by warfarin. Most cases of
hemoptysis presenting in the outpatient setting are due to
infection (eg, acute or chronic bronchitis, pneumonia,
tuberculosis, aspergillosis). Hemoptysis due to lung cancer
increases with age, causing up to 20% of cases among older
adults. Less commonly (less than 10% of cases), pulmonary
venous hypertension (eg, mitral stenosis, pulmonary
embolism) causes hemoptysis. Most cases of hemoptysis
that have no visible cause on CT scan or bronchoscopy will
resolve within 6 months without treatment, with the nota­
ble exception of patients at high risk for lung cancer (smok­
ers older than 40 years). Iatrogenic hemorrhage may follow
transbronchial lung biopsies, anticoagulation, or pulmo­
nary artery rupture due to distal placement of a balloon­
tipped catheter. Obstructive sleep apnea may be a risk
factor for hemoptysis. Amyloidosis of the lung can cause
hemoptysis. No cause is identified in up to 15-30% of
cases.
Clinical Findings
A. Symptoms
Blood-tinged sputum in the setting of an upper respiratory
tract infection in an otherwise healthy, young (age under
40 years) nonsmoker does not warrant an extensive diag­
nostic evaluation if the hemoptysis subsides with resolu­
tion of the infection. However, hemoptysis is frequently a
sign of serious disease, especially in patients with a high
prior probability of underlying pulmonary pathology.
Hemoptysis is the only symptom found to be a specific
predictor of lung cancer. There is no value in distinguish­
ing blood-streaked sputum and cough productive of blood
during evaluation; the goal of the history is to identify
patients at risk for one of the disorders listed earlier. Perti­
nent features include duration of symptoms, presence of
respiratory infection, and past or current tobacco use.
Nonpulmonary sources of hemorrhage—from the sinuses
or the gastrointestinal tract—must be excluded.
B. Physical Examination
Elevated pulse, hypotension, and decreased oxygen satura­
tion suggest large-volume hemorrhage that warrants emer­
gent evaluation and stabilization. The nares and oropharynx
should be carefully inspected to identify a potential upper
airway source of bleeding. Chest and cardiac examination
may reveal evidence of HF or mitral stenosis.
C. Diagnostic Studies
Diagnostic evaluation should include a chest radiograph
and complete blood count. Kidney function tests, urinaly­
sis, and coagulation studies are appropriate in specific cir­
cumstances. Hematuria that accompanies hemoptysis may
be a clue to Goodpasture syndrome or vasculitis. Flexible
bronchoscopy reveals endobronchial cancer in 3-6% of
patients with hemoptysis who have a normal (non-lateral-
izing) chest radiograph. Nearly all of these patients are
smokers over the age of 40, and most will have had symp­
toms for more than 1 week. High-resolution chest CT scan
complements bronchoscopy; it can visualize unsuspected
bronchiectasis and arteriovenous malformations and will
show central endobronchial cancers in many cases. It is the
test of choice for suspected small peripheral malignancies.
Helical CT pulmonary angiography is the initial test of
choice for evaluating patients with suspected pulmonary
embolism, although caution should be taken to avoid large
contrast loads in patients with even mild chronic kidney
disease (serum creatinine greater than 2.0 g/dL or rapidly
rising creatinine in normal range). Helical CT scanning
can be avoided in patients who are at “unlikely” risk for
pulmonary embolism using the Wells score or PERC rule
for pulmonary embolism and the sensitive D-dimer test.
Echocardiography may reveal evidence of HF or mitral
stenosis.
Treatment
Management of mild hemoptysis consists of identifying
and treating the specific cause. Massive hemoptysis is life­
threatening. The airway should be protected with endotra­
cheal intubation, ventilation ensured, and effective
circulation maintained. If the location of the bleeding site
is known, the patient should be placed in the decubitus
position with the involved lung dependent. Uncontrollable
hemorrhage warrants rigid bronchoscopy and surgical
consultation. In stable patients, flexible bronchoscopy may
localize the site of bleeding, and angiography can embolize
the involved bronchial arteries. Embolization is effective
initially in 85% of cases, although rebleeding may occur in
up to 20% of patients during the following year. The ante­
rior spinal artery arises from the bronchial artery in up to
5% of people, and paraplegia may result if it is inadver­
tently cannulated and embolized.
One double-blind, randomized controlled trial compared
treatment with inhalations of tranexamic acid (an antifibri-
nolytic drug) versus placebo (normal saline) in patients
hospitalized with mild hemoptysis (less than 200 mL of
expectorated blood per 24 hours). Compared to patients
receiving placebo (normal saline), more patients treated
 COMMON SYMPTOMS
with tranexamic acid experienced resolution of hemoptysis
within 5 days of admission (96% versus 50%; P < 0.0005).
In addition, mean hospital length of stay was shorter for
the tranexamic acid group and fewer patients required
invasive procedures (interventional bronchoscopy, angio­
graphic embolization) to control the hemorrhage.
When to Refer
• Patients should be referred to a pulmonologist when
bronchoscopy of the lower respiratory tract is needed.
• Patients should be referred to an otolaryngologist when
an upper respiratory tract bleeding source is identified.
• Patients with severe coagulopathy complicating man­
agement should be referred to a hematologist.
When to Admit
• To stabilize bleeding process in patients at risk for or
experiencing massive hemoptysis.
• To correct disordered coagulation (using clotting fac­
tors or platelets, or both) or to reverse anticoagulation.
• To stabilize gas exchange.
Davidson K et al. Managing massive hemoptysis. Chest. 2020
Jan;157(l):77-88. [PMID: 31374211]
Ittrich H et al. The diagnosis and treatment of hemoptysis. Dtsch
Arztebl Int. 2017 Jun 5;114(21):371-81. [PMID: 28625277]
Nasser M et al. Alveolar hemorrhage in vasculitis (primary and
secondary). Semin Respir Crit Care Med. 2018 Aug;39(4):
482-93. [PMID: 30404115]
Wand O et al. Inhaled tranexamic acid for hemoptysis treatment:
a randomized controlled trial. Chest. 2018 Dec; 154(6):
1379-84. [PMID: 30321510]
CHEST PAIN
ESSENTIAL INQUIRIES
► Pain onset, character, location/size, duration, peri­
odicity, and exacerbators; shortness of breath.
► Vital signs; chest and cardiac examinations.
► Electrocardiography and biomarkers of myocar­
dial necrosis in selected patients.
General Considerations
Chest pain (or chest discomfort) is a common symptom
that can occur as a result of cardiovascular, pulmonary,
pleural, or musculoskeletal disease; esophageal or other
gastrointestinal disorders; herpes zoster; cocaine use; or
anxiety states. The frequency and distribution of life­
threatening causes of chest pain, such as acute coronary
syndrome (ACS), pericarditis, aortic dissection, vasospas­
tic angina, pulmonary embolism, pneumonia, and esopha­
geal perforation, vary substantially between clinical
settings. Systemic lupus erythematosus, rheumatoid
CMDT 2021
arthritis, reduced estimated glomerular filtration rate, and
HIV infection are conditions that confer a strong risk of
coronary artery disease. Precocious ACS may represent
acute thrombosis independent of underlying atheroscle­
rotic disease. In patients aged 35 years or younger, risk
factors for ACS are obesity, hyperlipidemia, and smoking.
Chest pain characteristics that can lead to early diagno­
sis of acute myocardial infarction do not differ in fre­
quency or strength of association between men and
women. Because pulmonary embolism can present with a
wide variety of symptoms, consideration of the diagnosis
and rigorous risk factor assessment for venous thrombo­
embolism (VTE) is critical. Classic VTE risk factors
include cancer, trauma, recent surgery, prolonged immobi­
lization, pregnancy, oral contraceptives, and family history
and prior history of VTE. Other conditions associated with
increased risk of pulmonary embolism include HF and
COPD. Sickle cell anemia can cause acute chest syndrome.
Patients with this syndrome often have chest pain, fever,
and cough.
Clinical Findings
A. Symptoms
Myocardial ischemia is usually described as a dull, aching
sensation of “pressure,” “tightness,” “squeezing,” or “gas,”
rather than as sharp or spasmodic. Ischemic symptoms
usually subside within 5-20 minutes but may last longer.
Progressive symptoms or symptoms at rest may represent
unstable angina. Prolonged chest pain episodes might rep­
resent myocardial infarction, although up to one-third of
patients with acute myocardial infarction do not report
chest pain. When present, pain due to myocardial ischemia
is commonly accompanied by a sense of anxiety or uneasi­
ness. The location is usually retrosternal or left precordial.
Because the heart lacks somatic innervation, precise local­
ization of pain due to cardiac ischemia is difficult; the pain
is commonly referred to the throat, lower jaw, shoulders,
inner arms, upper abdomen, or back. Ischemic pain may be
precipitated or exacerbated by exertion, cold temperature,
meals, stress, or combinations of these factors and is usu­
ally relieved by rest. However, many episodes do not con­
form to these patterns, and atypical presentations of ACS
are more common in older adults, women, and persons
with diabetes mellitus. Other symptoms that are associated
with ACS include shortness of breath; dizziness; a feeling of
impending doom; and vagal symptoms, such as nausea and
diaphoresis. In older persons, fatigue is a common present­
ing complaint of ACS.
There are gender differences in the perception and pre­
senting symptoms of young patients with myocardial
infarction. Women were more likely than men to present
with three or more associated symptoms (eg, epigastric
symptoms, palpitations, and pain or discomfort in the jaw,
neck, arms, or between the shoulder blades; 61.9% for
women versus 54.8% for men, P < 0.001). In adjusted
analyses, women with an ST-segment-elevation acute myo­
cardial infarction were more likely than men to present
without chest pain (odds ratio, 1.51; 95% CI, 1.03-2.22). In
comparison with men, women were more likely to perceive
 CMDT 2021 CHAPTER 2
symptoms as stress/anxiety (20.9% versus 11.8%, P < 0.001)
but less likely to attribute symptoms to muscle pain (15.4%
versus 21.2%, P = 0.03.)
One analysis found the following clinical features to be
associated with acute myocardial infarction: (1) from the
history: chest pain that radiates to the left, right, or both
arms (LR+ 2.3, 2.9, 7.1); diaphoresis (LR+ 2.0); and nausea
and vomiting (LR+1.9); (2) from the physical examination:
third heart sound (LR+ 3.2), systolic blood pressure less than
or equal to 80 mm Hg (LR +3.1), pulmonary crackles
(LR+ 2.1); and (3) from the electrocardiogram: any ST-segment
elevation greater than or equal to 1 mm (LR+ 11.2), any ST
depression (LR 3.2), any Q wave (LR+ 3.9), any conduction
defect (LR+ 2.7), and new conduction defect (LR+ 6.3).
A meta-analysis found the clinical findings and risk fac­
tors most suggestive of ACS were prior abnormal stress test
(specificity, 96%; LR, 3.1 [95% CI, 2.0-4.7]), peripheral
arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5-4.8]),
and pain radiation to both arms (specificity, 96%; LR, 2.6
[95% CI, 1.8-3.7]). The ECG findings associated with ACS
were ST-segment depression (specificity, 95%; LR, 5.3 [95%
CI, 2.1-8.6]) and any evidence of ischemia (specificity,
91%; LR, 3.6 [95% CI, 1.6-5.7]). Risk scores derived from
both the History, Electrocardiogram, Age, Risk Factors,
Troponin (HEART) and Thrombolysis in Myocardial
Infarction (TIMI) trials performed well in detecting ACS
(LR, 13 [95% CI, 7.0-24] for HEART score of 7-10, and
LR, 6.8 [95% CI, 5.2-8.9] for TIMI score of 5-7).
Hypertrophy of either ventricle or aortic stenosis may
also give rise to chest pain with less typical features. Peri­
carditis produces pain that may be greater when supine
than upright and increases with respiration, coughing, or
swallowing. Pleuritic chest pain is usually not ischemic,
and pain on palpation may indicate a musculoskeletal
cause. Aortic dissection classically produces an abrupt
onset of tearing pain of great intensity that often radiates to
the back; however, this classic presentation occurs in a
small proportion of cases. Anterior aortic dissection can
also lead to myocardial or cerebrovascular ischemia.
Pulmonary embolism has a wide range of clinical pre­
sentations, with chest pain present in about 75% of cases.
The chief objective in evaluating patients with suspected
pulmonary embolism is to assess the patients clinical risk
for VTE based on medical history and associated symp­
toms and signs (see above and Chapter 9). Rupture of the
thoracic esophagus iatrogenically or secondary to vomiting
is another cause of chest pain.
B. Physical Examination
Findings on physical examination can occasionally yield
important clues to the underlying cause of chest pain; how­
ever, a normal physical examination should never be used
as the sole basis for ruling out most diagnoses, particularly
ACS and aortic dissection. Vital signs (including pulse
oximetry) and cardiopulmonary examination are always
the first steps for assessing the urgency and tempo of the
subsequent examination and diagnostic workup.
Although chest pain that is reproducible or worsened
with palpation strongly suggests a musculoskeletal cause,
up to 15% of patients with ACS will have reproducible
chest wall tenderness. Pointing to the location of the pain
with one finger has been shown to be highly correlated
with nonischemic chest pain. Aortic dissection can result
in differential blood pressures (greater than 20 mm Hg),
pulse amplitude deficits, and new diastolic murmurs.
Although hypertension is considered the rule in patients
with aortic dissection, systolic blood pressure less than
100 mm Hg is present in up to 25% of patients.
A cardiac friction rub represents pericarditis until
proven otherwise. It can best be heard with the patient sit­
ting forward at end-expiration. Tamponade should be
excluded in all patients with a clinical diagnosis of pericar­
ditis by assessing pulsus paradoxus (a decrease in systolic
blood pressure during inspiration greater than 10 mm Hg)
and inspection of jugular venous pulsations. Subcutaneous
emphysema is common following cervical esophageal per­
foration but present in only about one-third of thoracic
perforations (ie, those most commonly presenting with
chest pain).
