- •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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higher than 80%, and the more recent availability of rituximab may improve these results. Still patients may present with recurrences leading to sequential treatment; parenchymal or bronchial sequelae may ensue, leading to chronic obstructive disease or pulmonary brosis. Local and systemic recurrences develop in about 50% of cases, but are usually controllable with chemotherapy. Evolution to high-grade B-cell lymphoma is seen in less than 5% of cases.Young age at diagnosis is the most signi - cant favorable prognostic factor.
Cancer Mimics of Interstitial Lung Diseases
Besides lymphangitis carcinomatosis, several rare intrathoracic tumors may present with an interstitial and/or a micronodular pattern, such as epithelioid hemangio- endothelioma and lymphomatoid granulomatosis.
Lymphangitic Carcinomatosis
Pulmonary lymphangitic carcinomaosis is a metastatic lung disease characterized by the diffuse in ltration and obstruction of the pulmonary parenchymal system by tumor cells [22, 23]. Pulmonary lymphangitic carcinomatosis accounts for up to 10% of all thoracic metastases. Patients are usually diagnosed in their fth decade. Dyspnea is usually the chief symptom [22, 23]. Weight loss is also frequent, as well as cough. Hypoxemia is observed in 70% of patients.
Even if histologically con rmed, chest radiography may be normal in up to 30–40% of cases. High-resolution computed tomography (CT)-scan may show (1) uneven thickening of bronchovascular bundles, from the hilum to periphery, that resembles Kerley B lines, (2) a more limited or diffuse peripheral interlobular septal thickening producing polygonal arcades, and/or (3) a radiographic pattern referred to as “beaded chain” or “string of pearls” thickening of interlobular septa [22]. These features may be diffuse or localized, unior bilateral, and symmetric or not. Micronodules may be observed within the thickened septa. Rapidly progressive asymmetric lymph node involvement is found in 30% of patients. 18-FDG-PET scan shows diffuse parenchymal hypermetabolism in diffuse lymphangitic carcinomatosis, or a more linear or hazy area of FDG uptake.
Diagnosis is usually obtained through bronchial, transbronchial or open lung biopsy; percutaneous biopsy may also provide lung tissue materials allowing the diagnosis to be made. Pathological examination shows multiple tumor thrombi within the lymphatic vessels, associated with a desmoplastic reaction caused by tumor proliferation and lymphatic dilatation around the interlobular septa and peribronchovascular bundles. Tumor cells of adenocarcinoma type are the most likely to produce lymphangitic carcinomatosis, originating from the following primary anatomic locations: breast (33%), stomach (29%), lung (15%), pan-
creas (4%), and prostate (3%) [22]. Survival is usually poor, ranging from 3 to 6 months [21, 22].
Differential diagnosis includes other in ltrative lung diseases, sarcoidosis, as well as bacterial or fungal infections, such as pneumocystis jirovecii pneumonia (PJP), especially when immunosuppressive cytotoxic agents are employed for treatment of the primary cancer. Bronchoalveolar lavage is the key to making the diagnosis of PJP. Lymphangitic carcinomatosis may also be confused with drug-induced interstitial lung disease especially in patients receiving chemotherapy or targeted agents or immunotherapy, immune checkpoint inhibitors or antibodies (drug-conjugated or not). Imaging patterns are nonspeci c and may include ground-glass opacities and interlobular septal thickening. Multiple forms of interstitial lung disease may occur within individual cancer patients.
Epithelioid Hemangio-Endothelioma
Epithelioid hemangio-endothelioma (EHE) is a lowto intermediate-grade mixed epithelioid, endothelial, and vascular tumor [24, 25]. Lung is the most frequent extrahepatic location (10% of cases); EHE can also arise from the liver (63% of cases), the bone (8% of cases), and the skin (6% of cases) [24, 25]. EHE is characterized by polypoid nodules, with a central sclerotic paucicellular zone, growing into the alveolar spaces with an angiocentric distribution. Lymphangitic spread may mimic metastatic carcinoma. Around 90% of EHEs are caused by the fusion of transcriptional co-activator with a PDZ-motif (TAZ) with calmodulin binding transcription activator 1 (CAMTA1), a central nervous system-speci c transcription activator; the 10% of EHEs that lack the TAZ-CAMTA1 fusion instead have a fusion of yes-associated protein (YAP) and transcription factor E3 (TFE3) genes (YAP-TFE3) [26]. EBV RNA sequences are detected in 90% of cases. Overlapping entities with IgG4-related disease have been described. Clinically, 80% of cases of EHE are diagnosed in white females [24–26]. The tumor is asymptomatic in 50% of cases; when present, symptoms are nonspeci c and include pleuritic chest pain, nonproductive cough, dyspnea, and rarely hemoptysis. By CT imaging, EHE presents either with bilateral slow-growing perivascular multiple nodules, usually located adjacent to small vessels or bronchi, or with predominant in ltrative ground-glass opacities with a micronodular pattern, mimicking lymphangitic carcinomatous. EHE nodules usually range from 3 to 50 mm, and their numbers vary from 10 to 20 lesions. Nodules in patients with EHE may show increased uptake on 18-FDG PET scan. Although there are a few reports of spontaneous remission, the complete resection of all pulmonary nodules is the only curative treatment for EHE. Surgery remains effective even in cases of localized recurrence. In contrast, EHE is generally insensitive to chemotherapy (cisplatin-based) or radiotherapy. Treatment with rituximab or antiangiogenic kinase inhibitors, such as
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sorafenib or bevacizumab, have been reported to be effective in isolated case reports [27]. In most cases, EHE is a slow- growing tumor that rarely metastasizes and is associated with a median survival of 5–6 years. Endobronchial spread, pleural effusion, and extended endovascular disease have been identi ed as unfavorable prognostic factors.
