- •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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Finally, other cases initially reported as diffuse OP may have had acute exacerbation of interstitial lung disease (AE-ILD), an acute worsening of severe prognosis occurring in the natural history of idiopathic pulmonary brosis (IPF), NSIP and other brotic interstitial disorders [57]. AE-ILD has been associated with histological patterns of either OP or diffuse alveolar damage at lung biopsy, the former being correlated with a much better short term outcome [58]. Diffuse in ltrative OP still awaits better characterization. In the meanwhile, the above-mentioned disorders need to be considered in the differential diagnosis.
Other Imaging Patterns
Rarely, OP may present as multiple, sometimes cavitary nodules [59–62], a micronodular pattern, with multiple small wellor poorly-de ned nodules, or nodules with an air bronchogram [63]. Other variants include a bronchocentric pattern, a perilobular pattern resembling thickened interlobular septa, circumferential subpleural linear opacities, and radial opacities [29, 59, 63–66]. A “ring-like,” “reversed halo” or “atoll” pattern has rarely been reported in OP, consisting of a focal round area of ground glass surrounded by a crescent or ring of consolidation (Fig. 35.4b) [63]. Contrary to early beliefs, this sign is not speci c to OP and may also be found in eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), chronic eosinophilic pneumonia, lymphomatoid granulomatosis, tuberculosis, and various fungal infections [67].
Histopathological Diagnosis of OP Pattern
Buds of granulation tissue (Masson bodies) consisting ofbroblasts embedded in a myxoid matrix lling the distal airspaces (alveoli, alveolar ducts, and less commonly distal bronchioles) constitutes the histological hallmark of OP (Fig. 35.1). Associated features include mild interstitial infammatory in ltrate, type II cell hyperplasia, and intra- alveolar foamy macrophages [2, 11, 13]. However, buds of granulation tissue are not speci c and may be seen as an ancillary feature in many other disorders such as infections, the periphery of tumors, pneumonia distal to airway obstruction, hypersensitivity pneumonitis, NSIP, chronic idiopathic eosinophilic pneumonia, or GPA [11, 12, 68] (Table 35.3). For instance, OP pattern has been found in the vicinity of tumoral tissue in up to 40% of resected lung cancers [69]. Thus, a con dent histopathological diagnosis of OP pattern requires: (1) the presence of buds of granulation tissue within distal airspaces as the dominant histopathological lesion and not only a minor feature, and (2) the absence of features suggesting another diagnosis such as prominent eosinophilic or neutrophilic infammation, granulomas, hyaline membranes,
Table 35.3 Disorders in which organizing pneumonia pattern may be found as an ancillary histopathological feature
Neoplasms
Pulmonary infections
Organization distal to airway obstruction
Aspiration pneumonia
Nonspeci c interstitial pneumonia
Hypersensitivity pneumonitis
Desquamative interstitial pneumonia
Chronic idiopathic eosinophilic pneumonia
Secondary eosinophilic pneumonias
Eosinophilic granulomatosis with polyangiitis
Granulomatosis with polyangiitis
Primary pulmonary lymphoma
Diffuse alveolar damage
Drug reactions and toxic exposures
Others
acute bronchiolitis, or necrosis (see Box 35.1) [3, 11]. The main differential diagnosis of OP pattern at histopathology includes NSIP and the organizing stage of DAD [3].
Clinico-Pathological Diagnosis of OP
Syndrome
The clinico-pathological diagnosis of OP requires the combination of clinical, imaging, and histopathological features. Thus, OP is essentially a multidisciplinary diagnosis. BAL is recommended in virtually all cases presenting with multiple or diffuse opacities at imaging in which a diagnosis of OP is suspected. It allows to exclude an infectious process and to differentiate OP from other infammatory disorders having a similar picture such as eosinophilic pneumonias. A histological proof of OP should be obtained whenever possible [70]. Transbronchial lung biopsy (TBB) is the most commonly used method, whereas surgical lung biopsy is now performed in a minority of cases, although it can be considered as the gold standard for histological diagnosis of OP.
