21st Edition ® P R I N C I P L E S O F I N T E R N A L M E D I C I N E HPIM 21e_FM_VOL1_pi-pxl.indd 1 21/01/22 7:01 PM Editors of Previous Editions T. R. Harrison J. D. Wilson Editor-in-Chief, Editions 1, 2, 3, 4, 5 Editor, Editions 9, 10, 11, 13, 14 Editor-in-Chief, Edition 12 W. R. Resnick Editor, Editions 1, 2, 3, 4, 5 J. B. Martin Editor, Editions 10, 11, 12, 13, 14 M. M. Wintrobe Editor, Editions 1, 2, 3, 4, 5 A. S. Fauci Editor-in-Chief, Editions 6, 7 Editor, Editions 11, 12, 13, 15, 16, 18, 19, 20, 21 Editor-in-Chief, Editions 14, 17 G. W. Thorn Editor, Editions 1, 2, 3, 4, 5, 6, 7 R. Root Editor-in-Chief, Edition 8 Editor, Edition 12 R. D. Adams D. L. Kasper Editor, Editions 2, 3, 4, 5, 6, 7, 8, 9, 10 Editor, Editions 13, 14, 15, 17, 18, 20, 21 Editor-in-Chief, Editions 16, 19 P. B. Beeson Editor, Editions 1, 2 S. L. Hauser Editor, Editions 14, 15, 16, 17, 18, 19, 20, 21 I. L. Bennett, Jr. Editor, Editions 3, 4, 5, 6 D. L. Longo Editor, Editions 14, 15, 16, 17, 19, 20, 21 E. Braunwald Editor-in-Chief, Edition 18 Editor, Editions 6, 7, 8, 9, 10, 12, 13, 14, 16, 17 Editor-in-Chief, Editions 11, 15 J. L. Jameson Editor, Editions 15, 16, 17, 18, 19, 21 K. J. Isselbacher Editor-in-Chief, Edition 20 Editor, Editions 6, 7, 8, 10, 11, 12, 14 Editor-in-Chief, Editions 9, 13 J. Loscalzo Editor, Editions 17, 18, 19, 20 R. G. Petersdorf Editor-in-Chief, Edition 21 Editor, Editions 6, 7, 8, 9, 11, 12 Editor-in-Chief, Edition 10 HPIM 21e_FM_VOL1_pi-pxl.indd 2 21/01/22 7:01 PM 21st Edition ® P R I N C I P L E S O F I N T E R N A L M E D I C I N E Editors Joseph Loscalzo, MD, PhD Anthony S. Fauci, MD Hersey Professor of the Theory and Practice of Medicine, Harvard Chief, Laboratory of Immunoregulation; Director, National Institute Medical School; Chairman, Department of Medicine; Soma Weiss MD of Allergy and Infectious Diseases, National Institutes of Health, Distinguished Chair in Medicine; Physician-in-Chief, Brigham Bethesda, Maryland and Women’s Hospital, Boston, Massachusetts Stephen L. Hauser, MD Dennis L. Kasper, MD Robert A. Fishman Distinguished Professor, Department of William Ellery Channing Professor of Medicine and Professor of Neurology; Director, UCSF Weill Institute for Neurosciences, Immunology, Department of Immunology, Harvard Medical School; University of California, San Francisco, San Francisco, California Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts J. Larry Jameson, MD, PhD Robert G. Dunlop Professor of Medicine; Dean, Raymond and Ruth Dan L. Longo, MD Perelman School of Medicine; Executive Vice President, University of Professor of Medicine, Harvard Medical School; Senior Physician, Pennsylvania for the Health System, Philadelphia, Pennsylvania Brigham and Women’s Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts VOLUME I New York Chicago San Francisco Athens London Madrid Mexico City New Delhi Milan Singapore Sydney Toronto HPIM 21e_FM_VOL1_pi-pxl.indd 3 21/01/22 7:01 PM Copyright © 2022 by McGraw Hill LLC. Previous editions copyright © 2018, 2015 by McGraw-Hill Education; 2012, 2008, 2005, 2001, 1998, 1994, 1991, 1987, 1983, 1980, 1977, 1974, 1970, 1966, 1962, 1958 by The McGraw-Hill Companies, Inc. All rights re- served. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. 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HPIM 21e_FM_VOL1_pi-pxl.indd 5 21/01/22 7:01 PM Contents Contributors ............................................................................xviii SECTION 3  Nervous System Dysfunction Preface ....................................................................................xxxix 21 Syncope .........................................................................152 Harrison’s Related Resources ........................................................xl Roy Freeman 22 Dizziness and Vertigo.....................................................159 PART 1 The Profession of Medicine Mark F. Walker, Robert B. Daroff 23 Fatigue ..........................................................................162 1 The Practice of Medicine ...................................................1 Jeffrey M. Gelfand, Vanja C. Douglas The Editors 24 Neurologic Causes of Weakness and Paralysis .................165 2 Promoting Good Health ....................................................8 Stephen L. Hauser Donald