1. Cover 1 / 7122 2. Contents 1Cover .................................................................................................................................................. 2Preface: Harrison's Principles of Internal Medicine, 18e ......................... 4Copyright: Harrison's Principles of Internal Medicine, 18e .................... 5Contributors: Harrison's Principles of Internal Medicine, 18e ............. 49Part 1. Introduction to Clinical Medicine ............................................................. 49Chapter 1. The Practice of Medicine ............................................................................. 65Chapter 2. Global Issues in Medicine ........................................................................... 86Chapter 3. Decision-Making in Clinical Medicine ..................................................... 104Chapter 4. Screening and Prevention of Disease ................................................ 114Chapter 5. Principles of Clinical Pharmacology ..................................................... 141Chapter 6. Women's Health ........................................................................................... 147Chapter 7. Medical Disorders During Pregnancy .................................................. 161Chapter 8. Medical Evaluation of the Surgical Patient ....................................... 168Chapter 9. Palliative and End-of-Life Care .............................................................. 209Chapter 10. The Safety and Quality of Health Care ............................................ 221Chapter e1. Primary Care in Low- and Middle-Income Countries ................. 231Chapter e2. Complementary, Alternative, and Integrative Medicine ............ 242Chapter e3. The Economics of Medical Care ......................................................... 249Chapter e4. Racial and Ethnic Disparities in Health Care ................................ 258Chapter e5. Ethical Issues in Clinical Medicine ..................................................... 267Chapter e6. Neoplasia During Pregnancy ................................................................ 275Part 2. Cardinal Manifestations and Presentation of Diseases .... 275Section 1. Pain ..................................................................................................................... 275Chapter 11. Pain: Pathophysiology and Management ........................................... 293Chapter 12. Chest Discomfort ...................................................................................... 300Chapter 13. Abdominal Pain ......................................................................................... 310Chapter 14. Headache .................................................................................................... 341Chapter 15. Back and Neck Pain ................................................................................. 373Section 2. Alterations in Body Temperature ............................................................ 373Chapter 16. Fever and Hyperthermia ......................................................................... 384Chapter 17. Fever and Rash ......................................................................................... 401Chapter e7. Atlas of Rashes Associated With Fever .............................................. 448Chapter 18. Fever of Unknown Origin ........................................................................ 463Chapter 19. Hypothermia and Frostbite ..................................................................... 3. 472Section 3. Nervous System Dysfunction .................................................................. 472Chapter 20. Syncope ...................................................................................................... 480Chapter 21. Dizziness and Vertigo .............................................................................. 488Chapter 22. Weakness and Paralysis ........................................................................ 497Chapter 23. Numbness, Tingling, and Sensory Loss ............................................. 504Chapter 24. Gait and Balance Disorders ................................................................... 514Chapter e8. Video Library of Gait Disorders ............................................................. 515Chapter 25. Confusion and Delirium .......................................................................... 527Chapter 26. Aphasia, Memory Loss, and Other Focal Cerebral Disorders ...... 552Chapter e9. Memory Loss ............................................................................................. 560Chapter e10. Primary Progressive Aphasia, Memo ................................................ 561Chapter 27. Sleep Disorders ......................................................................................... 577Section 4. Disorders of Eyes, Ears, Nose, and Throat ....................................... 577Chapter 28. Disorders of the Eye ................................................................................ 611Chapter e11. Video Library of Neuro-Ophthalmology ............................................. 694Chapter 29. Disorders of Smell and Taste ................................................................ 704Chapter 30. Disorders of Hearing ................................................................................ 712Chapter 31. Pharyngitis, Sinusitis, Otitis, an ............................................................ 738Chapter 32. Oral Manifestations of Disease ............................................................. 756Chapter e12. Atlas of Oral Manifestations of Disease ........................................... 775Section 5. Alterations in Circulatory and Respiratory Functions .................... 775Chapter 33. Dyspnea ...................................................................................................... 784Chapter 34. Cough and Hemoptysis ........................................................................... 789Chapter 35. Hypoxia and Cyanosis ............................................................................. 797Chapter 36. Edema ......................................................................................................... 808Chapter e13. Approach to the Patient with a Heart Murmur ................................. 824Chapter 37. Palpitations ................................................................................................ 827Section 6. Alterations in Gastrointestinal Function ............................................... 827Chapter 38. Dysphagia ................................................................................................... 831Chapter 39. Nausea, Vomiting, and Indigestion ...................................................... 845Chapter 40. Diarrhea and Constipation ..................................................................... 867Chapter 41. Gastrointestinal Bleeding ....................................................................... 873Chapter 42. Jaundice ...................................................................................................... 883Chapter 43. Abdominal Swelling and Ascites ........................................................... 891Section 7. Alterations in Renal and Urinary Tract Function .............................. 891Chapter 44. Azotemia and Urinary Abnormalities ................................................... 904Chapter e14. Atlas of Urinary Sediments and Renal Biopsies ............................. 940Chapter 45. Fluid and Electrolyte Disturbances ...................................................... 4. 960Chapter e15. Fluid and Electrolyte Imbalances ...................................................... 985Chapter 46. Hypercalcemia and Hypocalcemia ....................................................... 993Chapter 47. Acidosis and Alkalosis ............................................................................. 1018Section 8. Alterations in Sexual Function and Reproduction ........................ 1018Chapter 48. Sexual Dysfunction ............................................................................... 1034Chapter 49. Hirsutism and Virilization ..................................................................... 1041Chapter 50. Menstrual Disorders and Pelvic Pain ............................................... 1047Section 9. Alterations in the Skin .............................................................................. 1047Chapter 51. Approach to the Patient with a Skin Disorder ................................. 1065Chapter 52. Eczema, Psoriasis, Cutaneous Infe .................................................. 1088Chapter 53. Skin Manifestations of Internal Disease .......................................... 1125Chapter 54. Immunologically Mediated Skin Diseases ....................................... 1145Chapter 55. Cutaneous Drug Reactions ................................................................. 1164Chapter 56. Photosensitivity and Other Reactions to Light ............................... 1181Chapter e16. Atlas of Skin Manifestations of Internal Disease ......................... 1246Section 10. Hematologic Alterations ....................................................................... 1246Chapter 57. Anemia and Polycythemia ................................................................... 1273Chapter 58. Bleeding and Thrombosis .................................................................... 1289Chapter 59. Enlargement of Lymph Nodes and Spleen ..................................... 1305Chapter 60. Disorders of Granulocytes and Monocytes ..................................... 1324Chapter e17. Atlas of Hematology and Analysis .................................................. 1364Part 3. Genes, the Environment, and Disease .................................................. 1364Chapter 61. Principles of Human Genetics ............................................................ 1396Chapter 62. Chromosome Disorders ....................................................................... 1409Chapter 63. The Practice of Genetics in Clinical Medicine ................................ 1426Chapter e18. Mitochondrial DNA and Heritable Traits and Diseases .............. 1441Chapter 64. The Human Microbiome ...................................................................... 1457Chapter e19. Systems Biology in Health and Disease ....................................... 