Murray and Nadel's Textbook of Respiratory Medicine E-Book

Robert J. Mason; V.Courtney Broaddus; Thomas R Martin; Talmadge E King; Dean Schraufnagel; John F. Murray; Jay A. Nadel

BOOK

Murray and Nadel's Textbook of Respiratory Medicine E-Book

(2010)

Additional Information

Book Details

ISBN: 978-1-4377-3553-6
Edition: 5
Language: English
Pages: 2400
Subjects: Respiratory medicine
Cardiothoracic surgery
Neurosciences

Abstract

Murray and Nadel’s Textbook of Respiratory Medicine has long been the definitive and comprehensive pulmonary disease reference. Robert J. Mason, MD now presents the fifth edition in full color with new images and highlighted clinical elements. The fully searchable text is also online at www.expertconsult.com, along with regular updates, video clips, additional images, and self-assessment questions. This new edition has been completely updated and remains the essential tool you need to care for patients with pulmonary disease.

Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability. Compatible with Kindle®, nook®, and other popular devices.
Master the scientific principles of respiratory medicine and its clinical applications.
Work through differential diagnosis using detailed explanations of each disease entity.
Learn new subjects in Pulmonary Medicine including Genetics, Ultrasound, and other key topics.
Grasp the Key Points in each chapter.

Search the full text online at expertconsult.com, along with downloadable images, regular updates, more than 50 videos, case studies, and self-assessment questions.
Consult new chapters covering Ultrasound, Innate Immunity, Adaptive Immunity, Deposition and Clearance, Ventilator-Associated Pneumonia.
Find critical information easily using the new full-color design that enhances teaching points and highlights challenging concepts.
Apply the expertise and fresh ideas of three new editors—Drs. Thomas R. Martin, Talmadge E. King, Jr., and Dean E. Schraufnagel.
Review the latest developments in genetics with advice on how the data will affect patient care.

Section Title	Page	Action	Price
e9781416047100v1.pdf	1
Front cover	1
Murray and Nadel's Textbook of Respiratory Medicine	2
Copyright page	5
Dedication	6
Contributors	8
Preface to the Fifth Edition	20
Preface to the First Edition	22
Video Contents	24
Table of Contents	26
I Scientific Principles of Respiratory Medicine	32
A Anatomy and Development of the Respiratory Tract	34
1 Anatomy of the Lungs	34
INTRODUCTION	34
GROSS AND SUBGROSS ORGANIZATION	34
AIRWAYS	37
Cellular Complexity	38
Bronchial Circulation	41
PULMONARY CIRCULATION	41
Pulmonary Vascular Endothelial Cells	43
TERMINAL RESPIRATORY UNITS	44
Type II Cell Structure	46
Type II Cell Functions	47
Type II Cell Proliferation	47
Type I Cell Structure	47
Type I Cell Functions	48
Type I Cell Proliferation	49
Relationship between Type II and Type I Cells In Vivo and In Vitro	49
INNERVATION	49
AIRSPACE MACROPHAGES, LYMPHATICS, LYMPHOID TISSUE, AND INNATE IMMUNITY	51
References	52
2 Lung Growth and Development	57
INTRODUCTION	57
STAGES OF LUNG DEVELOPMENT	57
TISSUE INTERACTIONS AND LUNG DEVELOPMENT	60
MOLECULAR REGULATION OF LUNG DEVELOPMENT	60
Diffusible Mediators of Lung Development	60
Fibroblast Growth Factors and Fibroblast Growth Factor Receptors	60
Retinoic Acid	62
Sonic Hedgehog	62
TGF-β Superfamily	62
Wnts and β-catenin	63
Platelet-Derived Growth Factor	63
VEGF	63
Glucocorticoids	63
Transcriptional Regulation of Lung Development	64
Thyroid Transcription Factor 1	64
FOX Family	64
GATA-6	65
SOX Family	65
Summary	65
References	66
3 Mendelian Genetics, Disease Modifying or Associated Genes, and Epigenetics of Lung Disease	69
INTRODUCTION	69
Scope of the Problem	70
Potential Impact of Human Genetics	70
MOLECULAR CHARACTERIZATION OF GENETIC VARIATION	70
Genomic Maps	71
Comparative Genomics	72
Public Databases	72
GENETIC EPIDEMIOLOGY	73
Genetic Markers and Their Inheritance	73
Linkage and Positional Cloning	73
Genetic Association and Candidate Genes	74
Genome-Wide Association Studies	75
Candidate Gene or Region-based Testing	75
Gene by Environment Interaction	75
EPIGENETICS	75
APPLICATION TO PULMONARY DISEASES	77
Asthma	77
Chronic Obstructive Lung Disease	79
Acute Respiratory Distress Syndrome	79
Lung Cancer	79
Interstitial Lung Disease	80
THE PATH FORWARD	80
ACKNOWLEDGMENTS	81
References	81
B Respiratory Physiology and Pharmacology	84
4 Ventilation, Blood Flow, and Gas Exchange	84
INTRODUCTION	84
VENTILATION	84
Lung Volumes	86
Functional Residual Capacity, Residual Volume, and Total Lung Capacity	86
Total and Alveolar Ventilation	87
Total Ventilation	87
Alveolar Ventilation	87
Anatomic Dead Space	87
Physiologic Dead Space	87
Inequality of Ventilation	88
Topographic Inequality	88
Airway Closure	89
Nontopographic Inequality	89
BLOOD FLOW	89
Pressures of the Pulmonary Circulation	89
Pressure Inside Blood Vessels	90
Pressures Outside Blood Vessels	90
Pulmonary Vascular Resistance	91
Pressure-Flow Relations	91
Effect of Lung Volume	93
Other Factors	93
Distribution of Pulmonary Blood Flow	94
Normal Distribution	94
Three-Zone Model for the Distribution of Blood Flow	94
The Effect of Lung Volume on the Distribution of Blood Flow—Zone 4	95
Increased Acceleration and Weightlessness.	95
Nongravitational Factors Influencing the Distribution of Pulmonary Blood Flow.	96
Abnormal Patterns of Blood Flow	96
Active Control of the Pulmonary Circulation	96
Hypoxia	97
Other Physiologic Substances	98
Damage to Pulmonary Capillaries by High Wall Stresses	98
Metabolic Functions of the Pulmonary Circulation	99
GAS EXCHANGE	100
Causes of Hypoxemia	101
Hypoventilation	101
Diffusion Limitation	102
Oxygen Uptake along the Pulmonary Capillary	103
Reaction Rates with Hemoglobin	104
Diffusing Capacity	104
Measurement.	105
Interpretation.	106
Shunt	106
Ventilation-Perfusion Relationships	107
Gas Exchange in a Single Lung Unit	107
Pattern in the Normal Lung	108
Traditional Assessment of Ventilation-Perfusion Inequality	109
Distributions of Ventilation-Perfusion Ratios	111
Multiple Inert Gas Elimination Technique.	111
Distribution in Normal Subjects.	113
Distributions in Lung Disease.	113
Ventilation-Perfusion Inequality and Carbon Dioxide Retention	114
Effect of Changes in Cardiac Output on Gas Exchange in the Presence of Ventilation-Perfusion Inequality	115
Blood-Gas Transport	115
Oxygen	115
Carbon Dioxide	116
References	117
5 Respiratory System Mechanics and Energetics	120
INTRODUCTION	120
TERMINOLOGY	120
Flow	120
Volume	120
Pressure	121
Compliance and Resistance	122
Time Constants	122
RESPIRATORY MECHANICS IN STATIC CONDITIONS	123
Elastic Recoil of the Lungs	123
Lung Connective Tissue	123
Alveolar Surface Forces and Surfactant	123
Hysteresis and Stress Adaptation	125
Recruitment Maneuvers in Acute Respiratory Distress Syndrome	125
