- •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
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Fig. 16.10 Radiographic manifestations of ocular ECD involvement. (a) 57 years old man presents with cellulitis and exophthalmos. Contrast enhanced orbit CT shows bilateral retrobulbar soft tissue masses. (b, c)
Axial T1 MRI with contrast con rms enhancing retrobulbar masses (arrows), and dural masses (arrowheads)
crine presentation is central diabetes insipidus [4, 32], followed by de cits in growth hormone [4], gonadotropins, thyrotropin [4], and rarely corticotropin [4, 32].
The heart is the most common extraskeletal site of ECD in ltration, which is rare in other non-Langerhans cell histiocytic diseases, and almost never occurs in Langerhans cell histiocytosis [4]. The histiocytes of ECD can in ltrate any cardiac layer, including the pericardium (up to 40%) [4]. Pericardial involvement can result in pericardial effusion [4, 26], although cardiac tamponade is rare [4]. There is a predilection for in ltration of the right atrium, which can present as a “pseudo-tumor” on cardiac imaging [1, 4, 10, 21], and can extend into the atrioventricular sulcus causing conduction blocks [4], and even direct valvular in ltration by histiocytes [10, 21, 27]. Vascular involvement can include periarterial in ltration [26, 27] and brosis [27] has been described to involve the coronary arteries in up to 55% (although the need for stent placement is uncommon), aorta, brachiocephalic trunk, subclavian arteries, pulmonary trunk, carotid arteries, celiac trunk, superior mesenteric trunk, and renal arteries [1, 4, 6]. Periarterial in ltration can lead to dire consequences if stenosis results in cerebral, myocardial, and/or mesenteric ischemia, and renovascular hypertension [27]. Additional clinical complications can include congestive heart failure, thromboembolic disease, and valvular dysfunction [27].
Retroperitoneal and kidney involvement is common [10, 21, 27, 32], with a higher frequency in males [21]. Histiocytes may in ltrate perinephric soft tissues leading to a “hairy kidney” appearance on imaging. Extension to the renal sinus, and the midand distal ureters can cause hydronephrosis necessitating stenting [4]. Mesenteric in ltration and brosis have also been described [32].
Other extra-pulmonary and extra-skeletal manifestations of ECD include skin nodules and soft tissue masses [21, 32], which increase in incidence with age [21]. ECD involve-
ment in the reticuloendothelial and hematopoietic systems is rare [4].
Investigation/Diagnosis
The diagnosis of ECD can be extremely challenging, often requiring a multidisciplinary approach that includes the integration of clinical, radiographic, pathologic, and genetic data. There are no speci c laboratory ndings that are diagnostic or speci c for ECD, but there are several that can offer insight into the extent or activity of the disease. Infammatory markers such as erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), lactate dehydrogenase (LDH) [10], and alkaline phosphatase (ALP) may be elevated [27]. Hypothalamic-pituitary axis involvement may be detected by elevations of prolactin, or decreased levels of luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, growth hormone, or thyroid stimulating hormone. Central diabetes insipidus can result in hypernatremia, and the diagnosis can be revealed by a doubling of urine osmolality after desmopressin administration or increased serum osmolality after water deprivation in a patient with polyuria [27]. Elevations in blood urea nitrogen and creatinine may point toward renal involvement [27].
Chest Studies
Imaging studies can offer aid in the initial diagnosis and provide important information for monitoring disease progression or treatment response. CXR may demonstrate prominent interstitial markings resembling Kerley B lines, due to lymphangitic involvement [20] (Fig. 16.7).
Computed tomography (CT) allows for the identi cation of lung, pleural, aortic, and skeletal lesions [26]. High-
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resolution computed tomography (HRCT) is the gold standard for the identi cation of pulmonary manifestations of ECD. The changes seen on HRCT are due to histiocytic in l- tration that typically manifests in a lymphangitic distribution involving the visceral pleura, interlobular septa, and bronchovascular bundles [27]. Other common ndings include centrilobular nodular opacities, thin-walled cysts, ground- glass opaci cation, pleural effusion, and mediastinal involvement [1, 4, 11, 34]. Gallego et al. [11] described a common pattern of pleural thickening due to histiocytic in ltration of the right paravertebral basal area of the retrocrural space which creates a pseudotumor-like structure(Fig. 16.7).
