LUNG: INTERSTITIAL DISEASES Arthur C. Aufderheide, M.D. Med Respiratory Medicine

INTERSTITIAL DISEASES: TYPES l Pneumoconioses (asbestos, silica, coal dust, beryllium) l Other: sarcoidosis, PAP (pulmonary alveolar proteinosis), DIP (desquamative interstitial pneumonitis) l Idiopathic

ASBESTOSIS: WORLD PRODUCTION l 1870 — 50 tons l 1970 — 4,000,000 tons l 2008 — Close to none

LUNG: ASBESTOSIS, FIBERS Serpentine: chrysotile (white) asbestos ♦Long, thin, curly (most common) ♦Amphibole: ♦Crocidolite (blue) asbestos ♦Straight, rigid (most carcinogenic) ♦Amosite (brown) asbestos ♦Anthophylite ♦Tremolite

ASBESTOSIS: TOXIC MECHANISMS l Macrophages phagocytose dust; dust kills cell, releasing fibrogenic factor, insulin-like growth factor, platelet-derived growth factor, et al.  fibrosis l Alveolar pneumocytes slough  “ulcer” l Dust  interstitium through “ulcer” l Macrophages “seal” ulcer; pneumocytes cover them, sealing them into interstitium l In interstitium, dust: u stimulates fibrosis u travels to nodes producing fibrosis

ASBESTOSIS: PATHOLOGY l Gross: diffuse; lower lobes > upper l Micro: u Alveoli: macrophages u Interstitium: edema  fibrosis u Ferruginous bodies 4 Macrophages product 4 Fiber core 4 Protein & hemosiderin coat (react positively with iron stains) 4 No. / gm lung = exposure index

ASBESTOSIS: PATHOLOGY (PLEURA) l Diffuse thickening l Plaques u Parietal pleura u Discrete u Benign u Lower chest l Effusion: often bloody

ASBESTOSIS: COMPLICATIONS l Latent period (exposure to disease) = years l Pulmonary insufficiency l Progressive massive fibrosis (rare) l Cor pulmonale l Bronchogenic carcinoma l Mesothelioma

ASBESTOSIS: BRONCHOGENIC CARCINOMA l Usually peripheral adenocarcinoma, but any histologic type can occur l Risk: no smoke 5x (“frustrated macrophage” produces cytokines, growth factors); smoking increases neoplasia 50x l About 14% get cancer; probability related to degree of pulmonary fibrosis l Latent period: mean = 17 years l Crocidolite worst. Chrysotile least.

ASBESTOSIS: MESOTHELIOMA (1) l Malignant mesothelioma: u Much less common than bronchus carcinoma u 80+% = asbestos history 4 Dose-dependent u Not related to smoking u Mostly pleural; some peritoneal

ASBESTOSIS: MESOTHELIOMA (2) l Malignant mesothelioma: (Cont.) u No ferruginous bodies in them u Latent period 30 years 4 Die < 1 year after diagnosis u Histology: 4 Epithelial & spindle forms 4 Resemble metastatic adenocarcinoma 4 Mesothelioma = PAS (+), Leu-1 neg, CEA (neg), keratin (+), procollagen type 1 (+), GLUT1

LUNG: SILICOSIS, GENERAL l Exposure: miners, sand-blasters, ceramicists, glassmakers & granite workers l Ingredient: silica (SiO 2 ) l Crystal form: Si l Crystal surface exposure: hydration  silicic acid  necrosis & fibrosis? Or: activated macrophages  fibroblast growth factor  fibrosis?

