dr rodney itaki lecturer anatomical pathology discipline
TRANSCRIPT
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Pathology of TuberculosisPathology of TuberculosisDr Rodney Itaki
LecturerAnatomical Pathology Discipline
University of Papua New GuineaSchool of Medicine & Health SciencesDivision of Pathology
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EpidemiologyEpidemiology• Single most important infectious disease• Affects 1/3 of world population• Kills about 3 million patients each year• PNG prevalence rate is 648 per 100 000 (WHO 2013).
• Mortality rate is around 57 per 100 000 (WHO 2013).
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Etiology & PathogenesisEtiology & Pathogenesis• Infection is caused by M.tuberculosis & M.bovis.
• Aerobic, non-spore-forming, non-motile bacilli with a waxy coat (which is responsible for retaining the red dye in acid-fast stains).
• Transmitted by inhalation of infective droplets or when sneezed into air by infected person.
• M.bovis transmitted by consumption of unpasteurized milk from infected animals.
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Etiology & PathogenesisEtiology & Pathogenesis• M.avium & M.intracellulare cause disseminated infection in 15-24% of AIDS patients.
• Pathogenicity: Related to its ability to escape killing by macrophages and induce delayed type hypersensitivity.
• Attributed to its cell wall components (Mycosides):– Cord factor – glycolipid found on virulent strains.
Inhibits neutrophil migration & damages mitochondria
– Lipoarabinomannam (LAM) – heteropolysaccharide, similar structure to gram negative endotoxin. Inhibits macrophage activation by interferon gamma.
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Mycolic Acid StructureMycolic Acid Structure
Ref: Yale School of Medicine, Laboratory Medicine Website
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PathogenesisPathogenesis• LAM also induces macrophages to secrete TNF-α, which causes wt loss, tissue damage – Induce macrophage to secrete IL-10 which
suppresses mycobacterium-induced T-cell proliferation.
• Complement activated on mycobacterium surface opsonize organism, facilitate its uptake by macrophages via complement receptor CR3 (MAC-1 integrin) without triggering respiratory burst necessary for killing intracellular organisms.
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Intracellular Respiratory BurstIntracellular Respiratory BurstO2 depdendent myleoperxodase-independent intracellular killing
O2 dependent myeloperoxidase-dependent intracellular killing
Ref: Online Microbiology & Immunology, University of Carolina School of Medicine
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PathogenesisPathogenesis• A highly immunogenic 65-kD heat shock protein – M. tuberculosis heat shock protein plays a role in autoimmune reactions induced by M. tuberculosis.
• M.tuberculosis resides in phagosomes which are not acidified into lyososomes. – Inhibition of acidification is by a urease secreted by
myocobacterium. Sulfatides (cell wall) also inhibit fusion of phagosome with lysosome.
• Uptake of mycobacterium is by compliment – or mannose binding proteins rather than Fc receptors.
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PathogenesisPathogenesis• Development of cell mediated immunity or type IV hypersensitivity reaction explains organisms destruction to tissues & emergence of resistance to organism.
• Primary infection is controlled via cellular immunity
• Secondary infection results from re-infection by virulent stains or reactivation and reduction in cellular immunity of infected individual.
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Primary Infection Primary Infection -- EventsEvents• Inhalation of mycobacterium & ends with T-cell mediated immunity response killing 95% of organism.
• Events in sequence:– Phagocytosis of organism by alveolar macrophages– And transportation to hilar lymp nodes.– Naïve macrophages unable to kill organism therefore
bacilli multiply within macrophages
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Primary InfectionPrimary Infection• Bacilli lyse (kill) host macrophages and infect other macrophages.
• Bacilli disseminate to other parts of the lungs and other parts of the body.
• T-cell immunity against mycobacterium develops after a few weeks (3-4 weeks).
• Development of T-cell immunity is demonstrated by a positive purified protein test (PPD or Mantoux).
•
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Type IV (delayed) Hypersensitivity• Sensitised CD4+ cells
process Ag and release lymphokines in association with MHC Class II molecules.
• Rxn begins in hrs & peaks in 2-3 days.
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Primary InfectionPrimary Infection• Mycobacterium activated T cells cause:• CD4+ helper T cells secrete interferon-γ which activates macrophages to kill intracellular mycobacterium via NO, NO2 & HNO3. This results in formation of epitheliod cell granulomas & clearance of organism.
• CD8+ suppressor T cell lyse infected macrophages through a Fas-dependent, granule-dependent reaction & kill mycobacterium.
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Primary InfectionPrimary Infection
Ref: Robins Pathological Basis of Diseases, 7th Ed.