M. Lloyd-Jones, Kathleen M. McKibbin 25 Numbness, Tingling, and Sensory Loss ..........................168 3 Vaccine Opposition and Hesitancy ...................................13 Stephen L. Hauser Julie A. Bettinger, Hana Mitchell 26 Gait Disorders, Imbalance, and Falls ..............................173 4 Decision-Making in Clinical Medicine.............................21 Jessica M. Baker Daniel B. Mark, John B. Wong 27 Confusion and Delirium ................................................178 5 Precision Medicine and Clinical Care ...............................30 S. Andrew Josephson, Bruce L. Miller The Editors 28 Coma.............................................................................183 6 Screening and Prevention of Disease ................................37 S. Andrew Josephson, Allan H. Ropper, Stephen L. Hauser Katrina A. Armstrong, Gary J. Martin 29 Dementia .......................................................................189 7 Global Diversity of Health System Financing William W. Seeley, Gil D. Rabinovici, Bruce L. Miller and Delivery ....................................................................42 Richard B. Saltman 30 Aphasia, Memory Loss, and Other Cognitive Disorders .......................................................................195 8 The Safety and Quality of Health Care .............................50 M.-Marsel Mesulam David W. Bates 31 Sleep Disorders ..............................................................204 9 Diagnosis: Reducing Errors and Improving Quality..........54 Thomas E. Scammell, Clifford B. Saper, Charles A. Czeisler Gordon Schiff 10 Racial and Ethnic Disparities in Health Care ....................59 SECTION 4  Disorders of Eyes, Ears, Nose, and Throat Lenny López, Joseph R. Betancourt 32 Disorders of the Eye .......................................................215 11 Ethical Issues in Clinical Medicine ...................................67 Jonathan C. Horton Christine Grady, Bernard Lo 33 Disorders of Smell and Taste ..........................................232 12 Palliative and End-of-Life Care .......................................72 Richard L. Doty, Steven M. Bromley Ezekiel J. Emanuel 34 Disorders of Hearing......................................................238 Anil K. Lalwani PART 2 Cardinal Manifestations and 35 Upper Respiratory Symptoms, Including Earache, Presentation of Diseases Sinus Symptoms, and Sore Throat ..................................247 Rachel L. Amdur, Jeffrey A. Linder SECTION 1  Pain 36 Oral Manifestations of Disease ......................................256 Samuel C. Durso 13 Pain: Pathophysiology and Management ..........................91 James P. Rathmell, Howard L. Fields SECTION 5  Alterations in Circulatory and Respiratory Functions 14 Chest Discomfort ..........................................................100 David A. Morrow 37 Dyspnea ........................................................................263 15 Abdominal Pain .............................................................108 Rebecca M. Baron Danny O. Jacobs 38 Cough ...........................................................................267 16 Headache .......................................................................112 Christopher H. Fanta Peter J. Goadsby 39 Hemoptysis ...................................................................270 17 Back and Neck Pain .......................................................117 Carolyn M. D’Ambrosio John W. Engstrom 40 Hypoxia and Cyanosis ....................................................272 Joseph Loscalzo SECTION 2  Alterations in Body Temperature 41 Edema ...........................................................................275 18 Fever .............................................................................130 Joseph Loscalzo Neeraj K. Surana, Charles A. Dinarello, Reuven Porat 42 Approach to the Patient with a Heart Murmur ...............278 19 Fever and Rash ..............................................................133 Patrick T. O’Gara, Joseph Loscalzo Elaine T. Kaye, Kenneth M. Kaye 43 Palpitations ....................................................................286 20 Fever of Unknown Origin ..............................................145 Joseph Loscalzo Chantal P. Bleeker-Rovers, Catharina