Front Cover 1
Title page 
2 
Copyright page 
3 
Contributors 4
Editor 4
Authors 4
Contents 8
Forthcoming Issues 13
Forthcoming Issues 13
June 2014 13
September 2014 13
December 2014 13
Recent Issues 13
December 2013 13
September 2013 13
June 2013 13
Chronic Obstructive Pulmonary Disease 14
COPD 16
Key points 16
Definition 16
Diagnostic criteria 17
ATS 1995 16
ERS 1995 16
Considerations for future diagnostic criteria 18
COPD phenotypes 19
Specific COPD phenotypes 19
References 20
Epidemiology and Prevalence of Chronic Obstructive Pulmonary Disease 22
Key points 22
Introduction 22
Definition of COPD 22
Measures of Airflow Limitation and Reversibility 23
Clinical Features and Overlap Syndromes 23
Risk factors 23
Active and Passive Cigarette Smoking 23
Occupational Risk Factors 24
Air Pollution 24
Genetic Factors 24
Prevalence of COPD 24
Criteria and Impact on Disease Prevalence 24
Prevalence Estimates 25
Prevalence of COPD and Gender Differences 26
Burden of COPD and mortality 26
Summary 29
References 29
Tobacco Smoking and Environmental Risk Factors for Chronic Obstructive Pulmonary Disease 32
Key points 32
Introduction 32
Tobacco smoking 33
Second-hand smoke or environmental tobacco smoke 34
Exposure to indoor biomass fuel smoke 35
Other indoor air pollutants 36
Occupational COPD 37
Farming 37
Other Occupations Associated with COPD 38
Outdoor air pollution 39
Summary 39
References 40
Genetic Susceptibility 44
Key points 44
Introduction 44
Unbiased approaches 45
Candidate gene approaches 45
The Extracellular Matrix 45
Protease-Antiprotease Balance 46
Reactive Oxygen Species 47
Inflammation 48
Summary 49
References 49
Alpha1-antitrypsin Review 54
Key points 54
Prevalence 54
Clinical impact 55
Pathophysiology 56
Susceptibility of Other Phenotypes 57
Augmentation 58
New treatments 61
Recombinant A1AT 61
Secretion Strategies 61
Gene Therapies 61
Drugs 61
Biomarkers 61
Summary 62
References 62
Chronic Obstructive Pulmonary Disease 66
Key points 66
Introduction 66
Mild COPD 66
Clinical Relevance 66
Resting Physiologic Abnormalities in Mild COPD 67
Small airways dysfunction 67
Ventilation-perfusion abnormalities 68
Responses to Exercise in Mild COPD 69
High ventilatory requirements 69
Impairment of dynamic respiratory mechanics 69
Cardiocirculatory impairment 69
Skeletal muscle dysfunction 71
Moderate-to-severe COPD 71
Resting Physiologic Abnormalities in Moderate-to-Severe COPD 71
Progression of resting lung hyperinflation 71
Pulmonary gas exchange abnormalities 72
Responses to Exercise in Moderate-to-Severe COPD 72
Increased central respiratory drive 72
Dynamic respiratory mechanics across the continuum of COPD 73
Cardiocirculatory impairment 74
Skeletal muscle dysfunction 76
Physiologic mechanisms of dyspnea in COPD 76
Summary 77
References 78
Cellular and Molecular Mechanisms of Chronic Obstructive Pulmonary Disease 86
Key points 86
Introduction 86
Pathology 86
COPD as an inflammatory disease 87
Inflammatory cells 87
Epithelial cells 87
Macrophages 87
Neutrophils 89
Eosinophils 89
Dendritic cells 89
T lymphocytes 90
Mediators of inflammation 90
Lipid Mediators 90
Cytokines 90
Chemokines 91
Growth Factors 91
Proteases 91
Oxidative stress 92
Systemic inflammation in COPD 93
Acute Phase Proteins 94
Cytokines 94
Defective resolution of inflammation and repair 94
Proresolving Lipid Mediators 95
Accelerated Aging 95
Airway Fibrosis 95
Implications for future therapy 95
Reversal of Corticosteroid Resistance 95
New Antiinflammatory Therapies 96
New Pathways 96
The Need for Biomarkers 96
Disease Phenotypes 96
Treating Acute Exacerbations 97
References 97
Role of Infections 102
Key points 102
Introduction 102
Acute infection 103
Causes of Exacerbations 103
Virus 103
Bacteria 104
Coinfection with virus and bacteria 106
Community-acquired Pneumonia 106
Epidemiology 106
Causes of CAP in COPD 106
Role of inhaled corticosteroids 106
Antimicrobial therapy in COPD and CAP 107
Chronic infection 107
Vicious-circle Hypothesis 107
