Symptoms and Signs
Early: cough, fatigue and dyspnea on exertion, chest exam may be unremarkable or reveal inspiratory crackles at lung bases.
Late: dyspnea at rest, weight loss; clubbing, cyanosis, and right ventricular failure.
Early: normal to ground-glass pattern and nodular, reticular or reticulonodular patterns.
Late (end-stage): coarsely reticular, cystic and honeycomb patterns.
Disseminated interstitial nodules
Acute: TB, histoplasmosis, coccidioidomycosis
Chronic: sarcoidosis, idiopathic pulmonary fibrosis (IPF), silicosis, rheumatoid arthritis (RA).
IPF, sarcoidosis, eosinophilic granuloma, RA, silicosis
High Resolution computer Tomography (HRCT)
CXR may be normal in up to 10% of patients with biopsy-proven interstitial disease where HRCT may be abnormal.
HRCT (using thin 1-2 mm sections) helpful in establishing diagnosis, in selecting type of biopsy and the optimal biopsy site.
Certain findings on HRCT may be disease specific
IPF: peripheral fibrosis, ground glass appearance
Lymphangioleiomyomatosis (LAM): multiple small cysts
Pulmonary Function Tests (PFTs): Reduction in vital capacity, total lung capacity, diffusion capacity of carbon monoxide (DLCO), and lung compliance; also arterial oxygen desaturation with exercise.
Usually a restrictive defect except for the following:
Combined obstruction/restriction: sarcoidosis, bronchiolitis obliterans and organizing pneumonia (BOOP), LAM, eosinophilic granuloma (although a pure restrictive defect with any of these disorders).
Isolated low DLCO: sarcoidosis, eosinophilic granuloma
Nonspecific: elevated ESR, angiotensin converting enzyme (ACE); circulating immune complexes may be present.
RF, ANA more helpful with collagen vascular causes of interstitial disease.
Serum precipitins to organic dusts helpful in hypersensitivity pneumonitis.
ANCA highly sensitive and specific when Wegener's granulomatosis or other vasculitides suspected.
Bronchoalveolar Lavage (BAL)
A way of sampling the epithelial lining fluid of the lower respiratory tract and analyzing the effector cell populations making up the alveolitis. (increased cells of either lymphocytic, neutrophilic, eosinophilic or mononuclear phagocytic predominance).
Types of Alveolitis
Macrophage-lymphocyte: T-lymphocytes and macrophages predominate with a few neutrophils and eosinophils. Examples: sarcoidosis, hypersensitivity pneumonitis, collagen vascular disease, drug-induced lung diseases, berylliosis.
Macrophage-neutrophil-lymphocyte: neutrophils and macrophages predominate with a few eosiniphils and lymphocytes. Examples: IPF, asbestosis, acute respiratory distress syndrome (ARDS).
Macrophage-eisinophil: eosinophils predominate. Examples: acute or chronic eosinophilic pneumonia, drug-induced lung disease.
BAL can be used to assess the intensity of alveolitis during therapy.
Best method available to diagnose and stage the alveolitis of ILD.
Transbronchial biopsy (1x2 mm tissue) is usually the first step and especially is the method of choice is sarcoidosis is suspected. However, ILD may be heterogeneous and transbronchial biopsies may not be representative of the extent or intensity of the existing alveolitis. Therefore, open lung biopsy (2x2 cm tissue) frequently becomes the method of choice.
ILD diagnosed by transbronchial lung biopsy: sarcoidosis, lymphangic carcinomatosis, alveolar proteinosis, bronchioalveolar carcinoma, eosinophilic pneumonia.
Pathogenesis of ILD
General Characteristics of Alveolitis
Alveolitis is defined as the chronic accumulation of inflammatory and immune effector cells within the alveolar structures. The increase in the number of effector cells in a result of both local proliferation and recruitment of cells from blood.
Activation of effector cells
Macrophages are capable of releasing a variety of mediators when activated by an exogenous stimulus. These mediators include interleukin-1 (IL-1; activates T-helper cells) and several growth factors such as platelet-derived growth factor (PDGF), fibronectin and insulin-like growth factor (IGF-1; formerly macrophage-derived growth factor). Alveolar macrophages also release neutrophil chemotactic factors) leukotriene B4 and interleukin 8).