1463Part 4. Regenerative Medicine .................................................................................. 1463Chapter 65. Stem Cell Biology .................................................................................. 1471Chapter 66. Hematopoietic Stem Cells ................................................................... 1476Chapter 67. Applications of Stem Cell Biology in Clinical Medicine ................ 1483Chapter 68. Gene Therapy in Clinical Medicine ................................................... 1489Chapter 69. Tissue Engineering ................................................................................ 1495Part 5. Aging ...................................................................................................................... 1495Chapter 70. World Demography of Aging .............................................................. 1508Chapter 71. The Biology of Aging ............................................................................. 1526Chapter 72. Clinical Problems of Aging .................................................................. 5. 1554Part 6. Nutrition ................................................................................................................. 1554Chapter 73. Nutrient Requirements and Dietary Assessment ........................... 1560Chapter 74. Vitamin and Trace Mineral Deficiency and Excess ....................... 1578Chapter 75. Malnutrition and Nutritional Assessment ......................................... 1593Chapter 76. Enteral and Parenteral Nutrition Therapy ........................................ 1609Chapter 77. Biology of Obesity ................................................................................. 1622Chapter 78. Evaluation and Management of Obesity ......................................... 1633Chapter 79. Eating Disorders .................................................................................... 1644Chapter 80. Involuntary Weight Loss ...................................................................... 1650Part 7. Oncology and Hematology ........................................................................... 1650Section 1. Neoplastic Disorders ................................................................................ 1650Chapter 81. Approach to the Patient with Cancer ........................................................ 1662Chapter 82. Prevention and Early Detection of Cancer ............................................... 1680Chapter 83. Cancer Genetics ...................................................................................... 1690Chapter 84. Cancer Cell Biology and Angiogenesis .................................................... 1710Chapter 85. Principles of Cancer Treatment ............................................................... 1748Chapter 86. Infections in Patients with Cancer ........................................................... 1769Chapter 87. Cancer of the Skin ................................................................................... 1779Chapter 88. Head and Neck Cancer ........................................................................... 1788Chapter 89. Neoplasms of the Lung ............................................................................ 1805Chapter 90. Breast Cancer .......................................................................................... 1827Chapter 91. Gastrointestinal Tract Cancer .................................................................. 1846Chapter 92. Tumors of the Liver and Biliary Tree ........................................................ 1857Chapter 93. Pancreatic Cancer ................................................................................... 1865Chapter 94. Bladder and Renal Cell Carcinomas ........................................................ 1869Chapter 95. Benign and Malignant Diseases of the Prostate ...................................... 1877Chapter 96. Testicular Cancer ..................................................................................... 1880Chapter 97. Gynecologic Malignancies ....................................................................... 1890Chapter 98. Soft Tissue and Bone Sarcomas and Bone Metastases .......................... 1900Chapter 99. Carcinoma of Unknown Primary .............................................................. 1906Chapter 100. Paraneoplastic Syndromes- Endocrinologic-Hematologic ..................... 1920Chapter 101. Paraneoplastic Neurologic Syndromes .................................................. 1935Chapter e20. Thymoma ............................................................................................... 1941Chapter 102. Late Consequences of Cancer and Its Treatment ................................. 1953Section 2. Hematopoietic Disorders ........................................................................ 1953Chapter 103. Iron Deficiency and Other HypoproliferativeAnemias ............................ 1971Chapter 104. Disorders of Hemoglobin ....................................................................... 1987Chapter 105. Megaloblastic Anemias .......................................................................... 6. 1999Chapter 106. Hemolytic Anemias and Anemia Due toAcute Blood Loss .................... 2014Chapter 107. Aplastic Anemia, Myelodysplasia, an ..................................................... 2042Chapter 108. Polycythemia Vera and Other Myeloproliferative Diseases .................... 2057Chapter 109. Acute and Chronic Myeloid Leukemia .................................................... 2070Chapter 110. Malignancies of Lymphoid Cells ............................................................. 2093Chapter e21. Less Common Hematologic Malignancies ............................................. 2107Chapter 111. Plasma Cell Disorders ........................................................................... 2118Chapter 112. Amyloidosis ............................................................................................ 2129Chapter 113. Transfusion Biology and Therapy ........................................................... 2144Chapter 114. Hematopoietic Cell Transplantation ........................................................ 2159Section 3. Disorders of Hemostasis ........................................................................ 2159Chapter 115. Disorders of Platelets and Vessel Wall .................................................. 2180Chapter 116. Coagulation Disorders ........................................................................... 2197Chapter 117. Arterial and Venous Thrombosis ............................................................ 2207Chapter 118. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs ................................. 2238Part 8. Infectious Diseases ........................................................................................ 2238Section 1. Basic Considerations in Infectious Diseases .............................................. 2238Chapter 119. Introduction to Infectious Diseases; Host-Pathogen Interactions ................ 2239Chapter 120. Molecular Mechanisms of Microbial Pathogenesis ................................... 2251Chapter 121. Approach to the Acutely Ill Infected Febrile Patient ................................... 2267Chapter 122. Immunization Principles and Vaccine Use ............................................... 2282Chapter 123. Health Recommendations for International Travel .................................... 2292Chapter e22. Laboratory Diagnosis of Infectious Diseases ........................................... 2301Section 2. Clinical Syndromes: Community-Acquired Infections ................................. 2301Chapter 124. Infective Endocarditis ........................................................................... 2315Chapter 125. Infections of the Skin, Muscles, and Soft Tissues ..................................... 2330Chapter 126. Osteomyelitis ...................................................................................... 2345Chapter 127. Intraabdominal Infections and Abscesses ............................................... 2361Chapter 128. Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning ............ 2375Chapter 129. Clostridium Difficile Infection, Including Pseudomembranous Colitis .......... 2385Chapter 130. Sexually Transmitted Infections; Overview and Clinical Approach .............. 2411Chapter e23. Infectious Complications of Burns .......................................................... 2419Chapter e24. Infectious Complications of Bites ........................................................... 2426Section 3. Clinical Syndromes: Health Care-Associated Infections ............................. 2426Chapter 131. Health Care-Associated Infections ......................................................... 2427Chapter 132. Infections in Transplant Recipients ......................................................... 2453Section 4. Approach to Therapy for Bacterial Diseases ............................................... 2453Chapter 134. Pneumococcal Infections ...................................................................... 7. 2453Section 5. Diseases Caused by Gram-Positive Bacteria ............................................. 2453Chapter 134. Pneumococcal Infections ...................................................................... 2463Chapter 135. Staphylococcal Infections ...................................................................... 2489Chapter 136. Streptococcal Infections ........................................................................ 2505Chapter 137. Enterococcal Infections ......................................................................... 2521Chapter 138. Diphtheria and Other Infections Caused ................................................ 2534Chapter 139. Listeria Monocytogenes Infections ......................................................... 2540Chapter 140. Tetanus ............................................................................................... 2544Chapter 141. Botulism ............................................................................................. 2552Chapter 142. Gas Gangrene and Other Clostridial Infections ........................................ 2567Section 6. Diseases Caused by Gram-Negative Bacteria ........................................... 