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A. Introduction navigator

  1. >100 described entities can cause ILD
  2. Most patients present with progressive dyspnea on exertion (DOE)
    1. May progress to shortness of breath at rest
    2. Pulmonary hypertension may develop
    3. Chronic versus acute disease process should be ascertained
  3. Often detected initially on chest radiography (CXR)
    1. Various patterns on CXR have been correlated with specific ILD types (see below)
    2. Computerized tomography (CT) scanning is generally more helpful in diagnosis
    3. Thin section (1.0mm) CT is preferred modality for limiting differential
  4. Pulmonary Function Tests
    1. ILD classically produces a restrictive pattern
    2. FEV1 and FVC both reduced, FEV1/FVC >80%
    3. Reduction in Diffusion Capacity (DLCO)
  5. Diagnosis
    1. Clinical course and radiography is generally helpful but not definitive
    2. Serologies are occasionally helpful
    3. Bronchoscopy and biopsy ± lavage is often sufficient
    4. Open or thorascopic lung biopsy specimen may be required for diagnosis

B. Differential Diagnosis [2]navigator

  1. Pulmonary Edema
    1. Cardiogenic versus Non-cardiogenic (ARDS)
    2. Atypical - especially in COPD
  2. Atypical Pneumonias
    1. Chlamydia pneumoniae and C. psittici
    2. Mycoplasma pneumoniae
    3. Legionella pneumoniae
    4. Severe influenza infection
    5. Tuberculosis / Atypical Mycobacteria
  3. Neoplastic Invasion
    1. Lymphangitic tumor spread
    2. Usually lymphomas (metastatic or pulmonary lymphoma)
    3. Breast, Lung, other neoplasms
  4. Idiopathic Pulmonary Fibrosis (IPF) [3]
    1. Also called usual interstitial pneumonitis or cryptogenic fibrosing alveolitis
    2. Rapidly progressive variant called Hamman-Rich Syndrome
    3. Large number of causes of secondary (versus idiopathic) pulmonary fibrosis [2]
    4. Reticular markings on CXR, usually lower lung fields
    5. High resolution CT scan findings usually required for diagnosis
    6. High risk of acute decompensation and ~20% death over 76 weeks in mild-moderate IPF [4]
    7. Glucocorticoids probably have some symptomatic benefit
  5. Other Pneumonitis
    1. Bronchiolitis obliterans
    2. Bronchiolitis obliterans organizing pneumonia (BOOP)
    3. Desquamative interstitial pneumonia
    4. Hypersensitivity pneumonitis (see below)
  6. Toxins
    1. Asbestosis (usually pleural involvement)
    2. Silicosis or Silicate Lung - "Coal Miner's Lung"
    3. Berylliosis - may be associated with liver failure also
    4. Nylon fiber - "Flock Worker's Lung" [5]
    5. Talcosis
    6. Often nodular pattern with granuloma (non-caseating) formation
    7. Serum osteopontin level elevation can distinguish persons with exposure to asbestos who do and who do not have pleural mesothelioma [26]
  7. Medications
    1. Amiodarone (see below)
    2. Methotrexate
    3. Bleomycin
    4. Busulfan
    5. Carmustine
    6. Nitrofurantoin
  8. Inflammatory Diseases
    1. Systemic Lupus Erythematosus - usually with pleuritis, effusions
    2. Rheumatoid Arthritis - pleural disease is common [7]
    3. Ankylosing Spondylitis - upper lobe fibrosis
    4. Progressive Systemic Sclerosis
    5. Sjogren Syndrome [8]
    6. Polymyositis and Dermatomyositis - ~8% of patients, usually with anti-Jo Abs
    7. Granulomatous vasculitis restricted to lung
    8. Primary Biliary Cirrhosis [9]
  9. Pulmonary-Renal Syndromes
    1. Goodpasture's Syndrome
    2. Wegener's Granulomatosis
    3. Amyloidosis (see below)
  10. Eosinophilic Pneumonias
    1. Hypersensitivity pneumonitis is one form
    2. More common in females
    3. Hypersensitivity reaction, usually to drugs
    4. Peripheral pattern of dense lung infiltrates most common
    5. Usually very sensitive to glucocorticoids
  11. Hypersensitivity Pneumonitis [10]
    1. Aspirgillus fumigatus
    2. Micropolyspora faeni
    3. Thermoactinomyces candidus
    4. T. sacchari
    5. T. vulgaris
    6. Pigeon serum
    7. Mycobacterium avium-intracellular (MAI) - "hot-tub" lung [25]
    8. Presence of pulmonary fibrosis with pneumonitis is associated with reduced survival [24]
  12. Sarcoidosis
    1. Most patients have hilar lymphadenopathy
    2. About 15% present with "stage 3" disease - interstitial infiltrates only
  13. Amyloidosis
    1. Typically reticular-nodular pattern
    2. Restrictive pulmonary function tests with reduced total and reserved volumes
    3. Majority of patients are asymptomatic
  14. Idiopathic Pulmonary Hemosiderosis [12,17]
    1. Diffuse alveolar hemorrhage without other organ invovlvement
    2. Usually a diagnosis of exclusion; requires biopsy
    3. May respond to glucocorticoids and/or chloroquine
  15. Pulmonary-Capillary Hemangiomatosis [13,14]
    1. Overgrowth of pulmonary capillaries throughout lungs
    2. Double layers of capillaries may be seen
    3. Proliferating capillaries invade airways and air spaces
    4. Pulmonary hypertension usually develops
    5. More common in children than adults
    6. Orthotopic heart-lung transplantation
  16. Bronchocentric Granulomatosis [16]
    1. Bronchioles with necrotic granulomas, not vessels
    2. May be associated with asthma
    3. Aspergillus may colonize the granulomas
  17. Other Lymphoid Diseases
    1. Angioimmunoblastic Lymphadenopathy
    2. Lymphomatoid Granulomatosis
    3. Histiocytosis X (Langerhans' cell; eosinophiloic granuloma)
  18. Lymphomatoid Granulomatosis [11,27]
    1. Continuum of abnormal lymphocyte diseases from benign to malignant
    2. Strongly associated with Epstein Barr Virus (EBV) transformation of B lymphocytes
    3. Reactive T lymphocytes ± eosinophils may be present in large numbers
    4. Necrotic granulomas of lungs, skin, CNS, and kidneys
    5. May act as benign diseases or as highly malignant lymphomas
    6. Strong male predisposition
    7. Multiple lung nodules and cavitary lesions frequently occur
    8. Lymphadopathy not usually seen; may be mistaken for sarcoidosis
    9. Minority will spontaneously resolve; most progress to aggressive lymphomas
    10. Combination chemotherapy for severe and aggressive disease, usually with rituximab
    11. Rituximab (Rituxan®), anti-CD20 mAb, has shown good efficacy
    12. Interferon alpha (IFNa) has shown efficacy ~67% in moderate to severe disease
  19. Lymphangioleiomyomatosis [18]
    1. Proliferation of immature smooth muscle cells around vascular and lymphatic structures
    2. Usually females of 20-40 years
    3. Initially, cystic lung disease, progressing to diffuse honeycombing
    4. Accompanied by abdominal tujmors (angiomyolipomas), meningiomas, other mass lesions
    5. Express progesterone receptors and are hormonally sensitive
    6. Probably related to hormonally induced smooth muscle proliferation
    7. Patients with lymphangioleiomyomatosis should be screened for meningiomas
    8. Hormonal manipulation used: oopherectomy, tamoxifen, progesterone may be effective
    9. Lung transplantation may be used in end-stage patients [19]
  20. Familial ILD [19]
    1. Present in childhood in most cases
    2. Usually with desquamative pathology (see below)
    3. Mutations in surfactant protein C cause a progressive ILD