Activated T-lymphocytes secrete interleukin-2 (IL-2; a T-cell growth factor), macrophage migration inhibition factor, monocyte chemotactic factor and neutrophil inhibitory factor which regulate other effector cells. In interstitial disorders where lymphocytes predominate, the recruitment of mononuclear phagocytes and additional lymphocytes may result in granuloma formation (sarcoidosis, hypersensitivity pneumonitis, berylliosis, TB, fungal infections).
Neutrophils, once activated, are capable of releasing collagenase, elastase, neutral protease and various oxidants which all markedly derange the alveolar structure.
Mechanism of Injury and Fibrosis
As the disease progresses, there is a loss of type I alveolar cells and capillary endothelial cells with proliferation of type II cells and interstitial fibroblasts and accumulation of type I collagen. Several cytokines are involved in inflammation and repair of the lung. The activated alveolar macrophage is thought to promote this process by releasing fibronectin, an adhesive glycoprotein chemotactic for mesenchymal cells (fibroblasts). The accumulation of mesenchymal cells and their products (connective tissue proteins) results in fibrosis. Stimuli such as fibrogenic dusts, immune complexes, and heat-killed bacteria are known to cause the release of mediators from macrophages.
The neutrophil is perhaps the most cytotoxic of the effector cells, capable of releasing oxygen metabolites and connective tissue proteases. Consequently, an alveolitis involving a large number of neutrophils (e.g., IPF) can be very damaging to alveolar structures.
Current Therapeutic Approaches to ILD
Corticosteroids: Work by suppressing inflammatory cell functions including chemotaxis and secretion of proteolytic enzymes.
There are only a few interstitial disorders in which corticosteroids are of proved efficacy:
Sarcoidosis (with intense alveolitis)
Miscellaneous: Colchicine, cyclosporine (IPF)
IPF, sarcoidosis, eosinophilic granuloma, lymphangioleiomyomatosis
Interstitial Lung Diseases
Idiopathic Pulmonary Fibrosis
Symptoms and signs: dyspnea; sometimes fever, arthralgias and Raynaud's phenomenon; basilar crackles; clubbing (40-75%).
In 25-45%, serum cryoglobulins, RF and ANA are present.
CXR: Normal to reticulonodular to honeycombing. HRCT may show ground glass appearance or honeycomb cysts.
BAL: Predominance of neutrophils.
Diagnosis: By exclusion, usually need open lung biopsy to confirm.
Early IPF: Desquamation predominates where alveolar macrophages fill alveolar spaces (desquamative interstitial pneumonitis or DIP).
Late IPF: Inflammation of alveolar walls continues and fibroblast proliferation with collagen formation occurs (usual interstitial pneumonitis or UIP).
Corticosteroids + immunosupressants (cyclophosphamide or azathioprine); anecdotal reports describing colchicine or methotrexate or cyclosporine.
Transplantation: 50% two year survival with single lung.
A multisystem granulomatous disorder of unknown etiology.
Mostly young adults.
Any organ may be involved with the lungs, lymphatics, skin, liver, eyes
most commonly affected in decreasing order. Some manifestations to watch for:
- Myocardial involvement (possible conduction disturbances)
- Cranial nerve VII involvement
- Erythema nodosa
PFTs: Decreased volumes, compliance, DLCO, hypoxemia.
BAL: Predominance of T-lymphocytes and macrophages.
Immunology: Activated T-lymphocytes secrete IL-2 which, as a monocyte chemotactic factor, recruit monocytes and thus contribute to granuloma formation.
- Stage 0 Clear
- Stage I Bilateral hilar adenopathy
- Stage II Hilar adenopathy and parenchymal infiltrates
- Stage III Parenchymal infiltrates only
- State IV Extensive fibrosis and distortion of lung architecture
Gallium-67 Imaging: increased pulmonary uptake with alveolitis.
Hypercalcemia (10-15%), hypercalciuria (20-30%)
Elevated ACE level (nonspecific); however, ACE may be followed for therapeutic response.
Hyperglobulinemia, impaired delayed hypersensitivity.
Diagnosis: Transbronchial lung biopsy showing non-caseating granulomas with compatible clinical picture.
Indications for prednisone therapy: active alveolitis with severe symptoms, uveitis, liver disease (marked), cardiac disease, CNS disease, hypercalcemia.