The diagnostic value of BAL and TBB to diagnose COP has been analyzed in one study [71]. In 37 consecutive patients presenting with clinical features suggestive of COP and bilateral patchy in ltrates at chest X-ray, BAL with >25% lymphocytes combined with 2 out of 3 other criteria (foamy macrophages >20%, neutrophils >5%, or eosinophils >2% and <25%) had a sensitivity of 63% and a speci city of 57% to diagnose COP [71]. A sensitivity of 20% and a speci city of 89% were found in another study using the same criteria [33]. Transbronchial biopsies showing buds of granulation tissue in distal airspaces, chronic infammation of the alveolar walls, and preserved lung architecture were 64% sensitive and 86% speci c for the diagnosis of COP [71]. Although generalization of these data is questionable, expert opinion- based current international guidelines consider that if the
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35 Organizing Pneumonias and Acute Interstitial Pneumonia |
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clinical and imaging picture are typical with multifocal opacities, a TBB showing also typical intra-alveolar buds of granulation tissue is suf cient to con dently diagnose OP [3, 53].
If the initial clinical and imaging features are atypical (solitary nodular opacity, diffuse in ltrative pattern) and if an infection or tumor have not been found at bronchoscopy, a video-assisted thoracoscopic surgical lung biopsy may be necessary to make sure that OP is the dominant histopathological pattern and not just an ancillary nding in the frame of another pathological process (Fig. 35.5a) [70].
Transthoracic HRCT-guided needle biopsy has been reported as a useful minimally invasive diagnostic method for OP with a high diagnostic yield [72, 73]. Most patients studied had unilateral or bilateral consolidations or tumorlike lesions, and only a few had a diffuse in ltrative pattern [72, 73]. The most frequent complications were sub-clinical pneumothorax and minor hemoptysis, occurring in around 30% of cases. As transthoracic needle biopsy usually provides larger tissue samples than transbronchial biopsy, it may constitute an alternative to surgical lung biopsy in some cases (Fig. 35.5b). However, experience with this technique for the diagnosis of OP is currently insuf cient to recommend it for routine clinical use.
Biopsy may be omitted in a minority of cases with typical clinico-radiological and BAL features, and a clearly identi-ed causal agent of OP such as radiotherapy for breast cancer within the past year, recent documented infectious pneumonia, or obvious drug toxicity. In COP, a combination of typical BAL and multiple patchy parenchymal consolidations at imaging has been found diagnostic in half of cases in one series in the absence biopsy, and this strategy deserves further studies [33]. If the risk/bene t ratio of lung biopsy is considered unfavorable due to old age, frailty, or signi cant
a
comorbidities, a presumptive diagnosis of OP and a therapeutic trial of prednisone may be an acceptable strategy. However, the disadvantages of prolonged empirical corticosteroid therapy in the absence of a clear diagnosis, and the risk of false diagnosis of OP, should also been kept in mind. Indeed, disorders mimicking the clinical and imaging features of OP may initially respond to corticosteroid treatment include GPA, primary pulmonary lymphoma, NSIP, or hypersensitivity pneumonitis. Therefore, if the disease follows an unusual course or the response to therapy is inadequate, the diagnosis of OP should be reconsidered, especially if the initial diagnosis was made without biopsy or with transbronchial biopsy only.
Diferential Diagnosis
After having assessed the clinical, imaging, and histopathological features, which make OP a likely diagnostic hypothesis, one must consider other disorders presenting with similar features such as infections, tumors, and other infammatory lung diseases. Imaging could be a starting point to address the differential diagnosis.