M. Mulders-Manders, Jos W. M. van der Meer HPIM 21e_FM_VOL1_pi-pxl.indd 6 21/01/22 7:01 PM vii SECTION 6  Alterations in Gastrointestinal Function PART 3 Pharmacology 44 Dysphagia......................................................................287 Ikuo Hirano, Peter J. Kahrilas 67 Principles of Clinical Pharmacology ...............................465 Dan M. Roden 45 Nausea, Vomiting, and Indigestion .................................291 C William L. Hasler 68 Pharmacogenomics ........................................................474 O Dan M. Roden N T 46 Diarrhea and Constipation .............................................297 E Michael Camilleri, Joseph A. Murray N PART 4 Oncology and Hematology TS 47 Unintentional Weight Loss ............................................309 J. Larry Jameson SECTION 1  Neoplastic Disorders 48 Gastrointestinal Bleeding ...............................................311 Loren Laine 69 Approach to the Patient with Cancer ..............................481 49 Jaundice .........................................................................315 Dan L. Longo Savio John, Daniel S. Pratt 70 Prevention and Early Detection of Cancer ......................490 50 Abdominal Swelling and Ascites ....................................321 Jennifer M. Croswell, Otis W. Brawley, Lawrence S. Friedman Barnett S. Kramer SECTION 7  Alterations in Renal and Urinary Tract 71 Cancer Genetics.............................................................498 Fred Bunz, Bert Vogelstein Function 72 Cancer Cell Biology .......................................................508 51 Interstitial Cystitis/Bladder Pain Syndrome ....................325 Jeffrey W. Clark, Dan L. Longo R. Christopher Doiron, J. Curtis Nickel 73 Principles of Cancer Treatment ......................................529 52 Azotemia and Urinary Abnormalities .............................331 Edward A. Sausville, Dan L. Longo David B. Mount 74 Infections in Patients with Cancer ..................................556 53 Fluid and Electrolyte Disturbances ................................338 Robert W. Finberg David B. Mount 75 Oncologic Emergencies ..................................................565 54 Hypercalcemia and Hypocalcemia ..................................356 Rasim Gucalp, Janice P. Dutcher Sundeep Khosla 76 Cancer of the Skin..........................................................578 55 Acidosis and Alkalosis ....................................................359 Brendan D. Curti, John T. Vetto, Sancy A. Leachman Thomas D. DuBose, Jr. 77 Head and Neck Cancer ..................................................590 Everett E. Vokes SECTION 8  Alterations in the Skin 78 Neoplasms of the Lung ..................................................594 56 Approach to the Patient with a Skin Disorder .................369 Leora Horn, Wade T. Iams Kim B. Yancey, Thomas J. Lawley 79 Breast Cancer ................................................................611 57 Eczema, Psoriasis, Cutaneous Infections, Acne, Daniel F. Hayes, Marc E. Lippman and Other Common Skin Disorders ...............................374 Leslie P. Lawley, Justin T. Cheeley, Robert A. Swerlick 80 Upper Gastrointestinal Tract Cancers .............................626 David Kelsen 58 Skin Manifestations of Internal Disease .........................383 Jean L. Bolognia, Jonathan S. Leventhal, Irwin M. Braverman 81 Lower Gastrointestinal Cancers .....................................636 Robert J. Mayer 59 Immunologically Mediated Skin Diseases ......................400 Kim B. Yancey, Benjamin F. Chong, Thomas J. Lawley 82 Tumors of the Liver and Biliary Tree ..............................643 Josep M. Llovet 60 Cutaneous Drug Reactions ............................................407 Robert G. Micheletti, Misha Rosenbach, 83 Pancreatic Cancer ..........................................................657 Daniel D. Von Hoff Bruce U. Wintroub, Kanade Shinkai 84 Gastrointestinal Neuroendocrine Tumors .......................663 61 Photosensitivity and Other Reactions to Sunlight ...........417 Matthew H. Kulke Alexander G. Marneros, David R. Bickers 85 Renal Cell Carcinoma ....................................................673 SECTION 9  Hematologic Alterations Robert J. Motzer, Martin H. Voss 62 Interpreting Peripheral Blood Smears .............................424 86 Cancer of the Bladder and Urinary Tract .........................676 Dan L. Longo Noah M. Hahn 63 Anemia and Polycythemia ..............................................431 87 Benign and Malignant Diseases of the Prostate ...............681 John W. Adamson, Dan L. Longo Howard I. Scher, James A. Eastham 64 Disorders of Granulocytes and Monocytes .....................439 88 Testicular Cancer ...........................................................689 Steven M. Holland, John I. Gallin David J. Vaughn 65 Bleeding and Thrombosis ...............................................450 89 Gynecologic Malignancies .............................................695 Barbara A. Konkle David Spriggs 66 Enlargement of Lymph Nodes and Spleen ......................457 90 Primary and Metastatic Tumors of the Dan L. Longo Nervous System .............................................................701 Lisa M. DeAngelis, Patrick Y. Wen 91 Soft Tissue and Bone Sarcomas and Bone Metastases ............................................................712 Shreyaskumar R. Patel HPIM 21e_FM_VOL1_pi-pxl.indd 7 21/01/22 7:01 PM viii 92 Carcinoma of Unknown Primary ....................................716 Kanwal Raghav, James L. Abbruzzese, Gauri R. Varadhachary 116 Coagulation Disorders ...................................................910 Jean M. Connors 93 Paraneoplastic Syndromes: Endocrinologic/ 117 Arterial and Venous Thrombosis ....................................919 Hematologic ..................................................................721 Jane E. Freedman, Joseph Loscalzo J. Larry Jameson, Dan L. Longo C O 118 Antiplatelet, Anticoagulant, and Fibrinolytic N 94 Paraneoplastic Neurologic Syndromes and T Drugs ............................................................................924 E Autoimmune Encephalitis ..............................................728 Jeffrey I. Weitz N Josep Dalmau, Myrna R. Rosenfeld, Francesc Graus T S 95 Cancer Survivorship and the Long-Term Impact PART 5 Infectious Diseases of Cancer and Its Treatment ...........................................736 Mark Roschewski, Dan L. Longo SECTION 1  Basic Considerations in Infectious Diseases SECTION 2  Hematopoietic Disorders 119 Approach to the Patient with an Infectious Disease .........941 96 Hematopoietic Stem Cells ..............................................743 Neeraj K. Surana, Dennis L. Kasper David T. Scadden, Dan L. Longo 120 Molecular Mechanisms of Microbial Pathogenesis ..........948 97 Iron Deficiency and Other Hypoproliferative Thomas E. Wood, Marcia B. Goldberg Anemias ........................................................................747 John W. Adamson 121 Microbial Genomics and Infectious Disease ...................960 Roby P. Bhattacharyya, Yonatan H. Grad, Deborah T. Hung 98 Disorders of Hemoglobin ...............................................754 Martin H. Steinberg 122 Approach to the Acutely Ill Infected Febrile Patient ........973 Tamar F. Barlam 99 Megaloblastic Anemias ..................................................766 A. Victor Hoffbrand 123 Immunization Principles and Vaccine Use ......................981 Sarah Mbaeyi, Amanda Cohn, Nancy Messonnier 100 Hemolytic Anemias .......................................................776 Lucio Luzzatto, Lucia De Franceschi 124 Health Recommendations for International Travel .........989 Jesse Waggoner, Henry M. Wu 101 Anemia Due to Acute Blood Loss ..................................791 Dan L. Longo 125 Climate Change and Infectious Disease ........................1001 Aaron S. Bernstein 102 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia ..............................792 SECTION 2  Clinical Syndromes: Neal S. Young Community-Acquired Infections 103 Polycythemia Vera and Other Myeloproliferative 126 Pneumonia ..................................................................1009 Neoplasms .....................................................................802 Lionel A. Mandell, Michael S. Niederman Jerry L. Spivak 127 Lung Abscess ...............................................................1020 104 Acute Myeloid Leukemia ...............................................809 Rebecca M. Baron, Beverly W. Baron, Miriam Baron Barshak William Blum 128 Infective Endocarditis ..................................................1022 105 Chronic Myeloid Leukemia ............................................818 Sara E. Cosgrove, Adolf W. Karchmer Hagop Kantarjian, Elias Jabbour, Jorge Cortes 129 Infections of the Skin, Muscles, and Soft Tissues ..........1034 106 Acute Lymphoid Leukemia ............................................828 Dennis L. Stevens, Amy E. Bryant Dieter Hoelzer 130 Infectious Arthritis ......................................................1040 107 Chronic Lymphocytic Leukemia ....................................834 Lawrence C. Madoff, Nongnooch Poowanawittayakom Jennifer A. Woyach, John C. Byrd 131 Osteomyelitis ...............................................................1046 108 Non-Hodgkin’s Lymphoma ...........................................841 Werner Zimmerli Caron A. Jacobson, Dan L. Longo 132 Intraabdominal Infections and Abscesses .....................1054 109 Hodgkin’s Lymphoma ....................................................852 Miriam Baron Barshak, Dennis L. Kasper Caron A. Jacobson, Dan L. Longo 133 Acute Infectious Diarrheal Diseases and Bacterial 110 Less Common Lymphoid and Myeloid Food Poisoning ............................................................1061 Malignancies .................................................................855 Richelle C. Charles, Regina C. LaRocque Ayalew Tefferi, Dan L. Longo 134 Clostridioides difficile Infection, Including 111 Plasma Cell Disorders ....................................................866 Nikhil C. Munshi, Dan L. Longo, Kenneth C. Anderson Pseudomembranous Colitis ..........................................1066 Dale N. Gerding, Stuart Johnson 112 Amyloidosis ...................................................................878 John L. Berk, Vaishali Sanchorawala 135 Urinary Tract Infections, Pyelonephritis, and Prostatitis ....................................................................1070 113 Transfusion Therapy and Biology ...................................884 Kalpana Gupta, Barbara W. Trautner Pierre Tiberghien, Olivier Garraud, Jacques Chiaroni 136 Sexually Transmitted Infections: Overview and 114 Hematopoietic Cell Transplantation ...............................897 Clinical Approach ........................................................1078 Frederick R. Appelbaum Jeanne M. Marrazzo, King K. Holmes SECTION 3  Disorders of Hemostasis 137 Encephalitis .................................................................1094 Karen L. Roos, Michael R. Wilson, Kenneth L. Tyler 115 Disorders of Platelets and Vessel Wall .............................903 138 Acute Meningitis .........................................................1100 Barbara A. Konkle Karen L. Roos, Kenneth L. Tyler HPIM 21e_FM_VOL1_pi-pxl.indd 8 21/01/22 7:01 PM ix 139 Chronic and Recurrent Meningitis ...............................1110 163 Helicobacter pylori Infections .........................................1279 Avindra Nath, Walter J. Koroshetz, Michael R. Wilson John C. Atherton, Martin J. Blaser 140 Brain Abscess and Empyema ........................................1117 164 Infections Due to Pseudomonas, Burkholderia, and Karen L. Roos, Kenneth L. Tyler Stenotrophomonas Species .............................................1284 Reuben Ramphal 141 Infectious Complications of Bites .................................1124 C Sandeep S. Jubbal, Florencia Pereyra Segal, Lawrence C. Madoff O 165 Salmonellosis ...............................................................1291 N David A. Pegues, Samuel I. Miller T E SECTION 3  Clinical Syndromes: Health N 166 Shigellosis ....................................................................1298 T Care–Associated Infections S Philippe J. Sansonetti, Jean Bergounioux 142 Infections Acquired in Health Care Facilities ................1128 167 Infections Due to Campylobacter and Related Robert A. Weinstein Organisms ...................................................................1302 Martin J. Blaser 143 Infections in Transplant Recipients ..............................1136 Robert W. Finberg 168 Cholera and Other Vibrioses ........................................1305 Matthew K. Waldor, Edward T. Ryan SECTION 4  Therapy for Bacterial Diseases 169 Brucellosis ...................................................................1310 Nicholas