2567Chapter 143. Meningococcal Infections ...................................................................... 2580Chapter 144. Gonococcal Infections .......................................................................... 2602Chapter 145. Haemophilus and Moraxella Infections ................................................... 2615Chapter 146. Infections Due to the HACEK Group and M ............................................. 2622Chapter 147. Legionella Infections ............................................................................. 2631Chapter 148. Pertussis and Other Bordetella Infections ............................................... 2639Chapter 149. Diseases Caused by Gram-Negative Enteric Bacilli ................................. 2659Chapter 150. Acinetobacter Infections ........................................................................ 2665Chapter 151. Helicobacter pylori Infections ................................................................. 2673Chapter 152. Infections Due to Pseudomonas Species and Related Organisms ............. 2689Chapter 153. Salmonellosis ...................................................................................... 2700Chapter 154. Shigellosis .......................................................................................... 2708Chapter 155. Infections Due to Campylobacter and Related Organisms ........................ 2715Chapter 156. Cholera and Other Vibrioses ................................................................. 2724Chapter 157. Brucellosis .......................................................................................... 2735Chapter 158. Tularemia ............................................................................................ 2745Chapter 159. Plague and Other Yersinia Infections ...................................................... 2760Chapter 160. Bartonella Infections, Including Cat-Scratch Disease ............................... 2774Chapter 161. Donovanosis ....................................................................................... 2779Section 7. Miscellaneous Bacterial Infections ............................................................. 2779Chapter 162. Nocardiosis ......................................................................................... 2791Chapter 163. Actinomycosis ..................................................................................... 2802Chapter 164. Infections Due to Mixed Anaerobic Organisms ......................................... 2821Section 8. Mycobacterial Diseases .............................................................................. 2821Chapter 165. Tuberculosis ........................................................................................ 2853Chapter 166. Leprosy ............................................................................................... 2866Chapter 167. Nontuberculous Mycobacterial Infections ................................................ 8. 2876Chapter 168. Antimycobacterial Agents ...................................................................... 2894Section 9. Spirochetal Diseases .................................................................................. 2894Chapter 169. Syphilis ............................................................................................... 2911Chapter 170. Endemic Treponematoses ..................................................................... 2916Chapter 171. Leptospirosis ....................................................................................... 2928Chapter 172. Relapsing Fever ................................................................................... 2935Chapter 173. Lyme Borreliosis .................................................................................. 2947Section 10. Diseases Caused by Rickettsiae, Mycoplasmas, and Chlamydiae ........... 2947Chapter 174. Rickettsial Diseases ............................................................................. 2960Chapter 175. Infections Due to Mycoplasmas ............................................................. 2968Chapter 176. Chlamydial Infections ........................................................................... 2990Section 11. Viral Diseases: General Considerations ................................................... 2990Chapter 177. Medical Virology ................................................................................... 3011Chapter 178. Antiviral Chemotherapy, Excluding Antiretroviral Drugs .............................. 3036Section 12. Infections Due to DNA Viruses ................................................................. 3036Chapter 179. Herpes Simplex Virus Infections ............................................................ 3056Chapter 180. Varicella-Zoster Virus Infections ............................................................ 3066Chapter 181. Epstein-Barr Virus Infections, Including Infectious Mononucleosis ............. 3077Chapter 182. Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8 ..................... 3088Chapter 183. Molluscum Contagiosum, Monkeypox, and Other Poxvirus Infections ......... 3092Chapter 184. Parvovirus Infections ............................................................................ 3097Chapter 185. Human Papillomavirus Infections ........................................................... 3104Section 13. Infections Due to DNA and RNA Respiratory Viruses .............................. 3104Chapter 186. Common Viral Respiratory Infections ..................................................... 3120Chapter 187. Influenza ............................................................................................. 3135Section 14. Infections Due to Human Immunodefici ................................................... 3135Chapter 188. The Human Retroviruses ...................................................................... 3146Chapter 189. Human Immunodeficiency Virus Disease: AIDS and Related Disorders ...... 3225Section 15. Infections Due to RNA Viruses ................................................................. 3225Chapter 190. Viral Gastroenteritis ............................................................................. 3232Chapter 191. Enteroviruses and Reoviruses ............................................................... 3247Chapter 192. Measles (Rubeola) ............................................................................... 3259Chapter 193. Rubella (German Measles) ................................................................... 3265Chapter 194. Mumps ............................................................................................... 3272Chapter 195. Rabies and Other Rhabdovirus Infections ............................................... 3283Chapter 196. Infections Caused byArthropod- and Rodent-Borne Viruses ..................... 3308Chapter 197. Ebola and Marburg Viruses ................................................................... 3317Section 16. Fungal Infections ...................................................................................... 9. 3317Chapter 198. Diagnosis and Treatment of Fungal Infections ......................................... 3324Chapter 199. Histoplasmosis .................................................................................... 3332Chapter 200. Coccidioidomycosis ............................................................................. 3341Chapter 201. Blastomycosis ..................................................................................... 3346Chapter 202. Cryptococcosis .................................................................................... 3353Chapter 203. Candidiasis ......................................................................................... 3362Chapter 204. Aspergillosis ........................................................................................ 3371Chapter 205. Mucormycosis ..................................................................................... 3380Chapter 206. Superficial Mycoses and Less Common Systemic Mycoses ...................... 3393Chapter 207. Pneumocystis Infections ....................................................................... 3401Section 17. Protozoal and Helminthic Infections: General Considerations .................. 3401Chapter e25. Laboratory Diagnosis of Parasitic Infections ............................................ 3411Chapter 208. Agents Used to Treat Parasitic Infections ................................................ 3419Chapter e26. Pharmacology of Agents Used to Treat Parasitic Infections ....................... 3438Section 18. Protozoal Infections .................................................................................. 3438Chapter 209. Amebiasis and Infection with Free-Living Amebas .................................... 3452Chapter 210. Malaria ............................................................................................... 3470Chapter 211. Babesiosis .......................................................................................... 3476Chapter e27. Atlas of Blood Smears of Malaria and Babesiosis .................................... 3509Chapter 212. Leishmaniasis ..................................................................................... 3518Chapter 213. Chagas' Disease and Trypanosomiasis .................................................. 3530Chapter 214. Toxoplasma Infections .......................................................................... 3543Chapter 215. Protozoal Intestinal Infections and Trichomoniasis ................................... 3554Section 19. Helminthic Infections ................................................................................ 3554Chapter 216. Trichinellosis and Other Tissue Nematode Infections ............................... 3562Chapter 217. Intestinal Nematode Infections ............................................................... 3572Chapter 218. Filarial and Related Infections ............................................................... 3588Chapter 219. Schistosomiasis and Other Trematode Infections .................................... 3608Chapter 220. Cestode Infections ............................................................................... 3614Part 9. Terrorism and Clinical Medicine ....................................................................... 3614Chapter 221. Microbial Bioterrorism .......................................................................... 