Elastic Recoil of the Chest Wall	125
Respiratory Muscles	125
Fatigue of Respiratory Muscles	127
Respiratory Muscle Atrophy during Positive-Pressure Mechanical Ventilation	127
Chest Wall Compliance	127
Integration of Lung and Chest Wall Mechanics	128
Calculation of Total Respiratory System Compliance from Lung and Chest Wall Compliance	129
Clinical Applications	129
The Impact of Positive End-Expiratory Pressure on Pleural Pressure	129
Plateau Pressures in Patients Receiving Positive-Pressure Mechanical Ventilation	129
THE RESPIRATORY SYSTEM IN DYNAMIC CONDITIONS	130
Resistive Work Due to Gas Flow through Airways	130
Laminar versus Turbulent Flow	130
Reynold’s Number	130
Clinical Effects of Heliox	131
Flow Limitation	131
Equal Pressure Point Theory (Fig. 5-20).	131
The Bernoulli Effect and Wave Speed Theory.	132
Other Resistive Work	132
Auto-PEEP during Positive-Pressure Ventilation of COPD	132
Measurement of Static Compliance and Resistance during Mechanical Ventilation	133
ENERGETICS AND WORK OF BREATHING	134
Measuring Work of Breathing Done by a Positive-Pressure Ventilator in a Paralyzed Patient	134
Measuring Work of Breathing in a Spontaneously Breathing Patient	135
Oxygen Cost of Breathing	135
References	136
6 Pulmonary Circulation and Regulation of Fluid Balance	139
INTRODUCTION	139
PULMONARY HEMODYNAMICS	139
Pulmonary Vascular Pressures	140
Pulmonary Vascular Resistance	140
Vascular Resistance Profile	141
Functional Description of Pulmonary Vessels	141
Extra-Alveolar Vessels.	142
Alveolar Vessels.	142
Corner Vessels.	142
Mechanical Effects on Pulmonary Vascular Resistance	142
Transmural Pressure.	142
Lung Volume.	143
Viscosity.	143
Pulmonary Vascular Compliance	143
Pulmonary Vascular Pressure-Volume Curve	143
Changes in Vascular Compliance	144
Pulmonary Perfusion	144
Distention and Recruitment	144
Distribution of Pulmonary Blood Flow	144
Mechanical Stress and Strain	145
Shear Stress	145
Cyclic Stretch	145
Pulmonary Vascular Response to Hypoxia	145
Response Elements	145
Neural Regulation of Pulmonary Vascular Resistance	147
Humoral Regulation of Pulmonary Vascular Resistance	147
LUNG FLUID AND SOLUTE EXCHANGE	148
Pathogenesis of Pulmonary Edema	148
Sites of Fluid Accumulation	148
Mechanisms of Pulmonary Edema	148
Increased Pulmonary Capillary Pressure.	148
Decreased Plasma Oncotic Pressure.	149
Increased Lung Vascular Permeability.	149
Lymphatic Insufficiency.	149
Safety Factors in Lung Fluid Homeostasis.	149
Transcapillary Exchange	150
Fluid Flux Equation	150
Solute Flux Equation	151
Diffusion	152
Sites of Fluid and Solute Exchange	152
Capillary Endothelium	152
Alveolar Epithelium	152
Alveolar-Capillary Septum	152
Pulmonary Lymphatic Vessels	153
Lung Interstitium	153
Interstitial Pressures	153
Interstitial Compliance	154
Transvascular Transport of Plasma Molecules	154
Capillary Endothelial Permeability	154
Pore Theory	154
Mechanisms of Increased Endothelial Permeability	155
Characteristics of Increased Vascular Endothelial Permeability.	155
Intracellular Ca2+ Shifts.	156
Protein Kinase C Activation and Other Barrier-Regulatory Signals.	157
Basement Membrane and Matrix Components.	157
Endothelial Water Permeability and Albumin Transcytosis.	157
Strategies to Reverse Permeability and Restore Barrier Integrity	158
PULMONARY VASCULAR GENOMICS	160
References	161
chapter 6 APPENDIX Endothelial Cell Function	165
EFFECTS OF CELLULAR AND MOLECULAR CHARGE	165
REGIONAL DIFFERENCES IN ENDOTHELIAL PERMEABILITY	165
CYTOSKELETAL ALTERATIONS	166
ANGIOGENESIS	167
APOPTOSIS AND ENDOTHELIAL CELL DYSFUNCTION	168
References	168
7 Acid-Base Balance	171
INTRODUCTION AND PHYSIOLOGY	171
Choice of Respiratory and Metabolic Parameters	171
The Strong Ion Approach	173
Nomenclature of Acid-Base Disorders	175
Compensations	176
Respiratory Acidosis	176
Respiratory Alkalosis	177
Metabolic Acidosis	177
Metabolic Alkalosis	177
Role of the Kidney in Acid-Base Balance	177
Response to Acidosis and Excretion of Acid	177
Response to Alkalosis	178
Intracellular Acid-Base Physiology	178
METABOLIC ACIDOSIS	179
Anion Gap Concept	179
Causes	180
Lactic Acidosis	180
Diabetic Ketoacidosis	183
Uremic Acidosis	184
Toxic Forms of Anion Gap Acidosis	184
Hyperchloremic Acidosis	185
Renal Tubular Acidosis	185
Type 1 Renal Tubular Acidosis.	185
Type 2 Renal Tubular Acidosis.	186
Type 3 Renal Tubular Acidosis.	186
Type 4 Renal Tubular Acidosis.	186
Acidosis of Progressive Renal Failure	186
Gastrointestinal Causes of Hyperchloremic Acidosis	186
Miscellaneous Causes of Hyperchloremic Acidosis	187
Urine Net Charge and Osmolar Gap	187
Dilutional Acidosis	187
Clinical Manifestations	187
Therapy	188
METABOLIC ALKALOSIS	188
Causes	189
Chloride Responsive Alkalosis	189
Gastrointestinal Losses.	189
Renal Losses.	189
Losses in Sweat.	189
Chloride-Resistant Alkalosis	189
Excessive Intake of	190
Extracellular Fluid Contraction	190
Clinical Manifestations	190
Therapy	190
RESPIRATORY ACIDOSIS	190
General Considerations	190
Causes	190
Clinical Manifestations	191
Therapy	191
RESPIRATORY ALKALOSIS	192
General Considerations	192
Causes	192
Clinical Manifestations	193
Therapy	193
References	193
8 Pharmacologic Principles	196
INTRODUCTION	197
CELL INTERACTIONS IN THE LUNG	197
Vascular Endothelium	197
Airway Epithelium	197
Inflammatory Cells	197
Nerves	198
RECEPTORS	198
Receptor Classification	198
G Protein–Coupled Receptors	198
Rhodopsin as a Model Receptor	199
Structure	199
Receptor Dimerization	200
G Proteins	200
Second Messengers	202
Adenylyl Cyclase	202
Phosphodiesterases	202
Phosphatidylinositol Hydrolysis	203
Guanylyl Cyclase	204
Ion Channel–Coupled Signaling	204
Cytokine Receptors	204
Chemokine Receptors	204
Enzyme-Linked Receptors	205
Receptor Tyrosine Kinases	205
Signal Transduction	205
MAPK Pathways	205
Receptor Serine/Threonine Kinases	205
Receptor Protein Tyrosine Phosphatases	206
Ion Channel Receptors	206
Intracellular Receptors	206
Steroid Receptors	206
Receptor Subtypes	207
Receptor Interactions	208
DRUG-RECEPTOR INTERACTIONS	209
Radioligand Binding	209
Agonists and Antagonists	209
RECEPTOR REGULATION	210
Desensitization	210
G Protein–Receptor Kinases	210
Arrestins	211
Down-Regulation	211
Steroid Modulation	211
Receptor Ontogeny	212
Pulmonary Diseases	212
Transcriptional Control	212
ION CHANNELS	212
Calcium Channels	212
Voltage-Gated Channels	212
Receptor-Operated Channels	213
ICRAC	213
Potassium Channels	213
Sodium Channels	214
Chloride Channels	214
ENZYMES	214
Protein Kinases	214
MAP Kinases	215
Phosphoinositide 3-Kinases	215
Protein Phosphatases	216
PHARMACOKINETICS	216
Absorption	216
Distribution	216
Clearance	216
ROUTES OF DRUG DELIVERY	217
Inhaled Route	217
Particle Size	217
Pharmacokinetics	217
Delivery Devices	217
Metered-Dose Inhalers.	217
Spacer Chambers.	217
Dry Powder Inhalers.	218
Nebulizers.	218
Oral Route	218
Parenteral Route	218
