- •Preface to the First Edition
- •Preface to the Second Edition
- •Contents
- •Diagnostic Challenges
- •Expert Centers
- •Patient Organizations
- •Clinical Trials
- •Research in Orphan Lung Diseases
- •Orphan Drugs
- •Orphanet
- •Empowerment of Patients
- •Conclusions
- •References
- •Introduction
- •Challenges to Overcome in Order to Undertake Quality Clinical Research
- •Lack of Reliable Data on Prevalence
- •Small Number of Patients
- •Identifying Causation/Disease Pathogenesis
- •Disease Complexity
- •Lack of Access to a Correct Diagnosis
- •Delay in Diagnosis
- •Challenges But Not Negativity
- •Some Success Stories
- •The Means to Overcome the Challenges of Clinical Research: Get Bigger Numbers of Well-Characterized Patients
- •The Importance of Patient Organizations
- •National and International Networks
- •End Points for Trials: Getting Them Right When Numbers Are Small and Change Is Modest
- •Orphan Drug Development
- •Importance of Referral Centers
- •Looking at the Future
- •The Arguments for Progress
- •Concluding Remarks
- •References
- •3: Chronic Bronchiolitis in Adults
- •Introduction
- •Cellular Bronchiolitis
- •Follicular Bronchiolitis
- •Respiratory Bronchiolitis
- •Airway-Centered Interstitial Fibrosis
- •Proliferative Bronchiolitis
- •Diagnosis
- •Chest Imaging Studies
- •Pulmonary Function Testing
- •Lung Biopsy
- •Mineral Dusts
- •Organic Dusts
- •Volatile Flavoring Agents
- •Infectious Causes of Bronchiolitis
- •Idiopathic Forms of Bronchiolitis
- •Connective Tissue Diseases
- •Organ Transplantation
- •Hematopoietic Stem Cell Transplantation
- •Drug-Induced Bronchiolitis
- •Treatment
- •Constrictive Bronchiolitis
- •Follicular Bronchiolitis
- •Airway-Centered Interstitial Fibrosis
- •Proliferative Bronchiolitis
- •References
- •Background and Epidemiology
- •Pathophysiology
- •Host Characteristics
- •Clinical Manifestations
- •Symptoms
- •Laboratory Evaluation
- •Skin Testing
- •Serum Precipitins
- •Eosinophil Count
- •Total Serum Immunoglobulin E Levels
- •Recombinant Antigens
- •Radiographic Imaging
- •Pulmonary Function Testing
- •Histology
- •Diagnostic Criteria
- •Historical Diagnostic Criteria
- •Rosenberg and Patterson Diagnostic Criteria
- •ISHAM Diagnostic Criteria
- •Cystic Fibrosis Foundation Diagnostic Criteria
- •General Diagnostic Recommendations
- •Allergic Aspergillus Sinusitis (AAS)
- •Natural History
- •Treatment
- •Corticosteroids
- •Antifungal Therapy
- •Monoclonal Antibodies
- •Monitoring for Treatment Response
- •Conclusions
- •References
- •5: Orphan Tracheopathies
- •Introduction
- •Anatomical Considerations
- •Clinical Presentation
- •Etiological Considerations
- •Idiopathic Subglottic Stenosis
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Introduction and Clinical Presentation
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheomalacia
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheobronchomegaly
- •Introduction
- •Clinical Features
- •Pathophysiology
- •Pulmonary Function Studies
- •Imaging Studies
- •Treatment
- •Tracheopathies Associated with Systemic Diseases
- •Relapsing Polychondritis
- •Introduction
- •Clinical Features
- •Laboratory Findings
- •Pulmonary Function and Imaging Studies
- •Treatment
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheobronchial Amyloidosis
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Sarcoidosis
- •Introduction
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Orphan Tracheopathies: Conclusions
- •References
- •6: Amyloidosis and the Lungs and Airways
- •Introduction
- •Diagnosis and Evaluation of Amyloidosis
- •Systemic AA Amyloidosis
- •Systemic AL Amyloidosis
- •Amyloidosis Localised to the Respiratory Tract
- •Laryngeal Amyloidosis
- •Tracheobronchial Amyloidosis
- •Parenchymal Pulmonary Amyloidosis
- •Pulmonary Amyloidosis Associated with Sjögren’s Disease
- •Conclusions
- •References
- •Introduction
- •Pathophysiology
- •Genetic Predisposition
- •Immune Dysregulation
- •Epidemiology
- •Incidence and Prevalence
- •Triggering Factors
- •Clinical Manifestations
- •General Symptoms
- •Pulmonary Manifestations
- •Ear, Nose, and Throat (ENT) Manifestations
- •Neurological Manifestations
- •Skin Manifestations
- •Cardiac Manifestations
- •Gastrointestinal Involvement
- •Renal Manifestations
- •Ophthalmological Manifestations
- •Complementary Investigations
- •Diagnosis
- •Diagnostic Criteria
- •Prognosis and Outcomes
- •Phenotypes According to the ANCA Status
- •Treatment
- •Therapeutic Strategies
- •Remission Induction
- •Maintenance Therapy
- •Other Treatments
- •Prevention of AEs
- •Conclusions
- •References
- •8: Granulomatosis with Polyangiitis
- •A Brief Historical Overview
- •Epidemiology
- •Pathogenesis
- •Clinical Manifestations
- •Constitutional Symptoms
- •Ear, Nose, and Throat (ENT) Manifestations
- •Pulmonary Manifestations