C. Pulmonary Alveolar Proteinosis (PAP) [15,23]navigator

  1. Epidemiology
    1. Rare disorder with alveolar accumulation of lipoproteinaceous material
    2. Prevalence 0.37 per 100,000 (or 1 per ~350,000) persons
  2. Three forms: congenital, secondary, idiopathic (acquired)
    1. Congenital PAP due to mutations in srufactants B or C or ß(C) chain of GM-CSF receptor
    2. Secondary PAP associated with conditions with reducted function of alveolar macrophages
    3. Secondary PAP associated with fine organic and inorganic dusts such as silica, some hematologic cancers, certain infections, pharmacologic immunosuppression
    4. Idiopathic appears to be autoimmune disorder targeting GM-CSF
  3. Pathogenesis [6]
    1. Autoantibodies (IgG) to GM-CSF found in bronchoalveolar lavage (BAL) from idiopathic PAP
    2. Neutrophils from PAP with anti-GM-CSF Abs have impaired basal and antimicrobial function
    3. GM-CSF could overcome anti-GM-CSF Ab effect on neutrophils in mice
  4. Diagnosis
    1. BAL demonstration of GM-CSF Abs, proteinosis
    2. Chest radiography shows nodular shadows usually radiating from hilar region
    3. Typically bilateral, symmetric disease
    4. Scarring may be present
    5. Rule out other causes; lung biopsy usually required
    6. Histopathology without inflammation, only intra-alveolar excess protein in tissue
  5. Treatment
    1. BAL to remove proteinacious material
    2. Glucocorticoids may be of some benefit
    3. Subcutaneous GM-CSF injections daily may improve symptoms in idiopathic and other PAP
    4. Consider rituxumab therapy (anti-CD20 Ab, B cell depleting) ±Intravenous Ig (IVIg)

