Tuberculosis Student Update

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Tuberculosis Student Update

  1. 1. TuberculosisStudent UpdateDr.T.V.Rao MD4/22/2013 Dr.T.V.Rao MD 1
  2. 2. HISTORY ofTuberculosisTuberculosis Isan AncientDiseaseSpinalTuberculosis inEgyptianMummiesHistory dates to1550 – 1080 BCIdentified by PCR4/22/2013 Dr.T.V.Rao MD 2
  3. 3. - Aristotle said…• 354-322 BC - Aristotle – “When onecomes near consumptives… onedoes contract their disease… Thereason is that the breath is bad andheavy…In approaching theconsumptive, one breathes thispernicious air. One takes the diseasebecause in this air there is somethingdisease producing.”4/22/2013 Dr.T.V.Rao MD 3
  4. 4. M tuberculosis as causativeagent for tuberculosisRobert Koch1886Robert Koch4/22/2013 Dr.T.V.Rao MD 4
  5. 5. Robert KochDiscovererofMycobacteriumTuberculosis4/22/2013 Dr.T.V.Rao MD 5
  6. 6. What are Mycobacteria?• Obligate aerobes growing mostsuccessfully in tissues with a highoxygen content, such as thelungs.• Facultative intracellular pathogensusually infecting mononuclearphagocytes (e.g. macrophages).4/22/2013 Dr.T.V.Rao MD 6
  7. 7. Mycobacterium differ from otherroutinely isolated Bacteria• Slow-growing with a generationtime of 12 to 18 hours (c.f. 20-30minutes for Escherichia coli).• Hydrophobic with a high lipid contentin the cell wall. Because the cells arehydrophobic and tend to clumptogether, they are impermeable to theusual stains, e.g. Grams stain4/22/2013 Dr.T.V.Rao MD 7
  8. 8. Acid fast bacilli• Known as “Acid-fastbacilli" because of theirlipid-rich cell walls, whichare relatively impermeableto various basic dyes unlessthe dyes are combined withphenol.4/22/2013 Dr.T.V.Rao MD 8
  9. 9. How they are Acid fast• Once stained, the cells resistdecolourization with acidifiedorganic solvents and aretherefore called "acid-fast". (Otherbacteria which also containmycolic acids, such as Nocardia,can also exhibit this feature.)4/22/2013 Dr.T.V.Rao MD 9
  10. 10. Mycobacterium tuberculosiscomplex• Includes Human and Bovinemycobacterium• M.africanum Tropical Africa• M.microti do not cause humaninfections but small mammalsCan be infected4/22/2013 Dr.T.V.Rao MD 10
  11. 11. Avian Tuberculosis• Transmitted by ingestion and inhalation of aerosolizedinfectious organisms from feces.• Oral ingestion of food and water contaminated withfeces is the most common method of infection.• Once ingested, the organism spreads throughout thebirds body and is shed in large numbers in the feces.• If the bacterium is inhaled, pulmonary lesions and skininvasions may occur• transmission of avian TB is from bird to human not fromhuman to human.4/22/2013 Dr.T.V.Rao MD 11
  12. 12. Bovine Tuberculosis• Bovine TB is most likely going toeffect the joints and bones.• people contract Bovine TB today,byeating food that has beencontaminated by the bacteria or fromdrinking un-pasteurized milk fromcows that are infected with the virus.4/22/2013 Dr.T.V.Rao MD 12
  13. 13. M.bovis• Primarily infection among thecattle• M.bovis infects Tonsils,Cervical nodes, can produceScrofula.• Enter through Intestines –infects the Ileocecal region.4/22/2013 Dr.T.V.Rao MD 13
  14. 14. What are atypicalMycobacterium• Infects birds, cold blooded animalsworm blooded animals• Present in environment• Opportunistic pathogens• Others – Saprophytic bacteriaM butryicum present in butterM.phleiM smegmatis – present in Smegma4/22/2013 Dr.T.V.Rao MD 14
  15. 15. Atypical Mycobacterium• 1 Photochromogens• 2 Scotochromogens• 3 Nonphotochromogens• 4 Rapid growers4/22/2013 Dr.T.V.Rao MD 15