The absence of abnormal physical examination findings
in patients with suspected pulmonary embolism usually
serves to increase the likelihood of pulmonary embolism,
although a normal physical examination is also compatible
with the much more common conditions of panic/anxiety
disorder and musculoskeletal disease.
C. Diagnostic Studies
Unless a competing diagnosis can be confirmed, an ECG is
warranted in the initial evaluation of most patients with
acute chest pain to help exclude ACS. ST-segment elevation
is the ECG finding that is the strongest predictor of acute
myocardial infarction; however, up to 20% of patients with
ACS can have a normal ECG. In the emergency depart­
ment, patients with suspected ACS can be safely removed
from cardiac monitoring if they are pain-free at initial
physician assessment and have a normal or nonspecific
ECG. This decision rule had 100% sensitivity for serious
arrhythmia (95% CI, 80-100%). Clinically stable patients
with cardiovascular disease risk factors, normal ECG, nor­
mal cardiac biomarkers, and no alternative diagnoses (such
as typical GERD or costochondritis) should be followed up
with a timely exercise stress test that includes perfusion
imaging. However, more than 25% of patients with stable
chest pain referred for noninvasive testing will have normal
coronary arteries and no long-term clinical events. The
ECG can also provide evidence for alternative diagnoses,
such as pericarditis and pulmonary embolism. Chest radi­
ography is often useful in the evaluation of chest pain, and
is always indicated when cough or shortness of breath
accompanies chest pain. Findings of pneumomediastinum
or new pleural effusion are consistent with esophageal
perforation. Stress echocardiography is useful in risk strati­
fying patients with chest pain, even among those with sig­
nificant obesity.
Diagnostic protocols using a single high-sensitivity
troponin assay combined with a standardized clinical
assessment are an efficient strategy to rapidly determine
whether patients with chest pain are at low risk and may be
discharged from the emergency department. Six estab­
lished risk scores are (1) the modified Goldman Risk Score,
 COMMON SYMPTOMS
(2) TIMI Risk Score, (3) Global Registry of Acute Cardiac
Events (GRACE) Risk Score, (4) HEART Risk Score, (5)
Vancouver Chest Pain Rule, and (6) the European Society
of Cardiology (ESC) 0/1-h algorithm. A study comparing
these risk scores (not including the ESC algorithm) for
predicting acute myocardial infarction within 30 days
reported a sensitivity of 98% (which correlates with a nega­
tive predictive value of greater than or equal to 99.5%).
Patients eligible for discharge (about 30%) were those with
a TIMI score of less than or equal to 1, modified Goldman
score of less than or equal to 1 with normal high-sensitivity
troponin T, TIMI score of 0, or HEART score of less than
or equal to 3 with normal high-sensitivity troponin I. In
African-American patients with average cardiovascular
risk, HEART score is a better predictive tool for 6-week
major adverse cardiac events (MACE) when compared to
TIMI score. Six-week MACE among patients with low-to-
moderate risk based on HEART score was 3.11 (95% CI,
1.43-6.76; P = 0.004).
While some studies of high-sensitivity cardiac troponin
suggest that it may be the best cardiac biomarker, it may
not outperform conventional troponin assays if an appro­
priate cutoff is used.
Patients who arrive at the emergency department with
chest pain of intermediate or high probability for ACS
without electrocardiographic or biomarker evidence of a
myocardial infarction can be safely discharged from an
observation unit after stress cardiac MRI. Sixty-four-slice
CT coronary angiography (CTA) is an alternative to stress
testing in the emergency department for detecting ACS
among patients with normal or nonspecific ECG and nor­
mal biomarkers. A meta-analysis of nine studies found
ACS in 10% of patients, and an estimated sensitivity of
CTA for ACS of 95% and specificity of 87%, yielding a
negative LR of 0.06 and a positive LR of 7.4. Coronary CTA
applied early in the evaluation of suspected ACS does not
identify more patients with significant coronary artery
disease requiring coronary revascularization, shorten hos­
pital stay, or allow for more direct discharge from the
emergency department compared to high-sensitivity tro­
ponins. Thus, functional testing appears to be the best ini­
tial noninvasive test in symptomatic patients with suspected
coronary artery disease. CTA is an option for patients who
do not have access to functional testing.
For patients at low risk for ACS, an initial diagnostic
strategy of stress echocardiography or cardiovascular mag­
netic resonance is associated with similar cardiac event
rates, but a substantially lower invasive testing rate.
A minimal-risk model developed by the PROMISE
investigators includes 10 clinical variables that correlate
with normal coronary CTA results and no clinical events
(C statistic = 0.725 for the derivation and validation sub­
sets; 95% CI, 0.705-0.746). These variables include (1)
younger age; (2) female sex; (3) racial or ethnic minority;
(4-6) no history of hypertension, diabetes, or dyslipidemia;
(7) no family history of premature coronary artery disease;
(8) never smoking; (9) symptoms unrelated to physical or
mental stress; and (10) higher high-density lipoprotein
cholesterol level. In the PROMISE trial, women had higher
rates of normal noninvasive testing compared with men,
CMDT 2021
but women with abnormalities on such testing were less
likely to be referred for catheterization or to receive statin
therapy.
In the evaluation of pulmonary embolism, diagnostic
test decisions and results must be interpreted in the context
of the clinical likelihood of VTE. A negative D-dimer test
is helpful for excluding pulmonary embolism in patients
with low clinical probability of VTE (3-month incidence =
0.5%); however, the 3-month risk of VTE among patients
with intermediate and high risk of VTE is sufficiently high
in the setting of a negative D-dimer test (3.5% and 21.4%,
respectively) to warrant further imaging given the life­
threatening nature of this condition if left untreated. CTA
(with helical or multidetector CT imaging) has replaced
ventilation-perfusion scanning as the preferred initial
diagnostic test, having approximately 90-95% sensitivity
and 95% specificity for detecting pulmonary embolism
(compared with pulmonary angiography). However, for
patients with high clinical probability of VTE, lower
extremity ultrasound or pulmonary angiogram may be
indicated even with a normal helical CT.
Panic disorder is a common cause of chest pain,
accounting for up to 25% of cases that present to emer­
gency departments and a higher proportion of cases pre­
senting in primary care office practices. Features that
correlate with an increased likelihood of panic disorder
include absence of coronary artery disease, atypical quality
of chest pain, female sex, younger age, and a high level of
self-reported anxiety. Depression is associated with recur­
rent chest pain with or without coronary artery disease
(odds ratio [OR], 2.11; 95% CI, 1.18-3.79).
Treatment
Treatment of chest pain should be guided by the underlying
etiology. The term “noncardiac chest pain” is used when a
diagnosis remains elusive after patients have undergone an
extensive workup. Almost half reported symptom improve­
ment with high-dose proton-pump inhibitor therapy. Relief
of constipation may be therapeutic in proton pump inhibi­
tor refractory noncardiac chest pain. A meta-analysis of 15
trials suggested modest to moderate benefit for psychologi­
cal (especially cognitive-behavioral) interventions. It is
unclear whether tricyclic or selective serotonin reuptake
inhibitor antidepressants have benefit in noncardiac chest
pain. Hypnotherapy may offer some benefit.
When to Refer
• Refer patients with poorly controlled, noncardiac chest
pain to a pain specialist.
• Refer patients with sickle cell anemia to a hematologist.
When to Admit
• Failure to adequately exclude life-threatening causes of
chest pain, particularly myocardial infarction, dissect­
ing aortic aneurysm, pulmonary embolism, and esoph­
ageal rupture.
• High risk of pulmonary embolism and a positive sensi­
tive D-dimer test.
 CMDT 2021 CHAPTER 2
• TIMI score of 1 or more, HEART score greater than 3,
abnormal ECG, and abnormal 0- and 2-hour troponin
tests.
• Pain control for rib fracture that impairs gas exchange.
Bhattacharya PT et al. Predictive risk stratification using HEART
(history, electrocardiogram, age, risk factors, and initial tropo­
nin) and TIMI (thrombolysis in myocardial infarction) scores
in non-high-risk chest pain patients: an African American
urban community-based hospital study. Medicine (Baltimore).
2019 Aug;98(32):el6370. [PMID: 31393346]
Januzzi JL Jr et al; PROMISE Investigators. Single-molecule hsTnl
and short-term risk in stable patients with chest pain. J Am
Coll Cardiol. 2019 Jan 29;73(3):251-60. [PMID: 30678753]
McCarthy CP et al. Myocardial injury in the era of high-
sensitivity cardiac troponin assays: a practical approach for
clinicians. JAMA Cardiol. 2019 Aug 7. [Epub ahead of print]
[PMID: 31389986]
Pagidipati NJ et al; PROMISE Investigators. Sex differences in
management and outcomes of patients with stable symptoms
suggestive of coronary artery disease: insights from the
PROMISE trial. Am Heart J. 2019 Feb;208:28-36. [PMID:
30529930]
Yang S et al. The role of coronary CT angiography for acute chest
pain in the era of high-sensitivity troponins. J Cardiovasc
Comput Tomogr. 2019 Sep-Oct;13(5):267-273. [PMID:
31235403]
PALPITATIONS
ESSENTIAL INQUIRIES
► Forceful, rapid, or irregular beating of the heart.
► Rate, duration, and degree of regularity of heart­
beat; age at first episode.
► Factors that precipitate or terminate episodes.
► Light-headedness or syncope; neck pounding.
► Chest pain; history of myocardial infarction or
structural heart disease.
General Considerations
Palpitations are defined as an unpleasant awareness of the
forceful, rapid, or irregular beating of the heart. They are
the primary symptom for approximately 16% of patients
presenting to an outpatient clinic with a cardiac complaint.
In an observational cohort study of palpitations at an out­
patient cardiac unit, cardiac arrhythmias were the cause of
palpitations in 81% of cases. Palpitations represent 5.8 of
every 1000 emergency department visits, with an admis­
sion rate of 24.6%. While palpitations are usually benign,
they are occasionally the symptom of a life-threatening
arrhythmia. To avoid missing a dangerous cause of the
patients symptom, clinicians sometimes pursue expensive
and invasive testing when a conservative diagnostic evalu­
ation is often sufficient. The converse is also true; in one
study, 54% of patients with supraventricular tachycardia
were initially wrongly diagnosed with panic, stress, or anxi­
ety disorder. A disproportionate number of these
Table 2-3. Palpitations: Patients at high risk for a car­
diovascular cause.
Historical risk factors
Family history of significant arrhythmias
Personal or family history of syncope or resuscitated sudden
death
History of myocardial infarction (and likely scarred myocardium)
Palpitations that occur during sleep
Anatomic abnormalities
Structural heart disease such as dilated or hypertrophic
cardiomyopathies
Valvular disease (stenotic or regurgitant)
ECG findings
Long QT syndrome
Bradycardia
Second- or third-degree heart block
Sustained ventricular arrhythmias
misdiagnosed patients are women. Table 2-3 lists history,
physical examination, and ECG findings suggesting a car­
diovascular cause for the palpitations.
Clinical Findings
A. Symptoms
Although described by patients in a myriad of ways, guid­
ing the patient through a careful description of their palpi­
tations may indicate a mechanism and narrow the
differential diagnosis. Pertinent questions include the age
at first episode; precipitants; and rate, duration, and degree
of regularity of the heartbeat during the subjective palpita­
tions. Palpitations lasting less than 5 minutes and a family
history of panic disorder reduce the likelihood of an
arrhythmic cause (LR = 0.38 and LR = 0.26, respectively).
To better understand the symptom, the examiner can ask
the patient to “tap out” the rhythm with his or her fingers.
The circumstances associated with onset and termination
can also be helpful in determining the cause. Palpitations
that start and stop abruptly suggest supraventricular or
ventricular tachycardias. Termination of palpitations using
vagal maneuvers (eg, Valsalva maneuver) suggests supra­
ventricular tachycardia.
Three common descriptions of palpitations are (1)
“flip-flopping” (or “stop and start”), often caused by pre­
mature contraction of the atrium or ventricle, with the
perceived “stop” from the pause following the contraction,
and the “start” from the subsequent forceful contraction;
(2) rapid “fluttering in the chest,” with regular “fluttering”
suggesting supraventricular or ventricular arrhythmias
(including sinus tachycardia) and irregular “fluttering”
suggesting atrial fibrillation, atrial flutter, or tachycardia
with variable block; and (3) “pounding in the neck” or neck
pulsations, often due to “cannon” A waves in the jugular
venous pulsations that occur when the right atrium con­
tracts against a closed tricuspid valve.
Palpitations associated with chest pain suggest ischemic
heart disease, or if the chest pain is relieved by leaning
forward, pericardial disease. Palpitations associated
with light-headedness, presyncope, or syncope suggest
 COMMON SYMPTOMS
hypotension and may signify a life-threatening cardiac
arrhythmia. Palpitations that occur regularly with exertion
suggest a rate-dependent bypass tract or hypertrophic car­
diomyopathy. If a benign etiology for these concerning
symptoms cannot be ascertained at the initial visit, then
ambulatory monitoring or prolonged cardiac monitoring
in the hospital might be warranted.
Noncardiac symptoms should also be elicited since the
palpitations may be caused by a normal heart responding
to a metabolic or inflammatory condition. Weight loss sug­
gests hyperthyroidism. Palpitations can be precipitated by
vomiting or diarrhea that leads to electrolyte disorders and
hypovolemia. Hyperventilation, hand tingling, and ner­
vousness are common when anxiety or panic disorder is
the cause of the palpitations. Palpitations associated with
flushing, episodic hypertension, headaches, anxiety, and
diaphoresis may be caused by a pheochromocytoma or