In cases presenting with single or multiple areas of parenchymal consolidation, the main differential diagnosis includes infections, minimally invasive or invasive adenocarcinoma, eosinophilic pneumonias (either idiopathic or secondary to a known cause), GPA, EGPA, and primary pulmonary lymphoma. The distinction between OP and GPA may be challenging in some cases, as GPA may present with clinical, imaging, and even histological features of OP pattern [11, 68]. Although the latter usually consist of small foci of OP at the vicinity of otherwise typical granulomatous
b
Fig. 35.5 (a) Transbronchial biopsy showing buds of granulation tissue lling alveolar spaces, with moderate lymphocytic infammatory in ltrates of the alveolar walls, in a patient with unilateral ground glass opacities attributed to aspiration. (b) CT-guided transthoracic needle
biopsy in organizing pneumonia. Numerous intra-alveolar buds of granulation tissue with broblasts and infammatory cells embedded in a loose myxoid matrix are visible
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lesions, OP pattern may occasionally be a prominent histological nding in GPA [11, 68].
In patients presenting with a solitary nodule or mass, lung cancer is the main working hypothesis until proven otherwise. When multiple nodules are present, the differential diagnosis includes metastatic tumors, lymphomas, and pulmonary infections including septic emboli.
If OP presents as a diffuse in ltrative disorder at imaging, the differential diagnosis mainly includes hypersensitivity pneumonitis, NSIP, acute interstitial pneumonia (AIP), other IIP, and AE-ILD.
Etiological Diagnosis of OP
The next step in the diagnostic process of OP is to distinguish between SOP and COP. The search for a cause or associated condition should not be overlooked, as removal of an offending agent, such as a drug, is an essential part of therapy. Since there is no clinical, radiological, or histological characteristic allowing to con dently distinguish COP from secondary OP [24], the diagnosis of COP is made by exclusion, when the search for a cause remains negative.
SOP has been associated with numerous causal agents and clinical contexts (Table 35.4) [24, 70]. It frequently occurs in association with various infections mostly caused by bacteria, but occasionally also by viral, fungal, and parasitic agents. Another frequent cause of OP is a drug reaction [70]. A comprehensive and updated list of incriminated drugs is available on www.pneumotox.com. OP can also arise in the context of connective tissue diseases such as idiopathic infammatory myopathies or rheumatoid arthritis, and in various types of solid cancers and hematologic malignancies, where it should not be mistaken for neoplasm progression or recurrence [74]. One example is provided by bleomycin toxicity: besides diffuse interstitial lung disease, bleomycin can also occasionally induce OP manifesting as pulmonary nodules mimicking metastatic tumor [75–77]. OP can also occur during myeloor lymphoproliferative syndromes, and after lung or bone marrow transplantation. In the latter, an association has been demonstrated between OP and both acute and chronic forms of graft-versus-host disease, suggesting that a causal relationship may exist between these two conditions [78]. Recently identi ed causes of OP or OP pattern at imaging or histopathology include treatment with immune checkpoint inhibitors [79–81], vaping-induced
Table 35.4 Causes of secondary organizing pneumonia, with relative frequencies of main categories (from reference [24])
Infections |
~45% |
Bacteria (Actinomyces, Chlamydia pneumoniae, Coxiella burnetii, Legionella pneumophila, Mycoplasma pneumoniae, Nocardia |
|
asteroides, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus group B, Streptococcus |
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pneumonia), virus (adenovirus, cytomegalovirus, hepatitis C, herpes virus, human immunode ciency virus, human T-cell |
|
lymphotropic virus, infuenza A and B, parainfuenza, SARS-CoV-2 coronavirus), parasites (Plasmodium vivax, hydatic cyst), |
|
fungi (Aspergillus fumgatus, Cryptococcus neoformans, Penicillium janthinellum, Pneumocystis jiroveci) |
|
Drugs |
~20% |
Adalimumab, 5-Aminosalicylic acid, amiodarone, amphotericin, azacitidine, azathioprin, barbiturates, betablockers, bleomycin, |
|
busulphan, carbamazepine, cephalosporin, certinib, cetuximab, clomipramine, cocaine, durvalumab, erlotinib, etanercept, |
|
everolimus, gemcitabine, gold salts, interferon, lamotrigine, l-tryptophane, mesalazine, minocycline, nitrofurantoin, nilutamide, |
|
nivolumab, oxaliplatin, paclitaxel, pegylated interferon α, pembrolizumab, phenytoin, propylthiouracil, rituximab, sulfasalazine, |
|
