Pathogenesis of Granulomatous & Interstitial Airways Disease

1. Pathogenesis of Granulomatous & Interstitial Airways Disease

2. Granulomatous DiseaseNecrotizing vs Non-necrotizing

3. 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.

4. Tuberculosis The 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

5. 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

6. Epidemiology • 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

7. 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

8. TB & HIV • 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

9. 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

10. 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

11. 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

14. Primary TBResolution vs. Progression • RESOLUTION: • Most common (if immunocompetent) • Development of a fibrous capsule - eventually calcified scar • Indefintely viable dormant bacteria

15. 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

16. Secondary TB • Reactivation of dormant lesion • Re-infection Associations - alcoholism, diabetes, silicosis & immunosuppression • Pulmonary • Resolution or progression • N.B. Extensive firosis in healing process: • Pulmonary & pleural fibrosis • Bronchiectasis

18. 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

19. Necrotizing Granulomas - Other Infectious Causes • Bacteria: • Brucellosis • Fungi: • Histoplasma, Coccidioides, Cryptococcus & Blastomyces • Parasitic roundworm: • Dirofilaria

20. 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

21. 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

22. 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

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

27. Sarcodosis in the Lung • 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

32. Sarcoidosis - Prognosis • Unpredictable clinical course • Progessive chronicity or alternating activity & remission • ~ 70% recover with steroid Rx • ~ 35% progress to interisital fibrosis & cor pulmonale

33. 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

34. Acute (e.g. DAD) vs. Chronic • NB - Clinical, Radiology & Pathology correlation! • Aetiology / associations: • idiopathic, collagen vascular disease, drugs & toxins, environmental

35. Chronic ILD • 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)

36. 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

37. 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

42. 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).

43. Farmer’s lung Thermophilic actinomycetes in hay Pigeon breeder’s Air-condition lung Thermophilic bacteria Hypersensitivity Pneumonitis • Immune-mediated granulomatous inflammation caused by inhaling organic dusts • Mix type III (immune-complex deposition) & type IV (cellular mediated) hypersensitivity • Diffuse interstitial fibrosis (> upper lobes) • Progressive - honeycomb & respiratory failure