Evidence to Support Chronic Infection 108
Mechanism of Increased Susceptibility to Infection in COPD 109
Host Defects: Innate Immunity 109
Mucociliary clearance 109
Immunoglobulin A 109
Antimicrobial peptides 109
Macrophage function 110
Pathogen Mechanisms 111
Tissue invasion 111
Biofilm formation 111
Antigenic alteration 111
Future directions 111
References 111
Comorbidities and Systemic Effects of Chronic Obstructive Pulmonary Disease 116
Key points 116
Introduction 116
Classification 116
Cardiovascular disease 116
Prevalence 117
Pathogenesis 117
Inflammation 117
Hypoxia 119
Effect of cigarette smoking 119
Polycythemia 119
Hypercapnic acidosis 119
Abnormalities in vascular endothelial function/vessel wall 120
Common Cardiovascular Complications 120
Interventions to Reduce Cardiovascular Complications 121
Smoking cessation 121
Effective management of COPD 121
Cardiovascular drugs 121
Skeletal muscle effects 122
Prevalence 122
Pathophysiologic Changes Associated with Muscle Dysfunction/Wasting 122
Factors Contributing to Muscle Dysfunction 122
Interventions to Improve Skeletal Muscle Dysfunction 124
Osteoporosis 124
Prevalence of Osteoporosis in COPD 125
Potential Contributors to Osteoporosis in COPD 125
Corticosteroids 125
Inflammation 125
Calcification paradox 126
Therapeutic Interventions 126
Nonpharmacologic measures 126
Pharmacologic measures 126
Nutritional effects in COPD 126
Prevalence and Implications 126
Factors Contributing to Nutritional Depletion 127
Therapeutic Interventions 127
Obesity and obstructive sleep apnea in COPD 127
Management of OSA and COPD 128
Anemia in COPD 128
Prevalence 128
Pathogenesis 128
Management 130
Autonomic Dysfunction 130
Prevalence and Clinical Implications 130
Lung Cancer and COPD 130
Prevalence 130
Pathogenesis and Clinical Implications of Lung Cancer in COPD 131
Psychological effects in COPD 132
Prevalence 132
Clinical Implications 132
Diabetes and metabolic syndrome in COPD 132
Prevalence and Pathogenesis 132
Management and Clinical Implications 132
Systemic inflammation in COPD 133
Summary 136
References 136
Biomarkers in COPD 146
Key points 146
Introduction 146
Markers and outcomes: general concepts 146
Biomarkers: definition and requirements 148
Biomarkers in COPD: where are we now? 148
Fibrinogen: the Most Promising Biomarker 148
Other Acute Phase Reactants Regulated by IL-6 150
Emerging Biomarkers 151
Pneumoproteins 151
Other Biomarkers 152
Biomarkers of Therapeutic Responses 152
A Network Approach to Inflammation: the Systemic Inflammome 152
How can we progress in the field? 153
Summary 154
References 154
Asthma and Chronic Obstructive Pulmonary Disease 158
Key points 158
Introduction 158
Definitions 159
Clinical features 159
Symptoms 159
Airway Obstruction and Reversibility 160
Atopy 161
Airway Hyperresponsiveness 161
The Overlap Phenotype 162
Genetics and environment 163
Overlap of Asthma and COPD 164
Inflammation and remodeling 165
Pharmacologic responses 166
Summary 167
References 168
Acute COPD Exacerbations 172
Key points 172
Impact of COPD exacerbations 172
Definition of exacerbations 172
Causes and pathogenesis of exacerbation 173
The frequent exacerbator phenotype 174
Exacerbation prevention 174
Vaccines 174
Inhaled Corticosteroids and Long-acting Bronchodilators 174
Dual Bronchodilators 175
Phosphodiesterase Inhibitors 176
Long-term Antibiotics 176
Pulmonary Rehabilitation, Home Oxygen, and Ventilatory Support 176
Management of the acute exacerbation 176
References 177
Smoking Cessation 180
Key points 180
Introduction 180
Physiology of smoking 180
Approach to a quit attempt 182
Strategy for the quit attempt 183
Pharmacotherapy 184
NRT 184
Nicotine polacrilex gum 185
Nicotine polacrilex lozenge 185
Transdermal nicotine 185
Nicotine inhaler 185
Nicotine nasal spray 186
Combinations of NRT 186
Bupropion 186
Varenicline 186
Off-label agents 187
Harm reduction 187
Summary 188
References 188
Current Drug Treatment, Chronic and Acute 192