When the lungs are involved, pulmonary function testing (PFT) should be completed. Findings may be normal early in the disease ranging to advanced obstructive or restrictive disease with reduced DLCO in more severely affected patients [4].
Cardiovascular Imaging
CT evaluation may also demonstrate an irregular appearance of the aortic intima, called “coated aorta,” related to brous encasement of the aorta by histiocytic in ltration of the adventitia, a pattern that is pathognomonic of ECD [10, 21, 27]. Echocardiography can be used to assess degrees of cardiac involvement [27].
CNS Imaging
Magnetic resonance imaging is the modality of choice for CNS imaging and may demonstrate masses in the pituitary stalk, cerebellum, and brainstem, as well as retro-orbital masses with and without meningeal involvement [27] (Fig. 16.10).
Bone Radiography
Plain lms demonstrating bilateral symmetric cortical osteosclerosis of the metadiaphyseal regions of long bones with sparing of the epiphyses is pathognomonic of ECD and seen in 96% of patients [1, 4, 10, 20]. The most commonly affected bones are the femur, tibia, and bula, and less frequently affected are the ulna, radius, and humerus [27] (Fig. 16.9). The axial skeleton is typically spared [27].
99mTc Bone scintigraphy can be used as a screening test for bony involvement including the identi cation of pathognomonic features of parallel, symmetric uptake in long bones of both extremities [4, 21, 26] (Fig. 16.9).
Positron emission tomography/computed tomography (PET-CT) offers good sensitivity for the detection of bone lesions and can detect subtle vertebral lesions and aid in targeting for biopsy [4, 26]. PET-CT can also detect visceral and vascular in ltration as ECD lesions exhibit increased radiotracer uptake [26].
Other Imaging Findings and Considerations
Contrast-enhanced CT may show lymphadenopathy and diffuse bilateral in ltration of the perinephric soft tissue leading to thickening in a stellate pattern, often described as having a “hairy kidney” appearance [1, 4, 6, 10]. Combinations of imaging studies have important roles at the time of diagnosis, and as part of monitoring for disease progression and/or response to treatment. Mazor et al. [27] have outlined a strategy for imaging at the time of initial presentation and over time. Initial evaluation including plain lms of the skeleton and whole-body bone scintigraphy may reveal pathognomonic symmetric osteosclerosis of the metadiaphyses of long bones. A whole-body PET-CT [1, 27] allows assessment of the extent of skeletal and extra-skeletal involvement, and identi cation of an optimal site for biopsy [1, 27]. Mazor et al. [1, 27] reported that PET-CT offers variable sensitivity, but excellent speci city for ECD lesions. A baseline MRI is the optimal study to evaluate patients for CNS involvement [1, 10, 26, 27], and baseline head CT aids investigation of skull and sinus involvement as well as guides biopsy site selection [1, 27]. HRCT screening is indicated at diagnosis and for patients who develop pulmonary symptoms [1, 27].
The gold standard for diagnosis of ECD is correlative tissue biopsy integrated with the clinical/radiographic ndings [1, 4, 21]. Histological demonstration of xanthogranulomatous family histiocytic in ltration with appropriate staining in the right clinical/radiographic setting is diagnostic [1, 21, 26, 27]. In patients with pulmonary manifestations, extra- pulmonary sites of involvement may be lower risk targets for biopsy [4, 11].
