Pathogenesis of Granulomatous & Interstitial Airways Disease.
Pathogenesis of Granulomatous & Interstitial Airways Disease
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Transcript of Pathogenesis of Granulomatous & Interstitial Airways Disease
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Pathogenesis of Granulomatous & Interstitial
Airways Disease
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Granulomatous DiseaseNecrotizing vs Non-necrotizing
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• 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.
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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
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• 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
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• 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
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• 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
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• 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
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• 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
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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
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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
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Primary TBResolution vs. Progression
• RESOLUTION:– Most common (if immunocompetent)
– Development of a fibrous capsule - eventually calcified scar
– Indefintely viable dormant bacteria
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• 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
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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
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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
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Necrotizing Granulomas - Other Infectious Causes
• Bacteria:– Brucellosis
• Fungi:– Histoplasma, Coccidioides, Cryptococcus &
Blastomyces
• Parasitic roundworm:– Dirofilaria
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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
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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
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• 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
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• Clinical:– Variable depending on organ(s)– Mild non-specific chest complaints, cough, dyspnoea– 1/3 – Erythema nodosum
• Radiology:– Bilateral hilar lymphadenopathy
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• 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
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• Unpredictable clinical course– Progessive chronicity or alternating activity &
remission
• ~ 70% recover with steroid Rx
• ~ 35% progress to interisital fibrosis & cor pulmonale
Sarcoidosis - Prognosis
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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
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• Acute (e.g. DAD) vs. Chronic
• NB - Clinical, Radiology & Pathology correlation!
• Aetiology / associations:– idiopathic, collagen vascular disease, drugs & toxins,
environmental
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• 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
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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
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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
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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).
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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