1. Pathogenesis of Granulomatous & Interstitial Airways Disease

2. Granulomatous Disease Necrotizing 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. Developed countries: –Considerable fall in incidence and mortality in 20 th century A disease of the elderly: –Reactivation of quiescent infection acquired in youth Recent resurgence: –AIDS, urban deprivation, immigrant & refugee populations Epidemiology

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. 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

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 TB Resolution 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 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

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 10 5 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. 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 (Ca 2+ & protein) –Asteroid bodies Stellate inclusions Histological diagnosis of exclusion –DDx – infection, berylliosis, HP, IVDA, adjacent to tumour / lymphoma Sarcodosis in the Lung

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

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. 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

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