- •Kidney and Urological Manifestations
- •Kidney Manifestations
- •Urological Manifestations
- •Neurological Manifestations
- •Peripheral Nervous System (PNS) Manifestations
- •Central Nervous System (CNS) Manifestations
- •Spinal Cord and Cranial Nerve Involvement
- •Skin and Oral Mucosal Manifestations
- •Eye Manifestations
- •Cardiac Involvement
- •Gastrointestinal Manifestations
- •Gynecological and Obstetric Manifestations
- •Venous Thrombosis and Other Vascular Events
- •Other Manifestations
- •Pediatric GPA
- •Diagnosis
- •Diagnostic Approach
- •Laboratory Investigations
- •Biology
- •Immunology
- •Pathology
- •Treatment
- •Glucocorticoids
- •Cyclophosphamide
- •Rituximab
- •Other Current Induction Approaches
- •Other Treatments in GPA
- •Intravenous Immunoglobulins
- •Plasma Exchange
- •CTLA4-Ig (Abatacept)
- •Cotrimoxazole
- •Other Agents
- •Principles of Treatment for Relapsing and Refractory GPA
- •Outcomes and Prognostic Factors
- •Survival and Causes of Deaths
- •Relapse
- •Damage and Disease Burden on Quality of Life
- •Conclusions
- •References
- •9: Alveolar Hemorrhage
- •Introduction
- •Clinical Presentation
- •Diagnosis (Table 9.1, Fig. 9.3)
- •Pulmonary Capillaritis
- •Histology (Fig. 9.4)
- •Etiologies
- •ANCA-Associated Small Vessel Vasculitis: Granulomatosis with Polyangiitis (GPA)
- •ANCA-Associated Small Vessel Vasculitis: Microscopic Polyangiitis
- •Isolated Pulmonary Capillaritis
- •Systemic Lupus Erythematosus
- •Antiphospholipid Antibody Syndrome
- •Anti-Basement Membrane Antibody Disease (Goodpasture Syndrome)
- •Lung Allograft Rejection
- •Others
- •Bland Pulmonary Hemorrhage (Fig. 9.5)
- •Histology
- •Etiologies
- •Idiopathic Pulmonary Hemosiderosis
- •Drugs and Medications
- •Coagulopathy
- •Valvular Heart Disease and Left Ventricular Dysfunction
- •Other
- •Histology
- •Etiologies
- •Hematopoietic Stem Cell Transplantation (HSCT)
- •Cocaine Inhalation
- •Acute Exacerbation of Interstitial Lung Disease
- •Acute Interstitial Pneumonia
- •Acute Respiratory Distress Syndrome
- •Miscellaneous Causes
- •Etiologies
- •Pulmonary Capillary Hemangiomatosis
- •Treatment
- •Conclusions
- •References
- •Takayasu Arteritis
- •Epidemiology
- •Pathologic Features
- •Pathogenesis
- •Clinical Features
- •Laboratory Findings
- •Imaging Studies
- •Therapeutic Management
- •Prognosis
- •Behçet’s Disease
- •Epidemiology
- •Pathologic Features
- •Pathogenesis
- •Diagnostic Criteria
- •Clinical Features
- •Pulmonary Artery Aneurysm
- •Pulmonary Artery Thrombosis
- •Pulmonary Parenchymal Involvement
- •Laboratory Findings
- •Imaging Studies
- •Therapeutic Management
- •Treatment of PAA
- •Treatment of PAT
- •Prognosis
- •References
- •Introduction
- •Portopulmonary Hypertension (PoPH)
- •Epidemiology and Risk Factors
- •Molecular Pathogenesis
- •PoPH Treatment
- •Hepatopulmonary Syndrome (HPS)
- •Epidemiology and Risk Factors
- •Molecular Pathogenesis
- •HPS Treatment
- •Conclusion
- •References
- •12: Systemic Sclerosis and the Lung
- •Introduction
- •Risk factors for SSc-ILD
- •Genetic Associations
- •Clinical Presentation of SSc-ILD
- •Pulmonary Function Tests (PFTs)
- •Imaging
- •Management
- •References
- •13: Rheumatoid Arthritis and the Lungs
- •Introduction
- •Epidemiology
- •Risk Factors for ILD (Table 13.3)
- •Pathogenesis
- •Clinical Features and Diagnosis
- •Treatments
- •Prognosis
- •Epidemiology
- •Risk Factors
- •Clinical Features, Diagnosis, and Outcome
- •Subtypes or RA-AD
- •Obliterative Bronchiolitis
- •Bronchiectasis
- •COPD
- •Cricoarytenoid Involvement
- •Pleural Disease
- •Conclusion
- •References
- •Introduction
- •Systemic Lupus Erythematosus
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Pleural Disease
- •Shrinking Lung Syndrome
- •Thrombotic Manifestations
- •Interstitial Lung Disease
- •Other Pulmonary Manifestations
- •Prognosis
- •Sjögren’s Syndrome
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Airway Disorders
- •Lymphoproliferative Disease
- •Interstitial Lung Disease
- •Prognosis
- •Mixed Connective Tissue Disease
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Pulmonary Hypertension
- •Interstitial Lung Disease
- •Prognosis
- •Myositis
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations and Treatments
- •Interstitial Lung Disease
- •Respiratory Muscle Weakness
- •Other Pulmonary Manifestations
- •Prognosis
- •Other Therapeutic Options in CTD-ILD
- •Lung Transplantation
- •Conclusion
- •References
- •Introduction
- •Diagnostic Criteria
- •Controversies in the Diagnostic Criteria
- •Typical Clinical Features
- •Disease Progression and Prognosis
- •Summary
- •References
- •Introduction
- •Histiocytes and Dendritic Cells
- •Introduction
- •Cellular and Molecular Pathogenesis
- •Pathology
- •Clinical Presentation
- •Treatment and Prognosis
- •Erdheim-Chester Disease
- •Epidemiology
- •Cellular and Molecular Pathogenesis