Secondary agent: methotrexate, antimalarial agents controversial.
Recurrent sarcoid granulomata noted in allografts; immunosuppression for transplantation may attenuate granulomatous responses in patients having recurrent disease.
A type III and IV hypersensitivity reaction to microbial spores, animal proteins and chemicals.
Farmer's lung is the prototypic disease caused by a reaction to Micropolyspora faeni.
Fever, chills, dyspnea, leukocytosis may occur 4-6 hours after exposure and eventually resolve; symptoms and signs may recur on re-exposure.
CXR: Acute - normal to reticulonodular pattern; Chronic - progressive fibrosis, honeycombing.
BAL: Predominance of lymphocytes; increased IgG, IgM.
Serum precipitins to offending antigen present.
Pathology: - Interstitial alveolitis with lymphocytes and non-caseating granulomas (nonspecific); foam cells present (nonspecific)
Diagnosis: Compatible clinical picture, BAL with lymphocytes; serum precipitins; (inhalational challenge).
Therapy: Avoidance of continued inhalational exposure to causative antigen; corticosteroids in severe cases.
Eosinophilic Granuloma (Histiocytosis X)
Subacute or chronic proliferation disorder of unknown cause characterized by granulomatous infiltration of lung and bone.
Most commonly in individuals 20-50 years of age; associated with smoking
Cough, dyspnea, chest pain.
Pneumothorax (10-30%); rarely diabetes insipidus.
CXR: Nodular to reticular densities in the middle and upper lung; honeycomb cysts may be present.
Diagnosis: biopsy showing aggregates of Langerhans cells (also called HX cells) which are large mononuclear phagocytes with prominently grooved nuclei.
Therapy (coarse variable with 6-25% mortality)
Necrotizing granulomas and vasculitis of upper and lower respiratory tracts; also systemic vasculitis with focal necrotizing glomerulonephritis.
Clinical triad: Rhinitis/sinusitis, nodular pulmonary lesions, renal failure.
Systemic vasculitis may be manifested by skin, eye and joint findings.
CXR: Bilateral nodules ranging from 1 to 9 cm in size; may also see diffuse interstitial disease and alveolar hemorrhage.
Diagnosis: Antineutrophilic cytoplasmic antibodies (ANCA) Percutaneous renal biopsy; lung biopsy.
Therapy: Cyclophosphamide and prednisone.
Churg-Strauss Syndrome (allergic angiitis and granulomatosis)
Syndrome of asthma, peripheral or tissue eosinophilia, systemic necrotizing vasculitis, and circulating ANCA (both p-ANCA and C-ANCA).
Symptoms of fever, weight loss, malaise: sinusitis/allergic rhinitis (70%); other sites of involvement include skin (65%), nervous system (40-63%), heart (30-50%), abdominal viscera (20-40%).
CXR: focal alveolar infiltrates.
Therapy: corticosteroids; add cyclophosphamide for fulminant cases.
Occurs exclusively in females, natural history variable.
Dyspnea (third of fourth decade of life); pneumothorax (50-80%), chylothorax (7-39%), hemoptysis (28-40%).
CXR: cystic or reticulonodular shadows, pneumothoraces, pleural effusions, or hyperinflation.
PFTs: airways obstruction with reductions in DLCO; lung volumes preserved.
Diagnosis: lung biopsy shows hamartamatous proliferation of interstitial smooth muscle and innumerable thin-walled parenchymal cysts.
oophorectomy and antiestrogen regimens tried but disappointing results.
Progressive dyspnea; CXR showing Kerley B lines, restrictive defect on PFTs; biopsy showing malignant cells.
Collagen Vascular Diseases (Pleuropulmonary Manifestations)
Systemic Lupus Erythematosis
Progressive Systemic Sclerosis
Polymyositis and Dermatomyositis
Chronic Alveolar Filling Diseases
CXR Features: Fluffy margins, early coalescence, segmental/lobar or butterfuly patterns, air bronchogram or alveologram.
Disseminated alveolar disease
Acute: pulmonary edema, alveolar hemorrhage, pneumonia.
Chronic: bronchoalveolar cell carcinoma, alveolar proteinosis, lymphoma, sarcoidosis.
Pulmonary Alveolar Proteinosis
Intra-alveolar lipoproteinaceous material
Also defective macrophage function leading to superinfection, notably Nocardia, Staphylococcus aureus, Mycobacterium.