paraganglioma. In patients with suspected pheochromocy­
toma or paraganglioma, a 24-hour urine collection for
fractionated plasma or urinary metanephrines and cate­
cholamines has a sensitivity and specificity of 98%.
A family history of palpitations or sudden death sug­
gests an inherited etiology such as long QT syndrome or
Brugada syndrome. Chagas disease may cause palpitations
and acute myocarditis. Younger patients should be asked
about consumption of “energy drinks.” Finally, dual use of
cigarettes and e-cigarettes may cause palpitations.
B. Physical Examination
Rarely does the clinician have the opportunity to examine
a patient during an episode of palpitations. However, care­
ful cardiovascular examination can find abnormalities that
can increase the likelihood of specific cardiac arrhythmias.
The midsystolic click of mitral valve prolapse can suggest
the diagnosis of a supraventricular arrhythmia. The harsh
holosystolic murmur of hypertrophic cardiomyopathy,
which occurs along the left sternal border and increases
with the Valsalva maneuver, suggests atrial fibrillation or
ventricular tachycardia. A crescendo mid-diastolic mur­
mur may be caused by an atrial myxoma. The presence of
dilated cardiomyopathy, suggested on examination by a
displaced and enlarged cardiac point-of-maximal impulse,
increases the likelihood of ventricular tachycardia and
atrial fibrillation. In patients with chronic atrial fibrillation,
in-office exercise (eg, a brisk walk in the hallway) may
reveal an intermittent accelerated ventricular response as
the cause of the palpitations. The clinician should also look
for signs of hyperthyroidism (eg, tremulousness, brisk deep
tendon reflexes, or fine hand tremor), or signs of stimulant
drug use (eg, dilated pupils or skin or nasal septal perfora­
tions). Visible neck pulsations (LR, 2.68; 95% CI, 1.25-5.78)
in association with palpitations increases the likelihood of
atrioventricular nodal reentry tachycardia.
C. Diagnostic Studies
1. ECG—A 12-lead ECG should be performed on all
patients reporting palpitations because it can provide evi­
dence for a wide variety of causes. Although in most
instances a specific arrhythmia will not be detected on the
CMDT 2021
tracing, a careful evaluation of the ECG can help the clini­
cian deduce a likely etiology in certain circumstances.
For instance, bradyarrhythmias and heart block can be
associated with ventricular ectopy or escape beats that may
be experienced as palpitations by the patient. Evidence of
prior myocardial infarction on ECG (eg, Q waves) increases
the patients risk for nonsustained or sustained ventricular
tachycardia. Ventricular preexcitation (Wolff-Parkinson-
White syndrome) is suggested by a short PR interval (less
than 0.20 ms) and delta waves (upsloping PR segments).
Left ventricular hypertrophy with deep septal Q waves in I,
AVL, and V4 through V6 is seen in patients with hypertro­
phic obstructive cardiomyopathy. The presence of left atrial
enlargement as suggested by a terminal P-wave force in V1
more negative than 0.04 msec and notching in lead II
reflects a patient at increased risk for atrial fibrillation. A
prolonged QT interval and abnormal T-wave morphology
suggest the long QT syndrome, which puts patients at
increased risk for ventricular tachycardia. Persistent ST-
segment elevations in ECG leads VI-V3 (particularly with a
coved or saddle-back pattern) suggest Brugada syndrome.
2. Monitoring devices—For high-risk patients (Table 2-3),
further diagnostic studies are warranted. A step-wise
approach has been suggested—starting with ambulatory
monitoring devices (ambulatory ECG [Holter] monitoring
if the palpitations are expected to occur within the subse­
quent 72-hour period, event monitoring if less frequent).
An implantable loop recorder can be used for extended
monitoring if clinical suspicion is high, especially if there is
syncope. A single-lead, lightweight, continuously record­
ing ambulatory adhesive patch monitor (Zio Patch) worn
for 14 days has been shown to be superior to 24-hour
ambulatory ECG (Holter) monitoring. This is then fol­
lowed by inpatient continuous monitoring if serious
arrhythmias are strongly suspected despite normal find­
ings on the ambulatory monitoring, and by invasive elec­
trophysiologic testing if the ambulatory or inpatient
monitor records a worrisome arrhythmia. Validation stud­
ies are underway on the use of smartphone-based event
recorders.
In patients with a prior myocardial infarction, ambula­
tory cardiac monitoring or signal-averaged ECG is an
appropriate next step to help exclude ventricular tachycar­
dia. ECG exercise testing is appropriate in patients with
suspected coronary artery disease and in patients who have
palpitations with physical exertion. Echocardiography is
useful when physical examination or ECG suggests struc­
tural abnormalities or decreased ventricular function.
Differential Diagnosis
When assessing a patient with palpitations in an urgent
care setting, the clinician must ascertain whether the
symptoms represent (1) an arrhythmia that is minor and
transient, (2) a significant cardiovascular disease, (3) a
cardiac manifestation of a systemic disease such as thyro­
toxicosis, or (4) a benign somatic symptom that is ampli­
fied by the patients underlying psychological state.
Patients with palpitations who seek medical attention
in an emergency department instead of a medical clinic
 CMDT 2021 CHAPTER 2
are more likely to have a cardiac cause (47% versus 21%),
whereas psychiatric causes are more common among
those who seek attention in office practices (45% versus
27%). In a study of patients who went to a university
medical clinic with the chief complaint of palpitations,
causes were cardiac in 43%, psychiatric in 31%, and mis­
cellaneous in 10%.
Cardiac arrhythmias that can result in symptoms of
palpitations include sinus bradycardia; sinus, supraven­
tricular, and ventricular tachycardia; premature ventricular
and atrial contractions; sick sinus syndrome; and advanced
atrioventricular block.
Cardiac nonarrhythmic causes of palpitations include
valvular heart diseases, such as aortic regurgitation or ste­
nosis, atrial or ventricular septal defect, cardiomyopathy,
congenital heart disease, pericarditis, arrhythmogenic right
ventricular cardiomyopathy, and atrial myxoma. Mitral
valve prolapse is not associated with arrhythmic events, but
ventricular arrhythmias are frequent in mitral annulus
disjunction.
The most common psychiatric causes of palpitations
are anxiety and panic disorder. The release of catechol­
amines during a significant stress or panic attack can trig­
ger an arrhythmia. Asking a single question, “Have you
experienced brief periods, for seconds or minutes, of an
overwhelming panic or terror that was accompanied by
racing heartbeats, shortness of breath, or dizziness?” can
help identify patients with panic disorder.
Miscellaneous causes of palpitations include fever,
dehydration, hypoglycemia, anemia, thyrotoxicosis, mas­
tocytosis, and pheochromocytoma. Drugs such as cocaine,
alcohol, caffeine, pseudoephedrine, and illicit ephedra can
precipitate palpitations, as can prescription medications,
including digoxin, amitriptyline, erythromycin and other
drugs that prolong the QT interval, class 1 antiarrhythmics,
dihydropyridine calcium channel blockers, phenothi­
azines, theophylline, and beta-agonists.
Treatment
After ambulatory monitoring, most patients with palpi­
tations are found to have benign atrial or ventricular
ectopy or nonsustained ventricular tachycardia. In
patients with structurally normal hearts, these arrhyth­
mias are not associated with adverse outcomes. Absten­
tion from caffeine and tobacco may help. Often,
reassurance suffices. If not, or in very symptomatic
patients, a trial of a beta-blocker may be prescribed. A
three-session course of cognitive-behavioral therapy that
includes some physical activity has proven effective for
patients with benign palpitations with or without chest
pain. For treatment of specific atrial or ventricular
arrhythmias, see Chapter 10.
When to Refer
• For electrophysiologic studies.
• For advice regarding treatment of atrial or ventricular
arrhythmias.
When to Admit
• Palpitations associated with syncope or near-syncope,
particularly when the patient is aged 75 years or older
and has an abnormal ECG, hematocrit less than 30%,
shortness of breath, respiratory rate higher than 24/min,
or a history of HF.
• Patients with risk factors for a serious arrhythmia.
Clementy N et al. Benefits of an early management of palpita­
tions. Medicine (Baltimore). 2018 Jul;97(28):ell466. [PMID:
29995805]
Giada F et al. Clinical approach to patients with palpitations.
Card Electrophysiol Clin. 2018 Jun;10(2):387-96. [PMID:
29784490]
Lewalter T et al; INSIGHT XT Study Investigators. “First-degree
AV block—a benign entity?” Insertable cardiac monitor in
patients with 1st-degree AV block reveals presence or pro­
gression to higher grade block or bradycardia requiring pace­
maker implant. J Interv Card Electrophysiol. 2018 Aug;52(3):
303-6. [PMID: 30105427]
Wang JB et al. Cigarette and e-cigarette dual use and risk of
cardiopulmonary symptoms in the Health eHeart Study. PLoS
One. 2018 Jul 25;13(7):e0198681. [PMID: 30044773]
LOWER EXTREMITY EDEMA
ESSENTIAL INQUIRIES
► History of venous thromboembolism.
► Symmetry of swelling.
► Pain.
► Change with dependence.
► Skin findings: hyperpigmentation, stasis dermatitis,
lipodermatosclerosis, atrophie blanche, ulceration.
General Considerations
Acute and chronic lower extremity edema present impor­
tant diagnostic and treatment challenges. Lower extremi­
ties can swell in response to increased venous or lymphatic
pressures, decreased intravascular oncotic pressure,
increased capillary leak, and local injury or infection.
Chronic venous insufficiency is by far the most common
cause, affecting up to 2% of the population, and the inci­
dence of venous insufficiency has not changed over the
past 25 years. Venous insufficiency is a common complica­
tion of DVT; however, only a small number of patients with
chronic venous insufficiency report a history of this disor­
der. Venous ulceration commonly affects patients with
chronic venous insufficiency, and its management is labor-
intensive and expensive. Normal lower extremity venous
pressure (in the erect position: 80 mm Hg in deep veins,
20-30 mm Hg in superficial veins) and cephalad venous
blood flow require competent bicuspid venous valves,
effective muscle contractions, normal ankle range of
motion, and normal respirations. When one or more of
 COMMON SYMPTOMS
these components fail, venous hypertension may result.
Chronic exposure to elevated venous pressure by the post­
capillary venules in the legs leads to leakage of fibrinogen
and growth factors into the interstitial space, leukocyte
aggregation and activation, and obliteration of the cutane­
ous lymphatic network.
Clinical Findings
A. Symptoms and Signs
1. Unilateral lower extremity edema—Among common
causes of unilateral lower extremity swelling, DVT is the
most life-threatening. Clues suggesting DVT include a his­
tory of cancer, recent limb immobilization, or confinement
to bed for at least 3 days following major surgery within the
past month (Table 2-4). Adults with varicose veins have a
significantly increased risk of DVT. Lower extremity swell­
ing and inflammation in a limb recently affected by DVT
could represent anticoagulation failure and thrombus
recurrence but more often are caused by postphlebitic
syndrome with valvular incompetence. A search for alter­
native explanations is equally important in excluding DVT.
Other causes of a painful, swollen calf include cellulitis,
musculoskeletal disorders (Baker cyst rupture [“pseudo­
thrombophlebitis”]), gastrocnemius tear or rupture, calf
strain or trauma, and left common iliac vein compression
Table 2-4. Risk stratification of adults referred for
ultrasound to rule out DVT.
Step 1:
Score 1 point for each
Untreated malignancy
Paralysis, paresis, or recent plaster immobilization
Recently bedridden for > 3 days due to major surgery within
4 weeks
Localized tenderness along distribution of deep venous system
Entire leg swelling
Swelling of one calf > 3 cm more than the other (measured
10 cm below tibial tuberosity)
Ipsilateral pitting edema
Collateral superficial (nonvaricose) veins
Previously documented DVT
Step 2:
Subtract 2 points if alternative diagnosis has equal or greater
likelihood than DVT
Step 3:
Obtain sensitive D-dimer for score > 0
Score D-Dimer Positive* 1 D-Dimer Negative
0-1 Obtain ultrasound Ultrasound notrequired
>2 Obtain ultrasound
DVT, deep venous thrombosis.
1"Positive"isabove local laboratory threshold based on specific test
and patient age.
CMDT 2021
(May-Thurner syndrome), as well as other sites of non-
thrombotic venous outflow obstruction, such as the ingui­
nal ligament, iliac bifurcation, and popliteal fossa. Swelling
of the ankle can be a manifestation of Charcot neuropathic
osteoarthropathy.
2. Bilateral lower extremity edema—Bilateral involve­
ment and significant improvement upon awakening favor
systemic causes (eg, venous insufficiency) and can be pre­
senting symptoms of volume overload (HF, cirrhosis,
kidney disease [eg, nephrotic syndrome]). The sensation of
“heavy legs” is the most frequent symptom of chronic
venous insufficiency, followed by itching. Chronic expo­
sure to elevated venous pressure accounts for the brawny,
fibrotic skin changes observed in patients with chronic
venous insufficiency as well as the predisposition toward
skin ulceration, particularly in the medial malleolar area.
Pain, particularly if severe, is uncommon in uncomplicated
venous insufficiency.
Lower extremity swelling is a familiar complication of
therapy with calcium channel blockers (particularly felo-
dipine and amlodipine), pioglitazone, gabapentin, and
minoxidil. Prolonged airline flights (longer than 10 hours)
are associated with edema even in the absence of DVT.
Lymphedema and lipedema are other causes of bilateral
lower extremity edema.
B. Physical Examination
Physical examination should include assessment of the
heart, lungs, and abdomen for evidence of pulmonary
hypertension (primary or secondary to chronic lung dis­
ease), HF, or cirrhosis. Some patients with cirrhosis have
pulmonary hypertension without lung disease. There is a
spectrum of skin findings related to chronic venous insuf­
ficiency that depends on the severity and chronicity of the
disease, ranging from hyperpigmentation and stasis der­
matitis to abnormalities highly specific for chronic venous