AUTONOMIC PHARMACOLOGY	218
Overview of Airway Innervation	218
Neural Interactions	219
Cotransmission	219
Afferent Nerves	219
Slowly Adapting Receptors	220
Rapidly Adapting Receptors	220
C Fibers	220
Defense Reflexes	220
Cough	221
Cholinergic Nerves	221
Cholinergic Control of Airways	221
Extraneuronal ACh	221
Muscarinic Receptors	221
Cholinergic Reflexes	222
Neurogenic Inflammation	222
Tachykinins	223
Calcitonin Gene–Related Peptide	223
Neurogenic Inflammation in Human Airways	223
Neurotrophins	224
Bronchodilator Nerves	224
Sympathetic Nerves	224
Circulating Catecholamines	224
Adrenergic Receptors	224
Inhibitory Nonadrenergic Noncholinergic Nerves	224
Neural Control in Disease	225
Asthma	225
COPD	225
INFLAMMATORY MEDIATORS	225
Histamine	226
Leukotrienes	226
Prostaglandins	226
Platelet-Activating Factor	226
Endothelins	226
Nitric Oxide	226
Oxygen-Derived Free Radicals	226
Adenosine	226
Bradykinin	226
Cytokines	227
Chemokines	227
Multiple Mediators	227
Anti-inflammatory Mediators	228
TRANSCRIPTION FACTORS	228
Activator Protein-1	228
Nuclear Factor-κB	229
JAK-STAT	229
GATA-3	230
T-Bet	230
CREB	230
Glucocorticoid Receptors	230
Nuclear Factor of Activated T Cells	230
Coactivators	230
Histone Modification	230
References	232
C Defense Mechanisms and Immunology	237
9 Pulmonary Surfactant	237
INTRODUCTION	237
PHYSIOLOGIC FUNCTIONS OF PULMONARY SURFACTANT	238
COMPOSITION	239
Lipids	239
Proteins	239
Surfactant Protein A	240
Synthesis and Secretion	240
Structure and Function	241
Binding to Infectious Organisms	241
Viruses.	241
Bacteria.	241
Mycobacteria, Fungi, Mycoplasma, and Pneumocystis.	241
Interaction with Phagocytic Cells	242
Surfactant Protein B	242
Surfactant Protein C	243
Surfactant Protein D	243
Structure and Function	244
Binding to Infectious Organisms	244
Viruses.	244
Bacteria.	244
Fungi, Mycobacteria, Mycoplasma, and Pneumocystis.	244
Interactions with Phagocytic Cells	244
SECRETION AND EXTRACELLULAR PROCESSING OF SURFACTANT	245
SURFACTANT ABNORMALITIES IN LUNG DISEASE	246
Primary Surfactant Deficiency of the Newborn	246
Epidemiology and Clinical Features	246
Treatment	246
Hereditary Surfactant Protein B Deficiency	246
Hereditary Surfactant Protein C Deficiency and Mutations	247
Acute Respiratory Distress Syndrome	247
Surfactant Alterations	247
Mechanisms Leading to Surfactant Dysfunction	247
Pneumonia	248
Interstitial Lung Diseases	248
Obstructive Lung Diseases	248
Other Lung Diseases	248
SURFACTANT THERAPY FOR ACUTE RESPIRATORY DISTRESS SYNDROME	249
Surfactant Preparation and Dose	249
Surfactant Delivery Methods	249
Effects of Mechanical Ventilation	250
Proposed Surfactant Treatment Strategies	250
ACKNOWLEDGMENT	250
References	250
10 Alveolar and Distal Airway Epithelial Fluid Transport	254
INTRODUCTION	254
LUNG EPITHELIAL FLUID ABSORPTION	254
EVIDENCE FOR ACTIVE FLUID TRANSPORT IN THE INTACT LUNG	255
ION TRANSPORT IN ALVEOLAR AND DISTAL AIRWAY EPITHELIAL CELLS	255
REGULATION OF LUNG EPITHELIAL FLUID TRANSPORT	256
MECHANISMS THAT CAN IMPAIR THE RESOLUTION OF ALVEOLAR EDEMA	258
ALVEOLAR FLUID TRANSPORT UNDER PATHOLOGIC CONDITIONS	259
FUTURE DIRECTIONS	260
References	261
11 Airway Epithelial Mucins and Mucous Hypersecretion	263
INTRODUCTION	263
COMPONENTS OF MUCUS	263
CHARACTERISTICS OF NORMAL AIRWAY MUCINS IN HEALTHY INDIVIDUALS	264
MUCOUS HYPERSECRETORY DISEASES AND THEIR CLINICAL CONSEQUENCES	264
IMPORTANCE OF MUCOUS HYPERSECRETION IN CHRONIC INFLAMMATORY AIRWAY DISEASES	264
Cystic Fibrosis	265
Asthma	266
Chronic Bronchitis and Chronic Obstructive Pulmonary Disease	267
EPITHELIAL SIGNALING PATHWAYS RESPONSIBLE FOR MUCIN PRODUCTION IN AIRWAYS	268
Early Studies of Mucins	268
Epidermal Growth Factor Receptor Activation Stimulates Mucin Production in Airways	268
Metalloproteases Cleave Membrane-Bound Epidermal Growth Factor Receptor Ligands to Produce Mucins	269
Roles of Reactive Oxygen Species in Airway Epithelial Mucin Production	269
Toll-like Receptors	269
THERAPEUTIC IMPLICATIONS	270
References	271
12 Aerosol Deposition and Clearance	273
INTRODUCTION	273
DEFINITION AND DESCRIPTION OF AN AEROSOL,	274
PRINCIPLES OF DEPOSITION	274
MEASUREMENTS OF PARTICLE SIZE	275
Evaluation of Aerosol Particle Size	275
Application of In Vitro Measurements of Particle Size to Clinical Studies,,	275
GENERATION OF THERAPEUTIC AEROSOLS	275
Dry Powder Devices,,	275
Pressurized Metered-Dose Inhalers,	276
Jet Nebulizers	277
New Developments in Aerosol Delivery Systems	277
PRINCIPLES OF ASSESSMENT OF DELIVERY SYSTEMS,	277
The Inhaled Mass	277
Deposition	278
STRATEGIES TO OPTIMIZE DEPOSITION OF THERAPEUTIC AEROSOLS	279
Getting Particles Past the Oropharynx	279
Control of Breathing Pattern and Aerosol Deposition	279
Expiration and Problems with Aerosol Deposition	280
Deposition and Dose versus Response	280
ADDITIONAL FACTORS INFLUENCING DEVELOPMENT OF THERAPEUTIC AEROSOLS	281
Asthma	282
Cystic Fibrosis	283
Delivery of Inhaled Medications to Young Children	283
Delivery of Therapeutic Aerosols to the Nasal Mucosa	283
Aerosol Delivery during Mechanical Ventilation,,	285
DIAGNOSTIC RADIOAEROSOLS	285
MUCOCILIARY CLEARANCE AND DISEASE	285
ALVEOLAR CLEARANCE	287
ENVIRONMENTAL AEROSOLS	287
References	289
13 Innate Immunity in the Lungs	292
INTRODUCTION	292
OVERVIEW OF THE COMPONENTS OF LUNG INNATE IMMUNITY	293
INNATE RECOGNITION IN THE LUNG	295
Secreted Pattern Recognition Receptors	295
Collectins	295
Complement	296
Pentraxins and Other Secreted Pattern Recognition Receptors	296
Cellular Pattern Recognition Receptors	296
Plasma Membrane and Endosomal Pattern Recognition Receptors	296
Toll-like Receptors.	296
Scavenger Receptors.	298
C-Type Lectin Receptors.	298
Cytoplasmic Pattern Recognition Receptors	300
Nucleotide-Binding and Oligomerization Domain–like Receptors.	300
Retinoic Acid–Inducible Gene-1–like Receptors.	301
Summary	301
EFFECTOR MECHANISMS	301
Epithelium	301
Neutrophils	302
Mononuclear Phagocytes	306
Resident Macrophages	306
Functions of Resident and Interstitial Alveolar Macrophages.	306
Recruitment of Mononuclear Phagocytes	308
Functions of Recruited Monocytes and Macrophages.	308
Dendritic Cells	309
Mouse and Human Lung Dendritic Cell Subsets.	311
Functions of Lung Dendritic Cells.	312
SYSTEM INTEGRATION	313
References	315
14 Adaptive Immunity	322
INTRODUCTION	322
COMPONENTS OF THE IMMUNE SYSTEM: OVERVIEW	322
IMMUNE RECOGNITION	325
B Cells and Antibodies	325
Structure of Immunoglobulin and the B-Cell Receptor for Antigen	325
Genetic Mechanisms Involved in the Formation of the B-Cell Receptor Repertoire	325
Isotype Switching and Function of the Different Immunoglobulin Classes	328
B-Cell Development	329
Immunoglobulin Interactions with Antigen	330
T Cells and Antigen-Presenting Cells	330
T-Cell Receptors	330
Genetic Mechanisms Involved in T-Cell Receptor Structure and T-Cell Receptor Repertoire Formation	331
