1. GRANULOMATOUS LUNG DISEASE & INTERSTITIAL LUNG DISEASE

2. GRANULOMATOUS DISEASE Necrotizing vs non-necrotizing Most necrotizing granulomatous disease is infectious Responsible organism usually demonstrable in tissue All specimens should be cultured Non-infectious granulomatous inflammation – sarcoidosis, Wegener’s granulomatosis & other angiitides

3. TUBERCULOSIS (Robert Koch – 1882) The mycobacteria that cause TB in man: Mycobacterium Tuberculosis – droplet infection = inhalation of infective droplets coughed or sneezed by a patient with TB Mycobacterium Bovis – drinking milk from infected cows – intestinal and tonsillar lesions M. Avium & M. Intracellulare (MAC complex) cause opportunistic infection in IC

4. Mycobacteria are Aerobic organisms Difficult to stain - waxy cell wall - scanty in tissue - slow growth in culture - PCR Difficult to kill They have no toxins or histolytic enzymes they inhibit phagosome-lysosome fusion and killing by macrophages they induce delayed hypersensitivity TUBERCULOSIS

5. Developed countries – considerable fall in incidence and mortality in 20 th century A disease of the elderly – recrudescence of quiescent infection acquired in youth Recent resurgence – AIDS, urban deprivation, immigrant & refugee populations TUBERCULOSIS - Epidemiology

6. 1/3 world population infected (1700 million) 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 > 80% of TB toll in developing countries is in the economically most productive age-group (15-60 years) TUBERCULOSIS - Epidemiology

7. Alarming 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 dissem. & poor host response HIV infection promotes infection with opportunistic mycobacteria TUBERCULOSIS – The impact of HIV infection

8. Primary TB First time infection Formerly found mainly in children, now encountered in adults Postprimary TB Adult type Previously sensitized fresh infection or reactivation of a dormant primary lesion TUBERCULOSIS

9. PRIMARY TB - Ghon Focus Inhaled tubercle 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 histiocytes CD8 – kill macrophages – resulting in caseous necrosis Fusion of macrophages to form Langerhan’s type giant cells Mantle of B lymphocytes

15. GHON COMPLEX (1) Parenchymal subpleural lesion at the subpleural fissure between upper and lower lobes & (2) the enlarged hilar / mediastinal caseous lymph nodes draining the parenchymal focus

16. PRIMARY TB – Possible outcomes Resolution – development of a fibrous capsule - eventually calcified scar Progression- erosion into bronchus – cavitation – dissemination within bronchial tree (galloping consumption!) Pleural spread – effusion, TB empyema Compression by caseous nodes of bronchus or trachea – collapse, compression, stridor Haematogenous dissemination = Miliary TB cervical lymph nodes (scrofula), meninges (tuberculous meningitis), kidneys, adrenals, bones (tuberculous osteomyelitis) [veterbral TB = Pott’s disease], fallopian tubes, epididymis

17. POSTPRIMARY TB Endogenous vs Exogenous Associations - alcoholism, diabetes, silicosis, immunosuppression Pulmonary Apical disease Caseous pneumonia in lower lobes Cavities – ca, colonization, bronchiectasis Pleural & pulmonary fibrosis Obliterative endarteritis of pulmonary & bronchial aa – but “Rasmussen’s aneurysm” Extrapulmonary complications – amyloid

23. Tuberculosis in the elderly & immunocompromised TB in the elderly Disseminated miliary TB – (non-reactive TB) little granulomatous response, necrosis, DAD TB in AIDS 1.conventional morphology 2.granulomas poorly formed 3.opportunistic MAC from environment, spindle cell pseudotumours

24. TB – Skin tests & vaccinations Old tuberculin – now purified protein derivative (ppd) Intradermal injection – Mantoux Multi-pronged devices – Heaf test Positive reaction indicates that a person has been infected by tubercle bacillus Prophyllactic immunization with strain of low virulence – Bacillus Calmette Guerin (BCG)

25. Necrotizing Granulomas other infectious causes Brucellosis Fungi – Histoplasma, Coccidioides Cryptococcus, Blastomyces Dirofilaria

28. SARCOIDOSIS A disease of unknown cause 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 Occurs worldwide, more prevalent at higher latitudes – Scandinavia, northern Europe and North America B>W, F>M, but rare in American Indians, Eskimos Communicable agent suspected but as yet undiscovered

29. Enhanced cellular hypersensitivity at involved sites – but depressed elsewhere Increased CD4 lymphocytes in the lung Clinical: mild non-specific chest complaints, cough, dyspnoea 1/3 – Erythema nodosum Increased serum Ca, ACE, gammaglobulins Radiographic Staging: IHilar adenopathy alone (best) IIHilar adenopathy & parenchymal infiltrates III Parenchymal infiltrates alone (worst) SARCOIDOSIS

33. Non-caseating granulomas Tight clusters of epithelioid histiocytes and occassional MNGCs Tight rim of concentric fibroblasts, scattered lymphocytes (naked granulomas) Laminated concretions – Schaumann Bodies Stellate inclusions – Asteroid Bodies Distribution – along lymphatics (TBBx) Granulomatous vasculitis DDx – infection, berylliosis, HP, IVDA, adjacent to tumour / lymphoma SARCOIDOSIS in the lung

40. INTERSTITIAL LUNG DISEASE A heterogeneous group of non-neoplastic disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis Interstitium (space between the epithelial and endothelial BM) - primary site of injury These disorders frequently also affect the airspaces, airways and vessels Clinical – Radiology – Pathology correlation NB Aetiology / associations: idiopathic, collagen vascular disease, drugs & toxins, environmental

43. Usual interstitial pneumonia (UIP) aka Cryptogenic fibrosing alveolitis (CFA) aka Idiopathic pulmonary fibrosis (IPF) Vs. The others: Non-specific interstitial pneumonia (NSIP) Organizing pneumonia (OP) Respiratory bronchiolitis (RB) Desquamative interstitial pneumonitis (DIP) Lymphocytic interstitial pneumonitis (LIP) INTERSTITIAL LUNG DISEASE

44. Patchy lung involvement – worst at bases, subpleural & paraseptal distribution Dense fibrosis – remodelling of lung architecture – “honeycombing” Fibroblast foci Gradual onset of symptoms: dyspnea, non-prod cough Median survival 2.5 – 3.5 years Usual Interstitial Pneumonia