Pathogenesis of Granulomatous & Interstitial

Airways Disease

Granulomatous DiseaseNecrotizing vs Non-necrotizing

• Most necrotizing granulomatous disease is infectious (TB!)

• Responsible organism usually demonstrable in tissue

• All specimens should be cultured

• Non-infectious granulomatous inflammation – sarcoidosis, Wegener’s granulomatosis, Crohn’s, etc.

TuberculosisThe mycobacteria that cause TB in man:

• Mycobacterium tuberculosis– Lung is most common primary site– Droplet infection = inhalation of infective droplets coughed or

sneezed by a patient with TB

• Mycobacterium bovis– Drinking milk from infected cows – intestinal & tonsillar lesions

• M. avium & M. intracellulare (MAC complex)– Opportunistic infection in IC

• Mycobacteria:– Aerobic organisms

– Difficult to stain• waxy cell wall• scanty in tissue• slow growth in culture• PCR

– Difficult to kill (dormancy) • No toxins or histolytic enzymes • Inhibition of phagosome-lysosome fusion & killing by macrophages • Induce delayed hypersensitivity (type IV - T cell mediated)

– Destructive effects

• Developed countries:– Considerable fall in incidence and mortality in 20th

century

• A disease of the elderly:– Reactivation of quiescent infection acquired in youth

• Recent resurgence:– AIDS, urban deprivation, immigrant & refugee

populations

Epidemiology

• 1/3 world population infected (~1.7 billion)

• 8 million new cases every year– 95% in developing countries

• 3 million deaths every year– Largest cause of a death from a single pathogen

• TB kills twice as many adults as AIDS, malaria and other parasitic diseases combined

• Marked resurgence– Poorer communities, drug abuse

• Multidrug resistant strains have emerged

• 6 million people world-wide have dual infection, majority in sub-Saharan Africa

• HIV infection – particularly aggressive TB – widespread, disseminated & poor host response

• HIV infection promotes infection with opportunistic mycobacteria

TB & HIV

• Primary TB:– First time infection

– Formerly found mainly in children, now encountered in adults

• Secondary/Postprimary TB:– Adult type

– Reactivation of a dormant primary lesion

– Re-infection from re-inhalation

Primary Tuberculosis

• Transmitted through inhalation of infected droplets

• Single tuberculous granuloma (tubercle):

– within parenchyma (usually subpleural/periphery) = Ghon focus

– also in hilar lymph nodes (common) = Ghon complex

Ghon Complex - Sequence of Events• Inhaled bacilli ingested by alveolar macrophages

• Macrophages with bacilli aggregate, forming microscopic nodules that deform architecture

• Development of T-cell mediated immunity: CD4 (helper) & CD8 (cytotoxic)

– CD4 – interferon – secretory changes in macrophages – epithelioid (activated) histiocytes

– CD8 – kill macrophages – resulting in caseous necrosis

• Fusion of macrophages to form Langerhan’s type giant cells

• Mantle of B lymphocytes

Primary TBResolution vs. Progression

• RESOLUTION:– Most common (if immunocompetent)

– Development of a fibrous capsule - eventually calcified scar

– Indefintely viable dormant bacteria

• PROGRESSION:

1. Tuberculous bronchopneumonia– Erosion into bronchus - dissemination within bronchial tree (‘galloping consumption’)– Continuing casseation - cavitary fibrocasseous lesions

2. Pleural spread– effusion, TB empyema

3. Miliary TB (haematogenous dissemination)– Remainder of lung– Cervical lymph nodes (scrofula)– Meninges (tuberculous meningitis)– Kidneys & adrenals– Bones (tuberculous osteomyelitis)

• veterbral TB = Pott’s disease

– Fallopian tubes & epididymis

Fibrocaseous

Miliary

Secondary TB

1. Reactivation of dormant lesion

2. Re-infection

Associations - alcoholism, diabetes, silicosis & immunosuppression

• Pulmonary – Resolution or progression

– N.B. Extensive firosis in healing process:• Pulmonary & pleural fibrosis

• Bronchiectasis

TB in the elderly & immunocompromised

• TB in the elderly:– Disseminated miliary TB – (non-reactive TB) little

granulomatous response, necrosis, DAD

• TB in AIDS: – Conventional morphology

– Granulomas poorly formed

– Opportunistic MAC from environment

Necrotizing Granulomas - Other Infectious Causes

• Bacteria:– Brucellosis

• Fungi:– Histoplasma, Coccidioides, Cryptococcus &

Blastomyces

• Parasitic roundworm:– Dirofilaria

Sarcoidosis

• Systemic disease of unkown aetiology

• Characterized by non-caseating granulomas in many tissues & organs– Lungs, lymph nodes, spleen, liver, bone marrow,

skin, eye, salivary glands and less frequently – heart, kidneys, CNS, endocrine glands – pituitary