- •Histopathology and Immunohistochemistry
- •Clinical Presentation
- •Investigation/Diagnosis
- •Chest Studies
- •Cardiovascular Imaging
- •CNS Imaging
- •Bone Radiography
- •Other Imaging Findings and Considerations
- •Disease Monitoring
- •Pathology
- •Management/Treatment
- •Prognosis
- •Rosai-Dorfman Destombes Disease
- •Epidemiology
- •Etiology/Pathophysiology
- •Histopathology and Immunohistochemistry
- •Clinical Presentation
- •Investigation/Diagnosis
- •Management/Treatment
- •Prognosis
- •Conclusions
- •Diagnostic Criteria for Primary Histiocytic Disorders of the Lung
- •References
- •17: Eosinophilic Pneumonia
- •Introduction
- •Eosinophil Biology
- •Physiologic and Immunologic Role of Eosinophils
- •Release of Mediators
- •Targeting the Eosinophil Cell Lineage
- •Historical Perspective
- •Clinical Presentation
- •Pathology
- •Diagnosis
- •Eosinophilic Lung Disease of Undetermined Cause
- •Idiopathic Chronic Eosinophilic Pneumonia
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Bronchoalveolar Lavage
- •Lung Function Tests
- •Treatment
- •Outcome and Perspectives
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Bronchoalveolar Lavage
- •Lung Function Tests
- •Lung Biopsy
- •Treatment and Prognosis
- •Eosinophilic Granulomatosis with Polyangiitis
- •History and Nomenclature
- •Pathology
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Pathogenesis
- •Diagnosis
- •Treatment and Prognosis
- •Long-Term Outcome
- •Hypereosinophilic Syndrome
- •Pathogenesis
- •Clinical and Imaging Features
- •Laboratory Studies
- •Treatment and Prognosis
- •Eosinophilic Pneumonias of Parasitic Origin
- •Tropical Eosinophilia [191]
- •Ascaris Pneumonia
- •Eosinophilic Pneumonia in Larva Migrans Syndrome
- •Strongyloides Stercoralis Infection
- •Eosinophilic Pneumonias in Other Infections
- •Allergic Bronchopulmonary Aspergillosis
- •Pathogenesis
- •Diagnostic Criteria
- •Biology
- •Imaging
- •Treatment
- •Bronchocentric Granulomatosis
- •Miscellaneous Lung Diseases with Associated Eosinophilia
- •References
- •Introduction
- •Pulmonary Langerhans’ Cell Histiocytosis
- •Epidemiology
- •Pathogenesis
- •Diagnosis
- •Clinical Features
- •Extrathoracic Lesions
- •Pulmonary Function Tests
- •Chest Radiography
- •High-Resolution Computed Tomography (HRCT)
- •Bronchoscopy and Bronchoalveolar Lavage (BAL)
- •Lung Biopsy
- •Pathology
- •Treatment
- •Course and Prognosis
- •Case Report I
- •Introduction
- •Epidemiology
- •Clinical Features
- •Histopathological Findings
- •Radiologic Findings
- •Prognosis and Therapy
- •Desquamative Interstitial Pneumonia
- •Epidemiologic and Clinical Features
- •Histopathological Findings
- •Radiological Findings
- •Prognosis and Therapy
- •Conclusion
- •References
- •19: Lymphangioleiomyomatosis
- •Introduction
- •Pathogenesis
- •Presentation
- •Prognosis
- •Management
- •General Measures
- •Parenchymal Lung Disease
- •Pleural Disease
- •Renal Angiomyolipoma
- •Abdominopelvic Lymphatic Disease
- •Pregnancy
- •Tuberous Sclerosis
- •Drug Treatment
- •Bronchodilators
- •mTOR Inhibitors
- •Anti-Oestrogen Therapy
- •Experimental Therapies
- •Interventions for Advanced Disease
- •Oxygen Therapy
- •Pulmonary Hypertension
- •References
- •20: Diffuse Cystic Lung Disease
- •Introduction
- •Lymphangioleiomyomatosis
- •Pathogenesis
- •Pathologic and Radiographic Characteristics
- •Diagnostic Approach
- •Pulmonary Langerhans Cell Histiocytosis (PLCH)
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Birt-Hogg-Dubé Syndrome (BHD)
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Lymphoproliferative Disorders
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Amyloidosis
- •Light Chain Deposition Disease (LCDD)
- •Conclusion
- •References
- •Introduction
- •Lymphatic Development
- •Clinical Presentation of Lymphatic Disorders
- •Approaches to Diagnosis and Management of Congenital Lymphatic Anomalies
- •Generalized Lymphatic Anomaly
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Course/Prognosis
- •Management
- •Kaposiform Lymphangiomatosis
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Gorham Stout Disease
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Channel-Type LM/Central Conducting LM
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Yellow Nail Syndrome
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Summary
- •References
- •Introduction
- •Historical Note
- •Epidemiology
- •Pathogenesis
- •Surfactant Homeostasis in PAP
- •GM-CSF Signaling Disruption
- •Myeloid Cell Dysfunction
- •GM-CSF Autoantibodies
- •Lymphocytosis
- •Clinical Manifestations
- •Clinical Presentation
- •Secondary Infections
- •Pulmonary Fibrosis
- •Diagnosis
- •Pulmonary Function Testing
- •Radiographic Assessment
- •Bronchoscopy and Bronchoalveolar Lavage
- •Laboratory Studies and Biomarkers
- •GM-CSF Autoantibodies
- •Genetic Testing
- •Lung Pathology