Key points 192
Introduction 192
Drug treatment in acute exacerbations 192
Drug treatment in chronic management 194
ICS and COPD 194
Evidence-based therapy 197
Evaluating patients 197
Initial drug therapy 198
Alternative therapies 198
Emerging issues 199
Summary 200
References 200
Bronchodilators 206
Key points 206
The importance of bronchodilation in COPD 206
Classes of bronchodilators 207
ß2-Agonists 207
Antimuscarinic Agents 207
Methylxanthines 208
The choice of bronchodilators in stable COPD 208
When Starting Treatment with Bronchodilators 208
Choice of Treatment Based on Effectiveness 208
Choice of Treatment Based on Safety 209
When Combining Two Bronchodilators with Different Mechanisms of Action 209
Future developments 210
Novel Classes 210
New Traditional Bronchodilators 211
References 213
How Phosphodiesterase 4 Inhibitors Work in Patients with Chronic Obstructive Pulmonary Disease of the Severe, Bronchitic, F ... 218
Key points 218
Introduction 218
PDE4 inhibitors and COPD 219
A triple combination therapy? 220
Scientific rationale for adding on a PDE4 inhibitor to an ICS/LABA combination therapy: a case for gene transactivation 220
Why ICS/LABA combination therapies are not enough 222
Candidate antiinflammatory genes 224
Mitogen-activated Protein Kinase Phosphatase 1 224
Glucocorticoid-induced Leucine Zipper 224
Regulator of G-protein Signaling 2 225
Cluster of Differentiation 200 225
Cysteine-rich Secretory Protein Limulus Clotting Factor C, Cochlin, Lgl1 Domain-containing 2 225
p57kip2 226
Suppressor of Cytokine Signaling 3 226
Cylindromatosis 226
Tristetraprolin 226
Gene transactivation and glucocorticoid resistance 227
A note on cAMP-induced, adverse-effect genes 227
Summary and future directions 227
Acknowledgments 228
References 228
New Drug Therapies for COPD 234
Key points 234
Introduction 234
Drugs to aid smoking cessation 236
Inhaled bronchodilators and corticosteroids 237
Inhaled Bronchodilators 237
ICS 237
Steroid Resistance 238
Antiinfective and antiinflammatory agents 238
Antibiotics 238
Antivirals 240
Agents Acting on Innate Immunity 240
Chemokine Receptor Antagonists 241
Chemoattractant Receptor-homologous Receptor Antagonism 241
LTB4 Receptor Antagonists 241
Selectin Antagonism 241
Phosphodiesterase Inhibitors 241
Kinase Inhibitors 242
Statins 242
Miscellaneous additional classes of new drugs 243
Antioxidants 243
Mucoactive Drugs 244
Proteases 244
Fibrosis and Remodeling 244
Biologics: MoABs 245
Aging and Autoimmunity 245
Lung Regeneration 245
Summary 246
References 246
Pulmonary Rehabilitation 256
Key points 256
Outline 256
Definition 256
The evidence base for pulmonary rehabilitation 257
Where can pulmonary rehabilitation be organized 258
A comprehensive intervention: program content 258
Patient screening and selection 260
Screening for the Extrapulmonary Consequences of COPD 261
Symptoms 262
Physical Activity 262
Severe Exacerbations 262
Maintaining the effects of pulmonary rehabilitation 262
Summary 263
References 263
Noninvasive Ventilation and Lung Volume Reduction 266
Key points 266
Introduction 266
NIV 266
NIV during acute hypercapnic respiratory failure 267
Indications 267
Predictors of Treatment Success and Treatment Failure 267
Ventilator Mode and Setup 268
Domiciliary NIV for chronic hypercapnic respiratory failure 268
Physiologic Basis 268
Respiratory Drive 268
Respiratory load 269
Respiratory muscle capacity 269
Early Trials 269
Current Data and Practice 269
Could Technical Factors Explain the Failure to Show a Benefit with NIV? 270
Summaries 270
LVR for the treatment of emphysema 270
Physiologic Basis 270
Surgical LVR 271
Bullectomy 271
LVRS 271
Bronchoscopic LVR 275
Endobronchial airway valves 275
Biologic LVR 276
Bronchoscopic thermal vapor ablation (steam) 277
RePneu LVR coils 277
Airways bypass stents 278
Summary 280
References 280
Index 286
A 286
B 286
C 287
D 289
E 289
F 289
G 289
H 290
I 290
K 290
L 290
M 291
N 291
O 291
P 291
Q 292
R 292
S 292
T 292
V 293