Dx: BAL or lung biopsy.
Rx: Whole lung lavage.
Alveolar Hemorrhage Syndromes
Goodpasture's Syndrome (antibasement membrane antibody disease)
Recurrent episodes of hemoptysis with alveolar hemorrhagic filling; hemosiderin-laden macrophages.
Renal involvement (glomerulonephritis) usually follows pulmonary
- Antiglomerular basement membrane antibodies in serum.
- Linear deposition of IgG and complement along glomerular and alveolocapillary basement membranes.
Therapy: Plasmaphereis and immunosuppressant agents (corticosteroids with either cyclophosphamide or azathioprine).
Idiopathic Pulmonary Hemosiderosis
Hemoptysis and intra-alveolar hemorrhage; no renal involvement.
Although common in children, about 20% of IPH are adults, usually younger than 30 y/o; mortality 30% within 3 years.
Therapy: corticosteroids tried but no proven benefit on overall outcome.
Diffuse alveolar hemorrhage also associated with systemic vasculitis, progressive glomerulonephritis, collagen vascular disease, and immunocompromised hosts.
Pulmonary infiltrates and blood/tissue eosinophilia may occur in several distinct diseases: Loffler's syndrome, acute tropical pneumonia, chronic eosinophilic pneumonia, drug-induced eosinophilic pneumonia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, and diverse infectious diseases (parasites).
Chronic Eosinophilic Pneumonia
Cough, dyspnea, wheezing, fever, malaise, blood eosinophilia, and dense focal alveolar infiltrates.
Cause unknown; course in subacute or chronic.
CXR: "photographic negative of pulmonary edema."
Diagnosis: lung biopsy with dense infiltration of eosinophiles.
Therapy: Corticosteroids (usually with dramatic improvement).
Aspiration of exogenous lipid (vegetable oils) over an extended period of time.
CXR shows focal or diffuse air space changes.
Drug Induced Pulmonary Disease
Adverse drug reactions account for 5% of hospital admissions and occur in 18% of hospitalized patients.
Causes an interstitial pneumonitis that may lead to fibrosis (10-20% of patients receiving bleomycin.)
Factors which increase the risk of bleomycin-induced pulmonary toxicity.
- Age (>70 yrs), dose, route of administration, radiation therapy, 02 therapy, renal function, other chemotherapeutic agents.
Symptoms include dyspnea, cough, fever.
CXR: Basilar reticular or fine nodular changes.
Diagnosis: Diffuse uptake on gallium scan; neutrophils on BAL; transbronchial biopsy (diagnosis made in setting of compatible clinical, radiologic and/or histologic findings).
Therapy: Reduce Fi02 if possible, trial of corticosteroids.
Injury mediated by both direct and indirect mechanisms.
Greater risk of toxicity with daily maintenance dose of more than 400 mg.
Acute and subacute forms exists; occasionally fulminant course with ARDS.
Symptoms include dyspnea and occasionally cough, fever, and chest pain.
CXR: Diffuse interstitial changes; sometimes upper lobe predilection.
PFT's: Decreased DLCO; reduced volumes.
Histology: Alveolar septal thickening with inflammatory cells, intra-alveolar foam macrophages.
Diagnosis: Usually by exclusion; compatible clinical picture.
Discontinue amiodarone and switch to alternative antiarrhythmic agent
Corticosteroids for severe cases.
Other drugs which may cause interstitial pneumonitis/fibrosis: alkylating agents
Other drugs which may cause hypersensitivity pneumonitis:
Drugs which may cause noncardiac pulmonary edema
Results in pneumonitis or fibrosis.
Pneumonitis generally appears between 2 to 6 months after radiation; steroids may benefit if given early.
Fibrosis appears between 6 to 12 months after radiation; may progress to respiratory failure; steroids usually not helpful.
A fibrotic lung disease that primarily affects the small conducting airways and spares most of the interstitium.
Pathology: epithelial injury with a repair process causing an excessive proliferation of granulation tissue which compromises or completely obliterates the airway lumen.
Physiology: obstructive or restrictive ventilatory defect.
CXR: airspace and/or interstitial changes.
Bronchiolitis obliterans of known etiology
Toxic Fume Inhalation (S02, N02, NH3)
Steroids occasionally helpful.