- •Diagnostic Approach to the Patient with PAP
- •Natural History and Prognosis
- •Treatment
- •Whole-Lung Lavage
- •Subcutaneous GM-CSF
- •Inhaled GM-CSF
- •Other Approaches
- •Conclusions and Future Directions
- •References
- •Introduction
- •Epidemiology
- •Gastric Contents
- •Pathobiology of GER/Microaspirate in the Lungs of Patients with IPF
- •GER and the Microbiome
- •Diagnosis
- •Clinical History/Physical Exam
- •Investigations
- •Esophageal Physiology
- •Upper Esophageal Sphincter
- •Esophagus and Peristalsis
- •Lower Esophageal Sphincter and Diaphragm
- •Esophageal pH and Impedance Testing
- •High Resolution Esophageal Manometry
- •Esophagram/Barium Swallow
- •Bronchoalveolar Lavage/Sputum: Biomarkers
- •Treatment
- •Anti-Acid Therapy (PPI/H2 Blocker)
- •GER and Acute Exacerbations of IPF
- •Suggested Approach
- •Summary and Future Directions
- •References
- •Introduction
- •Familial Interstitial Pneumonia
- •Telomere Related Genes
- •Genetic
- •Telomere Length
- •Pulmonary Involvement
- •Interstitial Lung Disease
- •Other Lung Disease
- •Hepatopulmonary Syndrome
- •Emphysema
- •Extrapulmonary Manifestations
- •Mucocutaneous Involvement
- •Hematological Involvement
- •Liver Involvement
- •Other Manifestations
- •Treatment
- •Telomerase Complex Agonists
- •Lung Transplantation
- •Surfactant Pathway
- •Surfactant Protein Genes
- •Pulmonary Involvement
- •Treatment
- •Heritable Forms of Pulmonary Fibrosis with Autoimmune Features
- •TMEM173
- •COPA
- •Pulmonary Alveolar Proteinosis
- •GMCSF Receptor Mutations
- •GATA2
- •MARS
- •Lysinuric Protein Intolerance
- •Lysosomal Diseases
- •Hermansky-Pudlak Syndrome
- •Lysosomal Storage Disorders
- •FAM111B, NDUFAF6, PEPD
- •Conclusion
- •References
- •Introduction
- •Pathophysiology
- •Clinical Presentation
- •Epidemiology
- •Genetic Causes of Bronchiectasis
- •Disorders of Mucociliary Clearance
- •Cystic Fibrosis
- •Primary Ciliary Dyskinesia
- •Other Ciliopathies
- •X-Linked Agammaglobulinemia
- •Chronic Granulomatous Disease and Other Disorders of Neutrophil Function
- •Other Genetic Disorders Predisposing to Bronchiectasis
- •Idiopathic Bronchiectasis
- •Diagnosis of Bronchiectasis
- •Management of Patients with Bronchiectasis
- •Airway Clearance Therapy (ACT)
- •Management of Infections
- •Immune Therapy
- •Surgery
- •Novel Therapies for Managing Cystic Fibrosis
- •Summary
- •References
- •Pulmonary Arteriovenous Malformations
- •Background Pulmonary AVMs
- •Anatomy Pulmonary AVMs
- •Clinical Presentation of Pulmonary AVMs
- •Screening Pulmonary AVMs
- •Treatment Pulmonary AVMs
- •Children with Hereditary Hemorrhagic Telangiectasia
- •Pulmonary Hypertension
- •Pulmonary Hypertension Secondary to Liver Vascular Malformations
- •Pulmonary Arterial Hypertension
- •Background HHT
- •Pathogenesis
- •References
- •27: Pulmonary Alveolar Microlithiasis
- •Introduction
- •Epidemiology
- •Pathogenesis
- •Clinical Features
- •Diagnosis
- •Management
- •Summary
- •References
- •Introduction
- •Hermansky-Pudlak Syndrome
- •Telomerase-Associated Pulmonary Fibrosis
- •Lysosomal Storage Diseases
- •Lysinuric Protein Intolerance
- •Familial Hypocalciuric Hypercalcemia
- •Surfactant Dysfunction Disorders
- •Concluding Remarks
- •References
- •Introduction
- •Background
- •Image Acquisition
- •Key Features of Fibrosis
- •Ancillary Features of Fibrosis
- •Other Imaging Findings in FLD
- •Probable UIP-IPF
- •Indeterminate
- •Alternative Diagnosis
- •UIP in Other Fibrosing Lung Diseases
- •Pleuroparenchymal Fibroelastosis (PPFE)
- •Combined Pulmonary Fibrosis and Emphysema
- •Chronic Hypersensitivity Pneumonitis
- •Other Fibrosing Lung Diseases
- •Fibrosing Sarcoidosis
- •CTD-ILD and Drug-Induced FLD
- •Complications
- •Prognosis
- •Computer Analysis of CT Imaging
- •The Progressive Fibrotic Phenotype
- •Other Imaging Techniques
- •Conclusion
- •References
- •Introduction
- •Bronchoalveolar Lavage (BAL)
- •Technique
- •Interpretation
- •Transbronchial Biopsy (TBB)
- •Transbronchial Lung Cryobiopsy (TLCB)
- •References
- •Introduction
- •Overview of ILD Diagnosis
- •Clinical Assessment
- •Radiological Assessment
- •Laboratory Assessment
- •Integration of Individual Features
- •Multidisciplinary Discussion
- •Diagnostic Ontology
- •Conclusions
- •References
- •Introduction
- •Idiopathic Pulmonary Fibrosis
- •Chronic Hypersensitivity Pneumonitis
- •Connective Tissue Disease
- •Drug-Induced Lung Diseases
- •Radiation Pneumonitis
- •Asbestosis
- •Hermansky-Pudlak Syndrome
- •Risk Factors for Progression
- •Diagnosis
- •Pharmacological Management
- •Conclusions
- •References
- •Historical Perspective
- •Epidemiology and Etiologies
- •Tobacco Smoking and Male Sex
- •Genetic Predisposition
- •Systemic Diseases
- •Other Etiological Contexts
- •Clinical Manifestations
- •Pulmonary Function and Physiology
- •Imaging