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Primary InfectionPrimary Infection• CD4-CD8- (double negative) T cells lyse infected macrophages without killing mycobacterium
• Lyses of macropahges results in formation of caseating granulomas. Direct toxicity of mycobacterium to macrophages also contributes.
• Mycobacterium cannot grow in this acidic, extracellular environment, low in oxygen hence infection is controlled.
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Primary InfectionPrimary Infection• Calcified hilar lymp node is called a Ghon focus• Together with calcified scar in the lung parenchyma is called a Ghon complex.
• This is latent TB infection.• LTBI diagnosed via PPD (low specificity, low sensitivity) and Quantiferon Function Test/QFT (high specificity, high sensitivity).
• Minimal lung changes. CXR normal most often. Look for Ghon complex/Focus.
• CXR screening for primary infection is not cost-effective.
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Secondary InfectionSecondary Infection• Secondary infection results from re-infection by virulent strains or activation of latent TB infection and drop in cellular immunity in host.
• Secondary infection can be disseminated through out the lung, kidneys, meninges and elsewhere.
• Granulomas of secondary infection most evident in lung apeces. But maybe widespread.
• Formation of granulomas is cause of tissue damage (delayed type hypersensitivity).
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Secondary InfectionSecondary Infection• 2 characteristic features are: caseous necrosis & cavities.
• Necrosis may rapture into blood vessels spreading organism throughout the body (miliary TB).
• Or break into airways releasing infectious mycobacterium in aerosols.
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Morphology Morphology –– Primary InfectionPrimary Infection
Ghon complex: hilar lymph node plus peripheral scar (yellow tan lesion).
Ref: Internet Pathology Laboratory, University of Utah.
Image Ref: mervis-research
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Primary InfectionPrimary InfectionGhon Complex Ghon Focus
Ref: Quizlet.comRef: University of Utah
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Secondary Pulmonary TBSecondary Pulmonary TB
Cavity formation, multiple yellow tan granulomas. Propensity for apex
Ref: Internet Pathology Laboratory, University of Utah.
Image Ref: wikipedia
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TB MorphologyTB Morphology
Image Ref: CDCRef: University of Utah
Multiple yellow tan granulomas
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Morphology Morphology –– Miliary TBMiliary TB
Multitude of small yellow tan granulomas 2-4mm in size resembling millet seeds.
Ref: Internet Pathology Laboratory, University of Utah
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Miliary TBMiliary TB
Ref: wikipediaRef: siamhealth.net
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Miliary TB Miliary TB –– Spleen & KidneySpleen & Kidney
Ref: granuloma-homestead.com Ref: radiographics.rsna.org
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TB Lung TB Lung -- MicroMicro
Ref: Internet Pathology Laboratory, University of Utah
•Multiple granulomas•Langhans giant cells•Caseous necrosis ringed by chronic inflammatory cells, epitheloid cells
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Role of T cell in granuloma formationRole of T cell in granuloma formation
Ref: Robins Pathological Basis of Diseases, 7th Ed
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Progressive Pulmonary TBProgressive Pulmonary TB
Ref: Robins Pathological Basis of Diseases, 7th Ed.
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Variable Forms of TBVariable Forms of TB• Cavitary fibrocaseous tuberculosis
– Cavity formation (usually apex) and walled off by fibrous tissue.
– May affect more than one lobe of the lung.– Involvement of pleura leads to serous pleural
effusions.• Tuberculous bronchopneumonia – large areas of lung parenchyma and lobar exudate.
• Miliary TB results from lymphohematogenous dissemination.– Common sites include liver, kidneys, BM, adrenals,
retina.
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Laboratory DiagnosisLaboratory DiagnosisLatent TB Diagnosis• Mantoux (PPD) & QFT• PPD false positive from BCG vaccindation
• CXR – poor sensitivity, not cost effective.
• Serology – Banned by WHO
QFT
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Laboratory DiagnosisLaboratory Diagnosis• Sputum/Tissue – AFB.
Ref: Internet Pathology Laboratory Ref: Sharma & Tiwari, Rural & Remote Health Journal, May 2007
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Laboratory DiagnosisLaboratory Diagnosis• Molecular biology – GenXpert, PCR• Culture – identification, drug sensitivity and specificity testing. Different methods of culture.
• GenXpert can also test for RIF and INH resistance by isolating and amplifying genes.
• Sample collection, storage, transporting and processing all determine test outcome!
• If rubbish goes in, rubbish comes out!
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ENDRef: Robins Pathological Basis of Diseases.
Images: Internet Pathology Laboratory, University of Utah.
http://library.med.utah.edu/WebPath/
Download PDF copy of seminar notes at:www.pathologyatsmhs.wordpress.com