SILICOSIS: PATHOLOGY l Pleura: adhesions l Fibrosis (macrophages release fibrogenic cytokines & other mediators that  fibrosis): u Nodular, both grossly & on x-ray (peribronchial, periarterial, nodes) u Black pigment at nodules periphery u Nodule confluence producing massive fibrosis l Tuberculosis in past: 2/3 (+); even today = 10-15% u Polarized light: silicate refractile l Small but distinct predisposition to bronchogenic carcinoma (controversial)

LUNG: ANTHRACOSIS l Black-pigmented lung l Without fibrosis or other damage

COAL-WORKER’S PNEUMOCONIOSIS: GENERAL l Frequency varies with geography and job l Lung injury due to silica in coal dust in some but not all l 2% of dust in lung = quartz

COAL-WORKER’S PNEUMOCONIOSIS: PATHOLOGY (1) l Simple (dust reticulation) pneumoconiosis u X-ray: streaks, periphery to hilum u Peribronchial nodules produce traction leading to centriacinar emphysema l Nodular lesions: u Exaggerated degree of dust reticulation form

COAL-WORKER’S PNEUMOCONIOSIS: PATHOLOGY (2) l Progressive massive fibrosis (PMF): only 10% develop this form u Massive lung fibrosis u Cause: 4 exposure degree? 4 host sensitivity ? 4 tuberculosis ? u Upper > lower lobe u Tuberculosis: increases but not as much in silicosis u Carcinoma: no

HEMATITE-MINER LUNG (SILICO-SIDEROSIS) l Mixed hematite (iron oxide) and silica-containing dust. Hematite partially suppresses fibrosis. l Early: iron-containing alveolar macrophages. l Late: patchy pulmonary interstitial pneumonitis; also fibrosis in minority. l Gross: Lung is red (hematite) and occasionally fibrotic.

SARCOID l Idiopathic (immune disorders) l Distribution in many body organs  In lung: peripheral  central l Clinical: 0 (1/3) to moderate pulmonary symptoms (dyspnea, cough) l Pathology: noncaseating granulomas in lung, skin (erythema nodosum on legs), eyes (iritis), liver l Diagnosis: biopsy l Treatment: none; steroid l Outcome: 15-20% some residual lung fibrosis; few severe

SARCOID l Idiopathic (immune disorders) l Distribution in many body organs  In lung: peripheral  central l Clinical: 0 (1/3) to moderate pulmonary symptoms (dyspnea, cough) l Pathology: noncaseating granulomas in lung, skin (erythema nodosum on legs), eyes (iritis), liver l Diagnosis: biopsy l Treatment: none; steroid l Outcome: 15-20% some residual lung fibrosis; few severe

BERYLLIOSIS (1) l Exposure: formerly: fluorescent light mfg; now: metal alloys l Frequency: 1-2% of exposed (host variation) l Clinical: u Acute: adult respiratory distress syndrome (ARDS) u Chronic: 4 immune response after latent interval 4 persons with HLA-DPBI glutamate 69 = susceptible  Be- specific CD4 + T-cell accumulation in lung

BERYLLIOSIS (2) l Pathology: u Sarcoid granulomas  fibrosis u Giant cell inclusions (concha bodies; Schaumann bodies) u Other organs involved u Lung Ca: little (if any) increase except in very extensive exposure u Prognosis: few (severe)  cor pulmonale

HARD METAL DISEASE (COBALT) l Cobalt is hardening agent for tungsten carbide production l Produces 3 types of pulmonary disease: u Acute allergic alveolitis (sloughed type 2 pneumocyte) u Interstitial pneumonitis with fibrosis u Asthma l Steroids (especially for acute form)

TALC GRANULOMATOSIS l To increase profits, drug dealers may dilute with talc l Talc is a powdered, insoluble ore l Injected intravenously, lungs are showered with talc particles l Lung treats talc like foreign body l Pathology: foreign body giant cell granulomas surround talc particles

PULMONARY ALVEOLAR PROTEINOSIS (1) l Disease: failure to catabolize surfactant  accumulation in alveoli l Clinical forms: congenital, secondary, acquired l Sx & Signs: cough, fever. x-ray = irregular streaks & nodules l Histology: u clusters of alveoli filled with PAS-positive staining, lipid-rich surfactant with tubular and lamellar bodies

PULMONARY ALVEOLAR PROTEINOSIS (2) l Mechanism: u autoimmune IgG antibody against GM-CSF (granulocyte macrophage colony stimulating factor) u this impairs GM-CSF which, in turn, inhibits surfactant catabolism u congenital: some = mutation in several surfactant genes l Dx: history, x-ray, bronchial lavage, biopsy l Rx & Prognosis: repeated bronchial lavage  75% 5 yrs

DESQUAMATIVE INTERSTITIAL PNEUMONITIS MISNOMER! Smoking-induced engorgement of alveoli by macrophages.