insufficiency: lipodermatosclerosis (thick, brawny skin; in
advanced cases, the lower leg resembles an inverted cham­
pagne bottle) and atrophie blanche (small depigmented
macules within areas of heavy pigmentation). The size of
both calves should be measured 10 cm below the tibial
tuberosity and pitting and tenderness elicited. Leg edema
may also be measured by ultrasonography with a gel pad if
physical examination is equivocal. Swelling of the entire leg
or of one leg 3 cm more than the other suggests deep
venous obstruction. The left calf is normally slightly larger
than the right as a result of the left common iliac vein
coursing under the aorta.
An ulcer located over the medial malleolus is a hall­
mark of chronic venous insufficiency but can be due to
other causes. Shallow, large, modestly painful ulcers are
characteristic of venous insufficiency, whereas small, deep,
and more painful ulcers are more apt to be due to arterial
insufficiency, vasculitis, or infection (including cutaneous
diphtheria). Diabetic vascular ulcers, however, may be
painless. When an ulcer is on the foot or above the mid­
calf, causes other than venous insufficiency should be
considered.
 1 CMDT 2021 CHAPTER 2
The physical examination is usually inadequate to dis­
tinguish lymphedema from venous insufficiency. Sensitiv­
ity and specificity of clinical signs in predicting
lymphoscintigraphy-confirmed lymphedema were 17%
and 88%, respectively. Only the Kaposi-Stemmer sign (the
inability to pinch or pick up a fold of skin at the base of the
second toe because of its thickness) was a significant pre­
dictor of lymphedema (odds ratio, 7.9; P = 0.02).
C. Diagnostic Studies
Patients without an obvious cause of acute lower extremity
swelling (eg, calf strain) should have an ultrasound per­
formed, since DVT is difficult to exclude on clinical
grounds. A prediction rule allows a clinician to exclude a
lower extremity DVT in patients without an ultrasound if
the patient has low pretest probability for DVT and a
negative sensitive D-dimer test (the “Wells prediction
rule”). The diagnostic study of choice to detect chronic
venous insufficiency due venous incompetence is duplex
ultrasonography. Assessment of the ankle-brachial pres­
sure index (ABPI) is important in the management of
chronic venous insufficiency, since peripheral arterial
disease may be exacerbated by compression therapy. This
can be performed at the same time as ultrasound. Caution
is required in interpreting the results of ABPI in older
patients and diabetics due to the decreased compressibility
of their arteries. A urine dipstick test that is strongly posi­
tive for protein can suggest nephrotic syndrome, and a
serum creatinine can help estimate kidney function. Lym­
phoscintigraphy can be used to confirm a clinical suspi­
cion of lymphedema. Ambulatory sensors for measuring
circumference of lower limbs to assist management of
chronic venous insufficiency and lymphedema are being
developed.
Treatment
Treatment of lower extremity edema should be guided by
the underlying cause. See relevant chapters for treatment
of edema in patients with HF (Chapter 10), nephrosis
(Chapter 22), cirrhosis (Chapter 16), and lymphedema and
venous stasis ulcers (Chapter 12). Edema resulting from
calcium channel blocker therapy responds to concomitant
therapy with ACE inhibitors or angiotensin receptor
blockers.
In patients with chronic venous insufficiency without
a comorbid volume overload state (eg, HF), it is best to
avoid diuretic therapy. These patients have relatively
decreased intravascular volume, and administration of
diuretics may first enhance sodium retention through
increased secretion of renin and angiotensin and then
result in acute kidney injury and oliguria. Instead, the
most effective treatment involves (1) leg elevation, above
the level of the heart, for 30 minutes three to four times
daily, and during sleep; (2) compression therapy; and (3)
ambulatory exercise to increase venous return through
calf muscle contractions. There is no evidence for benefit
or harm of valvuloplasty in the treatment of patients with
deep venous insufficiency secondary to primary valvular
incompetence.
A wide variety of stockings and devices are effective in
decreasing swelling and preventing ulcer formation. They
should be put on with awakening, before hydrostatic forces
result in edema. To control simple edema, 20-30 mm Hg
compression is usually sufficient, whereas 30-40 mm Hg
compression is usually required to control moderate to
severe edema associated with ulcer formation. To maintain
improvement, consider switching from an elastic stocking
to one made of inelastic grosgrain material. Patients with
decreased ABPI should be managed in concert with a vas­
cular surgeon. Compression stockings (12-18 mm Hg at
the ankle) are effective in preventing edema and asymp­
tomatic thrombosis associated with long airline flights in
low- to medium-risk persons. Support stockings are rec­
ommended for pregnant women during air travel. For
lymphedema, bandaging systems applied twice weekly can
be effective. Short-term manual lymphatic drainage treat­
ment may improve chronic venous insufficiency severity,
symptoms, and quality of life. For patients with reduced
mobility and leg edema, intermittent pneumatic compres­
sion treatment can reduce edema and improve ankle range
of motion.
Liposuction, suction-assisted lipectomy, and subcuta­
neous drainage may have treatment benefit if conservative
measures fail in treatment of lymphedema.
When to Refer
• Refer patients with chronic lower extremity ulcerations
requiring specialist wound care.
• Refer patients with nephrotic syndrome to a
nephrologist.
• Refer patients with coexisting severe arterial insuffi­
ciency (claudication) that would complicate treatment
with compression stockings to a vascular surgeon.
When to Admit
• Pending definitive diagnosis in patients at high risk for
DVT despite normal lower extremity ultrasound.
• Severe, acute swelling raising concern for an impending
compartment syndrome.
• Severe edema that impairs ability to ambulate or per­
form activities of daily living.
Bonkemeyer Millan S et al. Venous ulcers: diagnosis and treat­
ment. Am Fam Physician. 2019 Sep 1 ;100(5):298-305.
[PMID: 31478635]
Chang SL et al. Association of varicose veins with incident
venous thromboembolism and peripheral artery disease.
JAMA. 2018 Feb 27;319(8):807-17. [PMID: 29486040]
Garcia R et al. Duplex ultrasound for the diagnosis of acute and
chronic venous diseases. Surg Clin North Am. 2018 Apr;
98(2):201—18. [PMID: 29502767]
Jayaraj A et al. The diagnostic unreliability of classic physical
signs of lymphedema. J Vase Surg Venous Lymphat Disord.
2019 Nov;7(6):890-7. [PMID: 31281100]
Raffetto JD. Pathophysiology of chronic venous disease and
venous ulcers. Surg Clin North Am. 2018 Apr;98(2):337-47.
[PMID: 29502775]
 COMMON SYMPTOMS
FEVER & HYPERTHERMIA
ESSENTIAL INQUIRIES
► Age; injection substance use.
► Localizing symptoms; weight loss; joint pain.
► Immunosuppression or neutropenia; history of
cancer.
► Medications.
► Travel.
General Considerations
The average normal oral body temperature taken in mid­
morning is 36.7°C (range 36-37.4°C). This range includes
a mean and 2 standard deviations, thus encompassing 95%
of a normal population (normal diurnal temperature varia­
tion is 0.5-l°C). The normal rectal or vaginal temperature
is 0.5°C higher than the oral temperature, and the axillary
temperature is 0.5°C lower. Interestingly, in a pooled meta­
analysis comparing peripheral with central body tempera­
ture measurement, peripheral thermometers (tympanic
membrane, temporal artery, axillary, oral) showed low
sensitivity but high specificity. This suggests that a normal
body temperature based on a peripheral measurement
does not always exclude the presence of a fever. Thus, to
exclude a fever, a rectal temperature is more reliable than
an oral temperature (particularly in patients who breathe
through their mouth or are tachypneic or who are in an
intensive care unit setting where a rectal temperature probe
can be placed to detect fever). Wearable digital thermom­
eters may detect early mild increased temperature in
patients with low white blood cell counts.
Fever is a regulated rise to a new “set point” of body
temperature in the hypothalamus induced by pyrogenic
cytokines. These cytokines include interleukin-1 (IL-1),
tumor necrosis factor (TNF), interferon-gamma, and inter-
leukin-6 (IL-6). The elevation in temperature results from
either increased heat production (eg, shivering) or
decreased heat loss (eg, peripheral vasoconstriction). Body
temperature in cytokine-induced fever seldom exceeds
41.1 °C unless there is structural damage to hypothalamic
regulatory centers.
Clinical Findings
A.Fever
Fever as a symptom provides important information about
the presence of illness—particularly infections—and about
changes in the clinical status of the patient. Fever may be
more predictive of bacteremia in elderly patients. The fever
pattern, however, is of marginal value for most specific
diagnoses except for the relapsing fever of malaria, bor­
reliosis, and occasional cases of lymphoma, especially
Hodgkin disease. Furthermore, the degree of temperature
elevation does not necessarily correspond to the severity of
CMDT 2021 31
the illness. Contrary to common perceptions, a Swedish
study found that increased body temperature in the emer­
gency department was strongly associated with lower mor­
tality and shorter hospital stays in patients with severe
sepsis or septic shock subsequently admitted to the inten­
sive care unit even after adjustment for quality of care
measures. Fever, with rash and eosinophilia, define the
drug reaction with eosinophilia and systemic symptoms
(DRESS) syndrome.
In general, the febrile response tends to be greater in
children than in adults. In older persons, neonates, and
persons receiving certain medications (eg, nonsteroidal
anti-inflammatory drugs [NSAIDs], corticosteroids), a
normal temperature or even hypothermia maybe observed.
Markedly elevated body temperature may result in pro­
found metabolic disturbances. High temperature during
the first trimester of pregnancy may cause birth defects,
such as anencephaly. Fever increases insulin requirements
and alters the metabolism and disposition of drugs used for
the treatment of the diverse diseases associated with fever.
The source of fever varies by population and setting. In
a study involving patients who underwent shoulder arthro­
plasty, fever was documented in 92 patients. Among these
92 patients, an infectious cause was found in only 6 patients.
In the neurointensive care unit, fever can occur directly
from brain injury (called “central fever”). One model
predicted “central fever” with 90% probability if a patient
met all of the following criteria: (1) less than 72 hours of
neurologic intensive care unit admission; (2) presence of
subarachnoid hemorrhage, intraventricular hemorrhage, or
brain tumor; (3) absence of infiltrate on chest radiograph;
and (4) negative cultures.
Fever may also be more common in patients with other
forms of trauma. In a study enrolling 268 patients, including
patients with multiple injuries (n = 59), isolated head injuries
(n = 97), isolated body injuries (n = 100), and minor
trauma (n = 12), the incidence of fever was similar in all groups
irrespective of injury (11-24%). In all groups, there was a sig­
nificant association between the presence of early fever and
death in the hospital (6-18% versus 0-3%), as well as longer
median intensive care unit stays (3-7 days versus 2-3 days).
Among pregnant women, the prevalence of intrapar­
tum fever of 38°C or greater in pregnancies of 36 weeks’
gestation or more is 6.8% (or 1 in 15 women in labor). And
the neonatal sepsis rate among affected mothers is 0.24%
(or less than 1 in 400 babies). This finding calls into ques­
tion the need for universal laboratory work, cultures, and
antibiotic treatment pending culture results for this new­
born population.
There is increasing evidence that postoperative atelec­
tasis does not cause fever. However, febrile nonhemolytic
transfusion reaction is common, occurring in about 1% of
transfusion episodes, and is mediated by proinflammatory
cytokines elaborated by donor leukocytes during storage.
B. Hyperthermia
Hyperthermia—not mediated by cytokines—occurs when
body metabolic heat production (as in thyroid storm) or
environmental heat load exceeds normal heat loss capacity
or when there is impaired heat loss; heat stroke is an
 CMDT 2021 CHAPTER 2
example. Body temperature may rise to levels (more than
41.1 °C) capable of producing irreversible protein denatur­
ation and resultant brain damage; no diurnal variation is
observed.
Malignant catatonia is a disorder consisting of cata­
tonic symptoms, hyperthermia, autonomic instability, and
altered mental status.
Neuroleptic malignant syndrome, a variant of malig­
nant catatonia, is a rare and potentially lethal idiosyncratic
reaction to neuroleptic medications, particularly haloperi­
dol and fluphenazine; however, it has also been reported
with the atypical neuroleptics (such as olanzapine or ris­
peridone) (see Chapter 25). Serotonin syndrome resem­
bles neuroleptic malignant syndrome but occurs within
hours of ingestion of agents that increase levels of sero­
tonin in the central nervous system, including serotonin
reuptake inhibitors, monoamine oxidase inhibitors, tricy­
clic antidepressants, meperidine, dextromethorphan, bro­
mocriptine, tramadol, lithium, and psychostimulants (such
as cocaine, methamphetamine, and MDMA) (see Chapter 38).
Clonus and hyperreflexia are more common in serotonin
syndrome, whereas “lead pipe” rigidity is more common in
neuroleptic malignant syndrome. Neuroleptic malignant
and serotonin syndromes share common clinical and
pathophysiologic features with malignant hyperthermia
of anesthesia (see Chapter 38).
C. Fever of Undetermined Origin
See Fever of Unknown Origin, Chapter 30.
Treatment
Most fever is well tolerated. When the temperature is less
than 40°C, symptomatic treatment only is required. A tem­
perature greater than 41 °C is likely to be hyperthermia
rather than cytokine mediated, and emergent management
is indicated. (See Heat Stroke, Chapter 37.) The treatment
of fever with antipyretics does not appear to affect mortal­
ity of critically ill patients or affect the number of intensive
care unit-free days.
A. General Measures for Removal of Heat
Regardless of the cause of the fever, alcohol sponges, cold
sponges, ice bags, ice-water enemas, and ice baths will
lower body temperature (see Chapter 37). They are more