  16. 16. MOST IMPORTANT AMONGINFECTIOUS DISEASES• Tuberculosis (TB) is theleading cause of death in theworld from a bacterialinfectious disease. Thedisease affects 1.8 billionpeople/year which is equal toone-third of the entire worldpopulation.4/22/2013 Dr.T.V.Rao MD 16
  17. 17. Tuberculosis kills not only poorbut rich and famous4/22/2013 Dr.T.V.Rao MD 17
  18. 18. Poverty and Crowded livingspreads Tuberculosis4/22/2013 Dr.T.V.Rao MD 18
  19. 19. How Are TB GermsSpread?4/22/2013 Dr.T.V.Rao MD 19
  20. 20. What are Mycobacteria?• Obligate aerobes growing mostsuccessfully in tissues with a highoxygen content, such as thelungs.• Facultative intracellularpathogens usually infectingmononuclear phagocytes (e.g.macrophages).4/22/2013 Dr.T.V.Rao MD 20
  21. 21. Morphology of Mycobacteriumtuberculosis• Straight, slightlycurved Rod shaped 3x 0.3microns• May be single, inpairs or in smallclumps• On conditions ingrowth appears asfilamentous, clubshaped, or inBranched forms.4/22/2013 Dr.T.V.Rao MD 21
  22. 22. ACID FAST BACILLI• Known as “Acid-fast bacilli"because of their lipid-rich cellwalls, which are relativelyimpermeable to various basicdyes unless the dyes arecombined with phenol.4/22/2013 Dr.T.V.Rao MD 22
  23. 23. Important Mycobacterium• Mycobacterium tuberculosis, along with M.bovis, M. africanum, and M. microti allcause the disease known as tuberculosis(TB) and are members of the tuberculosisspecies complex. Each member of the TBcomplex is pathogenic, but M. tuberculosisis pathogenic for humans while M. bovis isusually pathogenic for animals4/22/2013 Dr.T.V.Rao MD 23
  24. 24. Acid Fast Bacilli seen in a specimenof Sputum4/22/2013 Dr.T.V.Rao MD 24
  25. 25. Acid fast Bacilli seen as inFlorescent Microscope• After staining with ZiehlNeelsen method orFluorescent method (Auramine or Rhodaminethey resist decolonizationby 20% Sulphuric acidand absolute alcohol for10 mt,• So called as Acid andAlchool fast.4/22/2013 Dr.T.V.Rao MD 25
  26. 26. Why they are Acid Fast• The character ofAcid fastness isdue to presenceof Unsapnofiablewax ( My colicacid and semipermeablemembranearound the cell)4/22/2013 Dr.T.V.Rao MD 26
  27. 27. Culturing Acid Fast Bacilli• Slow to grow ,• Generation time is 14– 15 hours• > 2 weeks minimalrequired period• Grows at 370c do notgrow below 250c• Ph between 6.4 to7.04/22/2013 Dr.T.V.Rao MD 27
  28. 28. Nature of Media Used• Helps the growthneeds• Solid Medium iscommonly used• LowensteinJensen’s medium• Petrangini• Middle brookmedium4/22/2013 Dr.T.V.Rao MD 28
  29. 29. Lowenstein Jensen’sMedium• Containcoagulated egg• Mineral saltsolution• Asparagines• Malachite green• Agar4/22/2013 Dr.T.V.Rao MD 29
  30. 30. Other Medium•Middle brook•Sula”s medium•But not routinelyused4/22/2013 Dr.T.V.Rao MD 30
  31. 31. Nature of Growth Characters• M tuberculosis is obligate aerobe• M.bovis Microaerophilic• M.tuberculosis grwoth luxierently• M.tuberculosis eugonic• M bovis is dysgonic• When grown on 0.5% glycerin M tuberculosisgrowth improves• Sodium pyruvate improves the grwoth of bothorganism.4/22/2013 Dr.T.V.Rao MD 31
  32. 32. On L J Medium• M.tuberculosis appeardry, rough raisedirregular colonies• Appear wrinkled• They appear creamywhite• Become yellowish• M.bovis appear as flatsmooth, moist, whiteand break up easily4/22/2013 Dr.T.V.Rao MD 32
  33. 33. On Liquid Medium• Appear as longserpentinecords in liquidmedium• Virulent strainsgrow in a moredispersedmanner.4/22/2013 Dr.T.V.Rao MD 33
  34. 34. Immunological Testing Tuberculin skin test/Mantoux: tuberculin purifiedprotein derivative (PPD) injected intradermally & cell-mediated response at 48-72h . +ve 5-14mminduration, strongly +ve >15mm +ve test indicated immunity (may be previousexposure, BCG) Strong +ve test = active infxn. Falseneg tests in immunosuppression (miliary TB, sarcoid,AIDS, lymphoma)4/22/2013 Dr.T.V.Rao MD 34
