2A Small Disclaimer…This presentation will NOT teach you everything there is to know about tuberculosis
3Image credit: National Library of Medicine History of TB (1)TB has affected humans for millenniaHistorically known by a variety of names, including:ConsumptionWasting diseaseWhite plagueTB was a death sentence for manyVintage image circa 1919Image credit: National Library of Medicine33
4History of TB (2) Scientific Discoveries in 1800s Until mid-1800s, many believed TB was hereditary1865 Jean Antoine-Villemin proved TB was contagious1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TBMycobacterium tuberculosisImage credit: Janice Haney Carr44
5History of TB (3) Sanatoriums Before TB antibiotics, many patients were sent to sanatoriumsPatients followed a regimen of bed rest, open air, and sunshineTB patients who could not afford sanatoriums often died at homeSanatorium patients resting outside55
6Breakthrough in the Fight Against TB (1) Drugs that could kill TBbacteria were discoveredin 1940s and 1950sStreptomycin (SM) discovered in 1943Isoniazid (INH) andp-aminosalicylic acid (PAS) discovered between 1943 and 195266
7most common and important agent of human disease is M. tuberculosis. M. bovis (characteristically resistant to pyrazinamide, once an important cause, currently the cause of a small percentage of cases worldwide)M. microti : less virulent and rarely encounteredM. pinnipedii (seals and sea lions in the southern hemisphere and recently isolated from humans )M. canettii (a rare isolate from East African cases that produces unusual smooth colonies on solid media)
8neutral on Gram's staining. M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic bacterium measuring 0.5μm by 3 μmneutral on Gram's staining.once stained, the bacilli cannot be decolorized by acid alcohol due mainly to the organism’s high content ofmycolic acids,long-chain cross-linked fatty acids,other cell-wall lipids
9cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low permeability of the cell wall, thus reducing the effectiveness of most antibioticscell wall, lipoarabinomannan, is involved in the pathogen-host interaction and facilitates the survival of M. tuberculosis within macrophages
10Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium
12TB Transmission (3)TB is spread person to person through the air via droplet nucleiM. tuberculosis may be expelled when an infectious person:CoughsSneezesSpeaksSingsTransmission occurs when another person inhales droplet nuclei1212
13Dots in air represent droplet nuclei containing TB Transmission (4)Dots in air represent droplet nuclei containingM. tuberculosis13
14SOURCE CASEOnly patients with pulmonary tuberculosis can be regarded as infectious. (placenta, skin, milk)Smear positiveCavitary pulmonary diseaseEndobronchial or laryngeal tuberculosisCoughing(wearing mask with patient)Use of chemotherapy (Isoniazide)persons with both HIV infection and tuberculosis are less likely to have cavitations, they may be less infectious than persons without HIV co-infection.
15A single bacillus in a tiny droplet nucleus is more hazardous than several bacilli in larger airborne particlesCoughing is the most effective mechanism for generating aerosols that create droplet nuclei.Thin, watery secretions are more easily fragmented into small respirable droplets than is more viscous mucus.
16Masks worn by persons exposed to an infectious source are less effective than are masks worn by patients, because most airborne droplet nuclei are much smaller than their parent droplets.
17prevalence of PPD + among young contacts of patients with newly discovered tuberculosis increased as the radiographic extent of involvement increasedcontacts of patients who have organisms + in sputum smears have a much higher prevalence of infectionpatients who had positive sputum smears but who were receiving antituberculosis drugs were much less infectious for guinea pigs than were untreated patients.
18under standard conditions of temperature and humidity indoors : survived 60% to 71% for 3 hours,48% to 56% for 6 hours,28% to 32% for 9 hours.exposure to ultraviolet radiation kills tubercle bacilli
19close contacts (generally household) 30% are infected, rate of tuberculosis is in the range of 15 per 1000nonclose contacts (generally out-of-household) 15% are infected, 3 per 1000 nonclose contacts develop tuberculosisBecause the risk of tuberculosis is higher among close contacts, they should also be considered high-priority candidates for INH preventive therapy.
