LUNG: INTERSTITIAL DISEASES

Arthur C. Aufderheide, M.D.

Med 6728. Respiratory Medicine

INTERSTITIAL DISEASES: TYPES

Pneumoconioses (asbestos, silica, coal dust, beryllium)

Other: sarcoidosis, PAP (pulmonary alveolar proteinosis), DIP (desquamative interstitial pneumonitis)

Idiopathic

ASBESTOSIS: WORLD PRODUCTION

1870 — 50 tons

1970 — 4,000,000 tons

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

Macrophages phagocytose dust; dust kills cell, releasing fibrogenic factor, insulin-like growth factor, platelet-derived growth factor, et al. fibrosis

Alveolar pneumocytes slough “ulcer” Dust interstitium through “ulcer” Macrophages “seal” ulcer; pneumocytes cover them,

sealing them into interstitium In interstitium, dust:

stimulates fibrosis travels to nodes producing fibrosis

ASBESTOSIS: PATHOLOGY

Gross: diffuse; lower lobes > upper Micro:

Alveoli: macrophages Interstitium: edema fibrosis Ferruginous bodies

Macrophages product Fiber core Protein & hemosiderin coat (react positively with

iron stains) No. / gm lung = exposure index

ASBESTOSIS: PATHOLOGY (PLEURA)

Diffuse thickening

Plaques

Parietal pleura

Discrete

Benign

Lower chest

Effusion: often bloody

ASBESTOSIS: COMPLICATIONS

Latent period (exposure to disease) = 15-30 years

Pulmonary insufficiency

Progressive massive fibrosis (rare)

Cor pulmonale

Bronchogenic carcinoma

Mesothelioma

ASBESTOSIS: BRONCHOGENIC CARCINOMA

Usually peripheral adenocarcinoma, but any histologic type

can occur

Risk: no smoke 5x (“frustrated macrophage” produces

cytokines, growth factors); smoking increases neoplasia 50x

About 14% get cancer; probability related to degree of

pulmonary fibrosis

Latent period: mean = 17 years

Crocidolite worst. Chrysotile least.

ASBESTOSIS: MESOTHELIOMA (1)

Malignant mesothelioma:

Much less common than bronchus carcinoma

80+% = asbestos history

Dose-dependent

Not related to smoking

Mostly pleural; some peritoneal

ASBESTOSIS: MESOTHELIOMA (2)

Malignant mesothelioma: (Cont.)

No ferruginous bodies in them

Latent period 30 years

Die < 1 year after diagnosis

Histology:

Epithelial & spindle forms

Resemble metastatic adenocarcinoma

Mesothelioma = PAS (+), Leu-1 neg, CEA (neg),

keratin (+), procollagen type 1 (+), GLUT1

LUNG: SILICOSIS, GENERAL

Exposure: miners, sand-blasters, ceramicists, glassmakers &

granite workers

Ingredient: silica (SiO2)

Crystal form:

Si

Crystal surface exposure: hydration silicic acid necrosis &

fibrosis?

Or: activated macrophages fibroblast growth factor fibrosis?

SILICOSIS: PATHOLOGY

Pleura: adhesions Fibrosis (macrophages release fibrogenic cytokines & other

mediators that fibrosis): Nodular, both grossly & on x-ray (peribronchial,

periarterial, nodes) Black pigment at nodules periphery Nodule confluence producing massive fibrosis

Tuberculosis in past: 2/3 (+); even today = 10-15% Polarized light: silicate refractile

Small but distinct predisposition to bronchogenic carcinoma (controversial)

LUNG: ANTHRACOSIS

Black-pigmented lung

Without fibrosis or other damage

COAL-WORKER’S PNEUMOCONIOSIS: GENERAL

Frequency varies with geography and job

Lung injury due to silica in coal dust in some but not all

2% of dust in lung = quartz

COAL-WORKER’S PNEUMOCONIOSIS: PATHOLOGY (1)

Simple (dust reticulation) pneumoconiosis

X-ray: streaks, periphery to hilum

Peribronchial nodules produce traction leading to

centriacinar emphysema

Nodular lesions:

Exaggerated degree of dust reticulation form

COAL-WORKER’S PNEUMOCONIOSIS: PATHOLOGY (2)

Progressive massive fibrosis (PMF): only 10% develop this form Massive lung fibrosis Cause:

exposure degree? host sensitivity ? tuberculosis ?

Upper > lower lobe

Tuberculosis: increases but not as much in silicosis

Carcinoma: no

HEMATITE-MINER LUNG (SILICO-SIDEROSIS)

Mixed hematite (iron oxide) and silica-containing dust.

Hematite partially suppresses fibrosis.

Early: iron-containing alveolar macrophages.

Late: patchy pulmonary interstitial pneumonitis; also

fibrosis in minority.

Gross: Lung is red (hematite) and occasionally fibrotic.