  35. 35. Resistance of Mycobacterium• Mycobacterium are killed at 600c in 15 –20 mt• In sputum they survive for 10 – 30 mt• Relatively resistant to several chemicalsincluding Phenol 5 %• Sensitive to Glutaraldehyde andFormaldehyde• Ethanol is suitable application tosuperficial surfaces and skin gloves4/22/2013 Dr.T.V.Rao MD 35
  36. 36. Resistance to severalagents• Bacilli survive in Droplets for 8 –10 days• Survive in5% phenol,15% Sulphuric acid3% Nitric acid,5% oxalic acid,4% Sodium hydroxide4/22/2013 Dr.T.V.Rao MD 36
  37. 37. Biochemical Tests onMycobacterium spp• Niacin test – 10%cyanogensbromide and 4%Aniline in 96%ethanol are addedto suspension of –C canary yellowcolor indicatespostive test.4/22/2013 Dr.T.V.Rao MD 37
  38. 38. Biochemical Tests• Aryl sulphatase test – Positive in AtypicalMycobacterium• Bacilli grown in 0.001 tripotassiumphenolpthalein disulphide / 2 N. Na oH addeddrop by drop a pink color develops• Catalase peroxidase test –Differentiates Atypical from TypicalMost Atypical are strongly Catalase positiveTubercle bacilli are weakly positiveTubercle bacilli are peroixidae positve – notatypicalINH resistant strains are negative for test4/22/2013 Dr.T.V.Rao MD 38
  39. 39. Catalase Test• 30 vol of H2O2 and 0.2 % alcohol indistilled water is added to 5 ml of testculture• Effervescence indicates Catalasepositive• Other testAmidase testNitrate reduction test4/22/2013 Dr.T.V.Rao MD 39
  40. 40. Antigenic Characters• Group specificity due to Polysaccharides• Type specificity to protein antigens• Delayed hypersensitivity to proteins• Related to each other species• Some relation between lepra and tuberclebacilli• Serology – Tests not usefulAntigenic homogeneity between < bovisand M.microti4/22/2013 Dr.T.V.Rao MD 40
  41. 41. Bacteriophages• There are 4 Bacteriophages A B C D• A worldwide• B. Europe and -American• C rare• I type nature between A and B andcommon in India• Phage 33 D M tuberculosis and not inBCG strains4/22/2013 Dr.T.V.Rao MD 41
  42. 42. Molecular Typing• DNA finger printingdifferentiates differentstrains of Mycobacteriumspecies• Treating the organismwith Restrictionendonulease yieldsNucleic acid fragments ofvarying length and strainspecific• Use in epidemiologicalstudies4/22/2013 Dr.T.V.Rao MD 42
  43. 43. Finger printing Methods• Finger printing is donewith Chromosomalinsertion sequence IS6110 present in moststrains of Tubercle bacilli• Now entire genome of Mtuberculosis is sequenced• Several Molecularmethods are avialble forstudies4/22/2013 Dr.T.V.Rao MD 43
  44. 44. Genome of Mycobacteriumtuberculosis4/22/2013 Dr.T.V.Rao MD 44
  45. 45. How tuberculosis spreads• Tuberculosis (TB) is a contagious disease.Like the common cold, it spreads throughthe air. Only people who are sick with TBin their lungs are infectious. Wheninfectious people cough, sneeze, talk orspit, they propel TB germs, known asbacilli, into the air. A person needs only toinhale a small number of these to beinfected.4/22/2013 Dr.T.V.Rao MD 45
  46. 46. Natural History of TB InfectionExposure to TBNo infection(70-90%)Infection(10-30%)Latent TB(90%)Active TB(10%)UntreatedDie within 2 years SurviveTreatedDie CuredNever developActive disease4/22/2013 Dr.T.V.Rao MD 46
  47. 47. Tuberculosis spread byRespiratory route4/22/2013 Dr.T.V.Rao MD 47
  48. 48. Importance of Tuberculosis• Someone in the world is newly infected with TBbacilli every second.• Overall, one-third of the worlds population iscurrently infected with the TB bacillus.• 5-10% of people who are infected with TB bacilli(but who are not infected with HIV) become sickor infectious at some time during their life.People with HIV and TB infection are much morelikely to develop TB.4/22/2013 Dr.T.V.Rao MD 48