Antigen-Presenting Cells and Molecules of the Major Histocompatibility Complex	332
Genetics and Nomenclature for the Human Leukocyte Antigen System	333
Presentation and T-Cell Recognition of Antigens	334
CD3 Complex and Intracellular Signaling after T-Cell Activation	336
T-Cell Accessory Molecules CD4 and CD8	336
T-Cell Development and Selection of the T-Cell Repertoire	336
T-Cell Tolerance: The Prevention of Self-Reactivity	337
GENERATION OF THE IMMUNE RESPONSE	338
T-Cell Activation and the Need for Co-stimulatory Molecules	338
Subsets of T Helper Cells	340
CD4+ T-Cell–B-Cell Collaboration and Regulation of Antibody Production	341
Generation and Regulation of Cell-Mediated Immune Responses	342
SPECIFIC IMMUNE RESPONSES IN THE LUNG	343
Lymphocyte Populations and Trafficking in the Lung	343
Antibody-Mediated Immune Responses in the Lung	344
Immune Response to Extracellular Pathogens	344
Immune Response to Autoantigens	345
Immune Response in Allergic Disease	345
Cell-Mediated Inflammatory Responses in the Lung	346
Granulomatous Lung Disease	346
Cytotoxic T-Cell Reactions in the Lung	346
References	347
D Respiratory Pathology and Inflammation	351
15 General Features of Non-neoplastic Respiratory Pathology	351
INTRODUCTION	351
LUNG PROCESSING	352
ACUTE LUNG PROCESSES	352
Diffuse Alveolar Damage	353
Acute Bronchopneumonia	353
Diffuse Alveolar Hemorrhage	353
Acute Eosinophilic Lung Processes	354
Acute/Subacute Lymphocytic Lung Processes	354
Organizing Pneumonia	355
INTERSTITIAL LUNG FIBROTIC PATTERNS	355
Acute Interstitial Pneumonitis	355
Usual Interstitial Pneumonitis	355
Desquamative Interstitial Pneumonitis	357
Lymphocytic Interstitial Pneumonitis	357
Nonspecific Interstitial Pneumonitis	357
Other Forms of Idiopathic Interstitial Lung Pattern	357
GRANULOMATOUS LUNG PATTERNS	358
BRONCHIOLAR DISEASE PATTERNS	359
Chronic Bronchiolitis	359
Granulomatous Bronchiolitis	361
Obliterative Bronchiolitis	361
PULMONARY VASCULAR DISEASE PATTERNS	362
TRANSBRONCHIAL BIOPSY	365
References	365
16 Injury and Repair of the Lung	367
INTRODUCTION	367
CONCEPTS OF LUNG INJURY AND REPAIR	367
Lung Injury	368
Lung Repair	368
Repair and Homeostasis	368
More Subtle Concepts of Injury and Repair	369
Tissue Homeostasis and Cell Turnover	369
Animal Models	369
THE CLINICAL CONTEXT: HETEROGENEITY IN THE INJURY AND REPAIR PROCESS	369
Representative Example: ALI/ARDS	370
Characteristics of the Injurious Insult	370
Characteristics of ALI/ARDS	370
Preexisting Acquired Disorders	371
Genetic Determinants	371
Physiology, Cell Biology, and Immunology of ALI	372
Common Pathway to ALI/ARDS	372
Clinical and Pathologic Manifestations	372
Distinct Phases of Injury	372
Extent of Epithelial Injury Predicts Outcome	372
CAUSES AND MECHANISMS OF LUNG INJURY	373
Causes of Injury	373
Mechanisms and Pathways of Lung Cell Injury	373
Cell Death: Programmed Cell Death versus Toxic and Necrotic Cell Death	374
Protection of Cells from Damage	374
Assessing Programmed Cell Death	375
Manifestations of Lung Injury: Loss of Structure Leads to Loss of Function	375
Modeling Acute Lung Injury in Animals	375
Feasible Assessment of Acute Lung Injury in Animal Models	375
Abnormalities of Gas Exchange.	376
Decreased Lung Compliance.	376
Assessment of Increased Permeability of the Alveolar-Capillary Membrane.	376
Histologic Assessment of Lung Injury.	376
REPAIR OF THE LUNG	376
Mechanisms and Pathways of Lung Cell Replacement	376
Stem Cells, Constitutive Cell Turnover, and Reparative Cell Types	376
Hierarchies of Reparative Cells	376
Classical Stem Cell Hierarchy	377
Cells Involved in Lung Repair	377
Progenitor Cell.	377
Tissue-Specific Stem Cells.	377
Facultative Progenitor Cell Pools.	378
Loss of Regenerative Potential: Depletion of the Facultative Progenitor Cell Pool	378
Gene-Environment Interactions in Lung Injury and Repair	378
Abnormal Cellular Repair	379
Does Lung Repair Recapitulate Lung Development?	379
References	380
II Diagnosis and Evaluation of Respiratory Disease	384
E Diagnosis	386
17 History and Physical Examination	386
INTRODUCTION	386
Electronic Medical Record	386
Communication Skills	387
MEDICAL INTERVIEW	387
Chief Complaint and Present Illness	387
Major Pulmonary Symptoms	388
Dyspnea	388
Clinical Features.	388
Cough	389
Clinical Features.	389
Hemoptysis	389
e9781416047100v2	1209
Front cover	1209
Murray and Nadel's Textbook of Respiratory Medicine	1210
Copyright page	1213
Dedication	1214
Contributors	1216
Preface to the Fifth Edition	1228
Preface to the First Edition	1230
Video Contents	1232
Table of Contents	1234
III - Continued Clinical Respiratory Medicine	1240
J Neoplasms of the Lung	1240
45 Biology of Non–Small Cell Lung Cancer	1240
INTRODUCTION	1240
PREDISPOSITION TO LUNG CANCER	1241
Smoking	1241
Genetic Susceptibility and Familial Predisposition	1241
EARLY EVENTS IN LUNG TUMORIGENESIS	1242
Mucosal Response to Injury, the Emergence of Critical Mutations	1242
Mutagens	1243
The Field Cancerization Effect	1244
Genomic Instability	1244
Role of Inflammation in Lung Tumorigenesis	1245
Role of Viruses in Lung Tumorigenesis	1246
OTHER MOLECULAR ALTERATIONS DRIVING THE TUMOR PHENOTYPE	1246
Chromosomal Changes	1246
Epigenetic Alterations of Gene Expression in Lung Cancer	1247
DNA Adducts	1247
DNA Methylation	1248
Histone Acetylation	1248
Expression Arrays	1248
RNA Regulation by miRNA	1249
Proteomic Alterations	1249
High-Throughput Profiling Techniques	1249
Molecular Networks, Pathway Analyses	1249
TRANSLATING LUNG CANCER BIOLOGY TO THE CLINIC	1250
Biomarkers	1250
Molecular Therapeutics	1251
EGFR Antagonists	1251
VEGF	1251
p53	1252
K-ras: Farnesyl Transferase Inhibitors	1252
COX-2 Inhibition	1252
References	1253
46 Epidemiology of Lung Cancer	1258
INTRODUCTION	1258
PATTERNS OF OCCURRENCE	1258
Temporal Trends	1258
Race and Ethnicity	1259
Geographic Patterns	1260
Lung Cancer Occurrence by Histologic Type	1260
THE ETIOLOGY OF LUNG CANCER: OVERVIEW	1262
ENVIRONMENTAL AND OCCUPATIONAL AGENTS	1263
Smoking	1263
Overview	1263
Quantitative Risks	1263
Smoking Cessation	1263
The Changing Cigarette	1263
Passive Smoking	1265
Diet	1265
Environmental Exposures	1266
Occupational Exposures	1266
Asbestos	1266
Radiation	1266
High-LET Radiation: Radon.	1267
Low-LET Radiation: X-Rays and Gamma-Rays.	1267
Air Pollution	1267
Atmospheric Air Pollution	1267
Indoor Air Pollution	1268
HOST FACTORS	1268
Overview	1268
Research Findings on the Genetic Basis of Lung Cancer	1268
Presence of Human Immunodeficiency Virus	1270
Presence of Acquired Lung Disease	1270
Gender	1271
FUTURE DIRECTIONS	1271
References	1271
47 Clinical Aspects of Lung Cancer	1276
INTRODUCTION	1276
SCREENING FOR LUNG CANCER	1277
PRESENTATION	1278
LUNG CANCER STAGING	1279
NONINVASIVE STAGING TECHNIQUES	1280
Chest Radiography	1280
Computed Tomography of the Chest	1280
