PRINCIPLES OF

INTERNAL

MEDICINE

21st Edition

®

T. R. Harrison

Editor-in-Chief, Editions 1, 2, 3, 4, 5

W. R. Resnick

Editor, Editions 1, 2, 3, 4, 5

M. M. Wintrobe

Editor, Editions 1, 2, 3, 4, 5

Editor-in-Chief, Editions 6, 7

G. W. Thorn

Editor, Editions 1, 2, 3, 4, 5, 6, 7

Editor-in-Chief, Edition 8

R. D. Adams

Editor, Editions 2, 3, 4, 5, 6, 7, 8, 9, 10

P. B. Beeson

Editor, Editions 1, 2

I. L. Bennett, Jr.

Editor, Editions 3, 4, 5, 6

E. Braunwald

Editor, Editions 6, 7, 8, 9, 10, 12, 13, 14, 16, 17

Editor-in-Chief, Editions 11, 15

K. J. Isselbacher

Editor, Editions 6, 7, 8, 10, 11, 12, 14

Editor-in-Chief, Editions 9, 13

R. G. Petersdorf

Editor, Editions 6, 7, 8, 9, 11, 12

Editor-in-Chief, Edition 10

J. D. Wilson

Editor, Editions 9, 10, 11, 13, 14

Editor-in-Chief, Edition 12

J. B. Martin

Editor, Editions 10, 11, 12, 13, 14

A. S. Fauci

Editor, Editions 11, 12, 13, 15, 16, 18, 19, 20, 21

Editor-in-Chief, Editions 14, 17

R. Root

Editor, Edition 12

D. L. Kasper

Editor, Editions 13, 14, 15, 17, 18, 20, 21

Editor-in-Chief, Editions 16, 19

S. L. Hauser

Editor, Editions 14, 15, 16, 17, 18, 19, 20, 21

D. L. Longo

Editor, Editions 14, 15, 16, 17, 19, 20, 21

Editor-in-Chief, Edition 18

J. L. Jameson

Editor, Editions 15, 16, 17, 18, 19, 21

Editor-in-Chief, Edition 20

J. Loscalzo

Editor, Editions 17, 18, 19, 20

Editor-in-Chief, Edition 21

Editors of Previous Editions

Joseph Loscalzo, MD, PhD

Hersey Professor of the Theory and Practice of Medicine, Harvard

Medical School; Chairman, Department of Medicine; Soma Weiss MD

Distinguished Chair in Medicine; Physician-in-Chief, Brigham

and Women’s Hospital, Boston, Massachusetts

Dennis L. Kasper, MD

William Ellery Channing Professor of Medicine and Professor of

Immunology, Department of Immunology, Harvard Medical School;

Division of Infectious Diseases, Brigham and Women’s Hospital,

Boston, Massachusetts

Dan L. Longo, MD

Professor of Medicine, Harvard Medical School; Senior Physician,

Brigham and Women’s Hospital; Deputy Editor, New England Journal

of Medicine, Boston, Massachusetts

Anthony S. Fauci, MD

Chief, Laboratory of Immunoregulation; Director, National Institute

of Allergy and Infectious Diseases, National Institutes of Health,

Bethesda, Maryland

Stephen L. Hauser, MD

Robert A. Fishman Distinguished Professor, Department of

Neurology; Director, UCSF Weill Institute for Neurosciences,

University of California, San Francisco, San Francisco, California

J. Larry Jameson, MD, PhD

Robert G. Dunlop Professor of Medicine; Dean, Raymond and Ruth

Perelman School of Medicine; Executive Vice President, University of

Pennsylvania for the Health System, Philadelphia, Pennsylvania

PRINCIPLES OF

INTERNAL

MEDICINE

21st Edition

®

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Contents

Contributors ............................................................................ xviii

Preface .................................................................................... xxxix

Harrison’s Related Resources ........................................................ xl

PART 1 The Profession of Medicine

1 The Practice of Medicine ...................................................1

The Editors

2 Promoting Good Health ....................................................8

Donald M. Lloyd-Jones, Kathleen M. McKibbin

3 Vaccine Opposition and Hesitancy ...................................13

Julie A. Bettinger, Hana Mitchell

4 Decision-Making in Clinical Medicine.............................21

Daniel B. Mark, John B. Wong

5 Precision Medicine and Clinical Care ...............................30

 The Editors

6 Screening and Prevention of Disease ................................37

Katrina A. Armstrong, Gary J. Martin

7 Global Diversity of Health System Financing

and Delivery ....................................................................42