  49. 49. Pathology and Pathogenesis ofTuberculosis• Source of Infection – Open case ofPulmonary Tuberculosis.• Every open case has potential to infect 20– 25 healthy persons before cured or dies• Coughing , Sneezing, or Talking.• Each act can spill 3000 infective nuclei inthe air,• Infective particles are engulfed by AlveolarMacrophages.4/22/2013 Dr.T.V.Rao MD 49
  50. 50. Spread of Tuberculosis4/22/2013 Dr.T.V.Rao MD 50
  51. 51. 4/22/2013 Dr.T.V.Rao MD 51
  52. 52. Predisposing Factors• Genetic basis,• Age• Stress,• Nutrition,• Co existing infections Eg HIV4/22/2013 Dr.T.V.Rao MD 52
  53. 53. Mechanisms of Infection• Mycobacterium do not produce toxins.• Allergy and Immunity plays the major role.• Only 1/10 of the infected will get disease.• Cell Mediated Immunity plays a crucialrole.• Humoral Immunity – not Important.• CD4 Cell plays role in ImmuneMechanisms.4/22/2013 Dr.T.V.Rao MD 53
  54. 54. Mechanisms of Infection• Within 10 days of entry of Bacilliclones of Antigen specific TLymphocytes are produced• Can actively produce Cytokines,Interferon γ which activateMacrophages form cluster orGranuloma4/22/2013 Dr.T.V.Rao MD 54
  55. 55. 4/22/2013 Dr.T.V.Rao MD 55
  56. 56. Tubercle with Caseous NecrosisGiant cellsTubercle bacilliPartially activatedmacrophageLymphocyteFully activatedmacrophage4/22/2013 Dr.T.V.Rao MD 56
  57. 57. TubercledischargingBronchial treeTNF- aTNF- a4/22/2013 Dr.T.V.Rao MD 57
  58. 58. Immunity inTuberculosis.• CD4 T Lymphocytes with Th 1 or Th 2 secrete - 1Cytokines,2 Interleukin 1,and 2 , 3 Interferons γ,4.Tumor necrosis factor.• The mechanisms with Th 1 secreteCytokines Activate MacrophagesResults in protective Immunity,and contain Infection.Th 2 manifests with Delayed HypersensitivityDTH causes Tissue destruction. and disease willprogress..4/22/2013 Dr.T.V.Rao MD 58
  59. 59. PathogenesisActivated Macrophages - Epitheliod cellsForms cluster a granulomaActivated macrophages turn into Giantcells.Granuloma contains necrotic tissue Deadmacrophages cheese like caesiation.Apoptosis of bacteria laden cellsContribute to protective immunity.4/22/2013 Dr.T.V.Rao MD 59
  60. 60. Basis of Tubercle formation.• Tubercle is a A vasculargranuloma Contain central zoneof giant cells with or withoutcaseation and peripheral zone ofLymphocytes and Fibroblasts.• Produce lesions may beExudative or Productive4/22/2013 Dr.T.V.Rao MD 60
  61. 61. 4/22/2013 Dr.T.V.Rao MD 61
  62. 62. Lesions in Tuberculosis• Exudative – and ProductiveExudative – Acute inflammatoryreaction with edema fluid – containsPolymorphs-Lymphocytes – later Mononuclearcells.Bacilli are virulent - Host respondswith DTH Injurious.Productive Type protective Immunity4/22/2013 Dr.T.V.Rao MD 62
  63. 63. Primary Tuberculosis• Initial response• In Endemic countries Young children• Events of Primary complex1 Bacilli are engulfed by Alveolar Macrophages2 Multiply and give raise to Sub pleural focus ofTuberculosis,Pneumonia,involve lower lobesand lower part of upper lobes.Called as Ghon’s focus.The Hilar Lymph nodes are also involved4/22/2013 Dr.T.V.Rao MD 63
  64. 64. Koch’s Phenomenon• Tuberculosis infected Guinea pig ifinjected with Living Tubercle bacilli• The site around the injection becomesnecrotic.• Koch found the same reaction wheninjected with old Tuberculin ( heated andconcentration of the tubercle bacilli )• It has produced the same reaction• This is called as Koch’s Phenomenon.4/22/2013 Dr.T.V.Rao MD 64