Positron Emission Tomography	1281
Magnetic Resonance Imaging	1282
The Search for Metastatic Disease	1282
Adrenal and Hepatic Imaging	1283
Brain Imaging	1283
Bone Imaging	1284
Summary	1284
INVASIVE DIAGNOSTIC AND STAGING TECHNIQUES	1284
Sputum Cytology	1284
Transthoracic Needle Aspiration	1284
Fiberoptic Bronchoscopy	1284
Submucosal and Peribronchial Lesions	1285
Bronchoscopy for Staging Lung Cancer	1285
Endoscopic Ultrasound	1285
Endobronchial Ultrasound	1285
Mediastinoscopy	1286
TREATMENT OF LUNG CANCER	1286
Prognostic Factors for Lung Cancer	1287
Non–Small Cell Lung Cancer Treatment by Stage	1288
Stage I	1288
Stage II	1289
Stage IIIA	1290
Stage IIIB	1291
Stage IV	1291
Small Cell Lung Cancer	1292
PALLIATIVE CARE	1293
SPECIAL CONSIDERATIONS IN LUNG CANCER	1294
Superior Sulcus Tumors and Pancoast’s Syndrome	1294
Superior Vena Cava Syndrome	1294
PARANEOPLASTIC SYNDROMES	1295
Musculoskeletal Effects	1295
Hematologic Effects	1295
Hypercalcemia	1296
Syndrome of Inappropriate Antidiuretic Hormone Secretion	1297
Ectopic Corticotropin Syndrome	1298
Neurologic Effects	1298
References	1299
48 Lymphoma, Lymphoproliferative Diseases, and Other Primary Malignant Tumors	1305
INTRODUCTION	1305
CHARACTERIZATION OF RARE LUNG TUMORS	1305
PRIMARY PULMONARY LYMPHOMA AND OTHER LYMPHOPROLIFERATIVE DISEASES	1306
Mucosa-Associated Lymphoid Tissue Lymphoma	1306
Lymphomatoid Granulomatosis	1308
Other Lymphomas and Lymphoproliferative Diseases	1309
Amyloidosis	1309
Nonamyloidotic Monoclonal Immunoglobulin Deposition Disease	1309
CARCINOIDS AND OTHER NEUROENDOCRINE TUMORS	1310
Pathologic Classification	1310
Carcinoid Tumors	1310
Large Cell Neuroendocrine Carcinoma	1311
RARE MALIGNANT PRIMARY PULMONARY EPITHELIAL TUMORS	1311
Mucoepidermoid Carcinoma	1311
Pneumoblastoma	1311
Sarcomatoid Carcinomas (Other Than Pneumoblastoma)	1312
PRIMARY PULMONARY SARCOMAS	1313
Parenchymal Sarcomas	1313
Vascular Sarcomas	1313
LESSONS LEARNED FOR THE MANAGEMENT OF RARE PRIMARY PULMONARY TUMORS	1315
Specific Radioclinical Presentation	1315
Specific Diagnostic Strategy	1315
Distinguishing Primary Tumors from Metastases	1315
General Therapeutic Management	1316
References	1316
49 Metastatic Malignant Tumors	1320
INTRODUCTION	1320
Epidemiology	1320
Clinical History	1320
MECHANISM OF METASTASIS TO THE LUNG	1321
DIAGNOSIS	1322
Differential Diagnosis	1322
Distinguishing Metastases from Primary Lung Tumors	1322
Pathology	1323
Molecular Classification	1323
Options for Obtaining a Tissue Diagnosis	1324
Bronchoscopy	1324
CT-Guided Biopsy	1324
Surgery	1324
TREATMENT OF LUNG METASTASES	1325
Multimodality Therapy of Systemic Disease	1325
Palliative Care	1325
Radiofrequency Ablation of Metastases	1326
Surgical Resection of Metastases	1326
SPECIAL CASES	1328
Airway Metastasis	1328
Vascular Embolic Metastasis	1328
References	1329
50 Benign Lung Tumors	1331
INTRODUCTION	1331
Clinical Manifestations	1331
BENIGN EPITHELIAL LESIONS	1331
Papillomas and Adenomas	1331
Solitary Papillomas	1331
Recurrent Respiratory Papillomatosis	1332
Adenomas	1333
Micronodular Pneumocyte Hyperplasia	1335
Sclerosing Hemangioma	1336
BENIGN NONEPITHELIAL LESIONS	1337
Hamartoma and Related Lesions	1337
Inflammatory Myofibroblastic Tumor	1338
Solitary Fibrous Tumor	1339
Meningothelial-like Nodules and Intrapulmonary Meningioma	1340
Miscellaneous	1340
References	1342
K Disorders of the Pulmonary Circulation	1346
51 Pulmonary Thromboembolism	1346
INTRODUCTION	1346
PATHOGENESIS AND RISK FACTORS	1347
NATURAL HISTORY: DEEP VENOUS THROMBOSIS	1349
NATURAL HISTORY: PULMONARY EMBOLISM	1349
CLINICAL PRESENTATION	1351
DIAGNOSIS OF VENOUS THROMBOSIS	1352
Contrast Venography	1352
Duplex Ultrasonography	1352
Impedance Plethysmography	1353
Magnetic Resonance Imaging	1353
Computed Tomography	1354
Hemostaseologic Assays	1354
Clinical Prediction Rules	1354
DIAGNOSIS OF PULMONARY EMBOLISM	1354
Standard Laboratory Evaluation	1355
Echocardiography	1356
Ventilation-Perfusion Scanning	1356
Spiral (Helical) Computed Tomography	1357
Lower Extremity Venous Evaluation	1359
d-Dimer Testing	1359
Pulmonary Angiography	1359
Clinical Prediction Rules	1360
PREVENTION OF VENOUS THROMBOEMBOLISM	1362
Low-Dose Unfractionated Heparin	1362
Low-Molecular-Weight Heparin	1362
Pneumatic Compression Devices	1362
Sodium Warfarin	1362
Miscellaneous Agents	1363
MANAGEMENT OF VENOUS THROMBOEMBOLISM	1363
Heparin	1363
Inferior Vena Cava Filters	1364
MASSIVE PULMONARY EMBOLISM	1365
Thrombolytic Therapy	1365
Pulmonary Embolectomy	1366
POSTEMBOLIC PROPHYLAXIS	1366
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION	1367
Diagnosis	1367
Treatment	1370
OTHER FORMS OF EMBOLISM	1374
Schistosomiasis	1374
Air Embolism	1374
Fat Embolism	1375
Amniotic Fluid Embolism	1375
Septic Embolism	1376
Other Emboli	1376
References	1376
52 Pulmonary Hypertension	1384
INTRODUCTION	1384
CLASSIFICATION	1384
EPIDEMIOLOGY	1384
PATHOLOGY	1385
PATHOGENESIS AND ETIOLOGY	1386
OTHER FORMS OF PULMONARY ARTERIAL HYPERTENSION	1387
SYMPTOMS	1388
PHYSICAL FINDINGS	1389
DIAGNOSIS	1389
TREATMENT AND PROGNOSIS	1392
Supportive Therapies	1392
Exercise and Physical Activity	1392
Avoidance of Altitude	1392
Avoidance of Pregnancy	1392
Warfarin	1392
Supplemental Oxygen	1393
Diuretics	1393
Calcium Channel Antagonists	1394
Targeted Therapies	1394
Prostacyclin Analogues	1395
Epoprostenal.	1395
Treprostinil Sodium.	1396
Iloprost.	1396
Endothelin Receptor Antagonists	1396
Bosentan.	1396
Ambrisentan.	1397
Phosphodiesterase Type 5 Inhibitors	1397
Sildenafil.	1397
Combination Therapy	1397
Lung Transplantation	1398
Overall Therapeutic Strategy: Challenges	1400
Survival	1400
Experimental Therapies	1400
References	1401
53 Pulmonary Vasculitis	1404
INTRODUCTION	1404
CLASSIFICATION	1404
EPIDEMIOLOGY	1405
NORMAL VASCULAR ANATOMY AND HISTOLOGY	1405
HISTOPATHOLOGY OF VASCULITIS	1406
PATHOGENESIS AND ETIOLOGY	1407
THE INITIAL DIAGNOSIS	1407
Clinical Scenarios Suggestive of Vasculitis	1407
Destructive Upper Airway Lesions	1407
Chest Imaging Findings of Cavitary or Nodular Disease	1408
Diffuse Alveolar Hemorrhage	1408
Acute Glomerulonephritis	1408
Pulmonary-Renal Syndrome	1409
Palpable Purpura	1409
Mononeuritis Multiplex	1409
Multisystem Disease	1409
Specific Testing	1409
Antinuclear Cytoplasmic Antibodies	1409
Other Laboratory Studies	1410
Chest Imaging	1410
Bronchoscopy	1410
Diagnostic Biopsy	1410
SPECIFIC CLINICAL DISORDERS	1411
Necrotizing Granulomatous Vasculitis (Formerly Wegener’s Granulomatosis)	1411
Churg-Strauss Syndrome	1411
Microscopic Polyangiitis	1414
TREATMENT	1415
General Principles	1415
Remission-Induction	1415
Limited Disease	1415
Early Generalized Disease	1415
Active Generalized Disease	1415
Severe Disease	1416
Refractory Disease	1416
Maintenance	1416
Monitoring for Complications	1416
References	1417
54 Pulmonary Arteriovenous Malformations and Other Vascular Abnormalities	1421