Richard B. Saltman

8 The Safety and Quality of Health Care.............................50

David W. Bates

9 Diagnosis: Reducing Errors and Improving Quality..........54

Gordon Schiff

10 Racial and Ethnic Disparities in Health Care....................59

Lenny López, Joseph R. Betancourt

11 Ethical Issues in Clinical Medicine...................................67

Christine Grady, Bernard Lo

12 Palliative and End-of-Life Care .......................................72

Ezekiel J. Emanuel

PART 2 Cardinal Manifestations and

Presentation of Diseases

SECTION 1 Pain

13 Pain: Pathophysiology and Management ..........................91

James P. Rathmell, Howard L. Fields

14 Chest Discomfort ..........................................................100

David A. Morrow

15 Abdominal Pain.............................................................108

Danny O. Jacobs

16 Headache.......................................................................112

Peter J. Goadsby

17 Back and Neck Pain .......................................................117

John W. Engstrom

SECTION 2 Alterations in Body Temperature

18 Fever .............................................................................130

Neeraj K. Surana, Charles A. Dinarello, Reuven Porat

19 Fever and Rash ..............................................................133

Elaine T. Kaye, Kenneth M. Kaye

20 Fever of Unknown Origin ..............................................145

Chantal P. Bleeker-Rovers, Catharina M. Mulders-Manders,

Jos W. M. van der Meer

SECTION 3  Nervous System Dysfunction

21 Syncope .........................................................................152

Roy Freeman

22 Dizziness and Vertigo.....................................................159

Mark F. Walker, Robert B. Daroff

23 Fatigue ..........................................................................162

Jeffrey M. Gelfand, Vanja C. Douglas

24 Neurologic Causes of Weakness and Paralysis................. 165

Stephen L. Hauser

25 Numbness, Tingling, and Sensory Loss .......................... 168

Stephen L. Hauser

26 Gait Disorders, Imbalance, and Falls.............................. 173

Jessica M. Baker

27 Confusion and Delirium ................................................178

S. Andrew Josephson, Bruce L. Miller

28 Coma.............................................................................183

S. Andrew Josephson, Allan H. Ropper, Stephen L. Hauser

29 Dementia.......................................................................189

William W. Seeley, Gil D. Rabinovici, Bruce L. Miller

30 Aphasia, Memory Loss, and Other Cognitive

Disorders.......................................................................195

M.-Marsel Mesulam

31 Sleep Disorders..............................................................204

Thomas E. Scammell, Clifford B. Saper, Charles A. Czeisler

SECTION 4 Disorders of Eyes, Ears, Nose, and Throat

32 Disorders of the Eye.......................................................215

Jonathan C. Horton

33 Disorders of Smell and Taste ..........................................232

Richard L. Doty, Steven M. Bromley

34 Disorders of Hearing......................................................238

Anil K. Lalwani

35 Upper Respiratory Symptoms, Including Earache,

Sinus Symptoms, and Sore Throat..................................247

Rachel L. Amdur, Jeffrey A. Linder

36 Oral Manifestations of Disease ......................................256

Samuel C. Durso

SECTION 5  Alterations in Circulatory and

Respiratory Functions

37 Dyspnea ........................................................................263

Rebecca M. Baron

38 Cough ...........................................................................267

Christopher H. Fanta

39 Hemoptysis ...................................................................270

Carolyn M. D’Ambrosio

40 Hypoxia and Cyanosis....................................................272

Joseph Loscalzo

41 Edema ...........................................................................275

Joseph Loscalzo

42 Approach to the Patient with a Heart Murmur ............... 278

Patrick T. O’Gara, Joseph Loscalzo

43 Palpitations....................................................................286

Joseph Loscalzo

CONTENTS vii

SECTION 6 Alterations in Gastrointestinal Function

44 Dysphagia......................................................................287

Ikuo Hirano, Peter J. Kahrilas

45 Nausea, Vomiting, and Indigestion................................. 291

William L. Hasler

46 Diarrhea and Constipation.............................................297

Michael Camilleri, Joseph A. Murray

47 Unintentional Weight Loss ............................................ 309

J. Larry Jameson

48 Gastrointestinal Bleeding...............................................311

Loren Laine

49 Jaundice.........................................................................315

Savio John, Daniel S. Pratt

50 Abdominal Swelling and Ascites .................................... 321

Lawrence S. Friedman

SECTION 7 Alterations in Renal and Urinary Tract

Function

51 Interstitial Cystitis/Bladder Pain Syndrome.................... 325

R. Christopher Doiron, J. Curtis Nickel

52 Azotemia and Urinary Abnormalities............................. 331

David B. Mount

53 Fluid and Electrolyte Disturbances ................................338

David B. Mount

54 Hypercalcemia and Hypocalcemia..................................356

Sundeep Khosla

55 Acidosis and Alkalosis....................................................359

Thomas D. DuBose, Jr.