Disease Monitoring
Progression of the disease can be followed over time with serial PET-CT, annual low-dose CT of the chest, abdomen, and pelvis, and contrast CT of the chest if the patient develops symptoms concerning cardiac or mediastinal in ltration. Echocardiography should be obtained if cardiac involvement is suspected [27]. Lu et al. suggest serial MRI of the CNS and spine over time [21]. Pulmonary function tests are useful for following pulmonary disease progression.
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Pathology
As shown in Fig. 16.8, pathologic evaluation of lung tissues reveals histiocytes with an abundance of pale, eosinophilic cytoplasm and bland appearing nuclei that in ltrate the pleura and lead to pleural thickening [20]. Histiocytic in l- tration of the lung parenchyma in a peri-lymphatic distribution leads to thickening of the interlobular septa and bronchovascular bundles, often sparing the alveoli. The histological ndings correlate with CT ndings that often include ground glass opacities and interstitial changes in a lymphatic distribution [20].
Management/Treatment
Treatment recommendations are summarized in Fig. 16.11. The FDA has approved vemurafenib, a BRAF V600 inhibitor, and given cobimetinib, a MEK-inhibitor Breakthrough Therapy Designation for the treatment of ECD [1, 24] Current treatment recommendations for other agents are drawn from case reports, case-series, small open-label trials
and retrospective studies [27]. In patients who are asymptomatic with indolent non-vital single organ disease, treatment may not be necessary for the short term, and adopting a “watch and wait” strategy with serial imaging may be reasonable [1, 10]. In patients who are symptomatic or progress with the disease that threatens to compromise major organs systems, (especially with pulmonary and CNS involvement), treatment should be initiated [1, 10].
The most thoroughly studied therapy for ECD is interferon-alpha (IFN-α) [10, 21, 26, 27, 32]. IFN-α has been reported to improve survival in multivariate retrospective studies [10, 32] but is often poorly tolerated [10, 21, 27, 32]. There is wide variability in reported dose ranges applied (from one million units three times weekly [10] to more than 18 million units total weekly [27]), with no consensus regarding the optimal regimen. Pegylated IFN-α has been reported to provide equal ef cacy, better tolerance, and more convenient dosing with weekly once administration [10, 27]. Gianfreda et al. report an untreated mortality rate in ECD of 60%, which was reduced to 26% with administration of IFN- α. Although the mechanism of action is not entirely clear, IFN-α is thought to promote immune-mediated clearance of
ERDHEIM CHESTER DISEASE TREATMENT REGIMENS
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Fig. 16.11 Treatment algorithm for ECD. (Adapted from NCCN [22])
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histiocytes and inhibit the terminal differentiation of immature histiocytes [27]. It is interesting to note that IFN-α levels are elevated in patients with untreated ECD [10, 32]. IFN-α results in durable regression of bone lesions and retro-orbital lesions, and reduction in pain and manifestations of diabetes insipidus [10, 27]. IFN-α does not appear to be effective for cardiac or central nervous system ECD lesions [10, 27, 32], and has a minor impact on pulmonary lesions [27]. There are currently no means to predict who will or will not respond to IFN-α therapy. Adverse effects of IFN-α include often intolerable fatigue (perhaps the most limiting adverse effect) [10], myalgia, pruritus, thrombocytopenia, and asthenia [27]. IFN-α should be used with caution in patients with a history of psychiatric disease as it can exacerbate these conditions [10], especially depression [10, 27]. As treatment is prolonged, often spanning more than 20 months, tolerance to treatment becomes a major limiting factor [27].
In patients who progress despite therapy, or cannot tolerate therapy with IFN-α, there are many other candidate therapies available. Many of these second-line therapies target key nodes in the pathogenic pathway outlined earlier.
