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1. Early: cough, fatigue and dyspnea on exertion, chest exam may be unremarkable or reveal inspiratory crackles at lung bases.
2. Late: dyspnea at rest, weight loss; clubbing, cyanosis, and right ventricular failure.
Chest Roentgenography
1. CXR may be normal in up to 10% of patients with biopsy-proven interstitial disease where HRCT may be abnormal.
2. HRCT (using thin 1-2 mm sections) helpful in establishing diagnosis, in selecting type of biopsy and the optimal biopsy site.
3. Certain findings on HRCT may be disease specific
a. IPF: peripheral fibrosis, ground glass appearance
b. Lymphangioleiomyomatosis (LAM): multiple small cysts
Physiologic Testing
1. 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.
1. Nonspecific: elevated ESR, angiotensin converting enzyme (ACE); circulating immune complexes may be present.
2. RF, ANA more helpful with collagen vascular causes of interstitial disease.
3. Serum precipitins to organic dusts helpful in hypersensitivity pneumonitis.
4. ANCA highly sensitive and specific when Wegener's granulomatosis or other vasculitides suspected.
Bronchoalveolar Lavage (BAL)
1. A way of sampling the epithelial lining fluid of the lower respiratory tract and analyzing the effector cell populations making
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up the alveolitis. (increased cells of either lymphocytic, neutrophilic, eosinophilic or mononuclear phagocytic predominance).
2. Types of Alveolitis
a. 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.
a. ILD diagnosed by transbronchial lung biopsy: sarcoidosis, lymphangic carcinomatosis, alveolar proteinosis,
bronchioalveolar carcinoma, eosinophilic pneumonia.
Pathogenesis of ILD
b. 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).
c. 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
1. 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.
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2. 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
A. Corticosteroids: Work by suppressing inflammatory cell functions including chemotaxis and secretion of proteolytic enzymes.
1. There are only a few interstitial disorders in which corticosteroids are of proved efficacy:
a. IPF
b. Sarcoidosis (with intense alveolitis)
2. Secondary agents:
a. Cyclophosphamide (IPF)
b. Azathioprine(IPF)
c. Methotrexate (sarcoidosis)
d. Miscellaneous: Colchicine, cyclosporine (IPF)
B. Lung Transplantation
1. IPF, sarcoidosis, eosinophilic granuloma, lymphangioleiomyomatosis
Interstitial Lung Diseases
b. Late IPF: Inflammation of alveolar walls continues and fibroblast proliferation with collagen formation occurs
(usual interstitial pneumonitis or UIP).
6. Therapy
a. Corticosteroids + immunosupressants (cyclophosphamide or azathioprine); anecdotal reports describing
colchicine or methotrexate or cyclosporine.
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A. sarcoidosis
1. A multisystem granulomatous disorder of unknown etiology.
2. Clinical manifestations
a. Mostly young adults.
b. 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)
- Uveitis
- Cranial nerve VII involvement
- Erythema nodosa
f. CXR:
- 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
B. Hypersensitivity Pneumonitis
1. A type III and IV hypersensitivity reaction to microbial spores, animal proteins and chemicals.
a. Farmer's lung is the prototypic disease caused by a reaction to Micropolyspora faeni.
b. Fever, chills, dyspnea, leukocytosis may occur 4-6 hours after exposure and eventually resolve; symptoms and
signs may recur on re-exposure.
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2. Diagnosis: Compatible clinical picture, BAL with lymphocytes; serum precipitins; (inhalational challenge).
3. Therapy: Avoidance of continued inhalational exposure to causative antigen; corticosteroids in severe cases.
C. Eosinophilic Granuloma (Histiocytosis X)
1. Subacute or chronic proliferation disorder of unknown cause characterized by granulomatous infiltration of lung and
bone.
2. Clinical manifestations
a. Most commonly in individuals 20-50 years of age; associated with smoking
b. Cough, dyspnea, chest pain.
c. Pneumothorax (10-30%); rarely diabetes insipidus.
d. CXR: Nodular to reticular densities in the middle and upper lung; honeycomb cysts may be present.
3. Diagnosis: biopsy showing aggregates of Langerhans cells (also called HX cells) which are large mononuclear
phagocytes with prominently grooved nuclei.
e. Diagnosis: Antineutrophilic cytoplasmic antibodies (ANCA) Percutaneous renal biopsy; lung biopsy.
f. Therapy: Cyclophosphamide and prednisone.
2. Churg-Strauss Syndrome (allergic angiitis and granulomatosis)
a. Syndrome of asthma, peripheral or tissue eosinophilia, systemic necrotizing vasculitis, and circulating ANCA
(both p-ANCA and C-ANCA).
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b. 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%).
6. Therapy:
a. oophorectomy and antiestrogen regimens tried but disappointing results.
b. Transplantation.
F. Lymphangitic Carcinomatosis
1. Progressive dyspnea; CXR showing Kerley B lines, restrictive defect on PFTs; biopsy showing malignant cells.
Collagen Vascular Diseases (Pleuropulmonary Manifestations)
A. Rheumatoid Arthritis
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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Pleuritis
Pulmonary hypertension
Interstitial fibrosis
Aspiration pneumonitis
Increased frequency of lung tumors
Pleuritis
Interstitial fibrosis
Lymphocytic interstitial pneumonitis
Pulmonary vasculitis and hypertension
Desiccation of tracheobronchial tree
Pulmonary lymphoma and pseudolymphoa
F. Ankylosing Spondylitis
1. Interstitial fibrosis (upper lobes)
2. Thoracic cage immobility
Chronic Alveolar Filling Diseases
A. CXR Features: Fluffy margins, early coalescence, segmental/lobar or butterfuly patterns, air bronchogram or alveologram.