SECTION 8 Alterations in the Skin

56 Approach to the Patient with a Skin Disorder................. 369

Kim B. Yancey, Thomas J. Lawley

57 Eczema, Psoriasis, Cutaneous Infections, Acne,

and Other Common Skin Disorders............................... 374

Leslie P. Lawley, Justin T. Cheeley, Robert A. Swerlick

58 Skin Manifestations of Internal Disease ......................... 383

Jean L. Bolognia, Jonathan S. Leventhal, Irwin M. Braverman

59 Immunologically Mediated Skin Diseases ...................... 400

Kim B. Yancey, Benjamin F. Chong, Thomas J. Lawley

60 Cutaneous Drug Reactions ............................................407

Robert G. Micheletti, Misha Rosenbach,

Bruce U. Wintroub, Kanade Shinkai

61 Photosensitivity and Other Reactions to Sunlight........... 417

Alexander G. Marneros, David R. Bickers

SECTION 9  Hematologic Alterations

62 Interpreting Peripheral Blood Smears.............................424

Dan L. Longo

63 Anemia and Polycythemia..............................................431

John W. Adamson, Dan L. Longo

64 Disorders of Granulocytes and Monocytes ..................... 439

Steven M. Holland, John I. Gallin

65 Bleeding and Thrombosis...............................................450

Barbara A. Konkle

66 Enlargement of Lymph Nodes and Spleen...................... 457

Dan L. Longo

PART 3 Pharmacology

67 Principles of Clinical Pharmacology ............................... 465

Dan M. Roden

68 Pharmacogenomics........................................................474

Dan M. Roden

PART 4 Oncology and Hematology

SECTION 1 Neoplastic Disorders

69 Approach to the Patient with Cancer.............................. 481

Dan L. Longo

70 Prevention and Early Detection of Cancer...................... 490

Jennifer M. Croswell, Otis W. Brawley,

Barnett S. Kramer

71 Cancer Genetics.............................................................498

Fred Bunz, Bert Vogelstein

72 Cancer Cell Biology .......................................................508

Jeffrey W. Clark, Dan L. Longo

73 Principles of Cancer Treatment ......................................529

Edward A. Sausville, Dan L. Longo

74 Infections in Patients with Cancer..................................556

Robert W. Finberg

75 Oncologic Emergencies..................................................565

Rasim Gucalp, Janice P. Dutcher

76 Cancer of the Skin..........................................................578

Brendan D. Curti, John T. Vetto, Sancy A. Leachman

77 Head and Neck Cancer ..................................................590

Everett E. Vokes

78 Neoplasms of the Lung ..................................................594

Leora Horn, Wade T. Iams

79 Breast Cancer ................................................................611

Daniel F. Hayes, Marc E. Lippman

80 Upper Gastrointestinal Tract Cancers............................. 626

David Kelsen

81 Lower Gastrointestinal Cancers..................................... 636

Robert J. Mayer

82 Tumors of the Liver and Biliary Tree .............................. 643

Josep M. Llovet

83 Pancreatic Cancer ..........................................................657

Daniel D. Von Hoff

84 Gastrointestinal Neuroendocrine Tumors....................... 663

Matthew H. Kulke

85 Renal Cell Carcinoma ....................................................673

Robert J. Motzer, Martin H. Voss

86 Cancer of the Bladder and Urinary Tract......................... 676

Noah M. Hahn

87 Benign and Malignant Diseases of the Prostate............... 681

Howard I. Scher, James A. Eastham

88 Testicular Cancer...........................................................689

David J. Vaughn

89 Gynecologic Malignancies .............................................695

David Spriggs

90 Primary and Metastatic Tumors of the

Nervous System .............................................................701

Lisa M. DeAngelis, Patrick Y. Wen

91 Soft Tissue and Bone Sarcomas and

Bone Metastases............................................................712

Shreyaskumar R. Patel

CONTENTS viii 92 Carcinoma of Unknown Primary.................................... 716

Kanwal Raghav, James L. Abbruzzese, Gauri R. Varadhachary

93 Paraneoplastic Syndromes: Endocrinologic/

Hematologic ..................................................................721

J. Larry Jameson, Dan L. Longo

94 Paraneoplastic Neurologic Syndromes and

Autoimmune Encephalitis..............................................728

Josep Dalmau, Myrna R. Rosenfeld, Francesc Graus

95 Cancer Survivorship and the Long-Term Impact

of Cancer and Its Treatment...........................................736

Mark Roschewski, Dan L. Longo

SECTION 2  Hematopoietic Disorders

96 Hematopoietic Stem Cells..............................................743

David T. Scadden, Dan L. Longo

97 Iron Deficiency and Other Hypoproliferative

Anemias ........................................................................747