tacrolimus, thalidomide, temozolomide, ticlopidine, transtuzumab. See also www.pneumotox.com |
|
Solid tumors and hematologic malignancies |
~15% |
|
|
Connective tissue diseases |
~11% |
|
|
Ankylosing spondylitis, Behçet disease, mixed connective-tissue disease, polymyalgia rheumatica, polymyositis and |
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dermatomyositis including anti-synthetase syndrome, rheumatoid arthritis, Sjögren syndrome, adult-onset Still’s disease, systemic |
|
lupus erythematosus, systemic sclerosis, undifferentiated connective tissue disease and interstitial pneumonia with autoimmune |
|
features |
|
|
|
Radiation therapy |
~9% |
breast carcinoma, lung carcinoma, rarely other tumors |
|
Allografts |
|
Lung, kidney, liver, bone marrow, hematopoietic stem cells |
|
Infammatory bowel diseases |
|
Toxic exposures |
|
|
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Acramin FWN (an aerosolized textile dye), crystalline silica, e-cigarette use, frying of jalapeño peppers, house re, nitric acid |
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fumes, paraf nic mineral oil, paraquat, sulfur dioxide, tetrachloroethylene, titanium dioxide nanoparticles in powder paint |
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Post-obstructive pneumonia and aspiration pneumonia |
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Others |
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Anthracosis, chronic recurrent noninfectious osteomyelitis, common variable immunode ciency, coronary artery bypass graft |
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surgery, essential mixed cryoglobulinemia, gastroesophageal refux disease, IgA nephropathy, IgG-4 disease, mesangiocapillary |
|
glomerulonephropathy, neuromyelitis optica, plasmocytoma, primary biliary cirrhosis, SAPHO syndrome, Sweet’s syndrome, |
|
thyroiditis |
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35 Organizing Pneumonias and Acute Interstitial Pneumonia |
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lung injury associated with e-cigarette use [82, 83], and SARS-CoV-2 infection [84–86].
OP has been reported after radiation therapy, especially in women irradiated for breast cancer [87–95], with a reported incidence of 1.4–1.8% in 2 large prospective series of 1176 and 2056 patients [91, 94]. Patients affected by this particular form of OP are women treated by tumorectomy or mastectomy followed by chemotherapy or hormonal therapy, and radiation therapy of approximately 50 Gy on the tumoral site and homolateral lymph nodes. The clinical picture is identical to COP and starts on average 14 weeks after the irradiation, although it can occur up to 1 year later [87]. In contrast to classical radiation pneumonitis, which is limited to the radiation eld, radiation-induced OP also affects the lung outside the radiation eld and frequently involves the contralateral lung. Opacities are frequently migratory [96]. BAL shows a typical mixed pattern alveolitis. The outcome is favorable under corticosteroid treatment [87]. Despite the frequent occurrence of relapses, a complete cured is usually observed. In milder cases, spontaneous disappearance without corticosteroids has been reported [93]. The particular tangential irradiation elds used for breast cancer might play a role in the occurrence of OP in this context. A bilateral lymphocytic alveolitis has been reported to occur in 85% of women receiving unilateral irradiation for breast cancer and, despite being asymptomatic in most cases, could be an early event in the occurrence of OP [97]. Hormonal factors could also be involved. Indeed, in one study, age >50 and anti- estrogen therapy were signi cantly correlated with the occurrence of OP, with odd ratios of, respectively, 8.88 and 3.05 [92]. However, given the importance of hormonal therapy for tumor control in these patients, avoidance or interruption of hormonal therapy to prevent or cure OP is not recommended. In another large study, older age and smoking were identi ed as risk factors, whereas the type of previous surgery (mastectomy or breast-conserving surgery) and the irradiated volume were not associated with OP [94]. Although more frequently described in women irradiated for breast carcinoma, radiation-induced OP has also been reported in individuals of both genders irradiated for other types of tumors, especially after stereotactic ablative radiotherapy for localized non-small cell lung cancer [98, 99]. In the latter cases, OP affected 5% of irradiated patients, and previous symptomatic radiation pneumonitis around the tumor site was strongly associated with the occurrence of OP (hazard ratio 62) outside the radiation elds 2–7 months later [98]. Radiation-induced activation of infammatory cells and pathways likely plays a role in this phenomenon.