- •Computed Tomography Characteristics and Patterns
- •Thick-Walled Large Cysts
- •Imaging Phenotypes
- •Pitfalls
- •Pathology
- •Diagnosis
- •CPFE Is a Syndrome
- •Biology
- •Complications and Outcome
- •Mortality
- •Pulmonary Hypertension
- •Lung Cancer
- •Acute Exacerbation of Pulmonary Fibrosis
- •Other Comorbidities and Complications
- •Management
- •General Measures and Treatment of Emphysema
- •Treatment of Pulmonary Fibrosis
- •Management of Pulmonary Hypertension
- •References
- •Acute Interstitial Pneumonia (AIP)
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Desquamative Interstitial Pneumonia (DIP)
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •References
- •Organizing Pneumonias
- •Epidemiology
- •Pathogenesis
- •Clinical Features
- •Imaging
- •Multifocal Form
- •Isolated Nodular Form
- •Other Imaging Patterns
- •Histopathological Diagnosis of OP Pattern
- •Etiological Diagnosis of OP
- •Treatment
- •Clinical Course and Outcome
- •Severe Forms of OP with Respiratory Failure
- •Acute Fibrinous and Organizing Pneumonia
- •Granulomatous Organizing Pneumonia
- •Acute Interstitial Pneumonia
- •Epidemiology
- •Clinical Picture
- •Imaging
- •Histopathology
- •Diagnosis
- •Treatment
- •Outcome
- •References
- •36: Pleuroparenchymal Fibroelastosis
- •Introduction
- •Epidemiology
- •Clinical Manifestations
- •Laboratory Findings
- •Respiratory Function
- •Radiologic Features
- •Pathologic Features
- •Diagnosis
- •Treatment
- •Prognosis
- •Conclusions
- •References
- •Introduction
- •Acute Berylliosis
- •Chronic Beryllium Disease
- •Exposure
- •Epidemiology
- •Immunopathogenesis and Pathology
- •Genetics
- •Clinical Description and Natural History
- •Treatment and Monitoring
- •Indium–Tin Oxide-Lung Disease
- •Hard Metal Lung
- •Flock Worker’s Disease
- •Asbestosis
- •Nanoparticle Induced ILD
- •Flavoring-Induced Lung Disease
- •Silica-Induced Interstitial Lung Disease
- •Chronic Silicosis
- •Acute and Accelerated Silicosis
- •Chronic Obstructive Disease in CMDLD
- •Simple CMDLD
- •Complicated CMDLD
- •Conclusion
- •References
- •38: Unclassifiable Interstitial Lung Disease
- •Introduction
- •Diagnostic Scenarios
- •Epidemiology
- •Clinical Presentation
- •Diagnosis
- •Clinical Features
- •Radiology
- •Laboratory Investigations
- •Pathology
- •Conclusion
- •References
- •39: Lymphoproliferative Lung Disorders
- •Introduction
- •Nodular Lymphoid Hyperplasia
- •Lymphocytic Interstitial Pneumonia (LIP)
- •Follicular Bronchitis/Bronchiolitis
- •Castleman Disease
- •Primary Pulmonary Lymphomas
- •Primary Pulmonary MALT B Cell Lymphoma
- •Pulmonary Plasmacytoma
- •Follicular Lymphoma
- •Lymphomatoid Granulomatosis
- •Primary Pulmonary Hodgkin Lymphoma (PPHL)
- •Treatment
- •References
- •Introduction
- •Late-Onset Pulmonary Complications
- •Bronchiolitis Obliterans (BO)
- •Pathophysiology
- •Diagnosis
- •Management of BOS
- •Post-HSCT Organizing Pneumonia
- •Other Late-Onset NonInfectious Pulmonary Complications (LONIPCs)
- •Conclusion
- •References
- •Introduction
- •Pulmonary Hypertension Associated with Sarcoidosis (Group 5.2)
- •PH Associated with Pulmonary Langerhans Cell Histiocytosis (Group 5.2)
- •PH in Combined Pulmonary Fibrosis and Emphysema (Group 3.3)
- •PH Associated with Lymphangioleiomyomatosis (Group 3)
- •Hereditary Hemorrhagic Telangiectasia (Group 1.2)
- •Pulmonary Veno-Occlusive Disease (Group 1.5)
- •Small Patella Syndrome (Group 1.2)
- •Conclusion
- •References
- •Introduction
- •Epidemiology
- •Timing, Chronology, Delay Time
- •Route of Administration
- •Patterns of Involvement [3, 4]
- •Drugs and Agents Fallen Out of Favor
- •Drug-Induced Noncardiac Pulmonary Edema
- •Drug-Induced Cardiogenic Pulmonary Edema
- •The “Chemotherapy Lung”
- •Drug-Induced/Iatrogenic Alveolar Hemorrhage
- •Drugs
- •Superwarfarin Rodenticides
- •Transfusion Reactions: TACO–TRALI
- •Acute Eosinophilic Pneumonia
- •Acute Granulomatous Interstitial Lung Disease
- •Acute Organizing Pneumonia (OP), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), or Acute Fibrinous Organizing Pneumonia (AFOP) Patterns
- •Acute Amiodarone-Induced Pulmonary Toxicity (AIPT)
- •Accelerated Pulmonary Fibrosis
- •Acute Exacerbation of Previously Known (Idiopathic) Pulmonary Fibrosis
- •Anaphylaxis
- •Acute Vasculopathy
- •Drug-Induced/Iatrogenic Airway Emergencies
- •Airway Obstruction as a Manifestation of Anaphylaxis
- •Drug-Induced Angioedema
- •Hematoma Around the Upper Airway
- •The “Pill Aspiration Syndrome”
- •Catastrophic Drug-Induced Bronchospasm
- •Peri-operative Emergencies (Table 42.8)
- •Other Rare Presentations
- •Pulmonary Nodules and Masses
- •Pleuroparenchymal Fibroelastosis
- •Late Radiation-Induced Injury
- •Chest Pain
- •Rebound Phenomenon
- •Recall Pneumonitis
- •Thoracic Bezoars: Gossipybomas
- •Respiratory Diseases Considered Idiopathic That May Be Drug-Induced (Table 42.4)