Sarcoidosis

• Occurs worldwide but geographical variation– more prevalent at higher latitudes – Ireland,

Scandinavia & North America (African Americans)– 10 per 105 in UK

• Females > Males, peak incidence 30 - 40 yrs

• Exact aetiology & pathogenesis unclear

• Several immunologic abnormlaities– Enhanced cellular hypersensitivity at involved sites –

but depressed elsewhere• Anergy to common skin test antigens

– Generally driven by CD4 T cells

– Increased CD4 lymphocytes in the lung

• Clinical:– Variable depending on organ(s)– Mild non-specific chest complaints, cough, dyspnoea– 1/3 – Erythema nodosum

• Radiology:– Bilateral hilar lymphadenopathy

• Non-caseating granulomas (classic)– Tight clusters of epithelioid histiocytes and occassional MNGCs– Tight rim of concentric fibroblasts , few lymphocytes (‘naked

granulomas’)

– Schaumann bodies• Laminated concretions (Ca2+ & protein)

– Asteroid bodies• Stellate inclusions

• Histological diagnosis of exclusion– DDx – infection, berylliosis, HP, IVDA, adjacent to tumour / lymphoma

Sarcodosis in the Lung

• Unpredictable clinical course– Progessive chronicity or alternating activity &

remission

• ~ 70% recover with steroid Rx

• ~ 35% progress to interisital fibrosis & cor pulmonale

Sarcoidosis - Prognosis

Interstitial Lung Disease

• Heterogeneous group of non-infectious, non-neoplastic disorders– Predominanly diffuse and usually chronic

– Damage to the lung parenchyma (varying intersitial inflammation & fibrosis)

• a.k.a alveolitis & pulmonary fibrosis

• Restrictive lung disorders

• Acute (e.g. DAD) vs. Chronic

• NB - Clinical, Radiology & Pathology correlation!

• Aetiology / associations:– idiopathic, collagen vascular disease, drugs & toxins,

environmental

• FIBROSING:– USUAL INTERSTITIAL PNEUMONIA (UIP/CFA/IPF)– Non-specific interstitial pneumonia (NSIP)– Cryptogenic organizing pneumonia (COP)– Connective tissue disease– Pneumoconiosis– Drug rections– Raditation pneumonitis– Lymphocytic interstitial pneumonitis (LIP)

• GRANULOMATOUS– Sarcoidosis– Hypersensitivity pneumonitis

• SMOKING-RELATED:– Respiratory bronchiolitis (RB)– Desquamative* interstitial pneumonitis (DIP)

Chronic ILD

Usual Interstitial Pneumonia

• Progressive fibrosing disorder of unknown cause– ? Repeated acute lung injury (unknown agent)

• Patchy lung involvement – worst at bases, subpleural & paraseptal distribution – Dense fibrosis – remodelling of lung architecture (‘honeycombing’)– Fibroblastic foci

Usual Interstitial Pneumonia

• Adults 30 to 60 yrs– Gradual onset of symptoms: dyspnea, non-prod cough

• Median survival ~ 3 years– Respiratory and heart failure (cor pulmonale)– Require transplantation

Pneumoconioses• Disorders caused by inhalation of inorganic

elements, primarily mineral dusts.• Injury is determined by:

– Length of exposure– Physicochemical characteristics– Host factors

• Carbon dust - Coal worker’s pneumoconiosis:– Anthracosis– Simple coal worker’s pneumoconiosis– Progressive massive fibrosis

• Silicosis– Silicotic nodules– TB risk

• Asbestos– Asbestosis (pulmonary fibrosis)– Pleural disease (fibrous plaques, mesothelioma).

Hypersensitivity Pneumonitis

• Immune-mediated granulomatous inflammation caused by inhaling organic dusts– Mix type III (immune-complex deposition) & type IV (cellular mediated)

hypersensitivity

Farmer’s lungThermophilic actinomycetes in hay

Pigeon breeder’s

Air-condition lungThermophilic bacteria

• Diffuse interstitial fibrosis (> upper lobes)– Progressive - honeycomb & respiratory failure