Angiosarcoma is a high-grade primary pulmonary vascular sarcoma that is considered to be a counterpart of EHE, although no direct transformation from EHE to angiosarcoma has been reported. Clinical features of angiosarcoma are similar to EHE, but massive hemoptysis is more frequent. Radiologic features of angiosarcoma include multiple nodules with a typical surrounding halo of ground-glass attenuation, and a characteristic “caulifower-like” appearance on T2-weighted MRI [28]. This aspect may be shared by other disorders, including malignancies (e.g., adenocarcinoma with lepidic pattern (e.g., bronchioloalveolar carcinoma), metastatic sarcomas, choriocarcinoma, melanoma, lymphoma), infectious diseases (e.g., mycobacteriosis, aspergillosis, cytomegalovirus infection), granulomatosis with polyangiitis, and eosinophilic conditions. Distinguishing primary pulmonary angiosarcoma from extrathoracic angiosarcoma metastatic to the lung can be challenging. Management of angiosarcoma is not established: surgical resection is rarely possible owing to local and regional invasion and radiotherapy and chemotherapy are typically ineffective as seen in other locations of angiosarcoma. In immunocompromised patients, reduction of immunosuppressive agents may lead to reduce the burden of the disease.
Lymphomatoid Granulomatosis
Lymphomatoid granulomatosis (LG), previously called “angiocentric lymphoma,” is a malignant B cell angiocentric and angiodestructive lymphoproliferative disorder [28– 30]. For a long time, LG was considered an infammatory granulomatous disease owing to a presentation similar to other granulomatosis, such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Now, LG is recognized as a true EBV-related lymphoid malignancy. Differential diagnosis also includes allergic bronchopulmonary aspergillosis. The lung is the most frequent location, but the disease may also involve the brain, the skin, and the liver [28–30].
Pathologically, LG forms multiple and confuent nodules composed of an atypical, angiocentric, and polymorphous lymphoid in ltration involving the vascular walls, from the subendothelium to the adventitial zones, with focal lumen obliteration. By immunohistochemistry, these lymphoid cells are characterized mostly as CD4+ T-lymphocytes, with scattered atypical B cells. Large B cells are infected with EBV in 65% of cases, and EBV status correlates with the grade of the lesion. Pulmonary biopsy is required in most cases to exclude other granulomatoses.
LG arises in middle-aged patients between 40 and 50 years old, with a male predominance. Nearly all patients present with respiratory and systemic symptoms, consisting of cough, dyspnea, hemoptysis, chest pain, fever, and weight loss. Peripheral and mediastinal lymphadenopathy is absent. Prolonged immunosuppression is a frequent underlying condition. Hypereosinophilia may be observed in the blood and/ or in the bronchioalveolar lavage. The typical radiologic presentation consists of multiple smooth bilateral nodules ranging from 2 to 10 cm mainly localized in the lower lobes, exhibiting a peribronchovascular pattern and mimicking multiple metastases. As in other granulomatoses, convergent nodules may migrate and form cavitated pseudotumoral masses.
LG is considered a low-grade or early-stage lymphoma, and a histopathologic grading system has been developed based on the degree of cellular atypia and necrosis to predict the risk of evolution to high-grade lymphoma and to select patients for early aggressive treatment [30]. Chemotherapy based on the use of cyclophosphamide with high-dose steroids is the most frequently reported treatment. The additional use of rituximab has been reported [30]. The overall prognosis is grim, with a 5-year survival of 30% to 40%, owing to progression to nodal diffuse aggressive lymphoma in 20% to 50% of patients.
Cancer Mimics of Multiple Cystic/Cavitary Lung
Disorders
Cystic Tumors
Multiple cystic lung disease (MCLD) is de ned by the presence of multiple rounded well-de ned lucencies of low- attenuating area in the lung parenchyma that have a wall thickness lower than 2 mm [31]. MCLD may lead to the development of spontaneous recurrent pneumothorax. As discussed elsewhere in this book, MCLD may be caused, among various disorders, by lymphangioleiomyomatosis, Langerhans cell histiocytosis, Sjögren disease or Birt-Hogg- Dubé syndrome.