1. Disseminated alveolar disease
a. Acute: pulmonary edema, alveolar hemorrhage, pneumonia.
b. Chronic: bronchoalveolar cell carcinoma, alveolar proteinosis, lymphoma, sarcoidosis.
B. Pulmonary Alveolar Proteinosis
1. Intra-alveolar lipoproteinaceous material
2. Also defective macrophage function leading to superinfection, notably Nocardia, Staphylococcus aureus,
Mycobacterium.
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D. Eosinophilic Pneumonia
1. 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).
A. Adverse drug reactions account for 5% of hospital admissions and occur in 18% of hospitalized patients.
B. Bleomycin
1. Causes an interstitial pneumonitis that may lead to fibrosis (10-20% of patients receiving bleomycin.)
a. 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.
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5. Mortality: 1-7%.
6. Therapy: Reduce Fi02 if possible, trial of corticosteroids.
C. Amiodarone
1. Injury mediated by both direct and indirect mechanisms.
a. Greater risk of toxicity with daily maintenance dose of more than 400 mg.
b. Acute and subacute forms exists; occasionally fulminant course with ARDS.
2. Symptoms include dyspnea and occasionally cough, fever, and chest pain.
3. CXR: Diffuse interstitial changes; sometimes upper lobe predilection.
4. PFT's: Decreased DLCO; reduced volumes.
5. Histology: Alveolar septal thickening with inflammatory cells, intra-alveolar foam macrophages.
6. Diagnosis: Usually by exclusion; compatible clinical picture.
7. Therapy:
a. Discontinue amiodarone and switch to alternative antiarrhythmic agent
b. Corticosteroids for severe cases.
D. Other drugs which may cause interstitial pneumonitis/fibrosis: alkylating agents
1. Alkylating agents (busulfan, cyclophosphamide, melphalan, chlorambucil)
2. Nitrosoureas (carmustine, lomustine)
3. Mitomycin.
E. Other drugs which may cause hypersensitivity pneumonitis:
1.
2.
3.
4.
Methotrexate
Gold salts
Nitrofurantoin
Sulfasalazine.
Salicylates
Thiazides
Narcotics
Tocolytic agents.
G. Radiation Therapy
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A. A fibrotic lung disease that primarily affects the small conducting airways and spares most of the interstitium.
1. Pathology: epithelial injury with a repair process causing an excessive proliferation of granulation tissue which
compromises or completely obliterates the airway lumen.
b. Heart/Lung transplantation
- May occur in 30-50% of long-term survivors.
IPF
Hypersensitivity pneumonitis
Eosinophilc granuloma
Chronic eosinophilic pneumonia.
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A. Silicosis
1. Fibrotic disease of the lungs caused by inhalation of crystalline silicone dioxide.
2. Occupations at risk: mining, manufacturing (glass, pottery, porcelain), sandblasting.
3. Pathogenesis: Macrophages exposed to silica release chemotactic and fibrogenic factors.
4. Pathology: Hyaline nodule having concentric whorls of connective tissue with an acellular central zone of free silica.
5. Clinical presentations
a. Chronic Silicosis: apparent 20 or more years after exposure.
b. Accelerated Silicosis: apparent 5-15 years after exposure.
c. Acute Silicosis: develops in 6 months to 2 years after massive exposure; fulminant course.
d. Silicoproteinosis: a variant characterized by intra-alveolar lipoproteinaceous material similar to that of
pulmonary alveolar proteinosis.
6. CXR findings
a. Simple: reticular and nodula patterns predominantly in the upper lobes; hilar adenopathy common, occasionally
with "eggshell" calcifications.
4. Clinical conditions
a. 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.
b. Pleural Plaques
- 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.
d. Malignancy
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b. Although there are immunologic abnormalities (elevated IgG, IgA, C3), the pathogenesis remains unknown.
2. Clinical manifestations (develop over 10-20 years)
a. Simple Coal Worker's Pneumoconiosis (SCWP)
- Few symptoms.
1. Barry, SG, Wesslius, LJ. Drug-induced lung disease; keys to diagnosis and management. Clin Pulm Med 1996; 3:157-63.
2. Case Records of the Massachusetts General Hospital. Goodpasture's syndrome. N Engl J Med 1993; 328:1183-90.
3. Cohen, A, King, TE, Jr, Downey, GP. Rapidly progessive bronchiolitis obliterans with organzing pneumonia. Am J Respir Crit
Med 1994; 149:1670-5.
4. Colby, TV, Swensen, SJ. Anatomic distribution and histopathologic patterns in diffuse lung disease: correlation with HRCT. J
Thorac Imaging. 1996; 11:1-26.
5. Lynch, JP III, Hunninghake, GW. Pulmonary complications of collagen vascular disease. In: Creger, WP, ed. Annual Review of
Medicine, Vol 42. Palo Alto: Annual Reviews Inc.; 1992; 43:17-35
6. Lynch, JP, McCune, WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disease. Am J Respir Crit Med
1997: 155:395-420.
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