Tuberculosis. A Small Disclaimer… This presentation will NOT teach you everything there is to know about tuberculosis.

Tuberculosis Tuberculosis

A Small Disclaimer…A Small Disclaimer…

This presentation will This presentation will NOTNOT teach you everything teach you everything there is to know about tuberculosisthere is to know about tuberculosis

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► TB has affected TB has affected humans for millenniahumans for millennia

► Historically known by Historically known by a variety of names, a variety of names, including:including: ConsumptionConsumption Wasting diseaseWasting disease White plagueWhite plague

► TB was a death TB was a death sentence for manysentence for many

History of TB (1)History of TB (1)

Vintage image circa 1919Image credit: National Library of Medicine

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► Until mid-1800s, Until mid-1800s, many believed TB many believed TB was hereditarywas hereditary

► 1865 Jean Antoine-1865 Jean Antoine-Villemin proved TB Villemin proved TB was contagiouswas contagious

► 1882 Robert Koch 1882 Robert Koch discovered discovered M. M. tuberculosis,tuberculosis, the the bacterium that bacterium that causes TB causes TB

Mycobacterium tuberculosisImage credit: Janice Haney Carr

History of TB (2)History of TB (2)Scientific Discoveries in 1800sScientific Discoveries in 1800s

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► Before TB antibiotics, Before TB antibiotics, many patients were many patients were sent to sanatoriumssent to sanatoriums

► Patients followed a Patients followed a regimen of bed rest, regimen of bed rest, open air, and sunshineopen air, and sunshine

► TB patients who could TB patients who could not afford sanatoriums not afford sanatoriums often died at homeoften died at home

History of TB (3)History of TB (3)SanatoriumsSanatoriums

Sanatorium patients resting outside

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Breakthrough in the Fight Breakthrough in the Fight Against TB (1)Against TB (1)

Drugs that could kill TBDrugs that could kill TB

bacteria were discoveredbacteria were discovered

in 1940s and 1950sin 1940s and 1950s

► Streptomycin (SM) Streptomycin (SM) discovered in 1943discovered in 1943

► Isoniazid (INH) andIsoniazid (INH) and

pp-aminosalicylic acid (PAS) -aminosalicylic acid (PAS) discovered between 1943 discovered between 1943 and 1952 and 1952

► most common and important agent of human most common and important agent of human disease is disease is M. tuberculosisM. tuberculosis. .

► M. bovisM. bovis (characteristically (characteristically resistant to resistant to pyrazinamidepyrazinamide, once an important cause, currently , once an important cause, currently the cause of a small percentage of cases worldwide)the cause of a small percentage of cases worldwide)

► M. microtiM. microti : less virulent and rarely encountered : less virulent and rarely encountered

► M. pinnipediiM. pinnipedii (seals and sea lions in the southern (seals and sea lions in the southern hemisphere and recently isolated from humans )hemisphere and recently isolated from humans )

► M. canettiiM. canettii (a rare isolate from East African cases (a rare isolate from East African cases that produces unusual smooth colonies on solid that produces unusual smooth colonies on solid media) media)

► cell wall, lipids are linked to underlying cell wall, lipids are linked to underlying arabinogalactanarabinogalactan and and peptidoglycanpeptidoglycan. . This structure confers This structure confers very low very low permeabilitypermeability of the cell wall, thus of the cell wall, thus reducing the effectiveness of most reducing the effectiveness of most antibiotics antibiotics

► cell wall, cell wall, lipoarabinomannanlipoarabinomannan, is involved , is involved in the pathogen-host interaction and in the pathogen-host interaction and facilitates the facilitates the survivalsurvival of of M. tuberculosisM. tuberculosis within within macrophagesmacrophages

► Microorganisms other than mycobacteria Microorganisms other than mycobacteria that display some acid fastness include that display some acid fastness include species of species of NocardiaNocardia and and RhodococcusRhodococcus, , Legionella micdadeiLegionella micdadei, and the protozoa , and the protozoa Isospora Isospora andand Cryptosporidium Cryptosporidium

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► TB is spread person to TB is spread person to person through the air person through the air via droplet nucleivia droplet nuclei

► M. tuberculosis M. tuberculosis may be may be expelled when an expelled when an infectious person:infectious person: CoughsCoughs SneezesSneezes Speaks Speaks SingsSings

► Transmission occurs Transmission occurs when another person when another person inhales droplet nucleiinhales droplet nuclei

TB Transmission (3)TB Transmission (3)

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TB Transmission (4)TB Transmission (4)

Dots in air represent droplet nuclei containingM. tuberculosis

SOURCE CASESOURCE CASE► Only patients with Only patients with pulmonarypulmonary tuberculosis can tuberculosis can

be regarded as infectious. (be regarded as infectious. (placenta, skin, placenta, skin, milk)milk)