D. Chest Radiography Patterns in ILD (Table 2, Ref [1])navigator

  1. Consolidation
    1. Acute: infection, ARDS, hemorrhage, aspiration, pneumonia, BOOP
    2. Chronic: infection (tuberculosis, fungal), chronic eosihophilic pneumonia, BOOP, lymphoid disorders, pulmonary alveolar proteinosis
  2. Linear or Reticular Opacities
    1. Acute: infection (viral, mycoplasma), pulmonary edema
    2. Chronic: IPF, inflammatory disease associated fibrosis, asbestosis, sarcoidosis, hypersensitivity pneumonitis, drug induced lung disease
  3. Small (<1cm diameter) Nodules
    1. Acute: infection (tuberculosis, fungal, viral), hypersensitivity pneumonitis
    2. Chronic: sarcoidosis, hypersensitivity pneumonitis, pneumoconiosis (silicosis, coal-worker's lung), bronchiolitis, metastases, alveolar microlithiasis
  4. Cystic Airspaces
    1. Acute: Pneumocystis carinii pneumonia (PCP), septic embolism
    2. Chronic: histiocytosis, lymphangioleiomyomatosis, honeycomb lung (IPF, others)
  5. Ground-Glass Opacities
    1. Acute: infection (PCP, cytomegalovirus), pulmonary edema, hemorrhage, hypersensitivity pneumonitis, acute inhalation exposure, drug induced lung disease, interstitial pneumonia
    2. Chronic: nonspecific interstitial pneumonia, desquamative interstitial pneumonia, drug- induced lung disease, pulmonary alveolar proteinosis
  6. Thickened Intralobular Septa
    1. Acute: pulmonary edema
    2. Chronic: lymphangitic carcinomatosis, pulmonary alveolar proteinosis, sarcoidosis, pulmonary veno-occlusive disease
  7. Lung Zone Involvement
    1. Upper Lung Predominance: histiocytosis, silicosis, ankylosing spondylitis, eosinophilic granuloma, PCP on pentamidine prophylaxis, coal worker's lung, reactivation tuberculosis
    2. Lower Lung Predominance: IPF, inflammatory disease associated fibrosis, asbestosis, chronic aspiration, lymphangitic carcinomatosis, scleroderma and rheumatoid lung disease
    3. Central (Perihilar) Predominance: sarcoidosis, berylliosis
    4. Peripheral Predominance: IPF, chronic eosinophilic pneumonia, BOOP
  8. Pleural Effusion or Thickening
    1. Pulmonary edema, connective tissue (inflammatory) diseases, asbestosis, lymphoma
    2. Lymphangitic carcinomatosis, lymphagniogioleiomyomatosis, drug induced
  9. Lymphadenopathy
    1. Infections
    2. Sarcoidosis (may be calcified)
    3. Silicosis (may be calcified)
    4. Berylliosis
    5. Neoplastic: lymphangitic carcinomatosis or lymphoma
    6. Lymphocytic interstitial pneumonia

E. Rapidly Progressive Interstitial Lung Disease [7]navigator

  1. Also called Hamman-Rich Syndrome
  2. Progressive decrease in lung function over a period of weeks
    1. Originally restricted to idiopathic pulmonary fibrosis
    2. Considered an accelerated end-stage phase of usual interstitial pneumonitis
  3. Diffuse alveolar damage is present
  4. Most patients die; some are able to live with mechanical ventilation

F. Desquamative Interstitial Pneumonitis (DIP) [21] navigator

  1. Previously thought to represent early stage IPF [3]
    1. However, IPF clearly has minimal inflammation
    2. DIP has a bronchiolitis picture
    3. Relatively uniform thickening or bornchiolar thickening in alveolar septa areas
    4. Striking accumulation of acitvated macrophages in DIP
  2. Histological overlap with other toxin-associated pulmonary inflammatory reactions
    1. Usual interstitial pneumonitis (UIP)
    2. Eosinophilic pneumonitis
    3. Respiratory bronchiolitis
  3. Etiology
    1. Reaction to inorganic dusts including asbestos, silica, and others
    2. Reaction to organic dusts including mycotoxins
    3. Idiopathic drug reaction
    4. Uncommon association with subacute myelomonocytic leukemia
    5. Childhood and adult forms may be distinct entities
  4. Histology
    1. Predominance of activated alveolar macrophages
    2. These macrophages were originally thought to be desquamated pneumocytes
  5. CT Scanning shows bilateral lower lobe grown-glass infiltrates

F. Amiodarone Pulmonary Disease [9] navigator

  1. Types of Disease
    1. Interstitial Pneumonitis is most common lung side effect of drug
    2. Nodular densities, exudative pleural effusions, subpleural nodules can also occur
  2. About ~5% on amiodarone develop some kind of pulmonary dysfunction
  3. Dose Effects
    1. Doses of 200mg/d are nearly always safe
    2. Daily dosing >400mg/d nearly always cause some pulmonary toxicity
    3. Doses of 400mg/d or less are usually well tolerated
  4. Baseline chest radiograph (CXR) should be done
    1. If CXR shows abnormalities, careful monitoring of amiodarone therapy is necessary
    2. In patients with CXR abnormalities, obtain baseline pulmonary function tests with DLCO
  5. Diagnosis
    1. CXR and Chest CT Scan (even thin section CT) are non-specific
    2. Most characteristic finding in amiodarone lung toxicity is foamy alveolar macrophages
    3. These may be seen on bronchoalveolar lavage (BAL) specimens
  6. Pneumonitis nearly always responds to glucocorticoids and drug discontinuation

Resources navigator

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References navigator

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