useful in hyperthermia, since patients with cytokine-
related fever will attempt to override these therapies.
B. Pharmacologic Treatment of Fever
1. Antipyretic drugs—Antipyretic therapy is not needed
except for patients with marginal hemodynamic status.
Early administration of acetaminophen to treat fever due
to probable infection did not affect the number of intensive
care unit-free days. Aspirin or acetaminophen, 325-650 mg
every 4 hours, is effective in reducing fever. These drugs are
best administered around the clock, rather than as needed,
since “as needed” dosing results in periodic chills and
sweats due to fluctuations in temperature caused by varying
levels of drug.
2. Antimicrobial therapy—Antibacterial and antifungal
prophylactic regimens are recommended only for patients
expected to have less than 100 neutrophils/mcL for more
than 7 days, unless other factors increase risks for compli­
cations or mortality. In most febrile patients, empiric anti­
biotic therapy should be deferred pending further
evaluation. However, empiric antibiotic therapy is some­
times warranted. Prompt broad-spectrum antimicrobials
are indicated for febrile patients who are clinically unstable,
even before infection can be documented. These include
patients with hemodynamic instability, those with severe
neutropenia (neutrophils less than 500/mcL), others who
are asplenic (surgically or secondary to sickle cell disease)
or immunosuppressed (including individuals taking sys­
temic corticosteroids, azathioprine, cyclosporine, or other
immunosuppressive medications) (Tables 30-4 and 30-5),
and those who are HIV infected (see Chapter 31).
Febrile neutropenic patients should receive initial doses
of empiric antibacterial therapy within an hour of triage and
should either be monitored for at least 4 hours to determine
suitability for outpatient management or be admitted to the
hospital (see Infections in the Immunocompromised
Patient, Chapter 30). Inpatient treatment is standard to
manage febrile neutropenic episodes, although carefully
selected patients may be managed as outpatients after sys­
tematic assessment beginning with a validated risk index
(eg, Multinational Association for Supportive Care in
Cancer [MASCC] score or Talcott rules). In the MASCC
index calculation, low-risk factors include the following: age
under 60 years (2 points), burden of illness (5 points for no
or mild symptoms and 3 points for moderate symptoms),
outpatient status (3 points), solid tumor or hematologic
malignancy with no previous fungal infection (4 points),
no COPD (4 points), no dehydration requiring parenteral
fluids (3 points), and systolic blood pressure greater than 90
mm Hg (5 points). Patients with MASCC scores 21 or higher
or in Talcott group 4 (presentation as an outpatient without
significant comorbidity or uncontrolled cancer), and with­
out other risk factors, can be managed safely as outpatients.
The carefully selected outpatients determined to be at
low risk by MASCC score (particularly in combination
with a normal serum C-reactive protein level) or by Talcott
rules can be managed with an oral fluoroquinolone plus
amoxicillin/clavulanate (or clindamycin, if penicillin
allergic), unless fluoroquinolone prophylaxis was used
before fever developed. For treatment of fever during neu­
tropenia following chemotherapy, outpatient parenteral
antimicrobial therapy can be provided effectively and
safely in low-risk patients with a single agent such as
cefepime, piperacillin/tazobactam, imipenem, merope-
nem, or doripenem. High-risk patients should be referred
for inpatient management with combination parenteral
antimicrobial therapy based on specific risk factors such as
pneumonia-causing pathogens or central line-associated
bloodstream infections (see Infections in the Immunocom­
promised Patient and Table 30-5 in Chapter 30, and see
Infections in Chapter 39).
If a fungal infection is suspected in patients with pro­
longed fever and neutropenia, fluconazole is an equally
effective but less toxic alternative to amphotericin B.
 COMMON SYMPTOMS
C. Treatment of Hyperthermia
Discontinuation of the offending agent is mandatory.
Treatment of neuroleptic malignant syndrome includes
dantrolene in combination with bromocriptine or levodopa
(see Chapter 25). Treatment of serotonin syndrome
includes administration of a central serotonin receptor
antagonist—cyproheptadine or chlorpromazine—alone or
in combination with a benzodiazepine (see Chapter 38). In
patients for whom it is difficult to distinguish which syn­
drome is present, treatment with a benzodiazepine may be
the safest therapeutic option.
When to Admit
• Presence of additional vital sign abnormalities or evi­
dence of end-organ dysfunction in clinical cases when
early sepsis is suspected.
• For measures to control a temperature higher than 41 °C
or when fever is associated with seizure or other mental
status changes.
• Heat stroke (see Chapter 37).
• Malignant catatonia; neuroleptic malignant syndrome;
serotonin syndrome; malignant hyperthermia of
anesthesia.
Copeland-Halperin LR et al. Clinical predictors of positive
postoperative blood cultures. Ann Surg. 2018 Feb;267(2):
297-302. [PMID: 27893534]
Hinson HE et al. Early fever after trauma: does it matter? J
Trauma Acute Care Surg. 2018 Jan;84(l):19-24. [PMID:
28640776]
INVOLUNTARY WEIGHT LOSS
ESSENTIAL INQUIRIES
► Age; caloric intake; secondary confirmation (eg,
changes in clothing size).
► Fever; change in bowel habits.
► Substance abuse.
► Age-appropriate cancer screening history.
General Considerations
Body weight is determined by a persons caloric intake,
absorptive capacity, metabolic rate, and energy losses.
Body weight normally peaks by the fifth or sixth decade
and then gradually declines at a rate of 1-2 kg per decade.
In NHANES II, a national survey of community-dwelling
elders (aged 50-80 years), recent involuntary weight loss
(more than 5% usual body weight) was reported by 7% of
respondents, and this was associated with a 24% higher
mortality. In contrast, one study found that a body mass
index of 33 or less is not associated with an increased mor­
tality in adults aged 65 years or older. In postmenopausal
women, unintentional weight loss was associated with
increased rates of hip and vertebral fractures.
CMDT 2021 33
Etiology
Involuntary weight loss is regarded as clinically significant
when it exceeds 5% or more of usual body weight over a
6- to 12-month period. It often indicates serious physical
or psychological illness. Physical causes are usually evident
during the initial evaluation. The most common causes are
cancer (about 30%), gastrointestinal disorders (about 15%),
and dementia or depression (about 15%). Nearly half of
patients with Parkinson disease have weight loss associated
with disease progression. When an adequately nourished-
appearing patient complains of weight loss, inquiry should
be made about exact weight changes (with approximate
dates) and about changes in clothing size. Family members
can provide confirmation of weight loss, as can old docu­
ments such as drivers licenses. A mild, gradual weight loss
occurs in some older individuals because of decreased
energy requirements. However, rapid involuntary weight
loss is predictive of morbidity and mortality. In addition to
various disease states, causes in older individuals include
loss of teeth and consequent difficulty with chewing, medi­
cations interfering with taste or causing nausea, alcohol­
ism, and social isolation.
Clinical Findings
Once the weight loss is established, the history, medication
profile, physical examination, and conventional laboratory
and radiologic investigations (eg, complete blood count,
liver biochemical tests, kidney panel, serologic tests includ­
ing HIV, thyroid-stimulating hormone [TSH] level, uri­
nalysis, fecal occult blood test, chest radiography, and
upper gastrointestinal series) usually reveal the cause.
Whole-body CT imaging is increasingly used for diagnosis;
one study found its diagnostic yield to be 33.5%. When
these tests are normal, the second phase of evaluation
should focus on more definitive gastrointestinal investiga­
tion (eg, tests for malabsorption, endoscopy) and cancer
screening (eg, Papanicolaou smear, mammography, pros­
tate-specific antigen [PSA]). However, one prospective
case study in patients with unintentional weight loss
showed that colonoscopy did not find colorectal cancer if
weight loss was the sole indication for the test.
If the initial evaluation is unrevealing, follow-up is pref­
erable to further diagnostic testing. Death at 2-year follow­
up was not nearly as common in patients with unexplained
involuntary weight loss (8%) as in those with weight loss
due to malignant (79%) and established nonmalignant
diseases (19%). Psychiatric consultation should be consid­
ered when there is evidence of depression, dementia,
anorexia nervosa, or other emotional problems. Ultimately,
in approximately 15-25% of cases, no cause for the weight
loss can be found.
Differential Diagnosis
Malignancy, gastrointestinal disorders (poorly fitting den­
tures, cavities, swallowing or malabsorption disorders,
pancreatic insufficiency), HF, psychological problems
(dementia, depression, paranoia), endocrine disorders
 CMDT 2021 CHAPTER 2
(hyperthyroidism, hypothyroidism, hyperparathyroidism,
hypoadrenalism), eating problems (dietary restrictions,
lack of money for food), social problems (alcohol use dis­
order, social isolation), and medication side effects are all
established causes.
Treatment
Weight stabilization occurs in most surviving patients with
both established and unknown causes of weight loss through
treatment of the underlying disorder and caloric supple­
mentation. Nutrient intake goals are established in relation
to the severity of weight loss, in general ranging from 30 to
40 kcal/kg/day. In order of preference, route of administra­
tion options include oral, temporary nasojejunal tube, or
percutaneous gastric or jejunal tube. Parenteral nutrition is
reserved for patients with serious associated problems. A
variety of pharmacologic agents have been proposed for the
treatment of weight loss. These can be categorized into
appetite stimulants (corticosteroids, progestational agents,
dronabinol, and serotonin antagonists); anabolic agents
(growth hormone and testosterone derivatives); and anti-
catabolic agents (omega-3 fatty acids, pentoxifylline, hydra­
zine sulfate, and thalidomide). There is no evidence that
appetite stimulants decrease mortality, and they may have
severe adverse side effects. Exercise training may prevent or
even reverse the process of muscle wasting in HF (“cardiac
cachexia”). Protein supplementation combined with resis­
tance exercise training and aerobic activity may prevent
aging-related muscle mass attenuation and functional per­
formance. Some patients with cancer-associated weight loss
may benefit from nutritional assessment and intervention as
decreased food intake may be playing a role.
When to Refer
• Weight loss caused by malabsorption.
• Persistent nutritional deficiencies despite adequate
supplementation.
• Weight loss as a result of anorexia or bulimia.
When to Admit
• Severe protein-energy malnutrition, including the syn­
dromes of kwashiorkor and marasmus.
• Vitamin deficiency syndromes.
• Cachexia with anticipated progressive weight loss sec­
ondary to unmanageable psychiatric disease.
• Careful electrolyte and fluid replacement in protein­
energy malnutrition and avoidance of “re-feeding
syndrome.”
Goh Y et al. Diagnostic utility of whole body CT scanning in
patients with unexplained weight loss. PLoS One. 2018
Jul 27;13(7):e0200686. [PMID: 30052642]
Martin L et al. How much does reduced food intake contribute
to cancer-associated weight loss? Curr Opin Support Palliat
Care. 2018 Dec;12(4):410-9. [PMID: 30124527]
Molfino A et al. Nutrition support for treating cancer-associated
weight loss: an update. Curr Opin Support Palliat Care.
2018 Dec;12(4):434-8. [PMID: 30382948]
FATIGUE & CHRONIC FATIGUE SYNDROME
General Considerations
Fatigue, as an isolated symptom, accounts for 1-3% of visits
to generalists. The symptom of fatigue is often poorly
described and less well defined by patients than symptoms
associated with specific dysfunction of organ systems.
Fatigue or lassitude and the closely related complaints of
weakness, tiredness, and lethargy are often attributed to
overexertion, poor physical conditioning, sleep disturbance,
obesity, undernutrition, and emotional problems. A history
of the patient’s daily living and working habits may obviate
the need for extensive and unproductive diagnostic studies.
The diagnosis of chronic fatigue syndrome remains
hotly debated because of the lack of a gold standard. Persons
with chronic fatigue syndrome meeting specific criteria
(such as those from the Centers for Disease Control and
Prevention) report a greater frequency of childhood trauma
and psychopathology and demonstrate higher levels of
emotional instability and self-reported stress than persons
who do not have chronic fatigue. Neuropsychological and
neuroendocrine studies reveal abnormalities in most
patients but no consistent pattern. Sleep disorders have
been reported in 40-80% of patients with chronic fatigue
syndrome, but polysomnographic studies have not shown a
greater incidence of primary sleep disorders in those with
chronic fatigue syndrome than in controls, suggesting that
the sleep disorders are comorbid rather than causative.
Older patients with chronic fatigue syndrome demonstrate
a greater disease impact than younger patients. A retrospec­
tive cohort study in Germany found an increased risk of
chronic fatigue syndrome after a first-time diagnosis of
gastrointestinal infection (hazard ratio, 1.35-1.82). The
phenomenon of central sensitization is a potential cause.
Clinical Findings
A. Fatigue
Clinically relevant fatigue is composed of three major com­
ponents: generalized weakness (difficulty in initiating
activities); easy fatigability (difficulty in completing activi­
ties); and mental fatigue (difficulty with concentration and
memory). Important diseases that can cause fatigue include
hyperthyroidism and hypothyroidism, HF, infections
(endocarditis, hepatitis), COPD, sleep apnea, anemia, auto­
immune disorders, multiple sclerosis, irritable bowel syn­
drome, Parkinson disease, cerebral vascular accident, and
cancer. Solution-focused therapy has a significant initial
beneficial effect on the severity of fatigue and quality of life
in patients with quiescent inflammatory bowel disease.
 COMMON SYMPTOMS CMDT 2021