INTRODUCTION	1421
PULMONARY ARTERIOVENOUS MALFORMATIONS	1421
Etiology	1422
Hereditary Hemorrhagic Telangiectasia	1423
Clinical Features and Diagnosis.	1423
Genetics and Pathogenesis.	1423
Phenotype-Genotype Correlations.	1424
Cavopulmonary Shunts.	1424
Pathophysiology	1425
Anatomic Basis	1425
Physiologic Attributes at Rest	1425
Right-to-Left Shunt.	1425
Pulmonary Hemodynamics.	1425
Pulmonary Function.	1426
Physiologic Consequences of Posture and Exercise	1426
Posture.	1426
Exercise.	1426
Pulmonary Hypertension	1426
Clinical Features	1427
Respiratory Symptoms	1427
Dyspnea.	1427
Hemoptysis.	1427
Chest Pain.	1427
Strokes and Cerebral Abscess	1427
Migraines	1428
Pregnancy	1428
Diagnosis	1428
Radiology	1428
Measurement of Right-to-Left Shunt	1429
100% Oxygen Breathing.	1429
Radiolabeled Particles.	1429
Contrast Echocardiography.	1429
Screening Patients	1431
Management	1431
Embolization	1431
Long-Term Outcome.	1431
Physiologic Outcome.	1432
Clinical Outcome.	1432
Risks of Embolization	1433
Development of Systemic Arterial Supply.	1433
Development of Pulmonary Hypertension.	1433
Nonembolization Options	1433
Surgery.	1433
Medical Management	1434
Dental Issues.	1434
Pregnancy.	1434
Thromboembolic Risks.	1434
SYSTEMIC-TO-PULMONARY VASCULAR COMMUNICATIONS	1434
Anatomy	1434
Adult (Acquired) Systemic-to-Pulmonary Communications	1435
Fetal- and Perinatal Systemic-to-Pulmonary Artery Collaterals	1435
Aberrant Congenital Systemic-to-Pulmonary Communications	1435
Cavopulmonary Anastomoses	1435
Treatment	1435
Managements of Hemoptysis	1436
BRONCHOPULMONARY SEQUESTRATION	1436
Classification	1436
Pathogenesis	1436
Clinical Features	1436
Treatment	1437
PULMONARY ARTERY ANEURYSMS	1437
Etiology and Pathogenesis	1438
Infection	1438
Vascular Trauma	1438
Weakness of the Arterial Wall	1438
Diagnosis and Treatment	1438
References	1439
55 Pulmonary Edema and Acute Lung Injury	1444
INTRODUCTION	1444
PATHOPHYSIOLOGY OF PULMONARY EDEMA AND ACUTE LUNG INJURY	1444
Increased Pressure Edema	1446
Pathophysiology	1446
Mechanisms	1448
Increased Microvascular Hydrostatic Pressure.	1448
Decreased Perimicrovascular Hydrostatic Pressure.	1450
Decreased Transmural Osmotic Pressure Difference.	1450
Alveolar Barrier Function.	1450
Increased Permeability Edema and Acute Lung Injury	1451
Pathophysiology	1452
Mechanisms	1454
Infection.	1455
Inflammation.	1455
Direct Toxicity.	1456
Host Factors.	1457
DIAGNOSIS	1457
Clinical Assessment	1457
Symptoms and Signs	1457
Diagnostic Studies and Definitions	1458
Chest Radiographs	1460
Arterial Blood Studies	1460
Pulmonary Edema Fluid Protein Concentration Measurement	1460
Pulmonary Function Tests	1461
Hemodynamic Measurements	1461
Measurement of Lung Water and Barrier Function	1461
Lung Density Methods	1461
Tracer Methods	1462
Multiple-Indicator Dilution Techniques.	1462
Measurement of Barrier Function	1462
Detection of Lung Injury	1462
Changes in Metabolic Functions of the Lung	1462
Biologic Markers of Lung Injury	1463
TREATMENT	1464
Immediate Therapy	1464
Hydrostatic Pulmonary Edema	1464
Major Options	1464
Vasodilators	1465
Diuretics	1466
Inotropic Agents	1466
Therapeutic Strategy	1467
Increased Pressure Edema	1468
Increased Permeability Edema	1468
Lung-Protective Ventilator Strategies.	1469
Specific Pharmacologic Therapies.	1470
Corticosteroids.	1471
Surfactant.	1471
Antioxidants.	1472
Pentoxifylline.	1472
Treatments for Sepsis.	1472
Prostaglandin E1 and Inhaled Nitric Oxide.	1473
OUTCOME	1473
Resolution of Edema	1473
Increased Pressure Edema	1474
Increased Permeability Edema	1475
overview	1476
References	1477
56 Cor Pulmonale	1487
INTRODUCTION	1487
PULMONARY CIRCULATION	1487
Pulmonary Artery Pressure	1489
Pulmonary Artery Wedge Pressure	1489
PATHOPHYSIOLOGY OF THE PULMONARY CIRCULATION	1490
Hypoxic Pulmonary Vasoconstriction	1490
Pulmonary Vascular Remodeling	1491
RIGHT VENTRICLE	1492
LEFT VENTRICLE	1494
NEUROHORMONES	1495
Angiotensin II	1496
NATRIURETIC PEPTIDES	1496
ENDOTHELIN-1	1497
SYMPTOMS AND SIGNS	1497
Chest Radiograph	1498
Electrocardiogram	1498
Echocardiography	1499
Computed Tomography	1500
Magnetic Resonance Imaging	1501
Hemodynamics	1501
DIFFERENTIAL DIAGNOSIS	1501
TREATMENT	1502
Oxygen	1504
Vasodilators	1504
Endothelin Receptor Antagonists	1505
Prostacyclin and Its Analogues	1506
Oral Phosphodiesterase V Inhibitors	1507
Nitric Oxide	1508
Angiotensin-Converting Enzyme Inhibitors	1509
Natriuretic Peptides	1509
Nonglycoside Inotropes	1509
Surgery	1509
Atrial Septostomy	1510
NATURAL HISTORY	1510
References	1512
L Infiltrative and Interstitial Lung Diseases	1517
57 Idiopathic Interstitial Pneumonias	1517
INTRODUCTION	1517
CLINICAL AND HISTOLOGIC CLASSIFICATION OF INTERSTITIAL LUNG DISEASE	1517
CLINICAL, RADIOLOGIC, AND PHYSIOLOGIC FEATURES OF INTERSTITIAL LUNG DISEASES	1519
Past History	1519
Occupational History	1519
Drug History	1520
Smoking History	1520
Family History	1520
Gender	1520
Symptoms	1520
Physical Findings	1520
Radiographic Features	1520
Plain Roentgenography	1521
Alveolar Filling Pattern (Table 57-4).	1521
Interstitial Pattern.	1522
Nodular Pattern.	1522
Linear or Reticular.	1522
Other Radiographic Features.	1523
Computed Tomography	1524
Functional Assessment	1526
Ventilatory Function	1526
Elastic Resistance	1526
Flow Resistance	1527
Gas Exchange	1527
Exercise	1528
Laboratory Findings	1529
Bronchoalveolar Lavage	1529
Histologic Diagnosis	1530
Transbronchial Biopsy	1530
Surgical Lung Biopsy	1530
DIAGNOSIS AND MANAGEMENT OF THE IDIOPATHIC INTERSTITIAL PNEUMONIAS	1530
Idiopathic Pulmonary Fibrosis	1531
Clinical Features	1531
Blood and Serologic Studies	1532
Chest Imaging Studies	1532
Chest Roentgenography.	1532
Computed Tomography Scan.	1532
Other Imaging Techniques	1533
Gallium Scanning.	1533
Ventilation-Perfusion Lung Scanning.	1533
Magnetic Resonance Imaging for Differentiating Inflammation and Fibrosis	1534
Imaging of Fibrogenesis by Positron Emission Tomography.	1534
Pulmonary Function Tests	1534
Pulmonary Hemodynamics	1535
Abnormalities during Sleep	1535
Histopathology	1536
Etiologic Factors and Pathogenic Mechanisms	1537
Diagnosis	1538
Staging of Disease Activity and Predicting Outcome	1539
Clinical Features.	1539
Serum Studies.	1539
Chest Roentgenography and High-Resolution Computed Tomography Scanning.	1539
Pulmonary Physiologic Tests.	1539
Bronchoalveolar Lavage.	1539
Histopathology.	1540
Prediction Models.	1540
Outcome and Causes of Death.	1540
Therapeutic Approach	1541
Corticosteroids.	1541
Immunomodulatory and Antifibrotic Agents.	1541
Azathioprine.	1541
N-Acetylcysteine.	1541
Cyclophosphamide.	1541
Other Agents.	1541
New Therapeutic Approaches.	1542
Interferon-γ.	1542
Pirfenidone.	1542
Endothelin-Receptor Antagonists.	1542
Etanercept.	1542
Lung Transplantation	1542
Rehabilitation	1543
Acute Exacerbations of Interstitial Pulmonary Fibrosis	1543