The cause and mechanisms of focal OP are probably different from the other forms of OP. Although some authors found focal OP to be idiopathic in most cases [38], others have reported underlying COPD in up to 67% of cases, and recurrent respiratory infections in up to 57% [37], suggesting
that focal OP may be triggered and preceded by an infectious process. In support of this hypothesis, one study reported the occurrence of small neutrophil aggregates in the vicinity of localized OP (with otherwise typical OP pattern at histopathology) in 73% of cases [39]. Aspiration of food particles may be another cause of focal OP [100]. In one retrospective study of 59 cases of aspiration pneumonia, OP pattern was the predominant histopathological pattern in 88%, usually associated with particulate foreign material, multinucleated giant cells, acute pneumonia, bronchiolitis, or suppurative granulomas [100]. Twenty-two percent of these cases presented as solitary nodules suspect of lung cancer, whereas food aspiration was clinically suspected in less than 10% [100]. Sub-clinical particulate matter aspiration pneumonia may thus be a relatively common cause of lung nodules presenting with OP pattern at histopathology.
In the majority of cases, OP has no recognizable cause [20] and is termed cryptogenic OP (COP). COP has been integrated in 2002 in the classi cation of idiopathic interstitial pneumonias [3], and maintained in the 2013 update of this classi cation in the category of acute/subacute disorders [4].
Treatment
Corticosteroids are the current standard treatment of OP [2, 14, 17, 19, 23, 28, 31], although spontaneous improvement has occasionally been reported [2, 93]. Clinical improvement usually occurs within 2–3 days after treatment onset. Pulmonary in ltrates at chest X-ray usually markedly improve within a few days. On average, a >50% improvement at imaging usually occurs within 3 weeks of treatment, and complete cure is observed after around 3 months [18, 19]. The spectacular and reproducible response to corticosteroids can even be considered as an additional diagnostic feature of the clinical syndrome of OP, and if this response is poor, the initial diagnosis should be reconsidered. Besides corticosteroids, removal of the causing agent should be done whenever possible in secondary OP.
Treatment intensity and duration have not been well de ned. In patients with typical COP, an initial dose of prednisone of 0.75 mg/kg/day has been proposed for 2–4 weeks [19, 53]. Corticosteroids are then usually tapered over 6 months and stopped. However, this duration can extend up to 12 months or even longer due to relapses in a signi cant proportion of patients. Side effects of prolonged corticosteroid treatment occur in up to 25% [19]. In an attempt to better de ne the corticosteroid treatment in COP, a standardized therapeutic regimen has been proposed by one group (Table 35.5) [19]. A retrospective comparison of patients having received this standardized protocol with a group treated with other therapeutic regimens did not reveal any
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Table 35.5 Proposed therapeutic regimen for typical COPa |
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Step |
Duration |
Doses of prednisone for the initial episode |
Doses of prednisone for the rst relapse |
1 |
4 weeks |
0.75 mg/kg/day |
20 mg/day |
|
|
|
|
2 |
4 weeks |
0.5 mg/kg/day |
20 mg/day |
3 |
4 weeks |
20 mg/day |
20 mg/day |
4 |
6 weeks |
10 mg/day |
10 mg/day |
5 |
6 weeks |
5 mg/day |
5 mg/day |
a Adapted from reference [19]
differences in terms of ef cacy, delay to remission, occurrence of relapses, morbidity, or nal outcome [19]. In contrast, cumulated doses of prednisone after 1 year were reduced twofold in the group who had received the standardized treatment [19]. This therapeutic regimen may thus provide a framework to guide management and limit the burden of corticosteroid therapy, while maintaining the same ef - cacy on disease control as higher doses of prednisone. However, given the wide clinical expression and severity of the disease, a unique treatment regimen cannot cover all clinical situations, and physicians need to adjust the prednisone dose to disease severity, response to therapy, and side effects. In severe OP, prednisolone IV boluses during 3 consecutive days [45–47] and immunosuppressive treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, tocilizumab or intravenous immunoglobulins have been used [43, 44, 48, 49, 101–108].