Metastatic cancers of extrapulmonary origin may mimic MCLD when metastasizing to the lung, especially soft tissue sarcomas including angiosarcomas [32, 33], leiomyosarcomas, osteosarcomas, and synovial sarcoma. Primary tumor locations include soft tissues, bones, the scalp or the uterine endometrium. The occurrence of spontaneous pneumothoraces, which may be bilateral and recur in more than 40% of cases, is more frequent in angiosarcoma, and is associated with worse outcomes. Metastatic cysts may be associated with small-size nodules. In cases for which the information is available, pathological examinations have shown tumor cells in the wall of the cysts. Several case reports describe patients for whom metastatic sarcoma was ultimately diag-
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nosed on lung biopsies, or even explanted lungs, after an initial diagnosis of lymphangioleiomyomatosis or pulmonary Langerhans cells histiocytosis [33].
In addition to sarcomas, MCLD-like metastases have been reported in bronchioloalveolar carcinoma, metastatic or primary germ-cell tumors, colorectal and pancreatic cancer.
Cavitating Tumors
The radiological features of cavities overlap with those of cysts. A cavity is a gaslled space, seen as a lucency or low- attenuation area within a parenchymal nodule, focus of consolidation or mass [34]. Cavitation is a classical feature of pulmonary involvement by granulomatosis with polyangiitis, in combination with multiple bilateral pulmonary nodules. Cavitation is also a common feature of bronchogenic carcinoma, especially of squamous cell histology, and typically is not associated with extrapulmonary manifestations in the head and neck area, the skin, the joints or the kidney [34]. Serum proteinase 3-speci c, cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA) are not elevated in patients with cancer. Granulomatosis with polyangiitis rarely presents with a solitary lung lesion; most solitary necrotising granulomas are actually of infectious nature and require histology in addition to typical clinical ndings to support the diagnosis.
Cancer Mimics of Pulmonary Hypertension:
Pulmonary Artery Sarcoma
Pulmonary artery sarcoma presents as an endoluminal polypoid or nodular mass, which spreads along the intima of the pulmonary artery. Histologic features consist of an undifferentiated spindle cell proliferation, with marked cellular pleomorphism and high mitotic index Leiomyosarcoma is the most frequent subtype (60% of cases) [35]. Pulmonary artery sarcomas mainly develop in patients in their fth to sixth decade [35]. Symptoms may mimic pulmonary embolism, with dyspnea, chest pain, cough, and hemoptysis. Failure of anticoagulants to resolve the vascular obstruction in this setting, as well as the presence of symptoms of weight loss and fever (arising in 40% of cases), may suggest the diagnosis. Imaging ndings also help differentiate between pulmonary artery sarcoma and pulmonary embolism: CT scanning may show a polypoid lling defect in the pulmonary artery but, in contrast to thromboembolic disease, sarcoma forms a contiguously soft, smooth, tapering tissue mass, sometimes accompanied by extravascular nodular spread in the parenchyma (40% of cases) and localized
Fig. 43.2 Primary pulmonary artery sarcoma. Contrast enhanced computed tomography scan of a 79-year-old woman, which shows complete obstruction and enlargement of the pulmonary artery trunk. Hypermetabolism is detected at 18-fuoro-2-desoxy-d-glucose positron emission tomography scan. The patient underwent pulmonary endarteriectomy, complete resection of the tumor, and extensive left pneumonectomy. The patient died 25 months after surgery
ground-glass opacities (Fig. 43.2) [36]. Sarcoma also presents with a heterogeneous appearance including areas of necrosis and hemorrhage, and with intense hyperactivity on 18-FDG-PET scanning. Magnetic resonance imaging (MRI) shows intermediate to mildly increased signal on T1-weighted images, often with heterogenous enhancement. T2-weighted images may reveal intermediate to diminished signal intensity relative to skeletal muscle, but in some cases may show enhancement of the intravascular mass, a feature not typically encountered with uncomplicated thromboembolic disease. Surgery is the only potentially curative treatment and, even if performed emergently in the setting of acute right-sided heart failure, is amenable to attempted resection in only 60% to 75% of cases [35– 37]. Alternatively, heart and lung transplantation may be an option for unresectable tumors, but has rarely been reported. A slight improvement of overall survival has also been reported following adjuvant chemotherapy and/or radiotherapy. Contrary to soft tissue sarcoma, prognosis is mainly related to tumor location, because half of the patients die as a result of the progressive obstruction of the pulmonary trunk [37]. In case of recurrence, reoperation is feasible in 30% of cases and radiation therapy and chemotherapy can be partially effective. However, in recent series, the overall median survival has remained low at 6–12 months.
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