3625Chapter 222. Chemical Terrorism .............................................................................. 3645Chapter 223. Radiation Terrorism .............................................................................. 3658Part 10. Disorders of the Cardiovascular System ........................................................ 3658Section 1. Introduction to Cardiovascular Disorders ..................................................... 3658Chapter 224. Basic Biology of the Cardiovascular System ................................................ 3679Chapter 225. Epidemiology of Cardiovascular Disease .................................................... 3688Chapter 226. Approach to the Patient with Possible Cardiovascular Disease ......................... 10. 3696Section 2. Diagnosis of Cardiovascular Disorders ....................................................... 3696Chapter 227. Physical Examination of the Cardiovascular System ...................................... 3719Chapter 228. Electrocardiography ............................................................................. 3732Chapter e28. Atlas of Electrocardiography ................................................................... 3749Chapter 229. Noninvasive Cardiac Imaging: Echocardiograph ........................................... 3775Chapter e29. Atlas of Noninvasive Cardiac Imaging ........................................................ 3795Chapter 230. Diagnostic Cardiac Catheterization and Coronary Angiography ......................... 3811Section 3. Disorders of Rhythm ................................................................................. 3811Chapter 231. Principles of Electrophysiology ................................................................ 3824Chapter 232. The Bradyarrhythmias ........................................................................... 3848Chapter 233. The Tachyarrhythmias ........................................................................... 3875Chapter e30. Atlas of Cardiac Arrhythmias ................................................................... 3888Section 4. Disorders of the Heart ............................................................................... 3888Chapter 234. Heart Failure and Cor Pulmonale ............................................................. 3923Chapter 235. Cardiac Transplantation and Prolonged Assisted Circulation ............................ 3928Chapter 236. Congenital Heart Disease in the Adult ....................................................... 3949Chapter 237. Valvular Heart Disease .......................................................................... 3970Chapter 238. Cardiomyopathy and Myocarditis ............................................................. 3992Chapter 239. Pericardial Disease .............................................................................. 4007Chapter 240. Tumors and Trauma of the Heart .............................................................. 4017Chapter e31. Cardiac Manifestations of Systemic Disease ............................................... 4024Section 5. Vascular Disease ..................................................................................... 4024Chapter 241. The Pathogenesis, Prevention, and Treatment of Atherosclerosis ...................... 4039Chapter e32. Atlas of Atherosclerosis ......................................................................... 4041Chapter 242. The Metabolic Syndrome ....................................................................... 4052Chapter 243. Ischemic Heart Disease ........................................................................ 4069Chapter 244. Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction ............... 4082Chapter 245. ST-Segment Elevation Myocardial Infarction ................................................ 4098Chapter 246. Percutaneous Coronary Interventions and Other Interventional Procedures .......... 4122Chapter e33. Atlas of Percutaneous Revascularization .................................................... 4139Chapter 247. Hypertensive Vascular Disease ............................................................... 4166Chapter 248. Diseases of the Aorta ........................................................................... 4182Chapter 249. Vascular Diseases of the Extremities ........................................................ 4205Chapter 250. Pulmonary Hypertension ....................................................................... 4219Part 11. Disorders of the Respiratory System .............................................................. 4219Section 1. Diagnosis of Respiratory Disorders .............................................................. 4219Chapter 251. Approach to the Patient with Disease of the Respiratory System .................................................. 4226Chapter 252. Disturbances of Respiratory Function ....................................................................... 11. 4236Chapter 253. Diagnostic Procedures in Respiratory Disease ................................................................ 4254Chapter e34. Atlas of Chest Imaging ................................................................................... 4274Section 2. Diseases of the Respiratory System ............................................................. 4274Chapter 254. Asthma ............................................................................................... 4296Chapter 255. Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia ........................................... 4309Chapter 256. Occupational and Environmental Lung Disease ................................................................ 4331Chapter 257. Pneumonia ............................................................................................ 4356Chapter 258. Bronchiectasis and Lung Abscess .......................................................................... 4370Chapter 259. Cystic Fibrosis ......................................................................................... 4377Chapter 260. Chronic Obstructive Pulmonary Disease ..................................................................... 4398Chapter 261. Interstitial Lung Diseases ................................................................................. 4414Chapter 262. Deep Venous Thrombosis and Pulmonary Thromboembolism .................................................... 4434Chapter 263. Disorders of the Pleura and Mediastinum .................................................................... 4444Chapter 264. Disorders of Ventilation .................................................................................. 4452Chapter 265. Sleep Apnea ........................................................................................... 4460Chapter 266. Lung Transplantation ..................................................................................... 4470Part 12. Critical Care Medicine ................................................................................. 4470Section 1. Respiratory Critical Care ................................................................................... 4470Chapter 267. Approach to the Patient with Critical Illness ...................................................................... 4488Chapter 268. Acute Respiratory Distress Syndrome ......................................................................... 4498Chapter 269. Mechanical Ventilatory Support ............................................................................. 4510Section 2. Shock and Cardiac Arrest ................................................................................... 4510Chapter 270. Approach to the Patient with Shock .......................................................................... 4519Chapter 271. Severe Sepsis and Septic Shock ............................................................................ 4539Chapter 272. Cardiogenic Shock and Pulmonary Edema ...................................................................... 4546Chapter 273. Cardiovascular Collapse, Cardiac Arrest, and Sudden Cardiac Death ...................................................... 4556Section 3. Neurologic Critical Care .................................................................................... 4556Chapter 274. Coma ............................................................................................. 4573Chapter 275. Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy, and Subarachnoid Hemorrhage ................................ 4603Section 4. Oncologic Emergencies .................................................................................... 4603Chapter 276. Oncologic Emergencies .................................................................................. 4617Part 13. Disorders of the Kidney and Urinary Tract ....................................................................... 4617Chapter 277. Cellular and Molecular Biology of the Kidney ..................................................................... 4630Chapter 278. Adaption of the Kidney to Renal Injury ......................................................................... 4635Chapter 279. Acute Kidney Injury ..................................................................................... 4650Chapter 280. Chronic Kidney Disease .................................................................................. 4670Chapter 281. Dialysis in the Treatment of Renal Failure ....................................................................... 4675Chapter 282. Transplantation in the Treatment of Renal Failure .................................................................. 12. 4689Chapter 283. Glomerular Diseases .................................................................................... 4724Chapter 284. Polycystic Kidney Disease and Other Inherited Tubular Disorders ....................................................... 4736Chapter 285. Tubulointerstitial Diseases of the Kidney ....................................................................... 4750Chapter 286. Vascular Injury to the Kidney ............................................................................... 4764Chapter 287. Nephrolithiasis ........................................................................................ 4773Chapter 288. Urinary Tract Infections, Pyelonephritis, and Prostatitis .............................................................. 