Alcohol use disorder, vitamin C deficiency (scurvy),

side effects from medications (eg, sedatives and beta­
blockers), and psychological conditions (eg, insomnia;
depression; anxiety; panic attacks; dysthmia; and somatic
symptom disorder, formerly called somatization disorder)
may be the cause. Common outpatient infectious causes
include mononucleosis and sinusitis. These conditions are
usually associated with other characteristic signs, but
patients may emphasize fatigue and not reveal their other
symptoms unless directly asked. The lifetime prevalence of
significant fatigue (present for at least 2 weeks) is about
25%. Fatigue of unknown cause or related to psychiatric
illness exceeds that due to physical illness, injury, alcohol,
or medications.
Although frequently associated with Lyme disease,
severe fatigue as a long-term sequela is rare.

B. Chronic Fatigue Syndrome/Systemic Exertion

Intolerance Disease
A working case definition of chronic fatigue syndrome
indicates that it is not a homogeneous abnormality, there is
no single pathogenic mechanism (Figure 2-1), and no
physical finding or laboratory test can be used to confirm
the diagnosis. Other conditions identified as causing
chronic fatigue include myalgic encephalitis and neurasthe­
nia, each with specific diagnostic criteria creating inconsis­
tent diagnoses and treatment plans. In 2015, the Institute of
Medicine (now called the National Academy of Medicine)
recommended using the term systemic exertion intoler­
ance disease (SEID). Diagnosis of SEID requires the
presence of all of the following three symptoms:
1. Substantial reduction or impairment in the ability to
engage in pre-illness levels of occupational, educational,
social, or personal activities that persists for more than
6 months and is accompanied by fatigue, which is often
profound, is of new or definite onset (not lifelong), is
not the result of ongoing excessive exertion, and is not
substantially alleviated by rest.
2. Postexertional malaise.
3. Unrefreshing sleep.
▲ Figure 2-1. Classification of chronic fatigue patients.
In addition, the patient must have at least one of the ALT, alanine aminotransferase; BUN, blood urea
following two manifestations: (1) cognitive impairment or nitrogen; Ca2+, calcium; CBC, complete blood count;
(2) orthostatic intolerance (lightheadedness, dizziness, and ESR, erythrocyte sedimentation rate; PO43-, phosphate;
headache that worsen with upright posture and improve TSH, thyroid-stimulating hormone; UA, urinalysis.
with recumbency).
The evaluation of chronic fatigue syndrome or SEID abnormally high rate of postural hypotension. Brain MRI is
includes a history and physical examination as well as com­ not routinely recommended.
plete blood count, erythrocyte sedimentation rate, chemis­
tries (blood urea nitrogen [BUN], serum electrolytes, Treatment
glucose, creatinine, calcium, liver biochemical tests, and
A. Fatigue
thyroid function tests), urinalysis, tuberculin skin test, and
screening questionnaires for psychiatric disorders. Other Management of fatigue involves identification and treat­
tests to be performed as clinically indicated are serum cor­ ment of conditions that contribute to fatigue, such as can­
tisol, antinuclear antibody, rheumatoid factor, immuno­ cer, pain, depression, disordered sleep, weight loss, and
globulin levels, Lyme serology in endemic areas (although anemia. Resistance training and aerobic exercise lessens
rarely a long-term complication of this infection), and HIV fatigue and improves performance for a number of chronic
antibody. More extensive testing is usually unhelpful, conditions associated with a high prevalence of fatigue,
including antibody to Epstein-Barr virus. There may be an including HF, COPD, arthritis, and cancer. Continuous
 CMDT 2021 CHAPTER 2
positive airway pressure is an effective treatment for
obstructive sleep apnea. Psychostimulants such as methyl­
phenidate have shown inconsistent results in randomized
trials of treatment of cancer-related fatigue. Modafinil and
armodafinil appear to be effective, well-tolerated agents in
HIV-positive patients with fatigue and as adjunctive agents
in patients with depression or bipolar disorder with fatigue.
Testosterone replacement in hypoandrogenic men over age
65 had no significant benefit with respect to walking dis­
tance or vitality, as assessed by the Functional Assessment
of Chronic Illness Therapy-Fatigue scale, but men who
received the testosterone reported slightly better mood and
lower severity of depressive symptoms than those who
received placebo.
Therapeutic Care (a complementary medicine modality
that uses acupressure) reduces fatigue in some patients
with breast cancer receiving chemotherapy, and Internet­
based cognitive-behavioral therapy is effective in reducing
severe fatigue in breast cancer survivors. Six weeks of
Swedish massage therapy reduced fatigue in female breast
cancer survivors who had surgery plus radiation and/or
chemotherapy/chemoprevention.
Methylphenidate, as well as cognitive-behavioral ther­
apy, may improve mental fatigue and cognitive functions in
patients with traumatic brain injury. The TRUST study
found that treatment of subclinical hypothyroidism with
levothyroxine did not improve symptoms of fatigue as
measured by the Tiredness score (3.2±17.7 in placebo
group and 3.8 in levothyroxine group ±18.4, respectively;
between-group difference, 0.4; 95% CI, -2.1 to +2.9).
Vitamin D treatment significantly improved fatigue in
kidney transplantation patients as well as in otherwise
healthy persons with vitamin D deficiency.
B. Chronic Fatigue Syndrome
A variety of agents and modalities have been tried for the
treatment of chronic fatigue syndrome. Acyclovir, intrave­
nous immunoglobulin, nystatin, clonidine (in adolescent
chronic fatigue syndrome), peripheral IL-1 inhibition with
anakinra, and low-dose hydrocortisone do not improve
symptoms. Inhibition of cytokine IL-1 with anakinra for
4 weeks does not result in a clinically significant reduction
in fatigue severity in women with chronic fatigue syn­
drome. Some patients with postural hypotension report
response to increases in dietary sodium as well as fludro­
cortisone, 0.1 mg orally daily. The immune modulator
rintatolimod improved some measures of exercise perfor­
mance compared with placebo in two trials (low strength
of evidence). There is very limited evidence that dietary
modification is beneficial.
There is a greater prevalence of past and current psychi­
atric diagnoses in patients with this syndrome. Affective
disorders are especially common. Patients with chronic
fatigue syndrome have benefited from a comprehensive
multidisciplinary intervention, including optimal medical
management, treating any ongoing affective or anxiety
disorder pharmacologically, and implementing a compre­
hensive cognitive-behavioral treatment program. At pres­
ent, cognitive-behavioral therapy and graded exercise are
the treatments of choice for patients with chronic fatigue
syndrome. Cognitive-behavioral therapy, a form of non-
pharmacologic treatment emphasizing self-help and aim­
ing to change perceptions and behaviors that may
perpetuate symptoms and disability, may be helpful in
some patients. Response to cognitive-behavioral therapy is
not predictable on the basis of severity or duration of
chronic fatigue syndrome. Patients with high neuroticism
or low acceptance show more improvement in mental
quality of life with cognitive-behavioral therapy.
Graded exercise may result in mild-to-moderate
improvements in functional work capacity and physical
function in some patients but may prove risky in others. A
2011 randomized trial (PACE trial) confirmed the inde­
pendent benefits of cognitive-behavioral therapy and
graded exercise, but recent meta-analyses and re-analysis
of PACE are calling into question the magnitude of the
benefit and safety of graded exercise. Physiologic studies
find an altered immune response to exercise in patients
with chronic fatigue syndrome. A self-help booklet describ­
ing a six-step graded exercise program over 12 weeks and
up to four guidance sessions with a physiotherapist over
8 weeks may be as helpful as specialist medical care alone.
A critical appraisal of the Cochrane reviews addressing
exercise and cognitive-behavioral therapy as treatments for
chronic fatigue syndrome reports that the evidence-base is
insufficient to exclude harms, and concludes that these treat­
ments are better characterized as “adjunctive therapies.”
In addition, the clinicians sympathetic listening and
explanatory responses can help overcome the patients
frustrations and debilitation by this still mysterious illness.
All patients should be encouraged to engage in normal
activities to the extent possible and should be reassured
that full recovery is eventually possible in most cases.
Chronic fatigue syndrome is not associated with increased
all-cause mortality, but one study showed a substantially
increased risk of completed suicide.
When to Refer
• Infections not responsive to standard treatment.
• Difficult-to-control hyperthyroidism or hypothyroidism.
• Severe psychological illness.
• Malignancy.
When to Admit
• Failure to thrive.
• Fatigue severe enough to impair activities of daily living.
Donnachie E et al. Incidence of irritable bowel syndrome and
chronic fatigue following GI infection: a population-level
study using routinely collected claims data. Gut. 2018 Jun;
67(6):1078-86. [PMID: 28601847]
Kinkead B et al. Massage therapy decreases cancer-related
fatigue: results from a randomized early phase trial. Cancer.
2018 Feb l;124(3):546-54. [PMID: 29044466]
Komaroff AL. Advances in understanding the pathophysiology
of chronic fatigue syndrome. JAMA. 2019 Aug 13;322(6):
499-500. [PMID: 31276153]
 COMMON SYMPTOMS
Vink M et al. Cognitive behavioural therapy for myalgic
encephalomyelitis/chronic fatigue syndrome is not effective.
Re-analysis of a Cochrane review. Health Psychol Open. 2019
May 2;6(l):2055102919840614. [PMID: 31080632]
Wilshire CE et al. Rethinking the treatment of chronic fatigue
syndrome—a reanalysis and evaluation of findings from a
recent major trial of graded exercise and CBT. BMC Psychol.
2018 Mar 22;6(1):6. [PMID: 29562932]
ACUTE HEADACHE
ESSENTIAL INQUIRIES
► Age older than 40 years.
► Rapid onset and severe intensity (ie, "thunderclap"
headache), trauma, onset during exertion.
► Fever, vision changes, neck stiffness.
► HIV infection.
► Current or past history of hypertension.
► Neurologic findings (mental status changes,
motor or sensory deficits, loss of consciousness).
General Considerations
Headache is a common reason that adults seek medical
care, accounting for approximately 13 million visits each
year in the United States to physicians’ offices, urgent care
clinics, and emergency departments. It is the fifth most
common reason for emergency department visits, and sec­
ond most common reason for neurologic consultation in
the emergency department. A broad range of disorders can
cause headache (see Chapter 24). This section deals only
with acute nontraumatic headache in adults and adoles­
cents. The challenge in the initial evaluation of acute head­
ache is to identify which patients are presenting with an
uncommon but life-threatening condition; approximately
1% of patients seeking care in emergency department set­
tings and considerably less in office practice settings fall
into this category.
Diminution of headache in response to typical migraine
therapies (such as serotonin receptor antagonists or ketoro­
lac) does not rule out critical conditions such as subarach­
noid hemorrhage or meningitis as the underlying cause.
Clinical Findings
A. Symptoms
A careful history and physical examination should aim to
identify causes of acute headache that require immediate
treatment. These causes can be broadly classified as immi­
nent or completed vascular events (intracranial hemor­
rhage, thrombosis, cavernous sinus thrombosis, vasculitis,
malignant hypertension, arterial dissection, cerebral venous
thrombosis, transient ischemic attack, or aneurysm), infec­
tions (abscess, encephalitis, or meningitis), intracranial
masses causing intracranial hypertension, preeclampsia,
and carbon monoxide poisoning. Having the patient
CMDT 2021
carefully describe the onset of headache can be helpful in
diagnosing a serious cause. Report of a sudden-onset head­
ache that reaches maximal and severe intensity within
seconds or a few minutes is the classic description of a
“thunderclap” headache; it should precipitate workup for
subarachnoid hemorrhage, since the estimated prevalence
of subarachnoid hemorrhage in patients with thunderclap
headache is 43%. Thunderclap headache during the post­
partum period precipitated by the Valsalva maneuver or
recumbent positioning may indicate reversible cerebral
vasoconstriction syndrome. Other historical features that
raise the need for diagnostic testing include headache
brought on by the Valsalva maneuver, cough, exertion, or
sexual activity.
The medical history can also guide the need for addi­
tional workup. Under most circumstances (including a
normal neurologic examination), new headache in a
patient older than 50 years or with HIV infection warrants
immediate neuroimaging (Table 2-5). When the patient
has a history of hypertension—particularly uncontrolled
hypertension—a complete search for other features of
“malignant hypertension” is appropriate to determine the
urgency of control of hypertension (see Chapter 11). Head­
ache and hypertension associated with pregnancy may be
due to preeclampsia. Episodic headache associated with the
triad of hypertension, palpitations, and sweats is suggestive
of pheochromocytoma. In the absence of thunderclap
headache, advanced age, and HIV infection, a careful
physical examination and detailed neurologic examination
will usually determine acuity of the workup and need for
further diagnostic testing. A history consistent with hyper­
coagulability is associated with an increased risk of cerebral
venous thrombosis.
Symptoms can also be useful for diagnosing migraine
headache in the absence of the “classic” migraine pattern of
scintillating scotoma followed by unilateral headache,
Table 2-5. Clinical features associated with acute
headache that warrant urgent or emergent
neuroimaging.
Prior to lumbar puncture
Abnormal neurologic examination
Abnormal mental status
Abnormal funduscopic examination (papilledema; loss of
venous pulsations)
Meningeal signs
Emergent (conduct prior to leaving office or emergency
department)
Abnormal neurologic examination
Abnormal mental status
"Thunderclap" headache
Urgent (scheduled prior to leaving office or emergency
department)
HIV-positive patient1
Age > 50 years (normal neurologic examination)
1Use CT with or without contrast or MRI if HIV positive.
Data from American College of Emergency Physicians. Clinical
policy: critical issues in the evaluation and management of
patients presenting to the emergency department with acute
headache. Ann Emerg Med. 2002 Jan;39(1 ):108-22.
 CMDT 2021 CHAPTER 2

A systematic list called the SNNOOPIO has been devel­

Table 2-6. Summary likelihood ratios (LRs) for oped as a screening method for secondary causes of head­
individual clinical features associated with migraine ache (Table 2-7).
diagnosis.
B. Physical Examination
Clinical Feature LR+ (95% Cl) LR- (95% Cl)
Critical components of the physical examination of the
Nausea 19(15-25) 0.19(0.18-0.20)
patient with acute headache include vital signs, neurologic
Photophobia 5.8 (5.1-6.6) 0.24 (0.23-0.26) examination, and vision testing with funduscopic exami­
Phonophobia 5.2 (4.5—5.9) 0.38 (0.36-0.40) nation. The finding of fever with acute headache warrants
Exacerbation by 3.7 (3.4-4.0) 0.24 (0.23-0.26)
additional maneuvers to elicit evidence of meningeal
physical activity inflammation, such as Kernig and Brudzinski signs. The
absence of jolt accentuation of headache cannot accurately
Cl, confidence interval. rule out meningitis. Patients older than 60 years should be
examined for scalp or temporal artery tenderness.
Careful assessment of visual acuity, ocular gaze, visual
photophobia, and nausea and vomiting (Table 2-6). The fields, pupillary defects, optic disks, and retinal vein pulsa­
presence of three or more of these symptoms (nausea, pho­ tions is crucial. Diminished visual acuity is suggestive of
tophobia, phonophobia, and exacerbation by physical glaucoma, temporal arteritis, or optic neuritis. Ophthal­
activity) can establish the diagnosis of migraine (in the moplegia or visual field defects may be signs of venous
absence of other clinical features that warrant neuroimag­ sinus thrombosis, tumor, or aneurysm. Afferent pupillary
ing studies), and the presence of only one or two symptoms defects can be due to intracranial masses or optic neuritis.
(provided one is not nausea) can help rule out migraine. In the setting of headache and hypertension, retinal cotton

Table 2-7. SNNOOP10 list of "red "flags for secondary causes of headache.

Sign or Symptom Related Secondary Headaches

Systemic symptoms1 Headache attributed to infection, nonvascular intracranial disorders, carcinoid, or

Neoplasm in history
Neurologic deficit/dysfunction
Onset of headache is sudden or abrupt
Older age (> 50 years)
Pattern change or recent onset of headache
Positional headache
Precipitated by sneezing, coughing, or exercise
Papilledema
Progressive headache and atypical presentations
Pregnancy or puerperium
Painful eye with autonomic features
Posttraumatic onset of headache
Immune system pathology, eg, HIV
Painkiller overuse or new drug at onset of headache
pheochromocytoma
Neoplasms of the brain; metastasis
Headaches attributed to vascular, nonvascular intracranial disorders; brain abscess
and other infections
Subarachnoid hemorrhage and other headache attributed to cranial or cervical
vascular disorders
Giant cell arteritis and other headache attributed to cranial or cervical vascular
disorders; neoplasms and other nonvascular intracranial disorders
Neoplasms, headaches attributed to vascular, nonvascular intracranial disorders
Intracranial hypertension or hypotension
Posterior fossa malformations; Chiari malformation
Neoplasms and other nonvascular intracranial disorders; intracranial hypertension
Neoplasms and other nonvascular intracranial disorders
Headaches attributed to cranial or cervical vascular disorders; postdural puncture
headache; hypertension-related disorders (eg, preeclampsia); cerebral sinus
thrombosis; hypothyroidism; anemia; diabetes mellitus
Pathology in posterior fossa, pituitary region, or cavernous sinus; Tolosa-Hunt
syndrome (severe, unilateral headaches with orbital pain and ophthalmoplegia
due to extraocular palsies); other ophthalmic causes
Acute and chronic posttraumatic headache; subdural hematoma and other head­
ache attributed to vascular disorders
Opportunistic infections
Medication overuse headache; drug incompatibility

1"Orange"flagfor isolated fever alone.