- •Eye Catchers
- •Conclusion
- •References
- •Cancer Mimics of Organizing Pneumonia
- •Lung Adenocarcinoma/Bronchioloalveolar Carcinoma
- •Primary Pulmonary Lymphoma
- •Cancer Mimics of Interstitial Lung Diseases
- •Lymphangitic Carcinomatosis
- •Epithelioid Hemangio-Endothelioma
- •Lymphomatoid Granulomatosis
- •Cystic Tumors
- •Cavitating Tumors
- •Intrathoracic Pseudotumors
- •Respiratory Papillomatosis
- •Pulmonary Langerhans Cell Histiocytosis
- •References
- •Index
25 Difuse Bronchiectasis of Genetic or Idiopathic Origin |
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almost invariably associated with wet cough; asthma can also co-exist with bronchiectasis.
The examination may be normal or may include crackles, wheeze, or chest deformity. Clubbing is reported to occur in some patients with bronchiectasis. Whilst it is an important sign it is not a sensitive one. In general, patients in less affuent settings have more severe diseases, presumably associated with later diagnosis and less aggressive/targeted management [16].
Epidemiology
The introduction of immunisations against pertussis in the 1950s and measles in the 1960s contributed greatly to the decline of post-infective bronchiectasis, as has the decline of pulmonary tuberculosis and the general improvement in social circumstances. However, the genetic and idiopathic disease has proportionally increased in recent times and disease prevalence has risen by more than 40% over the past 15 years. In the UK recent studies suggest a prevalence of 566 per 100,000 in women and 485 per 100,000 in men making bronchiectasis the third most common lung condition behind asthma and COPD [4]. One of the highest prevalence worldwide has recently been reported in the USA with an average of 701 patients per 100,000 people [2].
Bronchiectasis can occur at any age from early childhood, however, the average age in Western cohorts is 60–70 years [14]. It is more prevalent at a younger age in countries where there is a high incidence of pulmonary tuberculosis [17] or in certain indigenous subpopulations, including Paci c Islanders, Indigenous Australians and the Inuit community in North America [18–20]. Poor access to antibiotics and immunisations may partially explain these differences, although it is likely that genetic propensity may also play a role [21, 22]. Certainly, children of consanguineous parents are at a disproportionately high risk of genetic causes of bronchiectasis [23]. Moreover, although environmental, immune or anatomical factors may explain the observation that non-CF bronchiectasis is more common in females, this too may have a genetic basis [24]. Differences between nations may partly refect genetic and environmental discrepancies; however, it is likely that the diagnosis of bronchiectasis in children is often delayed or never considered, making true prevalence dif cult to establish.
The most common genetic cause of diffuse bronchiectasis is cystic brosis (CF), the incidence of which is estimated to be 1 in 2500 births in white Caucasians. Reports of primary ciliary dyskinesia (PCD) prevalence in European populations have varied greatly from older estimates of 1:40,000 to more recent estimates based on genetic data of 1:7500 [25, 26]. As with most orphan diseases this variation is likely to refect a lack of awareness of the disease amongst clinicians, absence of a gold standard test, and lack of facilities for
Table 25.1 Examples of genetic causes of bronchiectasis
Disorders of mucociliary |
Cystic brosis |
clearance |
Primary ciliary dyskinesia |
Primary immunode ciency |
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Hypogammaglobulinaemia |
Common variable immunode ciency |
Neutrophil de ciency |
X-linked agammaglobulinemia |
Innate immunity |
Chronic granulomatous disease |
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Shwachman-Bodian-Diamond |
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syndrome |
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Complement de ciency |
Collagen disorders |
Marfan syndrome |
Other associations |
Autoimmune disease e.g. rheumatoid |
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arthritis, infammatory bowel disease |
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investigation, all leading to considerable under-diagnosis. A survey by a European PCD Taskforce suggested that PCD in children is under-diagnosed and diagnosed late, particularly in countries with low health expenditures [27]. The prevalence of other genetic causes of bronchiectasis is low and is considered individually later in this chapter.
Genetic Causes of Bronchiectasis
Bronchiectasis associated with genetic mutations is usually a consequence of recurrent or persistent pulmonary infection caused by disorders of mucociliary clearance or primary immunode ciency (Table 25.1).
