GRANULOMATOUS LUNG DISEASE & INTERSTITIAL LUNG DISEASE

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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