202- nonimmunologic defenses , risk of developing disease after being infected depends on endogenous factors, such as the individual's:innate1- immunologic2- nonimmunologic defenses ,level of function of cell-mediated immunity (CMI)
21FROM INFECTION TO DISEASE PRIMARY TUBERCULOSIS -common among children (up to 4yr) -may be severe and disseminated -usually not transmissible -within two years after infectionSECONDARY TUBERCULOSIS -often infectious late adolescent and early adulthood -women(25-34yr)
22risk is much higher among HIV-infected persons one-third of cases of active tuberculosis in some inner-city communitieswere due to recent transmission rather than to reactivation of latent infection.
23Risk Factors for Active Tuberculosis Recent infection (<1 year)Fibrotic lesions (spontaneously healed)Intravenous drug useGastrectomyJejunoileal bypassPosttransplantation period (renal, cardiac)Malnutrition and severe underweightSilicosisLymphomaLeukemiaOther malignancyHIVHemophiliaCRFDiabetes(insulin dependent)Immunosuppresion
24Infection and Macrophage Invasion usually <10% of droplet nuclei reach the alveoliInvasion of macrophages results largely from binding of the bacterial cell wall with a variety of macrophage cell-surface moleculesPhagocytosis is enhanced by complement activation leading to opsonization of bacilli
25LAM inhibits the intracellular increase of Ca2+ LAM inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway (leading to phagosome-lysosome fusion) is impaired, and the bacilli may survive within the phagosomesreplication begins and the macrophage eventually ruptures and releases its bacillary contents
26Virulance of the bacillus lipid rich cell wallglycolipid capsulegenes confer virulance(katG,rpoV)number of invading bacillikatG gene encodes for catalase/peroxidase enzymes that protect against oxidative stressrpoV is the main sigma factor initiating transcription of several genes
27PATHOGENESISHost response tissue damage response(DTH) delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues-macrophage activating response (T-cell mediated phenomenon) activation of macrophages that are capable of killing and digesting tubercle bacilli
28Granuloma Formationdevelopment of specific immunity and the accumulation of large numbers of activated lymphocytes and macrophages that evolve toward epithelioid and giant cell morphologiesthe tissue-damaging response can limit mycobacterial growth within macrophagesgrowth is inhibited within this necrotic environment by low oxygen tension and low pHsome lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions.
29The Delayed-Type Hypersensitivity Reaction minority of cases, the macrophage-activating response is weak mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction.lesions enlarge and the surrounding tissue is progressively damaged cavities are formed liquefied caseous material, containing large numbers of bacilli, is drained through bronchi.
30In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous meningitisearly stages of infection, bacilli are transported by macrophages to regional lymph nodes gain access to the bloodstream and disseminate throughout the body.
31CELL MEDIATED IMMUNITY T lymphocyte,mainly Th1(CD4+)Local macrophageIL1- IL6 –TNFα- IL2- IFNγActive cell aggregate around lesion and effectively neutralize tubercle bacilliCaseous necrosisViable bacilli may remain dormantHealed lesion may undergo calcification (Ranke complex)
32TST, which is used primarily for the detection of M TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptomsrelated mainly to previously sensitized CD4+ T lymphocytesDTH is associated with protective immunity , it by no means guarantees protection against reactivationprevious latent or active tuberculosis may not confer fully protective immunity
33Interferon-γ Release Assays Compared with the tuberculin skin test, the INF-γ release assays have the advantage of :being accomplished with one patient visit,being more specificin the presence of BCG vaccinationinfection with nontuberculous mycobacteria,having less reader variability,not recalling waned immunity
34POSSIBLE OUTCOMES Immediate clearance of the organism Chronic or latent infectionPrimary diseaseReactivation
35Condition associated with reactivation HIV infectionEnd stage renal diseaseDiabetes mellitusCorticosteroid useDiminution in CMI associated with old age Reactivation TB tends to be localized
37Bacilli may reach any part of the body, but common sites include: Sites of TB Disease (1)Bacilli may reach any part of the body, but common sites include:3737