  65. 65. Primary complex• Ghon’s focus with Enlarged lymph nodes appearafter 3- 8 weeks after infection.• Heals in 2 – 6 months calcified,• Some bacteria remain alive and produce latentinfections.• Infection activated in Immunosupressedconditions Eg. HIV infections and AIDS• Can produce Meningitis, Miliary tuberculosis,other disseminated Tuberculosis.4/22/2013 Dr.T.V.Rao MD 65
  66. 66. Post Primary Tuberculosis• Mainly occurs due to Reactivation ofLatent infection.• May also due to Exogenous reinfection• Differs from Primary Infection.• Leads to –Cavitations of Lungs, Enlargement ofLymph nodes,Expectoration of Bacteria laden sputumDissemination into Lungs and other extrapulmonary areas.4/22/2013 Dr.T.V.Rao MD 66
  67. 67. Majority of the Tuberculosisare Pulmonary4/22/2013 Dr.T.V.Rao MD 67
  68. 68. Multiorgan Involvementin Tuberculosis.4/22/2013 Dr.T.V.Rao MD 68
  69. 69. Complication of Tuberculosis.1. Meningitis.2. Pleurisy,3. Involvement of Kidney,4. Spine ( Potts spine )5. Bone Joints,6. Miliary tuberculosis4/22/2013 Dr.T.V.Rao MD 69
  70. 70. Symptoms and Sings ofTuberculosis4/22/2013 Dr.T.V.Rao MD 70
  71. 71. Clinical Illness with Tuberculosis• Pulmonary Disease –Major manifestationwith involvement ofLungsHaemoptysis, Chestpain Fever sweetsAnorexiaCavity formation inLungs4/22/2013 Dr.T.V.Rao MD 71
  72. 72. Tuberculosis - Pneumothorax4/22/2013 Dr.T.V.Rao MD 72
  73. 73. Extra pulmonary Tuberculosis• Bacteria on circulation leads tobacteremia leads to involvement ofGUT, Genito urinary system,MeningitisGastro Intestinal system, skin, Lymphnodes Bone marrow.Spinal infection Potts spine, Arthritis4/22/2013 Dr.T.V.Rao MD 73
  74. 74. Tuberculosis - Lymphadenitis4/22/2013 Dr.T.V.Rao MD 74
  75. 75. Microbiologic Diagnosis of TBOverview:• Significance of microbiologic testing in TB care• Sputum staining and processing– Direct smears, unconcentrated– Fluorochrome staining and fluorescencemicroscopy– Concentration and chemical processing– Specimen collection and transport• Culture and drug-susceptibility testing• Rapid diagnostic testing4/22/2013 Dr.T.V.Rao MD 75
  76. 76. X - ray examination of chest mosteasily available Investigation.Dr.T.V.Rao MD 764/22/2013
  77. 77. Microscopy and TuberculosisMicroscopy with Ziehl –Neelsen’s stainingA century oldprocedureDr.T.V.Rao MD 774/22/2013
  78. 78. Standards for Diagnosis4/22/2013 Dr.T.V.Rao MD 78
  79. 79. Microbiologic Diagnosis of TBSummary:• Smear microscopyplays a central role inthe diagnosis andmanagement oftuberculosis.• It is important tounderstand the aspectsof specimen handlingand processing thatcan ensure or enhanceaccurate results.4/22/2013 Dr.T.V.Rao MD 79
  80. 80. Sputum Smear Microscopy• Sputum smear microscopyis the most important testfor the diagnosis ofpulmonary TB in manyareas of the world• Direct smears(unconcentratedspecimen) are mostcommon• Fluorescence microscopyand chemical processingcan increase sensitivity4/22/2013 Dr.T.V.Rao MD 80
  81. 81. Sputum Smear MicroscopyCarbol fuchsin-based stains• Utilize a regular light microscope• Must be read at a higher magnification• Two types: Ziehl-Neelsen and Kinyoun.Both use carbol fuchsin/phenol as theprimary dye• Smear is then decolorized with acid (HCI)alcohol and counter-stained withmethylene blue4/22/2013 Dr.T.V.Rao MD 81
  82. 82. Fluorescence MicroscopyAdvantages:• More accurate: 10% moresensitive than lightmicroscopy, with specificitycomparable to ZN staining• Faster to examine = lesstechnician timeDisadvantages:• Higher cost and technicalcomplexity, less feasible inmany areas Steingart KR, et al. Lancet Infect. Dis. 2006; 6 (9):570-814/22/2013 Dr.T.V.Rao MD 82