FARMER LUNG (HYPERSENSITIVITY DISEASE or EXTENSIVE ALLERGIC ALVEOLITIS) l Exposure: moldy hay and silage l Cause: spores actinomycetes  hypersensitivity (not infectious!!) l Clinical: u fever u dyspnea u okay 3-4 weeks

FARMER LUNG (HYPERSENSITIVITY DISEASE or EXTENSIVE ALLERGIC ALVEOLITIS) l Pathology: u Granulomas and giant cells in bronchioles & alveoli  fibrosis u Antibodies  actinomycetes in serum u Many recurrent attacks  lung fibrosis l Other antigens: u Mushroom compost, maple bark, moldy barley, “humidifier fever”— actinomycetes, coffee bean, pigeon-breeders, I- tryptophane—eosinophils

SILO-FILLER DISEASE l Acute, necrotizing bronchiolitis after exposure in recently filled silo l Bronchiolitis may go on to organizing pneumonia l Cause: u NO 2 + H 2 O  HNO 3 u This nitric acid can destroy the bronchi’s lining epithelium l Rx: u prevention u steroids

LANGERHANS CELL HISTIOCYTOSIS l Part of Histiocytosis-X: ( Robbins p.701) Letterer-Siwe disease < 2 yrs u Hand-Schüller-Christian disease (calvaria, orbit, diabetes insipidus)- multi-system u Eosinophilic granuloma l Interstitial nodular infiltrate of Langerhans cells (giant histiocyte with club-like “Birbeck” granules and antigen CD1A positive staining cell membrane), T-lymphocytes and eosinophils. 90% smoke.

GOODPASTURE SYNDROME l Antibody directed at basement membranes of lung & kidney l Acute glomerulonephritis with interstitial pulmonary necrosis & hemorrhage (hemoptysis) l Cause? M:F = 6:1. Immune complexes deposit in glomerulus & lung capillaries l Dx: Serologic identification of anti-glomerular basement membrane antibody l Rx: Eliminate antibody with plasmapheresis; immunosuppression. Treat early. l Prognosis: 50+% mortality (renal failure)

CHURG-STRAUSS SYNDROME l Sx: asthma, skin lesions, sinusitis, eosinophilia u some: bloody diarrhea, kidney l Path: diffuse pulmonary interstitial infiltrate with eosinophils l Cause: idiopathic. Some: leukotriene dysfunction l Anti-myeloperoxidase antibodies=vasculitis u Rx:immunosuppression u CysLt1 (cysteinyl leukotriene receptor type 1) antagonist

IDIOPATHIC PULMONARY FIBROSIS (IPF) / USUAL INTERSTITIAL PNEUMONIA (UIP) l Frequency: u Most common form of diffuse interstitial fibrosis l Rx:Steroids Nonspecific pulmonary fibrosis (NSPF): more regularly distributed. Better prognosis. u Chronic interstitial inflammation and irregularly- distributed, especially subpleural fibrosis l End-stage: “honey-comb lung” l Reactive process (immunoregulation disturbance ?) u Lymphocyte Infiltrates common in bone marrow, skin, lung, stomach.

IDIOPATHIC PULMONARY FIBROSIS (IPF) / USUAL INTERSTITIAL PNEUMONIA (UIP) l Etiology: unknown. Familial: point mutation in gene for prosurfactant protein C l Symptoms: u Age: >60 u Shortness of breath, cyanosis, right heart failure u. Caveolin normally protects against pulmonary fibrosis by suppression of transforming growth factor B1; caveolin is depressed in pulmonary fibrosis