John W. Adamson

98 Disorders of Hemoglobin...............................................754

Martin H. Steinberg

99 Megaloblastic Anemias..................................................766

A. Victor Hoffbrand

100 Hemolytic Anemias .......................................................776

Lucio Luzzatto, Lucia De Franceschi

101 Anemia Due to Acute Blood Loss .................................. 791

Dan L. Longo

102 Bone Marrow Failure Syndromes Including

Aplastic Anemia and Myelodysplasia.............................. 792

Neal S. Young

103 Polycythemia Vera and Other Myeloproliferative

Neoplasms.....................................................................802

Jerry L. Spivak

104 Acute Myeloid Leukemia ...............................................809

William Blum

105 Chronic Myeloid Leukemia............................................ 818

Hagop Kantarjian, Elias Jabbour, Jorge Cortes

106 Acute Lymphoid Leukemia............................................ 828

Dieter Hoelzer

107 Chronic Lymphocytic Leukemia .................................... 834

Jennifer A. Woyach, John C. Byrd

108 Non-Hodgkin’s Lymphoma ........................................... 841

Caron A. Jacobson, Dan L. Longo

109 Hodgkin’s Lymphoma....................................................852

Caron A. Jacobson, Dan L. Longo

110 Less Common Lymphoid and Myeloid

Malignancies .................................................................855

Ayalew Tefferi, Dan L. Longo

111 Plasma Cell Disorders....................................................866

Nikhil C. Munshi, Dan L. Longo, Kenneth C. Anderson

112 Amyloidosis...................................................................878

John L. Berk, Vaishali Sanchorawala

113 Transfusion Therapy and Biology...................................884

Pierre Tiberghien, Olivier Garraud, Jacques Chiaroni

114 Hematopoietic Cell Transplantation............................... 897

Frederick R. Appelbaum

SECTION 3 Disorders of Hemostasis

115 Disorders of Platelets and Vessel Wall............................. 903

Barbara A. Konkle

116 Coagulation Disorders...................................................910

Jean M. Connors

117 Arterial and Venous Thrombosis....................................919

Jane E. Freedman, Joseph Loscalzo

118 Antiplatelet, Anticoagulant, and Fibrinolytic

Drugs............................................................................924

Jeffrey I. Weitz

PART 5 Infectious Diseases

SECTION 1 Basic Considerations in Infectious Diseases

119 Approach to the Patient with an Infectious Disease......... 941

Neeraj K. Surana, Dennis L. Kasper

120 Molecular Mechanisms of Microbial Pathogenesis.......... 948

Thomas E. Wood, Marcia B. Goldberg

121 Microbial Genomics and Infectious Disease ................... 960

Roby P. Bhattacharyya, Yonatan H. Grad, Deborah T. Hung

122 Approach to the Acutely Ill Infected Febrile Patient........ 973

Tamar F. Barlam

123 Immunization Principles and Vaccine Use ...................... 981

Sarah Mbaeyi, Amanda Cohn, Nancy Messonnier

124 Health Recommendations for International Travel ......... 989

Jesse Waggoner, Henry M. Wu

125 Climate Change and Infectious Disease........................ 1001

Aaron S. Bernstein

SECTION 2 Clinical Syndromes:

Community-Acquired Infections

126 Pneumonia .................................................................. 1009

Lionel A. Mandell, Michael S. Niederman

127 Lung Abscess............................................................... 1020

Rebecca M. Baron, Beverly W. Baron, Miriam Baron Barshak

128 Infective Endocarditis.................................................. 1022

Sara E. Cosgrove, Adolf W. Karchmer

129 Infections of the Skin, Muscles, and Soft Tissues.......... 1034

Dennis L. Stevens, Amy E. Bryant

130 Infectious Arthritis ...................................................... 1040

Lawrence C. Madoff, Nongnooch Poowanawittayakom

131 Osteomyelitis............................................................... 1046

Werner Zimmerli

132 Intraabdominal Infections and Abscesses ..................... 1054

Miriam Baron Barshak, Dennis L. Kasper

133 Acute Infectious Diarrheal Diseases and Bacterial

Food Poisoning............................................................ 1061

Richelle C. Charles, Regina C. LaRocque

134 Clostridioides diff icile Infection, Including

Pseudomembranous Colitis.......................................... 1066

Dale N. Gerding, Stuart Johnson

135 Urinary Tract Infections, Pyelonephritis, and

Prostatitis .................................................................... 1070

Kalpana Gupta, Barbara W. Trautner

136 Sexually Transmitted Infections: Overview and

Clinical Approach........................................................ 1078

Jeanne M. Marrazzo, King K. Holmes

137 Encephalitis................................................................. 1094

Karen L. Roos, Michael R. Wilson, Kenneth L. Tyler

138 Acute Meningitis......................................................... 1100

Karen L. Roos, Kenneth L. Tyler