Reproduced, with permission, from Do TP et al. Red and orange flags for secondary headaches in clinical practice: SNNOOPIO list.
Neurology. 2019 Jan 15;92(3): 134-44.
 COMMON SYMPTOMS
wool spots, flame hemorrhages, and disk swelling indicate
acute severe hypertensive retinopathy. Ipsilateral ptosis and
miosis suggest Horner syndrome and in conjunction with
acute headache may signify carotid artery dissection.
Finally, papilledema or absent retinal venous pulsations are
signs of elevated intracranial pressure—findings that
should be followed by neuroimaging prior to performing
lumbar puncture (Table 2-5). On nonmydriatic fundos-
copy, up to 8.5% of patients who arrive at the emergency
department complaining of headache had abnormalities;
although few had other significant physical examination
findings, 59% of them had abnormal neuroimaging
studies.
Complete neurologic evaluations are also critical and
should include assessment of mental status, motor
and sensory systems, reflexes, gait, cerebellar function, and
pronator drift. Any abnormality on neurologic evaluation
(especially mental status) warrants emergent neuroimag­
ing (Table 2-5).
C. Diagnostic Studies
Neuroimaging is summarized in Table 2-5. Under most
circumstances, a noncontrast head CT is sufficient to
exclude intracranial hypertension with impending hernia­
tion, intracranial hemorrhage, and many types of intracra­
nial masses (notable exceptions include lymphoma and
toxoplasmosis in HIV-positive patients, herpes simplex
encephalitis, and brain abscess). When needed, a contrast
study can be ordered to follow a normal noncontrast study.
A normal neuroimaging study does not exclude subarach­
noid hemorrhage and should be followed by lumbar punc­
ture. One study supported a change of practice wherein a
lumbar puncture can be withheld when a head CT scan
was performed less than 6 hours after headache onset and
showed no evidence of subarachnoid hemorrhage (nega­
tive predictive value 99.9% [95% CI, 99.3-100.0%]).
In patients for whom there is a high level of suspicion
for subarachnoid hemorrhage or aneurysm, a normal CT
and lumbar puncture should be followed by angiography
within the next few days (provided the patient is medically
stable). Lumbar puncture is also indicated to exclude infec­
tious causes of acute headache, particularly in patients with
fever or meningeal signs. Cerebrospinal fluid tests should
routinely include Gram stain, white blood cell count with
differential, red blood cell count, glucose, total protein, and
bacterial culture. In appropriate patients, also consider
testing cerebrospinal fluid for VDRL (syphilis), cryptococ-
cal antigen (HIV-positive patients), acid-fast bacillus stain
and culture, and complement fixation and culture for coc­
cidioidomycosis. Storage of an extra tube with 5 mL of
cerebrospinal fluid is also prudent for conducting unantici­
pated tests in the immediate future. Polymerase chain reac­
tion tests for specific infectious pathogens (eg, herpes
simplex 2) should also be considered in patients with evi­
dence of central nervous system infection but no identifi­
able pathogen.
The Ottawa subarachnoid hemorrhage clinical decision
rule had 100% sensitivity (and 13-15% specificity in differ­
ent studies) in predicting subarachnoid hemorrhage.
CMDT 2021
According to it, patients who seek medical attention in an
emergency department complaining of an acute nontrau-
matic headache should be evaluated for subarachnoid
hemorrhage if they have one or more of the following fac­
tors: age 40 years or older, neck pain or stiffness, witnessed
loss of consciousness, onset during exertion, thunderclap
headache (instantly peaking pain), or limited neck flexion
on examination.
In addition to neuroimaging and lumbar puncture,
additional diagnostic tests for exclusion of life-threatening
causes of acute headache include erythrocyte sedimenta­
tion rate (temporal arteritis; endocarditis), urinalysis
(malignant hypertension; preeclampsia), and sinus CT
(bacterial sinusitis, independently or as a cause of venous
sinus thrombosis).
Treatment
Treatment should be directed at the cause of acute head­
ache. In patients in whom migraine or migraine-like
headache has been diagnosed, early treatment with
NSAIDs (oral, nasal, or intramuscular ketorolac), meto­
clopramide, dihydroergotamine, or triptans (oral, nasal,
subcutaneous) can often abort or provide significant
relief of symptoms (see Chapter 24). Intravenous pro­
chlorperazine plus diphenhydramine was more effective
for migraine pain relief than intravenous hydromorphone
in the emergency department. There appears to be no
benefit of adding intravenous diphenhydramine to intra­
venous metoclopramide. Prochlorperazine appears to be
superior to ketamine for the treatment of benign head­
aches in the emergency department. Sumatriptan may be
less effective as immediate therapy for migraine attacks
with aura compared to attacks without aura. There may
be a role for oral corticosteroids to prevent rebound head­
ache after emergency department discharge. Parenteral
morphine and hydromorphone are best avoided as first-
line therapy.
Subanesthetic ketamine infusions may be beneficial in
individuals with chronic migraine and new daily persis­
tent headache that has not responded to other aggressive
treatments. Peripheral nerve blocks may be a safe and
effective way to treat headaches in older adults. Surgical
decompression of peripheral cranial and spinal nerves at
trigger sites have been used to treat migraine. Noninva-
sive vagus nerve stimulation has shown promise in the
management of migraine and acute cluster headaches.
High-flow oxygen therapy may also provide effective
treatment for all headache types in the emergency
department setting. Peripheral nerve blocks for treatment­
refractory migraine may be an effective therapeutic option
in pregnancy. The oral 5-HT1F receptor agonist, lasmiditan,
has been approved for the acute treatment of migraine with
or without aura in adults. The CGRP monoclonal antibod­
ies (erenumab, fremanezumab, galcanezumab) have been
approved for prevention of migraine. Galcanezumab has
activity against cluster headache.
Regular exercise may have a prophylactic effect on
migraine frequency; however, new, intense exercise can
trigger migraine.
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[1]

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☞ Elke aflevering bevat een volledig verhaal. ☜

UITGAVE VAN DEN ROMAN-, BOEK- EN KUNSTHANDEL—SINGEL 236,—
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Een Avontuur van Koning Alfonso.
HOOFDSTUK I.
 Het raadsel der schijndooden.

Omstreeks het begin van November bevatte de eerste ochtendeditie

van de „Times” een tamelijk lang bericht, hetwelk in de hoogste mate
de belangstelling der lezers opwekte.

Zie hier de onverkorte inhoud van dit stuk hetwelk onder de

„Gemengde Berichten” was geplaatst:

Het geheim van een Ziekenhuis.

Moordaanslag op een gewonde!

„Het bekende ziekenhuis in de Sloanestreet is, zooals aan onze lezers

bekend zal zijn, reeds sedert enkele dagen het tooneel geweest van
geheimzinnige voorvallen.

In den afgeloopen nacht zijn deze bekroond door een gebeurtenis, die de
gemoederen van alle bewoners van het ziekenhuis, van de directie af tot
aan de minste hulpverpleegster en alle zieken, ten zeerste heeft ontroerd.

Eenige dagen geleden werd er in het ziekenhuis een zwaargewond man

gebracht, die uit verscheidene messteken bloedde en die gevonden was
door twee late voorbijgangers, die opgaven dat zij er getuigen van waren
geweest, hoe de gewonde man overvallen werd door een paar kerels, die
echter op hun nadering de vlucht hadden genomen.

Aanstonds zal blijken, dat er van deze bewering waarschijnlijk geen woord
waar was.

Reeds den volgenden dag werd de zwaargewonde bezocht door een paar
geheimzinnige heeren, die voorgaven tot zijn naaste familie te behooren en
hem dringend wenschten te spreken.

Gedurende het korte gesprek, dat nu volgde, verzocht de gewonde, die

verklaarde Dubois te heeten, aan de hoofdverpleegster der algemeene
mannenzaal, waar hij lag, te telefoneeren naar het logement „Het Vergulde
Hert” en daar navraag te doen naar een zekere Miss Bispham. De
gewonde scheen zeer opgewonden te zijn, het smartte hem [2]blijkbaar
zeer, toen hij ten antwoord kreeg, dat deze dame niet meer in het hotel
aanwezig was.

De beide bezoekers vertrokken, maar werden in de vestibule, juist toen zij

de lift zouden verlaten, gearresteerd door een tweetal particuliere
detectives—bedriegers, zooals later blijken zal!

Want reeds in den loop van denzelfden nacht werden de twee

geheimzinnige bezoekers van Dubois in hetzelfde ziekenhuis binnen
gebracht waar hij ook lag, een hunner zelfs in de groote mannenzaal. De
chauffeur, die hen beiden en de zoogenaamde detectives naar een huis in
het noorden van de stad had gereden, was nieuwsgierig geworden, en op
de loer gaan staan. Hij had er een paar agenten bijgehaald en deze
hadden in het huis twee volkomen bewustelooze personen gevonden, die
naderhand de beide bezoekers bleken te zijn.

Men stond hier voor een raadselachtig geval en de beste geneesheeren,

de directeur van het ziekenhuis dr. Hudson en die geneesheeren
Bushgrave en Greenway begrepen niet het minste van de eigenaardige
bewusteloosheid, waarin de twee mannen verkeerden.

Men kan dus over hun blijdschap en verwondering oordeelen, toen de

befaamde Fransche psychiater Dr. Edouard Dumoulin, zich met het geval
bemoeide en dringend verzocht de beide bewusteloozen te mogen
onderzoeken.

In een vorige editie hebben wij uitvoerig melding gemaakt van deze zaak
en Dr. Dumoulin wist de beide bewusteloozen, die wel schijndood leken
onder zijn wil te brengen, gelastte hen op te staan en zich aan te kleeden
en voerde hen weg. Ongeveer een uur later bleek pas dat de beroemde
Parijsche geneesheer van de geheele zaak niets afwist en verzekerde dat
men zijn plaats had ingenomen met een doel dat hij niet begreep.

Maar nog dienzelfden avond kwam er eenig licht in de zaak, want de beide
mannen, die in hun toestand van volkomen machteloosheid in een groot
restaurant in „Temple Bar” met twee andere heeren dineerden werden op
hun aanwijzing gearresteerd en bleken twee hoogstgevaarlijke bandieten;
bekend onder de bijnamen „Big Billy” en „Bittere Pil”, naar wie de politie
van onze stad reeds geruimen tijd zocht.
Maar toen men wilde omzien naar de beide personen met wie ze waren
binnengetreden en die hen hadden laten arresteeren, waren zij spoorloos
verdwenen!

Wat de beide bandieten betreft, zij wisten zich volstrekt niet meer te
herinneren wat zij gedaan of gezegd hadden van het oogenblik af dat zij
door de gewaande detectives in een huurauto van het gasthuis waren
weggeleid,—naar zij meenden met de gevangenis als bestemming—en
toen ieder een sterke prik in den pols hadden gekregen, waarop bijna
aanstonds het bewustzijn uit hun was weggevloden, althans zij herinnerden
zich volstrekt niets meer, tot op het tijdstip, dat zij tot hun groote
verwondering in de eetzaal van het restaurant in „Temple Bar” weder tot
bewustzijn kwamen.

En toch moeten deze mannen hebben kunnen zien en hooren, zij moeten
zich hebben kunnen bewegen, maar zij deden dit slechts op bevel van een
ander!

De zaak wend intusschen hoe langer hoe geheimzinniger! Wie was de

zwaargewonde in de ziekenzaal, die zulke eigenaardige bezoeken had
gekregen? Wie was de schoone jonge vrouw met het bleeke gelaat, die
voorgaf mevrouw Dubois te heeten, en die hem enkele keeren bezocht,
steeds in gezelschap van een grijsaard met spierwit haar, die haar vader
moest zijn.

De lezers zullen het spoedig vernemen.

In den afgeloopen nacht had er in het ziekenhuis aan de Sloane Street

opnieuw een opzienbarend voorval plaats.

Omstreeks half een kwam zich een jonge verpleegster aanmelden, die
zeide, door mevrouw Dubois gezonden te zijn met het doel om haren
echtgenoot speciaal op te passen, daar zijn toestand, een overbrenging
naar een afzonderlijke kamer, onmogelijk maakte in de eerste dagen.

De hoofdverpleegster stond haar dit verzoek geredelijk toe en het jonge

meisje nam haar plaats aan het ziekbed in, en kweet zich, volgens de
getuigenis [3]van de oude dame, met groote vaardigheid van haar
verpleegsterplichten.

Om één uur werd de groote zaal geheel donker gemaakt, of althans was zij
toen slechts verlicht door de kaarslantaarns van twee surveillanten.
Dezen waren onder den invloed van de stilte van de groote zaal
ingesluimerd, toen zij plotseling werden opgeschrikt door het op luiden toon
gegeven bevel: „Handen op”.

De jonge verpleegster had een der lange linnen gordijnen voor de groote
balkonramen terzijde gerukt, een electrische zaklantaarn opgestoken en
hield nu een revolver gericht op het voorhoofd van een man die achter het
gordijn had gestaan dicht bij het bed van den gewonde Dubois en blijkbaar
zooeven door het balkonraam was binnengedrongen.

De koele luchtstroom die door dit open raam naar binnen drong en die ook
het gordijn zachtjes deed bewegen, had zijn aanwezigheid verraden.

De man werd door de beide surveillanten met behulp van een stuk van het
gordijnkoord gebonden en daarop werden zijn zakken doorzocht.

Deze bleken behalve een revolver en een kleine scherp geslepen dolk, ook
een klein houten étui te bevatten, waarin zich een vaccinatienaald bevond,
waarvan de punt gedrenkt was in een uiterst giftige stof.

De man werd natuurlijk aanstonds in arrest gesteld, maar toen men nu de

verpleegster nader wilde ondervragen, bleek ook zij verdwenen te zijn.

Maar het eigenaardigste komt nog.

Want Big Billy, Bittere Pil, zoowel als de moordenaar achter het gordijn,
inziende dat alles voor hen verloren was, en dat hun een gevangenisstraf
van tientallen jaren wachtte, brachten onder andere aan het licht, dat de
zoogenaamde Dubois niemand anders was dan een Parijsche bandiet, een
man van adellijke afkomst en een authentiek markies Raoul Beaupré de la
Sardogne geheeten.