SARCOID

Idiopathic (immune disorders) Distribution in many body organs

In lung: peripheral central Clinical: 0 (1/3) to moderate pulmonary symptoms

(dyspnea, cough) Pathology: noncaseating granulomas in lung, skin

(erythema nodosum on legs), eyes (iritis), liver Diagnosis: biopsy Treatment: none; steroid Outcome: 15-20% some residual lung fibrosis; few severe

SARCOID

Idiopathic (immune disorders) Distribution in many body organs

In lung: peripheral central Clinical: 0 (1/3) to moderate pulmonary symptoms

(dyspnea, cough) Pathology: noncaseating granulomas in lung, skin

(erythema nodosum on legs), eyes (iritis), liver Diagnosis: biopsy Treatment: none; steroid Outcome: 15-20% some residual lung fibrosis; few severe

BERYLLIOSIS (1)

Exposure: formerly: fluorescent light mfg; now: metal alloys

Frequency: 1-2% of exposed (host variation)

Clinical:

Acute: adult respiratory distress syndrome (ARDS)

Chronic:

immune response after latent interval

persons with HLA-DPBI glutamate 69 = susceptible Be-

specific CD4 + T-cell accumulation in lung

BERYLLIOSIS (2)

Pathology:

Sarcoid granulomas fibrosis

Giant cell inclusions (concha bodies; Schaumann bodies)

Other organs involved

Lung Ca: little (if any) increase except in very extensive

exposure

Prognosis: few (severe) cor pulmonale

HARD METAL DISEASE (COBALT)

Cobalt is hardening agent for tungsten carbide production

Produces 3 types of pulmonary disease:

Acute allergic alveolitis (sloughed type 2 pneumocyte)

Interstitial pneumonitis with fibrosis

Asthma

Steroids (especially for acute form)

TALC GRANULOMATOSIS

To increase profits, drug dealers may dilute with talc Talc is a powdered, insoluble ore Injected intravenously, lungs are showered with talc

particles Lung treats talc like foreign body Pathology: foreign body giant cell granulomas

surround talc particles

PULMONARY ALVEOLAR PROTEINOSIS (1)

Disease: failure to catabolize surfactant accumulation in alveoli

Clinical forms: congenital, secondary, acquired Sx & Signs: cough, fever. x-ray = irregular streaks &

nodules Histology:

clusters of alveoli filled with PAS-positive staining, lipid-rich surfactant with tubular and lamellar bodies

PULMONARY ALVEOLAR PROTEINOSIS (2)

Mechanism: autoimmune IgG antibody against GM-CSF (granulocyte

macrophage colony stimulating factor) this impairs GM-CSF which, in turn, inhibits surfactant

catabolism congenital: some = mutation in several surfactant genes

Dx: history, x-ray, bronchial lavage, biopsy Rx & Prognosis: repeated bronchial lavage 75% survival

@ 5 yrs

DESQUAMATIVE INTERSTITIAL PNEUMONITIS

MISNOMER! Smoking-induced

engorgement of alveoli by

macrophages.

FARMER LUNG (HYPERSENSITIVITY DISEASE or EXTENSIVE ALLERGIC ALVEOLITIS)

Exposure: moldy hay and silage Cause: spores actinomycetes hypersensitivity (not

infectious!!) Clinical:

fever dyspnea okay 3-4 weeks

FARMER LUNG (HYPERSENSITIVITY DISEASEor EXTENSIVE ALLERGIC ALVEOLITIS)

Pathology: Granulomas and giant cells in bronchioles & alveoli

fibrosis Antibodies actinomycetes in serum Many recurrent attacks lung fibrosis

Other antigens: Mushroom compost, maple bark, moldy barley, “humidifier

fever”— actinomycetes, coffee bean, pigeon-breeders, I-tryptophane—eosinophils

SILO-FILLER DISEASE

Acute, necrotizing bronchiolitis after exposure in recently filled silo

Bronchiolitis may go on to organizing pneumonia Cause:

NO2 + H2O HNO3

This nitric acid can destroy the bronchi’s lining epithelium Rx:

prevention steroids

LANGERHANS CELL HISTIOCYTOSIS

Part of Histiocytosis-X: ( Robbins p.701) Letterer-Siwe disease < 2 yrs Hand-Schüller-Christian disease (calvaria, orbit, diabetes

insipidus)- multi-system Eosinophilic granuloma

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

Antibody directed at basement membranes of lung & kidney Acute glomerulonephritis with interstitial pulmonary

necrosis & hemorrhage (hemoptysis) Cause? M:F = 6:1. Immune complexes deposit in

glomerulus & lung capillaries Dx: Serologic identification of anti-glomerular basement

membrane antibody Rx: Eliminate antibody with plasmapheresis;

immunosuppression. Treat early. Prognosis: 50+% mortality (renal failure)

CHURG-STRAUSS SYNDROME

Sx: asthma, skin lesions, sinusitis, eosinophilia some: bloody diarrhea, kidney

Path: diffuse pulmonary interstitial infiltrate with eosinophils

Cause: idiopathic. Some: leukotriene dysfunction Anti-myeloperoxidase antibodies=vasculitis

Rx:immunosuppression CysLt1 (cysteinyl leukotriene receptor type 1)

antagonist

IDIOPATHIC PULMONARY FIBROSIS (IPF) / USUAL INTERSTITIAL PNEUMONIA (UIP)

Frequency: Most common form of diffuse interstitial fibrosis

Rx:Steroids

Nonspecific pulmonary fibrosis (NSPF): more regularly distributed. Better prognosis.

Chronic interstitial inflammation and irregularly-distributed, especially subpleural fibrosis

End-stage: “honey-comb lung”

Reactive process (immunoregulation disturbance ?) Lymphocyte Infiltrates common in bone marrow,

skin, lung, stomach.

IDIOPATHIC PULMONARY FIBROSIS (IPF) / USUAL INTERSTITIAL PNEUMONIA (UIP)

Etiology: unknown. Familial: point mutation in gene for prosurfactant protein C

Symptoms: Age: >60 Shortness of breath, cyanosis, right heart failure . Caveolin normally protects against pulmonary fibrosis by

suppression of transforming growth factor B1; caveolin is depressed in pulmonary fibrosis