Disorders of Mucociliary Clearance
Ciliated respiratory epithelium lines the airways. The cilia, bathed in periciliary fuid, beat in a coordinated fashion, to propel the overlying mucus along with particles and bacteria to the oropharynx where it can be swallowed or expectorated (Fig. 25.2). Diseases affecting ciliary function, or that change the composition of the periciliary fuid and mucus can impair mucociliary clearance, leading to recurrent infections and infammation which predispose to bronchiectasis.
Cystic Fibrosis
Cystic brosis (CF) is an autosomal recessive disorder and is the commonest inherited disease in white populations, with an estimated incidence of 1 per 2500 live births [28]. It is caused by mutations in the cystic brosis trans-mem- brane conductance regulator (CFTR) gene which is located on chromosome 7 and encodes for the CFTR chloride channel which sits in the cell membrane on the apical surface of the cell.
Mutations lead to abnormal ion transport regulation across the cell membrane which, in the lungs, results in abnormal airway fuid. Dehydrated mucus is characteristically highly viscoelastic, and adheres to the cilia and airway
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Fig. 25.2 In healthy persons, respiratory cilia beat in a coordinated sweeping pattern, which moves mucus and debris, including pathogens towards the oropharynx for swallowing or expectorating. In PCD, immotile or dyskinetic cilia do not beat effectively, and mucus and
debris persist in the airways. In CF the inef cient mucociliary clearance (MCC) is due to an abnormal periciliary fuid layer compromising ciliary beating and viscous mucus which is resistant to clearance. (Image provided by Robert Scott)
cells, causing airway plugging. The reduced-volume periciliary fuid layer does not adequately support and lubricate the cilia, and results in defects of ciliary function (Fig. 25.2). Adherent mucus and impaired ciliary function both contribute to reduced airway clearance, chronic infection and bio lm formation. Eventually, the chronic infection and infammation lead to bronchiectasis, which can develop very early in life [29]. Bronchiectasis in CF predominantly affects the upper lobes initially, spreading to all lobes over time; the disparity with PCD, which tends to have worse disease in the middle lobe, is dif cult to explain [30].
Since the CFTR gene was rst sequenced in 1989, [31] our understanding of the underlying pathophysiology of CF has developed rapidly. At the time of writing, over 2000 mutations in CFTR have been described, of which about 350 are thought to be pathogenic (https://www.cftr2.org/welcome). These mutations have been grouped into classes, dependent on their effect on the CFTR protein (Fig. 25.3). For example, class 2 mutations, which include the most common p. Phe508del mutation, lead to a failure of the correct folding of the protein which is then rapidly broken down and hence not expressed on the apical surface of the cell; whereas with class 3 mutations the protein is correctly folded and is present on the apical surface but the channel is blocked closed, termed ‘gating’ mutations. Our understanding of the effects of mutations in CFTR has been fundamental in recent ground-break- ing advances in the treatment of CF. It is now possible to correct CFTR dysfunction in patients with speci c classes of mutations, and therapies for other mutations are in late-phase trials (see Novel therapies for managing CF).
Although respiratory disease accounts for the majority of morbidity and mortality, [32] CF is a multisystem disorder with manifestations including meconium ileus, pancreatic insuf ciency leading to steatorrhea and failure to thrive, liver disease, diabetes, nasal polyposis, sinusitis and infertility in men due to congenital bilateral absence of the vas deferens . Since the widespread use of newborn screening (NBS) for
CF, measuring immuno-reactive trypsin (IRT) levels in the blood at about 7 days of life, most cases of CF are diagnosed in infancy. However later presentation, even in adulthood, is not unheard of, particularly where individuals were born prior to initiation of NBS programmes and who carry mutations other than p.Phe508del, hence are more likely to be pancreatic suf cient [33]. The diagnosis is con rmed by assessing the function of the CFTR channel by measuring sweat chloride levels, with a level > 60 mmol/L being diagnostic. Whilst not essential for diagnosis, given the advent of novel therapies based on CFTR mutation class, it is recommended that CF patients go on to be genotyped. Importantly, due to the fact that not all mutations in CFTR are pathogenic, any individualrst identi ed by genotyping (i.e. having two bi-allelic CFTR mutations) should go on to have a con rmatory functional CFTR assessment by sweat test. In dif cult diagnostic cases measurements of nasal potential difference can be helpful.
Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder, usually transmitted in an autosomal recessive pattern [34, 35]. Mutations of PCD-causing genes effect the genesis, structure and/or function of motile cilia leading to impaired mucociliary clearance (Fig. 25.2). Cilia dysmotility in the airways classically leads to unexplained neonatal respiratory distress in term infants, daily wet cough from early infancy, bronchiectasis, chronic rhinosinusitis, and conductive hearing impairment [36]. PCD is estimated to affect approximately 1 in 7750 people [26, 37], but many people are undiagnosed or diagnosed late in life, and the true prevalence is unknown [38]. Whilst data from international consortia and large clinics are improving our understanding of disease progression, information concerning morbidity and mortality remain sparse. The International PCD Cohort (iPCD) has reported that lung function impairment during childhood is similar to that found in CF, but by adulthood forced expiratory volume in 1 s (FEV1) is worse in CF [39]. Recent observations
25 Difuse Bronchiectasis of Genetic or Idiopathic Origin |
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445 |
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Cl– Cl– Cl– |
Cl– |
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Cl– Cl– Cl– |
Cl– |
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Cl– |
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Class of mutation |
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Channel |
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channel |
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half life |
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blocked |
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mutation' |
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Example |
Gly542X |
Phe508del |
Gly551Asp |
Arg117His |
3849+10kb |
4326delTC |
mutations |
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C T |
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Fig. 25.3 Mutations causing cystic brosis can be grouped into classes, dependent on their effect on the CFTR protein
from large adult clinics concur that pulmonary disease is heterogeneous in severity [40, 41]. Several studies have reported impaired growth in children with PCD, [42, 43] which may be associated with worse lung function [39, 42, 43].