38Sites of TB Disease (2) Location Frequency Pulmonary TB LungsMost TB cases are pulmonaryExtrapulmonary TBPlaces other than lungs such as:LarynxLymph nodesPleuraBrainKidneysBones and jointsFound more often in:HIV-infected orotherimmunosuppressedpersonsYoung childrenMiliary TBCarried to all parts of body, through bloodstreamRare3838
39Module 1 – Transmission and Pathogenesis of Tuberculosis TB Pathogenesis (4)Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)Module 1 – Transmission and Pathogenesis of Tuberculosis
40TB Pathogenesis (5) Tubercle bacilli multiply in alveoli, where infection beginsModule 1 – Transmission and Pathogenesis of Tuberculosis
41Module 1 – Transmission and Pathogenesis of Tuberculosis TB Pathogenesis (6)A small number of tubercle bacilli enter bloodstream and spread throughout bodyModule 1 – Transmission and Pathogenesis of Tuberculosis
42TB Pathogenesis (7) LTBI Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilliThese cells form a barrier shell that keeps the bacilli contained and under control (LTBI)Module 1 – Transmission and Pathogenesis of Tuberculosis
43TB Pathogenesis (8) TB Disease If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB diseaseThis process can occur in different places in the bodyModule 1 – Transmission and Pathogenesis of Tuberculosis
44Latent TB Infection (LTBI) TB Disease (in the lungs) LTBI vs. TB DiseaseLatent TB Infection (LTBI)TB Disease (in the lungs)Inactive, contained tubercle bacilli in the bodyActive, multiplying tubercle bacilli in the bodyTST or blood test results usually positiveChest x-ray usually normalChest x-ray usually abnormalSputum smears and cultures negativeSputum smears and cultures may be positiveNo symptomsSymptoms such as cough, fever, weight lossNot infectiousOften infectious before treatmentNot a case of TBA case of TBModule 1 – Transmission and Pathogenesis of Tuberculosis
45Signs and Symptoms of TB Cough for more than three weeksCoughing up bloodUnexplained weight lossNight sweatsFeverFeeling tiredNot everyone with TB looks really sick…
46Systemic effcts Fever Malaise Weight loss pancytopenia Leukocytosis AnemiaLeukopeniahyponatremia
47Primary pulmonary tuberculosis Often seen in childrenFrequently localized to middle and lower lung zoneParatracheal or hilar lymphadenopathyProgressive primary tuberculosis (cavation)Pleural effusion, collapse lung, BronchectasisDissemination ,may develop milliary tuberculosis and meningitisGhon lesion(healed lesion)
48Secondary tuberculosis Symptom: productive cough, hemoptysis, dyspnea, fever, night sweatSigns: not specific,dullness with decreased fermitus (pleural effusion),rales,sign of consolidation,amphoric sound,clubbing
49Chest.x.ray secondary tuberculosis Apical and post. segments of the upper lobes(80-90%)Superior segments of lower lobesInfiltration and cavitary lesionNodules and branching linear densities (tree in bud)Pleural effusionSolitary nodule(atypical)
66HIV-associated TB Presentation varies with the stage Late stage: primary pattern with miliary infiltrate and lymphadenopathy , no cavitationHigher incidence of extrapulmonary and pleural effusionSputum smear frequently negativeLack of classic granuloma formation
68Diagnosis Tuberculosis High index suspicionChest.x.rayAFB Microscopy:three sputum specimens, collected in the early morningStaining with ziehl neelsen or auramine-rhodamine
69Diagnosis Culture: Egg based (lowenstein-jensen), agar based (middelbrook);4-8 week may be requird for growthLiquid media with radiometric growth detection (bactec-460)High pressure liquid chromatography of mycolic acid(2-3 week)Nucleic acid amplification
70regional lymphadenitis, BCG VACCINATIONDerived from an attenuated strain of M.bovisEfficacy from 80% to nilRarely complication:ulceration,regional lymphadenitis,osteomyelitis,dissemination
71PPD Purified protein derivative PPD 5tu:0/1ml contain 0/0001mg Mantoax method (interadermaly, volar surface)Wheal 6-10mmReaction are read at 48 to72h(transverse diameter of induration in mm)A second skin test administered 1week or more after the first(two-step)
72Measuring TST Record induration (bump) only Measure transverse (across arm)Record: Date given, date read, mm
75TB Classification System (1) Based on pathogenesis of TBClassTypeDescriptionNo TB exposureNot infectedNo history of TB exposureNegative result to a TST or IGRA1TB exposureNo evidence of infectionHistory of TB exposureNegative result to a TST (given at least 8-10 weeks after exposure) or IGRA2TB infectionNo TB diseasePositive result to a TST or IGRANegative smears and cultures (if done)No clinical or x-ray evidence of activeTB diseaseModule 1 – Transmission and Pathogenesis of Tuberculosis