Whether SOP should be treated differently from COP is currently unclear, but likely depends on the clinical context. Some reports suggest that SOP is associated with less frequent resolution of symptoms and higher mortality than COP [23, 109] although other studies do not con rm thesendings [24, 110]. In a comparison of COP and OP secondary to connective tissue disease, treatment modalities, response rate and mortality rate were similar, although complete recovery was slightly more frequent in COP [111]. In clinically amyopathic dermatomyositis associated with anti- melanoma-differentiation-associated gene 5 (MDA5) auto- antibodies, a rapidly progressive interstitial lung disease may occur with a pattern of OP at imaging and histopathology [112–114], whereas other cases present with NSIP or DAD [114–116]. This acute or subacute life-threatening condition may lead to death within weeks after disease onset [117, 118], and is usually refractory to corticosteroids alone, event at high doses. In a retrospective comparison of two treatment strategies in Japan, patients receiving simultaneous triple immunosuppression with high-dose glucocorticoids, tacrolimus, and IV cyclophosphamide had better survival than historical controls who received step-up treatment with high-dose glucocorticoids alone initially, and other immunosuppressants at a later stage (89% versus 33%, p < 0.0001) [119]. One national treatment guideline recommends a combination of high-dose corticosteroids and calcineurin inhibitors, with or without cyclophosphamide, as a rst choice for
this condition [120]. A similar picture of acute/subacute, life-threatening, and steroid-resistant interstitial lung disease can also be observed in other idiopathic infammatory myopathies, especially those associated with anti-synthetase auto- antibodies, with lung histological patterns of OP, NSIP or DAD [121, 122]. In these cases, a combined therapy of high- dose corticosteroids with another immunosuppressive agent appears associated with better outcomes than initial corticosteroid monotherapy with later addition of other agents [123, 124]. A management algorithm has been proposed to guide decisions in these dif cult situations [125].
At the other end of the severity spectrum, not all cases of OP require treatment. In 6 large series totalizing 418 cases [2, 20, 24, 28, 50, 111], 12% of patients (range across series 3–23%) did not receive corticosteroids. Among 26 of these cases with reported outcome, spontaneous improvement was noted in 8/26 and complete cure in 16/26 [20, 50, 111]. In another study of 12 women with OP after radiation therapy for breast cancer detected by systematic chest X-ray, only six were symptomatic. Hormonal treatment was temporarily withheld in nine, and complete cure was observed in all without corticosteroids [93]. Thus, in asymptomatic patients with mild OP, corticosteroids may not be necessary, and careful clinical and chest-X-ray follow-up may be the best initial strategy.
Some macrolide antibiotics (erythromycin, clarithromycin, and azithromycin) possess anti-infammatory properties, which have rst proven bene cial in diffuse panbronchiolitis [126, 127], and later in cystic brosis, bronchiolitis obliterans syndrome after lung transplantation, bronchiectasis, and COPD. A therapeutic effect of erythromycin and clarithromycin has also been reported in series of COP and OP secondary to radiation therapy for breast cancer [128–133]. In three retrospective series of up to 40 cases published by one group, patients with mild to moderate COP received clarithromycin 1000 mg/day for 3–4 months. A complete cure was observed in more than 80% of cases, whereas a minority had only a partial response or no response, and required prednisone as rescue therapy [131–133]. As compared to a control group treated with prednisone for a mean of 9 ± 3 months, patients who received clarithromycin during 3 months had signi cantly less relapses (10% versus 55%, p < 0.0001) [132]. In responders to clarithromycin, a signi - cant reduction of serum and BAL interleukin-6 was observed,
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