J. Beeching 144 Treatment and Prophylaxis of Bacterial Infections ........1148 David C. Hooper, Erica S. Shenoy, Ramy H. Elshaboury 170 Tularemia ....................................................................1314 Max Maurin, Didier Raoult 145 Bacterial Resistance to Antimicrobial Agents................1163 David C. Hooper 171 Plague and Other Yersinia Infections ............................1320 Michael B. Prentice SECTION 5  Diseases Caused by Gram-Positive Bacteria 172 Bartonella Infections, Including Cat-Scratch 146 Pneumococcal Infections ..............................................1169 Disease ........................................................................1328 David Goldblatt, Katherine L. O’Brien Michael Giladi, Moshe Ephros 147 Staphylococcal Infections .............................................1178 173 Donovanosis ................................................................1334 Franklin D. Lowy Nigel O’Farrell 148 Streptococcal Infections ...............................................1188 SECTION 7  Miscellaneous Bacterial Infections Michael R. Wessels 149 Enterococcal Infections ................................................1197 174 Nocardiosis ..................................................................1335 William R. Miller, Cesar A. Arias, Barbara E. Murray Gregory A. Filice 150 Diphtheria and Other Corynebacterial Infections .........1203 175 Actinomycosis ..............................................................1340 William R. Bishai, John R. Murphy Thomas A. Russo 151 Listeria monocytogenes Infections ...................................1208 176 Whipple’s Disease ........................................................1344 Jennifer P. Collins, Patricia M. Griffin Thomas A. Russo, Seth R. Glassman 152 Tetanus ........................................................................1211 177 Infections Due to Mixed Anaerobic Organisms ............1347 C. Louise Thwaites, Lam Minh Yen Neeraj K. Surana, Dennis L. Kasper 153 Botulism ......................................................................1214 SECTION 8  Mycobacterial Diseases Carolina Lúquez, Jeremy Sobel 154 Gas Gangrene and Other Clostridial Infections ............1220 178 Tuberculosis .................................................................1357 Amy E. Bryant, Dennis L. Stevens Mario C. Raviglione, Andrea Gori 179 Leprosy ........................................................................1382 SECTION 6  Diseases Caused by Gram-Negative Bacteria Jan H. Richardus, Hemanta K. Kar, Zoica Bakirtzief, Wim H. van Brakel 155 Meningococcal Infections ............................................1225 Manish Sadarangani, Andrew J. Pollard 180 Nontuberculous Mycobacterial Infections ....................1392 Steven M. Holland 156 Gonococcal Infections .................................................1234 Sanjay Ram, Peter A. Rice 181 Antimycobacterial Agents ............................................1397 Divya Reddy, Sebastian G. Kurz, Max R. O’Donnell 157 Haemophilus and Moraxella Infections ...........................1241 Timothy F. Murphy SECTION 9  Spirochetal Diseases 158 Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria ........................1246 182 Syphilis ........................................................................1406 Tamar F. Barlam Sheila A. Lukehart 159 Legionella Infections .....................................................1249 183 Endemic Treponematoses ............................................1413 Steven A. Pergam, Thomas R. Hawn Sheila A. Lukehart, Lorenzo Giacani 160 Pertussis and Other Bordetella Infections ......................1257 184 Leptospirosis ...............................................................1417 Karina A. Top, Scott A. Halperin Jiři F. P. Wagenaar, Marga G.A. Goris 161 Diseases Caused by Gram-Negative Enteric 185 Relapsing Fever and Borrelia miyamotoi Disease ............1421 Alan G. Barbour Bacilli ..........................................................................1261 Thomas A. Russo, James R. Johnson 186 Lyme Borreliosis ..........................................................1425 Allen C. Steere 162 Acinetobacter Infections ................................................1275 Rossana Rosa, L. Silvia Munoz-Price HPIM 21e_FM_VOL1_pi-pxl.indd 9 21/01/22 7:01 PM