Vemurafenib, a BRAF V600E inhibitor, has been shown to have ef cacy in LCH and PLCH patients with this mutation [1, 21, 27, 32], and is an appropriate, FDA-approved consideration in the approximately 50% of ECD [10, 21, 27, 32] patients who harbor this mutation. Vemurafenib crosses the blood-brain barrier [21] suggesting potential ef cacy for ECD CNS lesions. There have been reports of dramatic responses within a few weeks of initiation of vemurafenib [10, 21, 27], and the drug is usually well tolerated; the most common adverse effects in the literature include skin rash, fatigue, and diarrhea [10] which do not usually limit use. A recent phase II trial demonstrated a 62% response rate, with rapid and durable clinical responses in multiple disease sites with reversal of critical disease burden in some patients [1]. It was also noted during this phase II trial that about 2/3 of patients who discontinued vemurafenib relapsed within 6 months [1]. Additional risks that have since been identi ed include an increased risk of secondary neoplasia, sarcoidosis, and pancreatitis [1]. Goyal et al. [1] have suggested a management strategy that includes screening for BRAF mutations at the time of initial pathology review. In the BRAF V600E mutation-positive patients rst-line therapy with vemurafenib should be offered [1]. If ECD is con rmed and no BRAF V600 mutation is found, a MEK inhibitor (targeting a downstream effector that will block signaling by other (undetected) activating mutations in the MAPK pathway) or therapy with IFN-α are reasonable next steps [1, 10, 24]. Furthermore, in patients who progress despite these therapies, or who cannot tolerate the drugs, a trial of second- line therapy with anakinra, imatinib, or cladribine is recommended [1, 6, 10].
Other mutations that have been identi ed in ECD include PIK3CA (approximately 13%) and NRAS mutations (approximately 4%), which cause activation of the mammalian target of rapamycin (mTOR) pathways [32]. mTOR inhibitors represent another attractive therapeutic option [32], offering anti-proliferative, anti-infammatory, and anti- senescence properties [1, 32]. Gianfreda et al. performed an open-label trial utilizing the mTOR inhibitor, sirolimus, in combination with prednisone in patients with ECD who were not candidates for IFN-α therapy and did not express the BRAF V600E mutation. They reported a signi cant response with regression of peri-renal and peri-ureteral lesions, as well as improvement in pericarditis [32]. There were varied responses in CNS lesions and marginal or absent responses at other sites of disease [32]. They concluded that therapy with sirolimus and prednisone led to stabilization or improvement of disease and was generally well tolerated in patients with ECD [32].
The recombinant human interleukin-1 receptor (IL-1R) antagonist, anakinra [21, 27, 32] has been used in patients with ECD. Inhibition of the IL-1R blocks aberrant MAP kinase activation in histiocytes [10]. Munoz et al. [10] postulated that IL-1R antagonism may also downregulate the expression of IL-1 alpha receptors on the membranes of monocytes and the IL1 beta receptors of in ltrating histiocytes. Treatment with anikinra has been reported to reduce fever and bone pain, improve skin lesions, and result in weight gain. The drug is generally well tolerated [10, 27] with the most common adverse effect reported to be local skin reactions at the site of injection, and reactivation of previous infections, such as tuberculosis. Given the favorable safety pro le, Munoz et al. [10] suggest that anikinra may be an appropriate therapy in elderly patients or patients with comorbidities.
Cladribine, also called chlorodeoxyadenosine, is an antineoplastic purine analog [32], often used for the treatment of LCH and PLCH, that represents another alternative for ECD therapy, although less data are available [10, 27]. Cladribine is toxic to monocytes [10] and has been reported to lead to partial regression of CNS lesions [27]. Adverse effects of bone marrow suppression and neurologic toxicity are dose- dependent [27].
The anti-tumor necrosis factor alpha (TNF-α) mononuclear antibody, infiximab, has been used to treat ECD [10, 21, 27]. TNF-α has been shown to play a role in regulating the recruitment of histiocytes [10]. Infiximab therapy has been reported to improve cardiac function and cause resolution of pericardial effusions [10] in ECD. The anti-IL-6 medication, tocilizumab, has also been utilized for the treatment of ECD [27].
Imatinib is a tyrosine kinase inhibitor that selectively targets cKIT, BCR-ABL, and platelet-derived growth factor