Hij was ook niet gewond door een overval, maar in een tweegevecht met
een mededinger.

Deze opzienbarende onthulling werd spoedig bevestigd, toen uit Parijs

door de Sureté een uitvoerig signalement werd overgeseind, dat in alles
overeenstemde met het uiterlijk van den gewonde, behalve wat den baard
betreft, dien hij in Engeland waarschijnlijk aanstonds had afgeschoren.

Te Parijs heeft deze markies nog een zestal jaren gevangenisstraf te goed,
en daar hij ook hier in Londen daadwerkelijk aandeel heeft genomen aan
een paar inbraken, zoo kan men wel zeggen dat het een goede dag is voor
onze politie.

Veel werd nu ook opgehelderd. Bijvoorbeeld de identiteit van de

zoogenaamde Madame Dubois, die waarschijnlijk niemand anders was
dan een Fransche bandiete, een zekere Marthe Debussy.

Waar deze vrouw zich echter thans bevindt is niet uit te maken; zeker
logeerde zij niet langer in het „Vergulde Hert”.

En wat het bezoek van de beide naderhand bewusteloos gevonden

schurken van den markies betreft, zij kwamen hem slechts dreigen dat zijn
minnares zich in handen van hun chef bevond en dat deze haar zou
dooden indien Beaupré niet zekere geheimen van zijn eigen bende verried
en zich verbond onder eede, hun chef nooit meer te bestrijden.

Het spreekt vanzelf, dat Dubois, alias markies Beaupré nu aanstonds

onder zeer strenge bewaking is geplaatst en met groote behoedzaamheid
naar een afzonderlijk vertrok is overgebracht, speciaal voor dergelijke
gevallen bestemd, met een zwaar getralied venster, een ijzeren deur en dat
op de vijfde verdieping van het ziekenhuis gelegen is. Zoodra de bandiet
genezen is, zal hij voor zijn rechters moeten verschijnen, en daarna zijn
rechtvaardige straf ondergaan.

De man achter het gordijn, eveneens een berucht misdadiger, trachtte zijn
straf blijkbaar verminderd te krijgen door te verklaren, dat hij handelde in
opdracht van den chef zijner bende, wiens naam hij echter weigerde te
noemen, evenals trouwens „Big Billy” en „Bittere Pil”.

Hij was gekomen om Beaupré te vermoorden, en aldus den aanvoerder te

beschermen tegen zijn aanval.

En voor de rest wilde hij niets loslaten. [4]

Met dit al moeten er nog vrij wat raadsels door de politie worden opgelost.

Zoo weet zij bijvoorbeeld volstrekt niet, wie de „edele grijsaard” was, die als
vader van de zoogenaamde mevrouw Dubois optrad, noch wie de beide
detectives waren, noch wie de rol van dr. Dumoulin vervuld heeft, en
evenmin wie op zulke geniale wijze de taak van verpleegster heeft vervuld,
maar de politie heeft vermoedens. Er wordt een naam gefluisterd, dien wij
nu niet zullen herhalen, ten einde het onderzoek van de politie niet te
 bemoeilijken, maar die waarschijnlijk dezer dagen alom bekend zal zijn
gemaakt; doch als Scotland Yard er ook ditmaal niet in slaagt hem
gevangen te nemen, dan zal het wel eeuwig een raadsel blijven wat hem er
toe bewoog als beschermer op te treden voor een man als Beaupré, daar
deze zich in een halsstarrig stilzwijgen hult, en weigert eenige inlichtingen
te geven.

In ieder geval is het niet te loochenen, dat de politie, dank zij het ingrijpen
van den geheimzinnigen man, wiens naam thans nog niet genoemd wordt,
wederom vier zeer gevaarlijke bandieten in handen heeft gekregen.

[Inhoud]
HOOFDSTUK II.
 Belofte maakt schuld.

Dit bericht in de „Times” verwekte, zooals gezegd, niet weinig

opschudding, niet alleen in kringen der politie, maar onder de
geheele burgerij, die het geval dagen lang besprak, terwijl men
daarbij de zonderlingste meeningen hoorde.

Onder die burgerij mag ook gerekend worden John Raffles, de

Groote Onbekende, die in dit alles zulk een groote rol had gespeeld,
met behulp van zijn trouwen vriend Charly Brand en den braven reus
Henderson, zijn chauffeur.

De gentleman-inbreker las het stukje, terwijl hij gezeten was in de vrij

schaars gemeubelde ontvangkamer van een splinternieuw huis in
een der noordelijkste wijken van Londen, gelegen in een straat,
waarvan de aanleg nog niet lang geleden begonnen was.

Zijn hoed en zijn stok lagen naast hem, en hij was blijkbaar zooeven
pas gekomen.

Het was tien uur in den morgen, toen Raffles eenig gerucht in een
aangrenzend vertrek hoorde, en het volgende oogenblik ging de deur
open en trad er een jonge vrouw met een mooi, maar zeer bleek
gelaat, binnen, die haastig op Raffles toetrad en zeide:

—Ik vraag u verschooning als ik u heb laten wachten, mijnheer—ik

heb een zeer slechten nacht doorgebracht!

—Het is eerder aan mij om u mijn verontschuldigingen aan te bieden,

dat ik u op zulk een onbehoorlijk [5]uur kom bezoeken, Madame,
hernam Raffles, die was opgestaan.

Er lag een ernstige klank in zijn stem toen hij vervolgde:

—Gij zult begrijpen, dat ik hier op dit uur niet zou gekomen zijn,
Marthe Debussy, wanneer het geen ernstige aangelegenheid gold, gij
moet sterk zijn—er is met uw vriend, met Raoul Beaupré, iets
voorgevallen hetwelk ik wel voorzien had, maar toch onmogelijk kon
vermijden.

De jonge vrouw wankelde en moest zich aan den rand van de tafel
vastgrijpen, terwijl zij de linkerhand op het hart drukte.

Bijna toonloos vroeg zij:

—De aanslag heeft dus plaats gehad en—wat?

—Stel u gerust, mijn vriend heeft den aanslag zelf kunnen verijdelen,
maar helaas niet de gevolgen! Big Billy zoowel als de Bittere Pil en
de man die den aanslag had willen plegen, hebben uw vriend
verraden, en zijn waren naam aan de politie opgegeven. Hier—lees.

Hij stak de jonge vrouw het nummer van de „Times” toe, en zij liet
zich op een stoel neervallen, nam het blad met een automatische
beweging aan, en trachtte te lezen.

Maar reeds na de eerste regels gaf zij Raffles het blad terug en zeide
met bevende stem:

—Ik kan niet! Het warrelt mij voor de oogen. Ik smeek u! lees gij het
mij voor.

Raffles nam nu het blad en las met heldere stem het bericht voor.

De jonge vrouw had al dien tijd bewegingloos zitten luisteren, de

zwarte oogen op den zwarten vloer gevestigd, de slanke witte vingers
ineen gestrengeld—het toonbeeld der wanhoop!
Toen Raffles de voorlezing van het noodlottige bericht had beëindigd,
bleef het geruimen tijd stil in het vertrek.

In dit huis, hetwelk hij slechts een week te voren gehuurd had, had
Raffles de vrouw, wie hij zijn hulp had toegezegd, omdat zij door zijn
toedoen in dezen toestand was gebracht en in groot gevaar had
verkeerd, voorloopig ondergebracht, ten einde haar buiten den greep
van den langen arm der justitie te houden.

Zij mocht volstrekt niet uitgaan zonder zijn toestemming en werd daar
steeds bewaakt, door Raffles zelf, door Charly Brand of door
Henderson, omdat haar leven gevaar liep. Zij immers had aan Raffles
het plan voor een inbraak verraden, ten einde Dr. Fox, den chef van
een groot misdadigersgenootschap, en de persoonlijke vijand van
haren minnaar, in handen der politie over te leveren en zich aldus te
wreken over de zware wonden, welke hij Beaupré had toegebracht.

Zij had zich reeds in handen van de mannen van Dr. Fox bevonden,
en het doodvonnis zou zeker aan haar voltrokken zijn geworden, als
Raffles en zijn twee vrienden niet tusschen beide waren gekomen.

De Groote Onbekende was de eerste die weder sprak. Hij had

eenigen tijd ernstig nagedacht en zeide nu:

—Ik mag er ook tegenover u geen geheim van maken Madame.

Raoul Beaupré is en blijft mijn vijand! Misschien zal de politie ons
over een kam scheren—ik denk daar echter anders over! Ja—ik weet
wat gij zeggen wilt: Ik heb mij niet als een vijand gedragen! Vergeet
echter niet dat ik dit voor een deel uit eigen belang deed! Als ik de
vijanden van Dr. Fox help, dan bestrijd ik hem zelf, maar er was nog
een overweging, die alle anderen in de schaduw stelde.

—Wat meent gij, vroeg Marthe Debussy op zachten toon.

—Gij hadt mijn woord! Het was mijn schuld dat gij in groot
levensgevaar hebt verkeerd en ik heb beloofd, u te beschermen en
wat uw vriend betreft—hij is in zekeren zin mijn bondgenoot, en wel
een zeer kostbare, want hij is een doodsvijand van Fox! en ik zou hier
met een kleinen variant kunnen zeggen: „De vijanden van mijn
vijanden zijn mijn vrienden”.

—Gij wilt dus zeggen …? stamelde Marthe, terwijl haar oogen vochtig
begonnen te glanzen.

—Ik wil zeggen, dat ik mijn hand nog niet van hem aftrek, maar dat ik
wil trachten hem toch nog voor u te redden.

De jonge vrouw liet een snikkend geluid hooren, greep de hand van
Raffles en voor hij het had kunnen verhinderen, had zij er een kus op
gedrukt.

—Dat moet gij niet doen, zeide Raffles hoofdschuddend, terwijl hij
zijn hand snel terug trok. Ik zeg u immers, dat ik handel uit eigen
belang! Ik wil u echter niet ontveinzen, dat het ditmaal zeer moeilijk
zal zijn. Ik vrees zelfs dat het volkomen onuitvoerbaar zal zijn,
zoolang Beaupré in het ziekenhuis ligt! Wij moeten [6]echter alles in
het werk stellen, om hem nog te redden vóór hij naar de gevangenis
wordt overgebracht, want daar zal het wellicht onmogelijk zijn.

—Kan ik u daarbij niet van dienst zijn, vroeg Marthe Debussy op

zachten toon. Ik zou u zoo gaarne helpen! Ik heb niets anders ter
wereld dan Raoul, en als ik mijn leven voor hem zou moeten offeren,
dan zou ik geen seconde twijfelen.

Raffles had even nagedacht, en zeide toen:

—Misschien kunnen wij uw hulp gebruiken, dan zal ik u wel laten

weten wat wij in de eerste dagen kunnen doen, want bij mijn
pogingen om Beaupré te bevrijden zal ik ook zijn eigen hulp noodig
hebben; hij moet mede werken, en daartoe is hij thans nog veel te
zwak. Maar ik beschik over middelen, waardoor ik de natuur ter hulp
zal kunnen komen en zijn herstel zal kunnen bespoedigen. De zaak
is slechts of het mogelijk zal zijn, tot hem door te dringen om hem dat
middel toe te dienen, want de directie zal nu natuurlijk zeer
wantrouwend zijn en goed acht geven op ieder die binnentreedt. Ik
vrees dat wij den truc met de zoogenaamde verpleegster niet
nogmaals kunnen toepassen—en om voor de tweede maal als dokter
Dumoulin op te treden, dat zal ook wel niet gaan. Wij hebben echter
den tijd om daarover na te denken, want in normale omstandigheden
zou het zeker nog minstens een week duren alvorens men Beaupré
naar de gevangenis zou kunnen overbrengen.

Raffles was opgestaan en had hoed en stok gegrepen, hij maakte

een buiging voor de jonge vrouw en zeide:

—Ik kom u vanmiddag halen om u met een mijner auto’s naar een
andere stad te brengen, hier dicht bij, want hier zijt ge nog altijd niet
veilig genoeg, en wij zouden u ook niet goed meer kunnen bewaken,
daar ik bij mijn plannen ter bevrijding van uw vriend de hulp van mijn
twee makkers niet zou kunnen ontberen. Als gij uw haar verft, of een
pruik opzet, zult gij vrijwel veilig zijn in een of andere provinciestad.
Kleed u zoo eenvoudig mogelijk en vertoon u tijdelijk zoo weinig
mogelijk in het publiek. Indien wij uw hulp kunnen gebruiker, zullen wij
u aanstonds laten halen!

—Ik voeg mij geheel maar uw aanwijzingen, mijnheer zeide Marthe

Debussy op zachten toon. Hoe laat komt gij?

—Om drie uur!

Nogmaals boog Raffles voor de jonge vrouw en het volgende

oogenblik had hij het vertrek en het huis verlaten.
Honderd schreden verder stapte hij in een wachtende auto, die hem
naar het einde van de Regent Street bracht, dicht bij Pall Mall.

In de eerstgenoemde straat bewoonde Raffles, onder den naam van

Lord William Aberdeen, een fraai heerenhuis, dat met een voor deze
buurt zeer grooten tuin omgeven was.

Hij kon dit huis steeds en ten allen tijde ongezien binnengaan, in
welke vermomming hij zich ook bevond, want een der tuinmuren
strekte zich over geruimen afstand uit langs een straat, welke zoo
goed als nimmer begaan werd, en welker overzijde werd ingenomen
door den blinden muur eener opslagplaats, tijdens den oorlog door de
regeering overgenomen en thans in het bezit van Raffles zelf, die het
groote gebouw voordeelig had verhuurd, op voorwaarden dat er aan
de bestemming niets mocht worden gewijzigd.

Niemand bespeurde er dus iets van, dat hij de kleine deur in den
tuinmuur opende en snel binnentrad.

Hij stak den grooten tuin dwars over en ging het huis aan de
achterzijde binnen.

Daarop beklom hij een smalle trap, die hem rechtstreeks naar zijn
slaapkamer bracht, waar hij de vermomming kon afleggen, welke hij
gedragen had bij zijn bezoek aan de minnares van den Franschen
Markies.

Terwijl hij hier mede bezig was, werd er op de deur geklopt en de

stem van Charly Brand liet zich hooren.

—Ben je hier, Edward?

—Ja, Charly! Wacht—ik zal open doen!