Postinfectious Bronchiolitis Obliterans
RSV most common cause in infants and young children.
Mycoplasma, legionella and several viruses most common cause in adults.
Bronchiolitis obliterans of unknown etiology
Bronchiolitis Obliterans and Organizing Pneumonia
Also known as BOOP.
Connective Tissue Disease
Rheumatoid arthritis, systemic lupus, polymyositis and dermatomyositis, Sjogren's syndrome.
Bone marrow transplantation
- May occur in 10% of long-term survivors.
- May occur in 30-50% of long-term survivors.
Associated with other disease
Occupational Lung Diseases (Pneumoconioses)
Fibrotic disease of the lungs caused by inhalation of crystalline silicone dioxide.
Occupations at risk: mining, manufacturing (glass, pottery, porcelain), sandblasting.
Pathogenesis: Macrophages exposed to silica release chemotactic and fibrogenic factors.
Pathology: Hyaline nodule having concentric whorls of connective tissue with an acellular central zone of free silica.
Chronic Silicosis: apparent 20 or more years after exposure.
Accelerated Silicosis: apparent 5-15 years after exposure.
Acute Silicosis: develops in 6 months to 2 years after massive exposure; fulminant course.
Silicoproteinosis: a variant characterized by intra-alveolar lipoproteinaceous material similar to that of pulmonary alveolar proteinosis.
Simple: reticular and nodula patterns predominantly in the upper lobes; hilar adenopathy common, occasionally with "eggshell" calcifications.
Progressive massive fibrosis: coalescence of larger nodules.
Silicoproteinosis: alveolar filling pattern.
Higher incidence of mycobacterial disease.
Dx: Compatible history and characteristic CXR.
Rx: None; INH for patients with positive PPD.
Asbestosis is a fibrous silicae containing silicon and oxygen.
Industries at risk: construction, manufacturing, shipbuilding, insulation
Chrysotile fibers (serpentine group) account for 95% of world's production of asbestos; amphibole group considered more pathogenic (fibers with greatest length-to-diameter ratio are cost carcinogenic).
Parenchymal Pulmonary Fibrosis (asbestosis)
- After 10-20 years of inhalational exposure.
- Fibers and asbestos bodies (fibers coated with protein-iron complexes) in lung biopsy.
- Interstitial CXR changes usually at lung bases with progression to upper lobes.
- Thickened fibrotic areas of pleura (visceral and parietal); may coalesce to involve large areas of the lung.
- Occasionally plaques calcify and are sometimes seen along the diaphragm.
Exudative Pleural Effusion
- Recurrent, blood-tinged; associated with pleural thickening or parenchymal fibrosis.
- Increased risk of lung cancer with asbestos exposure; dose-related.
- Smoking multiples this risk.
- Increased risk of pleural and peritoneal mesothelioma (smoking does not add to the risk of mesotheliomas).
- Increased risk of cancers of the GI tract, larynx, kidney, pancreas, ovary, and eye with asbestos exposure.
Coal Worker's Pneumoconiosis
Associated with coal dust exposure.
Risk increases with intensity, duration and higher ranks (hardness) of coals. Anthracite is the hightest rank (mined in eastern U.S.) followed by bituminous and lignite.
Although there are immunologic abnormalities (elevated IgG, IgA, C3), the pathogenesis remains unknown.
Clinical manifestations (develop over 10-20 years)
Simple Coal Worker's Pneumoconiosis (SCWP)
- Few symptoms.
Progressive Massive Fibrosis
- Associated with anthracite coal.
- May see melanoptysis due breakdown of lesions.
- Can appear after expsoure stops.
Caplan's Syndrome (Rheumatoid Pneumoconiosis)
- Associated with rheumatoid arthritis.
- Nodules (0.5-5cm) on CXR in individuals with SCWP; nodules may cavitate.
- Also occurs with other pneumoconioses.
- Rheumatoid factor positive in 70% of patients.
No increased risk of TB.
Dx: History of dust exposure and characteristic CXR.
Exposures: fluorescent light industry, ceramics, nuclear control equipment, electronics
Acute disease (rare): toxic, dose-related, bronchiolitis, pulmonary edema, chemical pneumonitis.
Chronic disease: multisystemic granulomatous disorder which involves the lung; course variable.
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