► SmearSmear positive positive1.1. Cavitary Cavitary pulmonary disease pulmonary disease

2.2. Endobronchial Endobronchial oror laryngeal laryngeal tuberculosis tuberculosis

► Coughing(wearing mask with patient)Coughing(wearing mask with patient)

► Use of chemotherapy (Isoniazide)Use of chemotherapy (Isoniazide)

► persons with both persons with both HIVHIV infection and infection and tuberculosistuberculosis are are less likely to have less likely to have cavitationscavitations, they may be less infectious than , they may be less infectious than persons without HIV co-infection. persons without HIV co-infection.

► A A singlesingle bacillus in a bacillus in a tinytiny droplet nucleus is droplet nucleus is more hazardousmore hazardous than several bacilli in than several bacilli in larger airborne particleslarger airborne particles

► CoughingCoughing is the most effective mechanism is the most effective mechanism for generating aerosols that create droplet for generating aerosols that create droplet nuclei.nuclei.

► Thin, watery secretionsThin, watery secretions are are more easilymore easily fragmented into small respirable droplets fragmented into small respirable droplets than is more viscous mucus.than is more viscous mucus.

► Masks worn by persons exposed to an Masks worn by persons exposed to an infectious source are less effective than are infectious source are less effective than are masks worn by patients, because masks worn by patients, because most most airborne droplet nuclei are much airborne droplet nuclei are much smaller than their parent dropletssmaller than their parent droplets. .

► prevalence of PPD + among young contacts of prevalence of PPD + among young contacts of patients with newlypatients with newly discovered tuberculosis discovered tuberculosis increased as the increased as the radiographic extentradiographic extent of of involvementinvolvement increased increased

► contacts of patients who have contacts of patients who have organisms + in organisms + in sputum smearssputum smears have a much higher have a much higher prevalence of infectionprevalence of infection

► patients who had positive sputum smears but patients who had positive sputum smears but who were who were receiving antituberculosis drugsreceiving antituberculosis drugs were much less infectious for guinea pigs than were much less infectious for guinea pigs than were untreated patients.were untreated patients.

under standard conditions of temperature under standard conditions of temperature and humidity indoors : and humidity indoors : survived survived

60% to 71% for 3 hours, 60% to 71% for 3 hours, 48% to 56% for 6 hours, 48% to 56% for 6 hours, 28% to 32% for 9 hours.28% to 32% for 9 hours.

exposure to ultraviolet radiation kills exposure to ultraviolet radiation kills tubercle bacillitubercle bacilli

► closeclose contacts (generally contacts (generally householdhousehold) ) 30% 30% are infected, rate of tuberculosis is in the range are infected, rate of tuberculosis is in the range of 15 per 1000 of 15 per 1000

► nonclosenonclose contacts (generally contacts (generally outout-of--of-household) household) 15% are infected, 3 per 1000 15% are infected, 3 per 1000 nonclose contacts develop tuberculosisnonclose contacts develop tuberculosis

► Because the risk of tuberculosis is higher Because the risk of tuberculosis is higher among among close contactsclose contacts, they should also be , they should also be considered considered high-priority high-priority candidates for candidates for INH INH preventivepreventive therapy. therapy.

► risk of developing disease after being risk of developing disease after being infected depends on endogenous factors, infected depends on endogenous factors, such as the individual's:such as the individual's:

► innate innate

1- immunologic 1- immunologic

2- nonimmunologic defenses ,2- nonimmunologic defenses ,

► level of function of cell-mediated immunity level of function of cell-mediated immunity (CMI) (CMI)

FROM INFECTION TO DISEASEFROM INFECTION TO DISEASE

► PRIMARY TUBERCULOSISPRIMARY TUBERCULOSIS-common among children (up to 4yr)-common among children (up to 4yr)

-may be severe and -may be severe and disseminateddisseminated -usually -usually notnot transmissible transmissible -within-within two two years after infection years after infection

► SECONDARY TUBERCULOSISSECONDARY TUBERCULOSIS-often infectious-often infectious

-late adolescent and early -late adolescent and early adulthoodadulthood -women(25-34yr)-women(25-34yr)

risk is much higher among HIV-infected persons

were due to recent transmission rather than to reactivation of latent infection. one-third of cases of active tuberculosis in some inner-city communities

Risk Factors for Active TuberculosisRisk Factors for Active Tuberculosis

Recent infection (<1 Recent infection (<1 year) year)

Fibrotic lesions Fibrotic lesions (spontaneously healed) (spontaneously healed)