  83. 83. Although sputummicroscopy is the firstbacteriologicdiagnostic test ofchoice, both cultureand drug susceptibilitytesting (DST) can offersignificant advantagesin the diagnosis andmanagement of TB.Culture and Drug Susceptibility Testing4/22/2013 Dr.T.V.Rao MD 83
  84. 84. Culture: Solid Media• Solid media have theadvantage thatorganisms (colonies) canbe seen on the surface ofthe medium• Types most commonlyused are:– Lowenstein-Jensen:egg-based– Middlebrook 7H 10 or7H11: agar-based– Ogawa4/22/2013 Dr.T.V.Rao MD 84
  85. 85. Methods of Culturing.• Culturing onLowensteinJenson’s culturemedium remainthe affordableeconomicalmethod indeveloping world.Dr.T.V.Rao MD 854/22/2013
  86. 86. MGIT IncubatorCulture: Liquid Media• More sophisticated equipment• Faster detection of growth• Higher sensitivity than solidmedia• Can also be used for drug-susceptibility testing• Two examples:– BACTEC– MGITMGITBACTEC4/22/2013 Dr.T.V.Rao MD 86
  87. 87. Smooth, buff-colored coloniessuggestive of Mycobacteriumavium complexRough, buff-colored colonies suggestive ofMycobacterium tuberculosisCulture: Identification ofMycobacteriaVisual assessment of colony morphology:4/22/2013 Dr.T.V.Rao MD 87
  88. 88. Culture: Drug Susceptibility Testing• Agar proportion method:Compares growth onsolid agar media with andwithout one of the fourprimary drugs (on discs)• Broth based (BACTEC,MGIT): Liquid broth isinoculated with each testdrug; growth in vialindicates resistance tothat drugMethods for susceptibility testing4/22/2013 Dr.T.V.Rao MD 88
  89. 89. Rapid Diagnostic TestingNucleic acid probe tests (non-amplified) toidentify organisms grown in culture:• DNA probe tests are species or complex specific– Commercial probes are available for M.tb complex,MAC, M. kansasii and M. gordonaeNucleic acid amplification tests (NAAT):• These tests are designed to amplify and detectDNA specific to M.tb• Enables direct detection of M.tb in clinicalspecimens4/22/2013 Dr.T.V.Rao MD 89
  90. 90. Real Time PCR replacing olderMethodsDr.T.V.Rao MD 904/22/2013
  91. 91. Other Rapid Diagnostic Tests• Loop-mediated isothermal amplification(LAMP)– Rapid, simplified NAAT still underinvestigation– May be more feasible in lower resourcesettings• Immunological tests– Serologic tests for antibody, antigens, andimmune complexes; not currently accurateenough to replace microscopy and culture.4/22/2013 Dr.T.V.Rao MD 91
  92. 92. Tuberculin Test( Mantoux Test )• Test to beinterpreted inrelation to clinicalevaluation.• Even the indurationof 5 mm to beconsidered positivewhen tested on HIVpatients.• Lacks specificity.Dr.T.V.Rao MD 924/22/2013
  93. 93. GeneXpert MTB/RIF• The Xpert MTB/RIF is a cartridge-based,automated diagnostic test that can identifyMycobacterium tuberculosis (MTB) andresistance to rifampicin (RIF). It was co-developed by Cepheid, Inc. and Foundation forInnovative New Diagnostics, with additionalfinancial support from the US National Institutesof Health (NIH) and technical support from theUniversity of Medicine and Dentistry of NewJerseyDr.T.V.Rao MD 934/22/2013
  94. 94. How the test works• The Xpert MTB/RIF detects DNAsequences specific forMycobacterium tuberculosis andrifampicin resistance by polymerasechain reaction It is based on theCepheid GeneXpert system, aplatform for rapid and simple-to-usenucleic acid amplification tests(NAAT). Dr.T.V.Rao MD 944/22/2013
  95. 95. Microscopy in TuberculosisTODAYIn spite of severalscientific, andmolecularadvancesMicroscopy inTuberculosiscontinues to beback bone inDiagnosis.Dr.T.V.Rao MD 954/22/2013
  96. 96. Epidemiology• An ancient disease, called as white plague• 1/3 of the world population is infected• 2 billion infected• Each year 9 lakhs to 1 million are infected• Poor nations phase the burnt of the disease.• In developing world > 4o% of the population iseffected• 15 million suffer the disease• 3 million are highly infective.4/22/2013 Dr.T.V.Rao MD 96