Familial Pulmonary Fibrosis	1544
Nonspecific Interstitial Pneumonia	1544
Clinical Features	1544
Chest Imaging Studies	1544
Chest Roentgenography.	1544
Computed Tomography Scan.	1544
Pulmonary Function Tests	1545
Pathologic Features	1545
Differential Diagnosis	1545
Clinical Course and Outcome	1546
Respiratory Bronchiolitis–Associated Interstitial Lung Disease/Desquamative Interstitial Pneumonia	1546
Clinical Features	1546
Chest Imaging Studies	1546
Chest Roentgenography.	1546
Computed Tomography Scan.	1546
Bronchoalveolar Lavage	1546
Pulmonary Function Tests	1546
Pathologic Features	1547
Clinical Course and Outcome	1548
Acute Interstitial Pneumonia	1548
Clinical Features	1548
Chest Imaging Studies	1548
Chest Roentgenography.	1548
Computed Tomography Scan.	1548
Pulmonary Function Tests	1548
Pathologic Features	1548
Clinical Course and Outcome	1549
Cryptogenic Organizing Pneumonia	1549
Clinical Features	1549
Chest Imaging Studies	1549
Chest Roentgenography.	1549
Computed Tomography Scan.	1549
Pulmonary Function Tests	1550
Bronchoalveolar Lavage	1550
Pathologic Features	1550
Clinical Course and Outcome	1550
Lymphocytic Interstitial Pneumonia	1551
Clinical Features	1551
Chest Imaging Studies	1551
Chest Roentgenography.	1551
Computed Tomography Scan.	1551
Pulmonary Function Tests	1552
Bronchoalveolar Lavage	1552
Pathologic Features	1552
Clinical Course and Outcome	1552
Conclusion	1552
References	1553
58 The Lungs and Connective Tissue Diseases	1559
INTRODUCTION	1559
SYSTEMIC SCLEROSIS (SCLERODERMA)	1559
Epidemiology and Risk Factors	1559
Chemically Induced Scleroderma-like Disorders	1560
Pulmonary Manifestations	1561
Interstitial Pulmonary Fibrosis	1561
Pathogenesis.	1561
Predisposition.	1561
Inflammation Amplification.	1561
Fibrogenetic Factors.	1561
Clinical Features.	1562
Imaging.	1562
Lung Function Tests.	1562
Bronchoalveolar Lavage.	1563
Biopsy.	1563
Serologic Investigations.	1564
Prognosis.	1565
Treatment.	1565
Pulmonary Vascular Disease in Systemic Sclerosis	1566
Other Pulmonary Complications	1566
RHEUMATOID ARTHRITIS	1567
Epidemiology and Risk Factors	1567
Pulmonary Manifestations	1567
Interstitial Pulmonary Fibrosis	1567
Organizing Pneumonia	1568
Obliterative Bronchiolitis	1569
Follicular Bronchiolitis	1570
Bronchiectasis	1570
Pulmonary Vasculitis	1570
Pulmonary Rheumatoid Nodules	1570
Pleural Disease	1571
Other Pulmonary Complications	1571
Drug-Induced Pulmonary Disease	1571
Pulmonary Function Tests	1571
Radiologic Features	1571
Treatment of Pulmonary Complications	1572
SYSTEMIC LUPUS ERYTHEMATOSUS	1572
Epidemiology and Risk Factors	1572
Pulmonary Manifestations	1572
Diffuse Lung Disease	1573
Interstitial Pneumonia.	1573
Acute Lupus Pneumonitis.	1573
Extrapulmonary Restriction	1573
Diffuse Alveolar Hemorrhage	1573
Pulmonary Hypertension	1574
Pleural Disease	1574
SJÖGREN’S SYNDROME	1574
Epidemiology and Risk Factors	1574
Pulmonary Manifestations	1574
Diffuse Lung Disease	1575
Tracheobronchial Disease	1575
POLYMYOSITIS AND DERMATOMYOSITIS	1576
Epidemiology and Risk Factors	1576
Pulmonary Manifestations	1576
Diffuse Lung Disease	1576
Clinical Features.	1576
Imaging.	1577
Pulmonary Function.	1577
Bronchoalveolar Lavage.	1577
Laboratory Tests.	1577
Other Pulmonary Manifestations	1577
Treatment of Pulmonary Complications	1578
MIXED CONNECTIVE TISSUE DISEASE	1578
UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE	1578
RELAPSING POLYCHONDRITIS	1578
BEHÇET’S SYNDROME	1580
ANKYLOSING SPONDYLITIS	1581
MARFAN SYNDROME	1581
References	1582
59 Sarcoidosis	1588
INTRODUCTION	1588
BACKGROUND	1588
EPIDEMIOLOGY	1588
ETIOLOGY AND PATHOGENESIS	1589
Environment	1589
Spatial and Temporal Clustering	1589
Infectious Agents	1589
Immunology	1590
Autoantigens	1590
Immune Response	1590
Fibrosis	1591
Anergy	1591
Genetics	1591
Familial Clustering	1591
HLA Class II Associations	1591
Other Candidate Genes	1592
CLINICAL PRESENTATION	1592
Acute Sarcoidosis	1592
Chronic Sarcoidosis	1592
CLINICAL FEATURES AND DIAGNOSIS	1592
Pulmonary Sarcoidosis	1592
Extrapulmonary Sarcoidosis	1596
Ears, Nose, and Throat	1596
Peripheral Lymph Nodes	1597
Heart	1597
Skin	1597
Eyes	1597
Nervous System	1597
Endocrine Glands	1598
Parotid Gland	1598
Liver and Spleen	1598
Joints	1598
Blood	1598
Other Sites	1598
DIFFERENTIAL DIAGNOSIS	1598
EVALUATION AND MANAGEMENT	1600
TREATMENT	1601
Corticosteroids	1601
Other Immunosuppressive Agents	1603
Methotrexate	1603
Cyclosporin A	1603
Azathioprine	1603
Antimalarials	1603
Cyclophosphamide	1604
Anti–Tumor Necrosis Factor-α Therapy	1604
Combination Treatment Regimens	1604
Management of Treatment Complications: Aspergilloma	1605
Lung Transplantation	1605
References	1606
60 Diffuse Alveolar Hemorrhage and Rare Infiltrative Disorders of the Lung	1610
INTRODUCTION	1610
DIFFUSE ALVEOLAR HEMORRHAGE	1610
DEFINITION	1610
CLINICAL PRESENTATION	1611
History and Physical Examination	1611
Radiology and Laboratory Evaluation	1611
Physiology	1611
CLASSIFICATION SCHEMA	1612
DIAGNOSTIC APPROACH	1613
Diagnosis of Diffuse Alveolar Hemorrhage	1613
Diagnosis of Underlying Cause	1613
Role of Surgical Lung Biopsy	1613
SPECIFIC CAUSES OF DIFFUSE ALVEOLAR HEMORRHAGE	1615
Vasculitis	1615
Wegener’s Granulomatosis	1615
Microscopic Polyangiitis	1616
Isolated Pulmonary Capillaritis	1616
Mixed Cryoglobulinemia	1616
Behçet’s Syndrome	1616
Henoch-Schönlein Purpura	1617
Pauci-immune Glomerulonephritis	1617
Immunologic	1617
Goodpasture’s Syndrome	1617
Connective Tissue Disease	1618
Immune Complex–Related Crescentic Glomerulonephritis	1619
Acute Pulmonary Allograft Rejection	1619
Coagulation Disorders	1619
Idiopathic Pulmonary Hemosiderosis	1619
Other Causes of Diffuse Alveolar Hemorrhage	1620
Drugs/Toxins	1620
Diffuse Alveolar Damage	1620
Mitral Stenosis	1621
Pulmonary Veno-occlusive Disease	1621
Pulmonary Capillary Hemangiomatosis	1621
Lymphangioleiomyomatosis and Tuberous Sclerosis	1622
RARE INFILTRATIVE DISORDERS OF THE LUNG	1622
Neurofibromatosis	1622
Hermansky-Pudlak Syndrome	1622
Dyskeratosis Congenita	1623
Gaucher’s Disease	1623
Niemann-Pick Disease	1623
Pulmonary Alveolar Microlithiasis	1623
References	1625
61 Eosinophilic Lung Diseases	1630
INTRODUCTION	1630
EOSINOPHIL BIOLOGY	1630
GENERAL FEATURES OF EOSINOPHILIC PNEUMONIAS	1632
Historical Perspective	1632
Clinical Presentation	1632
Pathology	1632
Diagnosis	1633
EOSINOPHILIC LUNG DISEASE OF UNDETERMINED CAUSE	1634
Idiopathic Chronic Eosinophilic Pneumonia	1634
Clinical Features	1634
Imaging	1634
Laboratory Studies	1635
Bronchoalveolar Lavage	1635
Differential Diagnosis	1635
Lung Function Tests	1635
Treatment and Prognosis	1635
Idiopathic Acute Eosinophilic Pneumonia	1636
Clinical Features	1636
Imaging	1636
Laboratory Studies	1637
Bronchoalveolar Lavage	1637
Lung Function Tests	1637
Lung Biopsy	1637
Treatment and Prognosis	1637
Churg-Strauss Syndrome	1637