Intravenous drug use Intravenous drug use Gastrectomy Gastrectomy Jejunoileal bypass Jejunoileal bypass Posttransplantation Posttransplantation

period (renal, cardiac) period (renal, cardiac) Malnutrition and severe Malnutrition and severe

underweight underweight

SilicosisSilicosis LymphomaLymphoma LeukemiaLeukemia Other malignancyOther malignancy HIVHIV HemophiliaHemophilia

CRFCRF Diabetes(insulin Diabetes(insulin

dependent)dependent) ImmunosuppresionImmunosuppresion

Infection and Macrophage InvasionInfection and Macrophage Invasion

► usually <10% of droplet nuclei reach the usually <10% of droplet nuclei reach the alveoli alveoli

► Invasion of macrophages results largely Invasion of macrophages results largely from binding of the bacterial cell wall with from binding of the bacterial cell wall with a variety of macrophage cell-surface a variety of macrophage cell-surface moleculesmolecules

► Phagocytosis is enhanced by complement Phagocytosis is enhanced by complement

activation leading to opsonization of bacilli activation leading to opsonization of bacilli

► LAM LAM inhibits the intracellular increase of inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway Ca2+. Thus the Ca2+/calmodulin pathway (leading to (leading to phagosome-lysosomephagosome-lysosome fusion) fusion) is impaired, and the bacilli may survive is impaired, and the bacilli may survive within the phagosomes within the phagosomes

► replication begins and the macrophage replication begins and the macrophage eventually ruptures and releases its eventually ruptures and releases its bacillary contentsbacillary contents

Virulance of the bacillusVirulance of the bacillus

lipid rich cell walllipid rich cell wall glycolipid capsuleglycolipid capsule

genes confer virulance(katG,rpoV)genes confer virulance(katG,rpoV) number of invading bacilli number of invading bacilli

katGkatG gene encodes for gene encodes for catalase/peroxidascatalase/peroxidase e enzymes that protect enzymes that protect against oxidative against oxidative stressstress

rpoVrpoV is the main sigma factor is the main sigma factor initiating initiating transcriptiontranscription of several genes of several genes

PATHOGENESISPATHOGENESIS

►Host responseHost response--tissue damage response(DTH)tissue damage response(DTH)

delayed-type hypersensitivity (DTH) delayed-type hypersensitivity (DTH) reaction to reaction to various bacillary antigens;various bacillary antigens; it destroys it destroys unactivated unactivated macrophagesmacrophages that that contain contain multiplying bacilli but multiplying bacilli but also causes also causes caseous necrosiscaseous necrosis of the involved tissues of the involved tissues

--macrophage activating responsemacrophage activating response(T-cell mediated phenomenon) (T-cell mediated phenomenon)

activation of macrophages that are capable of activation of macrophages that are capable of killing and digesting tubercle bacilli killing and digesting tubercle bacilli

Granuloma Formation Granuloma Formation

development of specific immunity and the development of specific immunity and the accumulation of large numbers of activated accumulation of large numbers of activated lymphocytes and macrophages that evolve toward lymphocytes and macrophages that evolve toward epithelioid and giant cell morphologies epithelioid and giant cell morphologies

the tissue-damaging response can limit mycobacterial the tissue-damaging response can limit mycobacterial growth within macrophages growth within macrophages

growth is inhibited within this necrotic environment by growth is inhibited within this necrotic environment by low oxygen tension and low pHlow oxygen tension and low pH

some lesions may heal by fibrosis, with subsequent some lesions may heal by fibrosis, with subsequent

calcification, whereas inflammation and necrosis occur calcification, whereas inflammation and necrosis occur in other lesions. in other lesions.

The Delayed-Type Hypersensitivity The Delayed-Type Hypersensitivity

ReactionReaction ► minority of cases, the macrophage-minority of cases, the macrophage-

activating response is weakactivating response is weak mycobacterial growth can be inhibited only mycobacterial growth can be inhibited only by by intensified DTHintensified DTH reactions, which lead reactions, which lead to to lung tissue destructionlung tissue destruction..

► lesions enlarge and the surrounding tissue lesions enlarge and the surrounding tissue is progressively damaged is progressively damaged cavities are cavities are formed formed liquefied caseous material, liquefied caseous material, containing large numbers of bacilli, is containing large numbers of bacilli, is drained through bronchi. drained through bronchi.

► In young children with poor natural immunity, In young children with poor natural immunity,

hematogenous dissemination may result in hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous fatal miliary tuberculosis or tuberculous meningitis meningitis

► early stages of infection, bacilli are early stages of infection, bacilli are transported by macrophages to regional transported by macrophages to regional lymph nodeslymph nodes gain access to the bloodstream gain access to the bloodstream and disseminate throughout the body.and disseminate throughout the body.