  97. 97. Tuberculosis and HIVinfection• HIV associationhas become athreat to thedevelopedcountries too• HIV association willlead to rapidspread oftuberculosis4/22/2013 Dr.T.V.Rao MD 97
  98. 98. HIV Considerations• HIV is the strongest risk factor forprogression to active disease• HIV kills CD4+ T Helper cellswhich normally inhibit M.tuberculosis• HIV interferes with PPD skin test• Protease inhibitors interfere withrifampin4/22/2013 Dr.T.V.Rao MD 98
  99. 99. MDR tuberculosis• Multidrug resistant tuberculosis hasbecome a global threat.• In 1993 WHO declared Tuberculosis aGlobal emergency• Animals shed the bacilli in Milk, human’sget infected after drinking the unsterilisedMilk• Pasteurization has reduced the incidenceof Bovine tuberculosis.4/22/2013 Dr.T.V.Rao MD 99
  100. 100. 4/22/2013 Dr.T.V.Rao MD 100
  101. 101. Some one infected every Second• Someone in the world is newly infectedwith TB bacilli every second.• Overall, one-third of the worlds populationis currently infected with the TB bacillus.• 5-10% of people who are infected with TBbacilli (but who are not infected with HIV)become sick or infectious at some timeduring their life. People with HIV and TBinfection are much more likely to developTB.4/22/2013 Dr.T.V.Rao MD 101
  102. 102. TB as a WorldwidePublic Health Issue• World population ~ 6 billion• ~ 1in 3 people in world infected• ~ 9.4 million new cases of activeTB/year• 1.7 million deaths/year• US population 280 million• ~ 3-5% infected• ~ 11,000 cases/year• ~ 5-7% mortality4/22/2013 Dr.T.V.Rao MD 102
  103. 103. Treatment for TB Disease• TB disease is treated with medicineto kill the TB germs• Usually, the treatment will last for 6-9 months• TB disease can be cured if themedicine is taken as prescribed,even after you no longer feel sick4/22/2013 Dr.T.V.Rao MD 103
  104. 104. Treatment of pulmonary TB• NB of compliance (helps cure pt & preventsspread of resistance)• Before tx baseline FBC, LFTs (incl alt), RP• Isoniazid, rifampicin & pyrazinamide allhepatotoxic• Test colour vision (Ishihara chart) & acuity(Snellen chart) before & after tx (ethambutol maycause (reversible) ocular toxicity• TB treated in 2 phases – initial phase using atleast 3-4 drugs & continuation phase using 2drugs in fully sensitive cases4/22/2013 Dr.T.V.Rao MD 104
  105. 105. First-Line Anti-TB Drugs (1)Essential Drug(abbreviation)Recommended Daily Dose in mg/kg body weight(range)Isoniazid (H) Adults: 5 mg (4-6) kg/d, 300mg/d maximumChildren: 10-15 mg/kg/d, 300 mg/d maximumRifampicin (R) Adults: 10 mg (8-12), 600mg/d maximumChildren: 10-20 mg/kg/d, 600 mg/d maximum4/22/2013 Dr.T.V.Rao MD 105
  106. 106. Essential Drug(abbreviation)Recommended Daily Dose in mg/kg bodyweight (range)Pyrazinamide(Z)25 mg (20-30), 2000 mg/d maximumEthambutol (E) Adults: 15 mg (15-25), 1600 mg/dmaximumChildren: 20 mg/kg (range 15-25 mg/kg)dailyStreptomycin(S)15 mg (12-18)Maximum for <40 years = 1gMaximum for ≥ 40 years = 0.75gFirst-Line Anti-TB Drugs (2)
  107. 107. Modern TB Chemotherapy• INH – kills rapidly growing organisms(early bactericidal activity)• INH and RMP protect each other fromdevelopment of resistance• Rifampicin and pyrazinamide killslowly growing organisms–Sterilizing activitySource: Combs D et al., Ann Intern Med., 1990.4/22/2013 Dr.T.V.Rao MD 107