4783Chapter e35. Interstitial Cystitis-Painful Bladder Syndrome .................................................................... 4790Chapter 289. Urinary Tract Obstruction ................................................................................. 4796Part 14. Disorders of the Gastrointestinal System ......................................................................... 4796Section 1. Disorders of theAlimentary Tract .............................................................................. 5044Section 2. Liver and Biliary Tract Disease ............................................................................... 5257Section 3. Disorders of the Pancreas .................................................................................. 5302Part 15. Disorders of the Joints andAdjacent Tissues ........................................................................ 13. Close Window Preface Welcome to the 18th edition of Harrison's Principles of Internal Medicine. In the 62 years since the first edition of this textbook was published, virtually every area of medicine has evolved substantially and many new areas have emerged. In 1949, when the first edition appeared, peptic ulcer disease was thought to be caused by stress, nearly every tumor that was not resected resulted in death, rheumatic heart disease was widely prevalent, and hepatitis B and HIV infection were unknown. In the intervening years, both the infectious cause of and the cure for peptic ulcer disease were identified; advances in diagnosis and treatment made it possible to cure two-thirds of cancers; rheumatic heart disease virtually disappeared; atherosclerotic coronary artery disease waxed and thenat least in part through management of modifiable risk factorsbegan to wane; hepatitis B and its consequences, cirrhosis and hepatocellular carcinoma, became preventable by a vaccine; and HIV, first viewed as a uniformly fatal worldwide scourge, became a treatable chronic disease. During this same period, the amount of information required for the effective practice of medicine grew unabated, and learning options for students, residents, and practicing physicians also burgeoned to include multiple sources of information in print and electronic formats. While retaining the founding goals of Harrison's, this edition has been modified extensively in light of the varied needs of the book's readers and the diverse methods and formats by which information is now acquired. The print version of the 18th edition is more reader-friendly in several respects: the book is printed in type that is easier to read than prior editions, the graphics and tables have been enhanced for ease of interpretation, and more than 300 new figures are included. This improved format requires publication of the print edition in two volumes conveniently divided by subject matter. A DVD accompanies the book and contains additional e-chapters, videos, and atlases; its image bank includes figures and photographs from the book that can be incorporated into slide presentations. All chapters have been extensively updated by experts in the field. In addition, this edition includes 25 new chapters and more than 100 new authors. The pathophysiologic approach to evaluating patients on the basis of their presentation continues to receive emphasis in an enriched section on the cardinal manifestations of disease. A new section focuses on aging, its demographics and biology, and distinctive clinical issues affecting older patients. The e-chapters have increased in number from 39 to 57 and include a new video atlas of neuro-ophthalmology, an audio- enhanced chapter on the approach to a patient with a heart murmur, a case-based teaching exercise in fluid and electrolyte imbalances and acid-base disturbances, and explorations of infectious complications of burns and bites. New videos demonstrate the neurologic examination and several commonly performed medical procedures. A new chapter focuses on neuropsychiatric problems among war veterans. E-chapters on altitude sickness and hyperbaric and diving medicine form a new section on medical effects of changes in environmental pressure. For readers who wish to continue using Harrison's in a single-volume format, we are pleased to offer two new eBook versions of the 18th edition: a traditional eBook, with text and illustrations from the new edition included for reading on a portable e-reader or on a desktop, and an enhanced eBook developed especially for new tablet devices (e.g., iPad, Galaxy, Playbook, Nook) that offer high-definition resolution of multimedia content and interactive features. The Harrison's 18th edition enhanced eBook will contain extensive embedded video footage, including all of the new clinical procedural videos; the wonderful neurologic examination videos from Samuels and Lowenstein; examples of cardiovascular imaging and assessment; and high-resolution versions of more than 2000 color images from the book and the Harrison's atlases on the companion DVD. Along with other social media features, the enhanced eBook offers users the opportunity to take and share notes from lectures and their Preface: Harrison's Principles of Internal Medicine, 18e 2 / 7122 14. own reading. Additional resources include Harrison's Online, a continuously updated electronic resource that highlights and summarizes newly published articles on significant medical findings and advances. Harrison's Self-Assessment and Board Review , a useful study guide for board review based on information in the 18th edition, will soon be produced. Harrison's Manual of Medicine, a pocket version of Harrison's Principles of Internal Medicine, is available in both print and electronic formats. We have many people to thank for their efforts in producing this book. First, the authors have done a superb job of producing authoritative chapters that synthesize vast amounts of scientific and clinical data to create state-of-the-art descriptions of medical disorders encompassed by internal medicine. In today's information-rich, rapidly evolving environment, they have ensured that this information is current. Helpful suggestions and critical input have been provided by a number of colleagues; particularly notable was the advice of Chung Owyang on the Gastroenterology Section. We are most grateful to our colleagues in each of our editorial offices who have kept track of the work in its various phases and facilitated communication with the authors, with the McGraw-Hill staff, and among the editors: Patricia Conrad, Emily Cowan, Patricia L. Duffey, Gregory K. Folkers, Julie B. McCoy, Elizabeth Robbins, Kristine Shontz, and Stephanie Tribuna. The staff at McGraw-Hill has been a constant source of support and expertise. James Shanahan, Editor-in-Chief, Internal Medicine, for McGraw-Hill's Professional Publishing Division, has been a superb and insightful partner to the editors, guiding the development of the book and its related products in new formats. Kim Davis seamlessly stepped into the position of Associate Managing Editor, ensuring that the complex production of this multi- authored textbook proceeded in an efficient fashion. Paula Torres, Dominik Pucek, and Michael Crumsho oversaw the production of the new procedural and neurology videos. Phil Galea again served as Production Director on this, his final edition, and did so with a peak performance. Mary A. Murray, Director, International Rights, is retiring from McGraw Hill in 2012, after 50 years with the company. Mary joined the Blakiston Division of McGraw Hill in 1961, when Tinsley Harrison was still the editor of the book. Her first assignment was to distribute reprints of Harrison's chapters to the editors and contributors. For the next 23 years, Mary continued to be involved in the editorial process of Harrison's. In the early 1990s, she was given responsibility for licensing McGraw-Hill's medical titles; making use of her many cordial connections in global medical publishing, she licensed translations of Harrison's into 19 languages. We are extremely grateful to Mary for her many accomplishments in support of the book through 13 editions. We are privileged to have compiled this 18th edition and are enthusiastic about all that it offers our readers. We learned much in the process of editing Harrison's and hope that you will find this edition a uniquely valuable educational resource. The Editors Preface: Harrison's Principles of Internal Medicine, 18e 3 / 7122 15. Close Window Copyright Information Harrison's PRINCIPLES OF INTERNAL MEDICINE Eighteenth Edition Note: Dr. Fauci's work as editor and author was performed outside the scope of his employment as a U.S. government employee. This work represents his personal and professional views and not necessarily those of the U.S. government. Copyright 2012, 2008, 2005, 2001, 1998, 1994, 1991, 1987, 1983, 1980, 1977, 1974, 1970, 1966, 1962, 1958 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America. 