76TB Classification System (2) Based on pathogenesis of TBClassTypeDescription3TB, clinically activePositive culture (if done) for M. tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease4Previous TB disease (not clinically active)Medical history of TB diseaseAbnormal but stable x-ray findingsPositive result to a TST or IGRANegative smears and cultures (if done) No clinical or x-ray evidence of active TB disease5TB suspectedSigns and symptoms of TB disease, but evaluation not completeModule 1 – Transmission and Pathogenesis of Tuberculosis
77Short course treatment(6 month) First line drugs: Rifampin, Isoniazid, Ethambutol, Pyrazinamid, streptomycinShort course treatment(6 month)2month initial phase (bactericidal): rifampin, isoniazid, ethambutol, pyrazinamide4month continuation (sterilizing): rifampin and isoniazid
78Treatment Pyridoxin (vit B6) should be given to: -ALCOHOLICS -Malnurished-pregnant and lactating woman-chronic renal failure-diabetes-HIV infection
79history of hepatic disease HepatitisMost common adverse reactionBaseline assessment of liver function in all adult patientmonitoring monthly :Older patientalcoholicspregnancyHIVhistory of hepatic diseaseTreatment should be stopped: symptomatic hepatitis or three to five fold elevation LFT
80First Line Drugs INH : RIF: GI-upset,Drug Raised LFT Interactions HepatitisPeripheral-neuropathyDrug interactionsMild effect on CNSdrug induced lupusRIF:GI-upset,DrugInteractionsHepatitisThrombocytopeniaRashInterstitial nephritisFlu like
82Adjunctive corticosteroid MeningitisPericarditisAcute life threatening pulmonary tuberculosisLow serum albuminSevere weight lossAdenitis in children
83Monitoring response to treatment Sputum culture monthly until become negativeAFB smear conversion may follow culture conversionIf culture not practical,AFB smear should be undertaken at 2,5and 6 monthsCulture/smear positive after 3month and smear positive after 5months are indicative treatment failureSerial c.x.ray not recommended ,except at the end of treatment
84A cardinal rule in the latter situation results of susceptibility testing are expected to become available within a few weeks changes in the regimen can be postponed until that time.If the patient's clinical condition is deteriorating, an earlier change in regimen may be indicated.A cardinal rule in the latter situationalways add more than one drug at a time to a failing regimen:at least two and preferably three drugs that have never been used and to which the bacilli are likely to be susceptibleThe patient may continue to take isoniazid and rifampin along with these new agents pending the results of susceptibility tests.
85Patients who experience a recurrence after apparently successful treatment (relapses) are less likely to harbor drug-resistant strains than are patients in whom treatment has failed.If the regimen administered initially does not contain rifampin, the probability of isoniazid resistance is high.begin the treatment of all patients who have relapsed with all four first-line drugs plus streptomycin, pending the results of susceptibility testing.
86Drug-Resistant TBM. tuberculosis resistant to individual drugs spontaneous point mutations in the mycobacterial genomethere is no cross-resistance among the commonly used drugs probability that a strain will be resistant to two drugs : product of the probabilities of resistance to each drugdrug-resistant TB is invariably the result ofMonotherapy —i.e., the failure of the health care provider to prescribe at least two drugs to which tubercle bacilli are susceptiblethe patient to take properly prescribed therapy
87Drug-resistant TB may be either primary or acquired Primary : develops in a strain infecting a patient who has not previously been treatedAcquired : during treatment with an inappropriate regimenMultidrug-resistant tuberculosis (MDR-TB)defined as resistance to at least isoniazid and rifampin (also known as rifampicin in many countries),
88Module 1 – Transmission and Pathogenesis of Tuberculosis Drug-Resistant TB (3)Mono-resistantResistant to any one TB treatment drugPoly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin)Multidrug resistant(MDR TB)Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugsExtensively drug resistant(XDR TB)Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)Module 1 – Transmission and Pathogenesis of Tuberculosis
89MDR strains that are resistant to : all fluoroquinolones and XDR-TBMDR strains that are resistant to :all fluoroquinolones andat least one of three second-line injectable agents (amikacin, kanamycin, and capreomycin).Drug-resistant TB can be prevented by adherence :the inclusion of at least two bactericidal drugs to which the organism is susceptiblethe use of fixed-drug-combination productsthe verification that patients complete the prescribed course.