  108. 108. Beginning in New era in TreatmentDOTS• The technical strategy for DOTS was developed by Dr.Karel Styblo in the 1980s, primarily in Tanzania. In 1989,the World Health Organization and the World Bankbegan investigating the potential expansion of thisstrategy. In July 1990, the World Bank, under RichardBumgarners direction, invited Dr. Styblo and WHO todesign a TB control project for China. By the end of1991, this pilot project was achieving phenomenalresults, more than doubling cure rates among TBpatients. China soon extended this project to cover halfthe country.4/22/2013 Dr.T.V.Rao MD 108
  109. 109. DOTS• DOTS (directly observed treatment, short-course), is the name given to the WorldHealth Organization-recommendedtuberculosis control strategy that combinesfive components:• Government commitment (includingboth political will at all levels, andestablishing a centralized and prioritizedsystem of TB monitoring, recording andtraining)4/22/2013 Dr.T.V.Rao MD 109
  110. 110. DOTS helps in ……• Case detection by sputum smearmicroscopyStandardized treatment regimen directlyobserved by a healthcare worker orcommunity health worker for at least the firsttwo months• A regular drug supply• A standardized recording and reportingsystem that allows assessment oftreatment results4/22/2013 Dr.T.V.Rao MD 110
  111. 111. RNTCP and DOTSIndia• The DOTS strategy along with theother components of the Stop TBstrategy, implemented under theRevised National TuberculosisControl Programme (RNTCP) inIndia, is a comprehensivepackage for TB control.4/22/2013 Dr.T.V.Rao MD 111
  112. 112. India’s success with DOTS• The Revised National Tuberculosis Control Programme(RNTCP), based on the DOTS strategy, began as a pilotin 1993 and was launched as a national programme in1997. Rapid RNTCP expansion began in late 1998. Bythe end of 2000, 30%of the country’s population wascovered, and by the end of 2002, 50%of the country’spopulation was covered under the RNTCP. By the end of2003, 778 million population was covered, and at theend of year 2004 the coverage reached to 997 million.By December 2005, around 97% (about 1080 million) ofthe population had been covered, and the entire countrywas covered under DOTS by 24th March 2006.4/22/2013 Dr.T.V.Rao MD 112
  113. 113. Stop –TBUse DOTS4/22/2013 Dr.T.V.Rao MD 113
  114. 114. MDR TB• MDRTB refers to strains of thebacterium which are proven in alaboratory to be resistant to thetwo most active anti-TB drugs,isoniazid and rifampicin.Treatment of MDRTB is extremelyexpensive, toxic, arduous, andoften unsuccessful.4/22/2013 Dr.T.V.Rao MD 114
  115. 115. DOTS prevents MDR- TB• DOTS has been proven to preventthe emergence of MDRTB, and alsoto reverse the incidence of MDRTBwhere it has emerged. MDRTB is atragedy for individual patients and asymptom of poor TB management.The best way to confront thischallenge is to improve TB treatmentand implement DOTS.4/22/2013 Dr.T.V.Rao MD 115
  116. 116. BCG vaccine• BCG is live attenuated strain derived from M. bovis → stimulatesdevelopment of hypersensitivity to M. tuberculosis• Within 2-4wks swelling at injection site, progresses to papule about10mm diam & heals in 6-12 wks• BCG recommended if immunisation not previously carried out & negfor tuberculoprotein hypersensitivity Infants in area of TB incidence > 40/100,000 Infants with parent/grandparent born in country with incidence ofTB >40/100,000 Contacts of pts with active pulmonary TB Health care staff Veterinary staff Prison staff If intending to stay for >1 mth in country with high incidence TB4/22/2013 Dr.T.V.Rao MD 116
  117. 117. Do not Forget4/22/2013 Dr.T.V.Rao MD 117
  118. 118. • Programme Created byDr.T.V.Rao MD for Medical andparamedical Students in theDeveloping World• Email• doctortvrao@gmail.com4/22/2013 Dr.T.V.Rao MD 118

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