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 data base or retrieval system, without the prior written permission of the publisher. Harrison's is a trademark of The McGraw-Hill Companies, Inc. Two Volume Set ISBN 978-0-07174889-6; MHID 0-07-174889-X Volume 1 ISBN 978-0-07-163244-7; MHID 0-07-163244-1 Volume 2 ISBN 978-0-07-174887-2; MHID 0-07-174887-3 DVD ISBN 978-0-07-174888-9; MHID 0-07-174888-1 Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Copyright: Harrison's Principles of Internal Medicine, 18e 4 / 7122 16. Close Window Contributors Editors Dan L. Longo, MD Lecturer, Department of Medicine, Harvard Medical School; Senior Physician, Brigham and Women's Hospital; Deputy Editor, New England Journal of Medicine, Boston, Massachusetts; Adjunct Investigator, National Institute on Aging, National Institutes of Health, Baltimore, Maryland Dennis L. Kasper, MD William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts J. Larry Jameson, MD, PhD Robert G. Dunlop Professor of Medicine; Dean, University of Pennsylvania School of Medicine; Executive Vice-President of the University of Pennsylvania for the Health System, Philadelphia, Pennsylvania 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 and Chairman, Department of Neurology, University of California, San Francisco, San Francisco, California Joseph Loscalzo, MD, PhD Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women's Hospital, Boston, Massachusetts Contributors James L. Abbruzzese, MD Professor and Chair, Department of GI Medical Oncology; M.G. and Lillie Johnson Chair for Cancer Treatment and Research, University of Texas, MD Anderson Cancer Center, Houston, Texas [99] Jamil Aboulhosn, MD Assistant Professor, Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California [236] John C. Achermann, MD, PhD Wellcome Trust Senior Fellow, UCL Institute of Child Health, University College London, London, United Kingdom [349] John W. Adamson, MD Clinical Professor of Medicine, Department of Hematology/Oncology, University of California, San Diego, San Diego, California [57, 103] Contributors: Harrison's Principles of Internal Medicine, 18e 5 / 7122 17. AnthonyA. Amato, MD Professor of Neurology, Harvard Medical School; Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts [384, 385, 387] Michael J. Aminoff, MD, DSc Professor of Neurology, University of California, San Francisco School of Medicine, San Francisco, California [22, 23, e45] Neil M. Ampel, MD Professor of Medicine, University of Arizona, Tucson, Arizona [200] Kenneth C. Anderson, MD Kraft Family Professor of Medicine, Harvard Medical School; Chief, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts [111, 113] Elliott M. Antman, MD Professor of Medicine, Harvard Medical School; Brigham and Women's Hospital; Boston, Massachusetts [243, 245] Frederick R. Appelbaum, MD Director, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington [114] Gordon L. Archer, MD Professor of Medicine and Microbiology/Immunology; Senior Associate Dean for Research and Research Training, Virginia Commonwealth University School of Medicine, Richmond, Virginia [133] Cesar A. Arias, MD, PhD Assistant Professor, University of Texas Medical School, Houston, Texas; Director, Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogot, Colombia [137] Wiebke Arlt, MD, DSc, FRCP, FMedSci Professor of Medicine, Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham; Consultant Endocrinologist, University Hospital Birmingham, Birmingham, United Kingdom [342] Valder R. Arruda, MD, PhD Associate Professor of Pediatrics, University of Pennsylvania School of Medicine; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania [116] Arthur K. Asbury, MD, FRCP Van Meter Professor Emeritus of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [23] John R. Asplin, MD Medical Director, Litholink Corporation; Chicago, Illinois [287] John C. Atherton, MD, FRCP Nottingham Digestive Diseases Centre Biomedical Research Unit (NDDC BRU), University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom [151] Evelyn Attia, MD Professor of Clinical Psychiatry, Columbia College of Physicians and Surgeons; Weill Cornell Medical College, New York, New York [79] Contributors: Harrison's Principles of Internal Medicine, 18e 6 / 7122 18. Paul S. Auerbach, MD, MS Redlich Family Professor, Department of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Palo Alto, California [396] K. Frank Austen, MD AstraZeneca Professor of Respiratory and Inflammatory Diseases; Director, Inflammation and Allergic Diseases Research Section, Harvard Medical School; Brigham and Women's Hospital, Boston, Massachusetts [317] Eric H. Awtry, MD Assistant Professor of Medicine, Boston University School of Medicine; Inpatient Clinical Director, Section of Cardiology, Boston Medical Center Boston, Massachusetts [240, e31] Bruce R. Bacon, MD James F. King, MD Endowed Chair in Gastroenterology; Professor of Internal Medicine, St. Louis University Liver Center, St. Louis University School of Medicine, St. Louis, Missouri [308, 309] Lindsey R. Baden, MD Associate Professor of Medicine, Harvard Medical School; Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts [178] John R. Balmes, MD Professor of Medicine, San Francisco General Hospital, San Francisco, California [256] Manisha Balwani, MD, MS Assistant Professor, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York [358] Peter A. Banks, MD Professor of Medicine, Harvard Medical School; Senior Physician, Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts [312, 313] Robert L. Barbieri, MD Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School; Chairperson, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts [7] Joanne M. Bargman, MD, FRCPC Professor of Medicine, University of Toronto; Staff Nephrologist, University Health Network; Director, Home Peritoneal Dialysis Unit and Co-Director, Renal Rheumatology Lupus Clinic, University Health Network, Toronto, Ontario, Canada [280] Tamar F. Barlam, MD Associate Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts [121, 146] Peter J. Barnes, DM, DSc, FMedSci, FRS Head of Respiratory Medicine, Imperial College, London, United Kingdom [254] Richard J. Barohn, MD Chairman, Department of Neurology; Gertrude and Dewey Ziegler Professor of Neurology, University of Kansas Medical Center, Kansas City, Kansas [384] Miriam J. Baron, MD Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Brigham and Contributors: Harrison's Principles of Internal Medicine, 18e 7 / 7122 19. Women's Hospital, Boston, Massachusetts [127] Rebecca M. Baron, MD Assistant Professor, Harvard Medical School; Associate Physician, Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts [258] John G. Bartlett, MD Professor of Medicine and Chief, Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland [258] Robert C. Basner, MD Professor of Clinical Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York [Appendix] Buddha Basnyat, MD, MSc, FACP, FRCP(E) Principal Investigator, Oxford University Clinical Research Unit-Patan Academy of Health Sciences; Medical Director, Nepal International Clinic, Kathmandu, Nepal [e51] Shari S. Bassuk, ScD Epidemiologist, Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts [348] John F. Bateman, PhD Director, Cell Biology, Development and Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia [363] David W. Bates, MD, MSc Professor of Medicine, Harvard Medical School; Chief, General Internal Medicine and Primary Care Division, Brigham and Women's Hospital; Medical Director, Clinical and Quality Analysis, Partners HealthCare System, Inc., Boston, Massachusetts [10] Robert P. Baughman, MD Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio [329] M. Flint Beal, MD Chairman of Neurology and Neuroscience; Neurologist-in-Chief, New York Presbyterian Hospital; Weill Cornell Medical College, New York, New York [366, 376] Laurence H. Beck, Jr., MD, PhD Assistant Professor of Medicine, Boston University School of Medicine, Boston, Massachusetts [285] Nicholas J. Beeching, MA, BM BCh, FRCP, FRACP, FFTM RCPS (Glasg), DCH, DTM&H Senior Lecturer (Clinical) in Infectious Diseases, Liverpool School of Tropical Medicine; Clinical Lead, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital; Honorary Consultant, Health Protection Agency; Honorary Civilian Consultant in Infectious Diseases, Army Medical Directorate, Liverpool, United Kingdom [157] Robert S. Benjamin, MD P.H. and Fay E. Robinson Distinguished Professor and Chair, Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas [98] Michael H. Bennett, MD, MBBS Conjoint Associate Professor in Anesthesia and Hyperbaric Medicine; Faculty of Medicine, University of New South Wales; Senior Staff Specialist, Department of Diving and Hyperbaric Contributors: Harrison's Principles of Internal Medicine, 18e 8 / 7122 20. Medicine, Prince of Wales Hospital, Sydney, Australia [e52] Edward J. Benz, Jr., MD Richard and Susan Smith Professor of Medicine, Professor of Pediatrics, Professor of Genetics, Harvard Medical School; President and CEO, Dana-Farber Cancer Institute; Director, Dana-Farber/Harvard Cancer Center (DF/HCC), Boston, Massachusetts [104] Jean Bergounioux, MD, PhD Pediatric Intensive Care Unit, Hpital Necker-Enfants Malades, Paris, France [154] Joseph R. Betancourt, MD, MPH Associate Professor of Medicine, Harvard Medical School; Director, The Disparities Solutions Center, Massachusetts General Hospital, Boston, Massachusetts [e4] Atul K. Bhan, MBBS, MD Professor of Pathology, Harvard Medical School; Director of Immunopathology, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts [e38] Shalender Bhasin, MD Professor of Medicine; Section Chief, Division of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, Massachusetts [346] Deepak L. Bhatt, MD, MPH Associate Professor of Medicine, Harvard Medical School; Chief of Cardiology, VA Boston Healthcare System; Director, Integrated Interventional Cardiovascular Program, Brigham and Women's Hospital and VA Boston Healthcare System; Senior Investigator, TIMI Study Group, Boston, Massachusetts [246, e33] David R. Bickers, MD Carl Truman Nelson Professor and Chair, Department of Dermatology, College of Physicians and Surgeons, Columbia University Medical Center; Dermatologist-in-Chief, New York Presbyterian Hospital, New York, New York [56] Henry J. Binder, MD Professor Emeritus of Medicine; Senior Research Scientist, Yale University, New Haven, Connecticut [294, e37] William R. Bishai, MD, PhD Professor and Co-Director, Center for Tuberculosis Research, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland [138] Bruce R. Bistrian, MD, PhD Professor of Medicine, Harvard Medical School; Chief, Clinical Nutrition, Beth Israel Deaconess Medical Center, Boston, Massachusetts [76] Martin J. Blaser, MD Frederick H. King Professor of Internal Medicine; Chair, Department of Medicine; Professor of Microbiology, New York University School of Medicine, New York, New York [151, 155] Gijs Bleijenberg, PhD Professor; Head, Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands [389] Clara D. Bloomfield, MD Distinguished University Professor; William G. Pace, III Professor of Cancer Research; Cancer Contributors: Harrison's Principles of Internal Medicine, 18e 9 / 7122 21. Scholar and Senior Advisor, The Ohio State University Comprehensive Cancer Center; Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio [109] Richard S. Blumberg, MD Chief, Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts [295] Jean L. Bolognia, MD Professor of Dermatology, Yale University School of Medicine, New Haven, Connecticut [53] Joseph V. Bonventre, MD, PhD Samuel A. Levine Professor of Medicine, Harvard Medical School; Chief, Renal Division; Chief, BWH HST Division of Bioengineering, Brigham and Women's Hospital, Boston, Massachusetts [279] George J. Bosl, MD Professor of Medicine, Weill Cornell Medical College; Chair, Department of Medicine; Patrick M. Byrne Chair in Clinical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York [96] Richard C. Boucher, MD Kenan Professor of Medicine, Pulmonary and Critical Care Medicine; Director, Cystic Fibrosis/Pulmonary Reseach and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina [259] Eugene Braunwald, MD, MA(Hon), ScD (Hon) FRCP Distinguished Hersey Professor of Medicine, Harvard Medical School; Founding Chairman, TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts [36, 239, 244] Irwin M. Braverman, MD Professor of Dermatology, Yale University School of Medicine, New Haven, Connecticut [53] Otis W. Brawley, MD Chief Medical Officer, American Cancer Society Professor of Hematology, Oncology, Medicine, and Epidemiology, Emory University, Atlanta, Georgia [82] Joel G. Breman, MD, DTPH Scientist Emeritus, Fogarty International Center, National Institutes of Health, Bethesda, Maryland [210, e27] George J. Brewer, MD Morton S. and Henrietta K. Sellner Professor Emeritus of Human Genetics; Emeritus Professor of Internal Medicine, University of Michigan Medical School, Senior Vice President for Research and Development, Adeona Pharmaceuticals, Inc., Ann Arbor, Michigan [360] Josephine P. Briggs, MD Director, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland [e2] F. Richard Bringhurst, MD Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [352] Steven M. Bromley, MD Clinical Assistant Professor of Neurology, Department of Medicine, New Jersey School of Medicine and DentistryRobert Wood Johnson Medical School, Camden, New Jersey [29] Contributors: Harrison's Principles of Internal Medicine, 18e 10 / 7122 22. Kevin E. Brown, MD, MRCP, FRCPath Consultant Medical Virologist, Virus Reference Department, Health Protection Agency, London, United Kingdom [184] Robert H. Brown, Jr., MD, PhD Chairman, Department of Neurology, University of Massachusetts Medical School, Worchester, Massachusetts [374, 387] Amy E. Bryant, PhD Research Scientist, Veterans Affairs Medical Center, Boise, Idaho; Affiliate Assistant Professor, University of Washington School of Medicine, Seattle, Washington [142] Christopher M. Burns, MD Assistant Professor, Department of Medicine, Section of Rheumatology, Dartmouth Medical School; Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire [359] David M. Burns, MD Professor Emeritus, Department of Family and Preventive Medicine, University of California, San Diego School of Medicine, San Diego, California [395] Stephen B. Calderwood, MD Morton Swartz MD Academy Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts [128] Michael V. Callahan, MD, DTM&H (UK), MSPH Clinical Associate Physician, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts; Program Manager, Biodefense, Defense Advanced Research Project Agency (DARPA), United States Department of Defense, Washington, DC [18] Michael Camilleri, MD Atherton and Winifred W. Bean Professor; Professor of Medicine and Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota [40] Christopher P. Cannon, MD Associate Professor of Medicine, Harvard Medical School; Senior Investigator, TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts [244] Jonathan Carapetis, PhD, MBBS, FRACP, FAFPHM Director, Menzies School of Health Research, Charles Darwin University, Darwin, Australia [322] Kathryn M. Carbone, MD Deputy Scientific Director, Division of Intramural Research, National Institute of Dental and Craniofacial Research, Bethesda, Maryland [194] Brian I. Carr, MD, PhD, FRCP Professor of Oncology and Hepatology, IRCCS De Bellis Medical Research Institute, Castellana Grotte, Italy [92] Arturo Casadevall, MD, PhD Chair, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York [202] Agustin Castellanos, MD Contributors: Harrison's Principles of Internal Medicine, 18e 11 / 7122 23. Professor of Medicine, and Director, Clinical Electrophysiology, Division of Cardiology, University of Miami Miller School of Medicine, Miami, Florida [273] Bartolome R. Celli, MD Lecturer on Medicine, Harvard Medical School; Staff Physician, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts [269] Murali Chakinala, MD Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri [234] Anil Chandraker, MD, FASN, FRCP Associate Professor of Medicine, Harvard Medical School; Medical Director of Kidney and Pancreas Transplantation; Assistant Director, Schuster Family Transplantation Research Center, Brigham and Women's Hospital; Children's Hospital, Boston, Massachusetts [282] Stanley W. Chapman, MD Professor of Medicine, University of Mississippi Medical Center, Jackson, Mississippi [201] Panithaya Chareonthaitawee, MD Associate Professor of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota [229, e29] Lan X. Chen, MD, PhD Penn Presbyterian Medical Center, Philadelphia, Pennsylvania [333] Yuan-Tsong Chen, MD, PhD Distinguished Research Fellow, Institute of Biomedical Sciences, Academia Sinica, Taiwan [362] Glenn M. Chertow, MD, MPH Norman S. Coplon/Satellite Healthcare Professor of Medicine; Chief, Division of Nephrology, Stanford University School of Medicine, Palo Alto, California [281] John S. Child, MD, FACC, FAHA, FASE Streisand Professor of Medicine and Cardiology, Geffen School of Medicine, University of California, Los Angeles (UCLA); Director, Ahmanson-UCLAAdult Congenital Heart Disease Center; Director, UCLA Adult Noninvasive Cardiodiagnostics Laboratory, Ronald Reagan- UCLA Medical Center; Los Angeles, California [236] Augustine M. K. Choi, MD Parker B. Francis Professor of Medicine, Harvard Medical School; Chief, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts [251, 253, 268] Irene Chong, MRCP, FRCR Clinical Research Fellow, Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom [93] Raymond T. Chung, MD Associate Professor of Medicine, Harvard Medical School; Director of Hepatology; Vice Chief, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts [310] Fredric L. Coe, MD Professor of Medicine, University of Chicago, Chicago, Illinois [287] Contributors: Harrison's Principles of Internal Medicine, 18e 12 / 7122 24. Jeffrey I. Cohen, MD Chief, Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland [181, 191] Ronit Cohen-Poradosu, MD Senior Physician, Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew Medical Center, Jerusalem, Israel [164] Francis S. Collins, MD, PhD Director, National Institutes of Health, Bethesda, Maryland [83] Wilson S. Colucci, MD Thomas J. Ryan Professor of Medicine, Boston University School of Medicine; Chief of Cardiovascular Medicine, Boston Medical Center, Boston, Massachusetts [240, e31] Darwin L. Conwell, MD Associate Professor of Medicine, Harvard Medical School; Associate Physician, Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts [312, 313] Michael J. Corbel, PhD, DSc, FRCPath Head, Division of Bacteriology, National Institute for Biological Standards and Control, Hertfordshire, United Kingdom [157] William Edward Corcoran, V, MD Clinical Instructor, Harvard Medical School; Cardiothoracic Fellow, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts [e54] Kathleen E. Corey, MD, MPH Clinical and Research Fellow, Harvard Medical School; Fellow, Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts [43] Lawrence Corey, MD Professor of Medicine and Laboratory Medicine and Head, Virology Division, Department of Laboratory Medicine, University of Washington; Head, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington [179] Felicia Cosman, MD Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons, New York [354] Mark A. Creager, MD Professor of Medicine, Harvard Medical School; Simon C. Fireman Scholar in Cardiovascular Medicine; Director, Vascular Center, Brigham and Women's Hospital, Boston, Massachusetts [248, 249] Leslie J. Crofford, MD Gloria W. Singletary Professor of Internal Medicine; Chief, Division of Rheumatology, University of Kentucky, Lexington, Kentucky [335] Jennifer M. Croswell, MD, MPH Acting Director, Office of Medical Applications of Research, National Institutes of Health, Bethesda, Maryland [82] Philip E. Cryer, MD Irene E. and Michael M. Karl Professor of Endocrinology and Metabolism in Medicine, Contributors: Harrison's Principles of Internal Medicine, 18e 13 / 7122 25. Washington University School of Medicine; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [345] David Cunningham, MD, FRCP Professor of Cancer Medicine, Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom [93] John J. Cush, MD Director of Clinical Rheumatology, Baylor Research Institute, Dallas, Texas [331] Charles A. Czeisler, MD, PhD, FRCP Baldino Professor of Sleep Medicine; Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts [27] Marinos C. Dalakas, MD, FAAN Professor of Neurology, Department of Pathophysiology, National University of Athens Medical School, Athens, Greece [388] Josep Dalmau, MD, PhD ICREA Research Professor, Institute for Biomedical Investigations, August Pi i Sunyer (IDIBAPS)/Hospital Clinic, Department of Neurology, University of Barcelona, Barcelona, Spain; Adjunct Professor of Neurology University of Pennsylvania, Philadelphia, Pennsylvania [101] Daniel F. Danzl, MD University of Louisville, Department of Emergency Medicine, Louisville, Kentucky [19] Robert B. Daroff, MD Professor and Chair Emeritus, Department of Neurology, Case Western Reserve University School of Medicine; University HospitalsCase Medical Center, Cleveland, Ohio [21] Charles E. Davis, MD Professor of Pathology and Medicine, Emeritus, University of California, San Diego School of Medicine; Director Emeritus, Microbiology, University of California, San Diego Medical Center, San Diego, California [e25] Stephen N. Davis, MBBS, FRCP Theodore E. Woodward Professor and Chairman, Department of Medicine, University of Maryland School of Medicine; Physician-in-Chief, University of Maryland Medical Center, Baltimore, Maryland [345] Lisa M. DeAngelis, MD Professor of Neurology, Weill Cornell Medical College; Chair, Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York [379] John Del Valle, MD Professor and Senior Associate Chair of Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan [293] Marie B. Demay, MD Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts [352] Bradley M. Denker, MD Associate Professor, Harvard Medical School; Physician, Department of Medicine, Brigham and Women's Hospital; Chief of Nephrology, Harvard Vanguard Medical Associates, Boston, Contributors: Harrison's Principles of Internal Medicine, 18e 14 / 7122 26. Massachusetts [44] David W. Denning, MB BS, FRCP, FRCPath Professor of Medicine and Medical Mycology; Director, National