Neonates typically present with respiratory distress of unknown cause and some have rhinitis [44]. Infants continue to have a persistent wet cough, and usually develop recurrent respiratory tract infections, rhinitis, and serous otitis media associated with conductive hearing dif culty. Respiratory symptoms continue into later childhood and adulthood. Bronchiectasis has been described in pre-school children and is almost universal by early adulthood (Fig. 25.4); in contrast to CF, disease typically affects the middle and lower lobes, with relative sparing of the upper lobes [45–48]. Bacterial pathogens isolated from the airways are similar to those describedinCF,namelyHaemophilusinfuenza,Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae and Moraxella catarrhalis [49–53].
Motile cilia are important in organs besides the respiratory tract, such as the Eustachian tubes, embryonic node, sperm fagella, the female reproductive tract, and epen-
dyma of the brain and spinal cord. Extra-pulmonary symptoms caused by dysmotile cilia are therefore common, for example, serous otitis media, infertility and rarely hydrocephalus. Embryonic node motile cilia are responsible for left-right asymmetry, and 50% of people with PCD have situs inversus (Kartagener syndrome) or situs ambiguous
(Fig. 25.4); associated congenital heart disease is relatively common [34, 54, 55].
Whilst the individual symptoms found in PCD are non- speci c, a combination of symptoms indicates a need for prompt referral for PCD diagnostic testing (Table 25.2). Patients are symptomatic from birth or early infancy, yet the mean age of diagnosis is approximately 5 years. Large numbers of patients, particularly adults, have not been investigated and are therefore inappropriately labelled ‘idiopathic bronchiectasis’. The variability in diagnostic rates between countries is considerable probably refecting clinical knowledge amongst physicians as well as geographical access to diagnostic facilities [27, 58].
Recent European and North American Guidelines concur that diagnosis of PCD requires specialist investigation using
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Fig. 25.4 (a) HRCT of the chest in a 49-years old man with primary ciliary dyskinesia and Kartagener syndrome at the time of evaluation for lung transplantation, demonstrating severe bronchiectasis and consolidation in the anterior lateral segment of the left lower lobe, and (b)
Table 25.2 Recommendations for who should be referred for PCD diagnostic testing, based on the European Respiratory Society guidelines [52]
Which patients should be referred for diagnostic testing?
• Patients should be tested for PCD if they have several of the following features:
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symptoms or neonatal intensive care admittance, |
• Patients with normal situs presenting with other symptoms suggestive of PCD should be referred for diagnostic testing
• Siblings of patients should be tested for PCD, particularly if they have symptoms suggestive of PCD
• The use of combinations of distinct PCD symptoms and predictive tools (e.g. PICADAR [189]) is recommended
a combination of tests [56, 59]. Extremely low levels of nasal nitric oxide support the diagnosis of PCD [60]. However, some patients with PCD have normal nitric oxide levels, and levels can be low in other conditions including CF. Nasal nitric oxide measurement is therefore used as part of the diagnostic algorithm, but can neither con rm nor refute the diagnosis with certainty [25]. High-speed video microscopy can identify ciliary dysfunction (e.g. static, hyperfrequent, or circling cilia). Both nasal nitric oxide and cilia pattern observed by a high-speed video are highly predictive of PCD, and since analyses are available on the day of testing, counselling and treatment can be based on these provisional results [61]. However, con rmation of diagnosis by transmission electron microscopy or genetic testing is required
bilateral bronchiectasis in the lung bases (associated with centrilobular nodules and tree-in-bud pattern suggestive of bronchiolitis). Note the presence of situs inversus
for a de nitive diagnosis [56, 59, 62]. Most, patients with PCD have diagnostic abnormalities of ciliary ultrastructure on transmission electron microscopy, and “hallmark abnormalities” con rm the diagnosis [63]. Electron microscopy used to be considered the ‘gold standard’ investigation but it is now recognised that approximately 15–20% of patients with PCD have normal ciliary ultrastructure. Similarly, immunofuorescence labelling to detect and localise intraciliary proteins (e.g. DNAH5) has excellent speci city but limited sensitivity to diagnose PCD [64].
Mutations in over 40 genes have been associated with PCD to date (reviewed in [34, 56], and summarised in Fig. 25.5). Bi-allelic pathogenic mutation or hemizygous X-linked mutation in a known PCD gene can con rm a diagnosis, [34, 56, 59] and approximately 70% of PCD cases diagnosed by other methods can be genetically con rmed. The diagnostic sensitivity should continue to improve as new genes are identi ed. The number and size of the genes results in a large number of variants, many of which are not pathogenic. To avoid false positive diagnoses, it is therefore important to ensure that the reported genotype correlates with phenotypic ciliary ultrastructure and function (Fig. 25.5b) [56]. For example, disease causing genetic variants in DNAH5 are associated with absence of the outer dynein arms and static cilia. Mutations in DNAH11 are associated with normal ciliary ultrastructure by transmission electron microscopy, and the cilia have a hyperfrequent vibratory pattern [34].
Whatever the genetic defect, people with PCD generally have severely impaired mucociliary clearance leading to the previously described features. However, only some genes are associated with laterality defects or infertility, and some