Clinical Features	1638
Imaging	1638
Laboratory Studies	1638
Pathogenesis	1639
Diagnosis	1640
Differential Diagnosis	1640
Treatment and Prognosis	1641
Hypereosinophilic Syndrome	1641
Pathogenensis	1641
Clinical Features	1642
Imaging	1642
Laboratory Studies	1643
Treatment and Prognosis	1643
EOSINOPHILIC LUNG DISEASE OF DETERMINED CAUSE	1643
Eosinophilic Pneumonias of Parasitic Origin	1643
Tropical Eosinophilia	1643
Clinical Features.	1643
Pathogenesis.	1643
Laboratory Studies.	1643
Treatment.	1644
Ascaris Pneumonia	1644
Eosinophilic Pneumonia in Larva Migrans Syndrome	1644
Strongyloides stercoralis Infection	1644
Eosinophilic Pneumonias in Other Parasitic Infections	1645
Eosinophilic Pneumonias of Other Infectious Causes	1645
Allergic Bronchopulmonary Aspergillosis and Related Syndromes	1645
Allergic Bronchopulmonary Aspergillosis	1645
Pathogenesis.	1645
Clinical Features.	1646
Imaging.	1646
Treatment.	1646
Other Allergic Bronchopulmonary Syndromes Associated with Fungi or Yeasts	1647
Bronchocentric Granulomatosis	1647
Drug, Toxic Agents, and Radiation-Induced Eosinophilic Pneumonias	1647
Drugs	1647
Toxic Oil Syndrome	1647
Radiation Therapy	1648
MISCELLANEOUS LUNG DISEASES WITH ASSOCIATED EOSINOPHILIA	1648
Organizing Pneumonia	1648
Asthma and Eosinophilic Bronchitis	1649
Idiopathic Interstitial Pneumonias	1649
Langerhans Cell Granulomatosis	1649
Lung Transplantation	1649
Other Lung Diseases with Occasional Eosinophilia	1649
References	1650
62 Lymphangioleiomyomatosis	1657
INTRODUCTION	1657
EPIDEMIOLOGY	1657
GENETIC AND MOLECULAR BASIS OF TUBEROUS SCLEROSIS COMPLEX AND LYMPHANGIOLEIOMYOMATOSIS	1658
Inheritance	1658
Molecular Pathogenesis	1659
Tumor Suppressor Proteins Control Cell Growth	1659
The Tuberous Sclerosis Complex Proteins Regulate Signaling through the Akt Pathway	1659
Tuberous Sclerosis Complex Mutations Are Found in the Lung and Kidney Lesions of Patients with Sporadic Lymphangioleiomyomatosis	1659
Genetic Evidence Suggests That Lymphangioleiomyomatosis is a Metastatic Neoplasm	1660
Role of Lymphangiogenesis and Lymphatic Spread in Dissemination of Lymphangioleiomatosis	1661
Mechanisms of Matrix Remodeling in Lymphangioleiomyomatosis	1661
Preclinical Evidence and Human Trials	1661
Estrogen	1661
Sirolimus	1661
CLINICAL FEATURES	1662
PHYSICAL EXAMINATION	1663
IMAGING STUDIES	1663
PULMONARY FUNCTION TESTING	1665
PATHOLOGY	1665
DIAGNOSIS	1667
Clinical Diagnosis	1667
Differential Diagnosis	1667
Lung Biopsy	1668
TREATMENT	1668
General Recommendations	1668
Pregnancy	1669
Air Travel	1669
Pleural Disease	1670
Pulmonary Transplantation	1670
Angiomyolipomas	1670
PROGRESSION AND PROGNOSIS	1670
FUTURE CLINICAL TRIALS IN LYMPHANGIOLEIOMYOMATOSIS	1671
References	1672
63 Pulmonary Alveolar Proteinosis Syndrome	1677
INTRODUCTION	1677
PATHOGENESIS	1678
Surfactant Composition and Homeostasis	1678
Granulocyte-Macrophage Colony-Stimulating Factor	1678
Murine Models of Disordered Surfactant Homeostasis	1678
Historical Overview of Human Disorders of Surfactant Homeostasis	1679
Role of GM-CSF Autoantibodies	1680
Genetic Factors	1681
Disease Associations	1682
Environmental Factors	1683
Mechanisms of Disruption of Surfactant Homeostasis	1683
NOMENCLATURE AND CLASSIFICATION	1684
EPIDEMIOLOGY	1685
CLINICAL PRESENTATION	1686
EVALUATION AND DIFFERENTIAL DIAGNOSIS	1686
Radiographic Appearance	1686
Pulmonary Function Testing	1687
Bronchoscopy, Bronchoalveolar Lavage, and Transbronchial Biopsy	1687
Surgical Lung Biopsy	1688
Laboratory Studies	1689
Approach to Diagnosis	1690
NATURAL HISTORY	1690
Secondary Infections	1690
Pulmonary Fibrosis	1690
Spontaneous Resolution	1690
TREATMENT	1690
Autoimmune PAP	1691
Whole-Lung Lavage	1691
Granulocyte-Macrophage Colony-Stimulating Factor	1692
Other Approaches	1692
Familial PAP	1693
Secondary PAP	1693
Surfactant Metabolic Dysfunction Disorders	1693
GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS	1693
Etiology	1693
Clinical Practice Guidelines	1693
Novel Therapeutic Approaches	1693
Conclusion	1693
References	1694
M Environmental and Occupational Disorders	1698
64 Asthma in the Workplace and Occupational Asthma	1698
INTRODUCTION	1698
DEFINITION AND CLASSIFICATION	1698
HISTORICAL ASPECTS	1699
ETIOLOGIC AGENTS	1700
GENETIC, PHYSIOPATHOLOGIC ASPECTS, AND ANIMAL MODELS	1700
Genetics	1700
Physiopathology	1701
Occupational Asthma with a Latency Period	1701
Immunologic, Immunoglobulin E–Mediated.	1702
Immunologic, Non–Immunoglobulin E– Mediated.	1702
Occupational Asthma without a Latency Period	1702
Role of Irritant Exposure in Sensitization	1703
Animal Models	1703
Occupational Asthma with a Latency Period	1703
Occupational Asthma without a Latency Period	1704
FREQUENCY	1704
DIAGNOSIS	1706
EXPOSURE AND ENVIRONMENTAL MONITORING	1707
MEDICOLEGAL ASPECTS AND COMPENSATION ISSUES	1708
PREVENTION AND SURVEILLANCE	1708
Primary Prevention	1708
Secondary Prevention	1709
Tertiary Prevention	1709
IRRITANT-INDUCED ASTHMA AND REACTIVE AIRWAY DYSFUNCTION SYNDROME	1709
ACKNOWLEDGMENTS	1710
References	1711
65 Pneumoconioses and Other Mineral Dust–Related Diseases	1715
INTRODUCTION	1716
Definitions	1716
Accumulation of Dust in the Lung and Tissue Reactions	1716
Exposure-Response Relationships	1716
Chest Imaging	1716
Clinical Issues, Lung Function, and Principles of Management	1717
Epidemiology and Implications for Clinical Practice	1718
SILICOSIS	1719
Definition	1719
Industries and Occupations Still at Risk	1719
Pathology	1719
Pathogenesis	1720
Epidemiology: Secular Trends and Their Implications for the Clinician	1721
Tuberculosis	1722
Airflow Obstruction and Chronic Bronchitis	1722
Connective Tissue Diseases and Renal Disease	1722
Lung Cancer	1722
Clinical Features	1722
Radiographic Features	1723
Lung Function	1724
Diagnosis and Complications	1724
Management and Control	1724
COAL WORKERS’ PNEUMOCONIOSIS	1725
Definition and Occupations at Risk	1725
Pathology	1725
Pathogenesis	1727
Epidemiology and Natural History	1727
Rheumatoid Pneumoconiosis	1727
Role of Silica	1727
Airflow Obstruction and Chronic Bronchitis	1728
Tuberculosis and Cancer	1728
Clinical Features	1728
Chest Radiography	1728
Lung Function	1729
Diagnosis, Complications, and Management	1729
ASBESTOS-RELATED FIBROSIS OF THE LUNGS (ASBESTOSIS) AND PLEURA	1729
Asbestos Minerals	1729
History and Uses	1729
Sources of Human Exposure	1731
The Fate of Inhaled Fibers	1731
Exposure versus Dose-Response Relationships	1732
Asbestosis (Pulmonary Parenchymal Fibrosis)	1732
Pathology and Pathogenesis	1732
Epidemiology and Natural History	1733
Clinical Features	1733
Radiographic Features	1733
Lung Function	1734
Diagnosis and Complications	1734
Asbestosis, Asbestos Exposure, Lung Cancer, and Mesothelioma	1734
Pleural Plaques	1736
Pathology and Pathogenesis	1736
Clinical Features	1736

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