Aspergillosis Centre, The University of Manchester and Wythenshawe Hospital, Manchester, United Kingdom [204] Robert J. Desnick, MD, PhD Dean for Genetics and Genomics; Professor and Chairman, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, New York [358] Richard A. Deyo, MD, MPH Kaiser Permanente Professor of Evidence-Based Family Medicine, Department of Family Medicine, Department of Medicine, Department of Public Health and Preventive Medicine, Center for Research in Occupational and Environmental Toxicology, Oregon Health and Science University; Clinical Investigator, Kaiser Permanente Center for Health Research, Portland, Oregon [15] Betty Diamond, MD The Feinstein Institute for Medical Research, North Shore LIJ Health System; Center for Autoimmunity and Musculoskeletal Diseases, Manhasset, New York [318] Jules L. Dienstag, MD Carl W. Walter Professor of Medicine and Dean for Medical Education, Harvard Medical School; Physician, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts [304, 305, 306, 310, e38] William P. Dillon, MD Elizabeth Guillaumin Professor of Radiology, Neurology and Neurosurgery; Executive Vice- Chair, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California [368, e44] Charles A. Dinarello, MD Professor of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado [16] Raphael Dolin, MD Maxwell Finland Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Beth Israel Deaconess Medical Center; Brigham and Women's Hospital, Boston, Massachusetts [178, 186, 187] Richard L. Doty, PhD Professor, Department of Otorhinolaryngology: Head and Neck Surgery; Director, Smell and Taste Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [29] Neil J. Douglas, MD, MB ChB, DSc, Hon MD, FRCPE Professor of Respiratory and Sleep Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom [265] Daniel B. Drachman, MD Professor of Neurology and Neuroscience, W. W. Smith Charitable Trust Professor of Neuroimmunology, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland [386] David F. Driscoll, PhD Associate Professor of Medicine, University of Massachusetts Medical School, Worchester, Contributors: Harrison's Principles of Internal Medicine, 18e 15 / 7122 27. Massachusetts [76] Thomas D. DuBose, Jr., MD, MACP Tinsley R. Harrison Professor and Chair, Internal Medicine; Professor of Physiology and Pharmacology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina [47, e15] J. Stephen Dumler, MD Professor, Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland [174] Andrea Dunaif, MD Charles F. Kettering Professor of Endocrinology and Metabolism; Vice-Chair for Research, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois [6] Samuel C. Durso, MD, MBA Mason F. Lord Professor of Medicine; Director, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland [32, e12] Janice Dutcher, MD Department of Oncology, New York Medical College, Montefiore, Bronx, New York [276] Mark S. Dworkin, MD, MPH&TM Associate Professor, Division of Epidemiology and Biostatistics, University of Illinois at Chicago School of Public Health, Chicago, Illinois [172] Johanna Dwyer, DSc, RD Professor of Medicine (Nutrition), Friedman School of Nutrition Science and Policy, Tufts University School of Medicine; Director, Frances Stern Nutrition Center, Tufts Medical Center, Boston, Massachusetts [73] Jeffery S. Dzieczkowski, MD Physician, St. Alphonsus Regional Medical Center; Medical Director, Coagulation Clinic, Saint Alphonsus Medical Group, International Medicine and Travel Medicine, Boise, Idaho [113] KimA. Eagle, MD Albion Walter Hewlett Professor of Internal Medicine; Director, Cardiovascular Center, University of Michigan Health System, Ann Arbor, Michigan [8] Robert H. Eckel, MD Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, Division of Cardiology; Professor of Physiology and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis, University of Colorado School of Medicine, Anschutz Medical Campus, Director Lipid Clinic, University of Colorado Hospital, Aurora, Colorado [242] John E. Edwards, Jr,. MD Chief, Division of Infectious Diseases, Harbor/University of California, Los Angeles (UCLA) Medical Center, Torrance, California; Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California [198, 203] David A. Ehrmann, MD Professor of Medicine, The University of Chicago, Chicago, Illinois [49] Andrew J. Einstein, MD, PhD Assistant Professor of Clinical Medicine, Columbia University College of Physicians and Contributors: Harrison's Principles of Internal Medicine, 18e 16 / 7122 28. Surgeons; Department of Medicine, Division of Cardiology, Department of Radiology, Columbia University Medical Center and New York-Presbyterian Hospital, New York, New York [Appendix] Ezekiel J. Emanuel, MD, PhD Chief, Department of Clinical Bioethics, National Institutes of Health, Bethesda, Maryland [9] Joey D. English, MD Assistant Clinical Professor, Department of Neurology, Univeristy of California, San Francisco, San Francisco, California [370] John W. Engstrom, MD Betty Anker Fife Distinguished Professor of Neurology; Neurology Residency Program Director; Clinical Chief of Service, University of California, San Francisco, San Francisco, California [15, 375] Moshe Ephros, MD Senior Lecturer, Faculty of Medicine, TechnionIsrael Institute of Technology; Pediatric Infectious Disease Unit, Carmel Medical Center; Haifa, Israel [160] Jonathan A. Epstein, MD, DTMH William Wikoff Smith Professor of Medicine; Chairman, Department of Cell and Developmental Biology; Scientific Director, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania [224] Tim Evans, MD, PhD Assistant Director-General, Information, Evidence, and Research, World Health Organization, Geneva, Switzerland [e1] Christopher Fanta, MD Associate Professor of Medicine, Harvard Medical School; Member, Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, Massachusetts [34] Paul Farmer, MD, PhD Kolokotrones University Professor, Harvard University; Chair, Department of Global Health and Social Medicine, Harvard Medical School; Chief, Division of Global Health Equity, Brigham and Women's Hospital; Co-Founder, Partners in Health, Boston, Massachusetts [2] Anthony S. Fauci, MD, DSc (Hon), DM&S (Hon), DHL (Hon), DPS (Hon), DLM (Hon), DMS (Hon) Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland [1, 188, 189, 221, 314, 326, e40] Murray J. Favus, MD Professor, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, Director Bone Program, University of Chicago Pritzker School of Medicine, Chicago, Illinois [287, 355] David P. Faxon, MD Senior Lecturer, Harvard Medical School; Vice Chair of Medicine for Strategic Planning, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts [230, 246, e33] David T. Felson, MD, MPH Professor of Medicine and Epidemiology; Chair, Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts [332] Contributors: Harrison's Principles of Internal Medicine, 18e 17 / 7122 29. Luigi Ferrucci, MD, PhD Director, Baltimore Longitudinal Study of Aging National Institute of Health, Baltimore, Maryland [72] Howard L. Fields, MD, PhD Professor of Neurology, University of California, San Francisco, San Francisco, California [11] GregoryA. Filice, MD Professor of Medicine, University of Minnesota; Chief, Infectious Disease Section, Veterans Affairs Medical Center, Minneapolis, Minnesota [162] Robert Finberg, MD Chair, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [86, 132] Joyce Fingeroth, MD Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts [132] Alain Fischer, MD, PhD University Paris Descartes, Inserm Unit 768; Immunology and Pediatric Hematology Unit, Necker Children's Hospital, Paris, France [316, e39] Jeffrey S. Flier, MD Caroline Shields Walker Professor of Medicine and Dean, Harvard Medical School, Boston, Massachusetts [77] Agnes B. Fogo, MD John L. Shapiro Professor of Pathology; Professor of Medicine and Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee [e14] Larry C. Ford, MD Associate Researcher, Divisions of Clinical Epidemiology and Infectious Diseases, University of Utah, Salt Lake City, Utah [31] Jane E. Freedman, MD Professor, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts [117] Roy Freeman, MBCHB Professor of Neurology, Harvard Medical School, Boston, Massachusetts [20] Gyorgy Frendl, MD, PhD Assistant Professor of Anesthesia and Critical Care, Harvard Medical School; Director of Research, Surgical Critical Care, Brigham and Women's Hospital, Boston, Massachusetts [e54] Carl E. Freter, MD, PhD Professor, Department of Internal Medicine, Division of Hematology/Medical Oncology, University of Missouri; Ellis Fischel Cancer Center, Columbia, Missouri [102] Lawrence S. Friedman, MD Professor of Medicine, Harvard Medical School; Professor of Medicine, Tufts University School of Medicine; Assistant Chief of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Chair, Department of Medicine, Newton-Wellesley Hospital, Newton, Massachusetts [43] Contributors: Harrison's Principles of Internal Medicine, 18e 18 / 7122 30. Sonia Friedman, MD Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts [295] Anne L. Fuhlbrigge, MD, MS Assistant Professor, Harvard Medical School; Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, Massachusetts [253] Andre Furtado, MD Associate Specialist at the Department of Radiology, Neuroradiology Section, University of California, San Francisco, San Francisco, California [e44] Robert F. Gagel, MD Professor of Medicine and Head, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas [351] Nicholas B. Galifianakis, MD, MPH Assistant Clinical Professor, Surgical Movement Disorders Center, Department of Neurology, University of California, San Francisco, San Francisco, California [e8] John I. Gallin, MD Director, Clinical Center, National Institutes of Health, Bethesda, Maryland [60] Charlotte A. Gaydos, DrPh, MPH, MS Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland [176] J. Michael Gaziano, MD, MPH Professor of Medicine, Harvard Medical School; Chief, Division of Aging, Brigham and Women's Hospital; Director, Massachusetts Veterans Epidemiology Center, Boston VA Healthcare System, Boston, Massachusetts [225] Thomas A. Gaziano, MD, MSc Assistant Professor, Harvard Medical School; Assistant Professor, Health Policy and Management, Center for Health Decision Sciences, Harvard School of Public Health; Associate Physician in Cardiovascular Medicine, Department of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts [225] Susan L. Gearhart, MD Assistant Prof