CELL MEDIATED IMMUNITYCELL MEDIATED IMMUNITY

T lymphocyte,mainly Th1(CD4+)T lymphocyte,mainly Th1(CD4+) Local macrophageLocal macrophage IL1- IL6 –TNFIL1- IL6 –TNFαα- IL2- IFN- IL2- IFNγγ Active cell aggregate around lesion and effectively Active cell aggregate around lesion and effectively

neutralize tubercle bacillineutralize tubercle bacilli Caseous necrosisCaseous necrosis Viable bacilli may remain dormantViable bacilli may remain dormant Healed lesion may undergo calcificationHealed lesion may undergo calcification

(Ranke complex)(Ranke complex)

► TSTTST, which is used primarily for the detection of , which is used primarily for the detection of M. tuberculosisM. tuberculosis infection in persons infection in persons without without symptomssymptoms

► related mainly to previously sensitized related mainly to previously sensitized CD4+ TCD4+ T lymphocytes lymphocytes

► DTH is associated with protective immunity , it by DTH is associated with protective immunity , it by no means guarantees protection against no means guarantees protection against reactivationreactivation

► previous latent or active tuberculosis may not previous latent or active tuberculosis may not confer fully protective immunity confer fully protective immunity

Interferon-γ Release AssaysInterferon-γ Release Assays

Compared with the tuberculin skin test, the INF-γ Compared with the tuberculin skin test, the INF-γ release assays have the advantage of :release assays have the advantage of :

► being accomplished with one patient visit, being accomplished with one patient visit,

► being more specific being more specific in the presence of BCG vaccinationin the presence of BCG vaccination

infection with nontuberculous mycobacteria, infection with nontuberculous mycobacteria,

► having less reader variability,having less reader variability,

► not recalling waned immunity not recalling waned immunity

POSSIBLE OUTCOMESPOSSIBLE OUTCOMES

Immediate clearance of the organismImmediate clearance of the organism

Chronic or latent infectionChronic or latent infection

Primary diseasePrimary disease

ReactivationReactivation

Condition associated with Condition associated with reactivationreactivation

► HIV infectionHIV infection► End stage renal diseaseEnd stage renal disease► Diabetes mellitusDiabetes mellitus► Corticosteroid useCorticosteroid use► Diminution in CMI associated with old ageDiminution in CMI associated with old age

Reactivation TB tends to be Reactivation TB tends to be localizedlocalized

Clinical manifeststionClinical manifeststion

► Extra pulmonary tuberculosisExtra pulmonary tuberculosis Tuberculous lymphadenitisTuberculous lymphadenitis

Pleural tuberculosisPleural tuberculosis Upper airway tuberculosis Upper airway tuberculosis

Genitourinary Genitourinary tuberculosistuberculosis Skeletal TB , Skeletal TB ,

Meningitis & tuberculoma Meningitis & tuberculoma Gastrointestinal , Gastrointestinal ,

PericardialPericardial Miliary or disseminated TBMiliary or disseminated TB

Eye TB Eye TB ► Pulmonary tuberculosisPulmonary tuberculosis

--primary -Secondaryprimary -Secondary

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Sites of TB Disease (1)Sites of TB Disease (1)

Bacilli may reach any part of the body, but Bacilli may reach any part of the body, but common sites include:common sites include:

Brain

Lym ph node

Pleura

Lung

SpineKidney

Bone

Larynx

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Sites of TB Disease (2)Sites of TB Disease (2)LocationLocation FrequencyFrequency

Pulmonary TBPulmonary TB LungsLungs Most TB cases are Most TB cases are pulmonarypulmonary

Extrapulmonary Extrapulmonary TBTB

Places other than Places other than lungs such as:lungs such as:► LarynxLarynx► Lymph nodesLymph nodes► PleuraPleura► BrainBrain► KidneysKidneys► Bones and jointsBones and joints

Found more often Found more often in:in:

► HIV-infected orHIV-infected or

otherother

immunosuppressedimmunosuppressed

personspersons

► Young childrenYoung children

Miliary TBMiliary TB Carried to all parts Carried to all parts of body, through of body, through bloodstreambloodstream

RareRare

Module 1 – Transmission and Pathogenesis of Tuberculosis

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TB Pathogenesis (4)TB Pathogenesis (4)

Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to

small air sacs (alveoli)


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bronchio leblood vessel

tubercle bacilli

a lveoli

2

Tubercle bacilli multiply in alveoli, where infection begins


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A small number of tubercle bacilli enter bloodstream and spread throughout

body

brain

lung

kidney

bone3


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TB Pathogenesis (7)TB Pathogenesis (7)LTBILTBI

specialim m une cells form a barrier shell (in th isexam ple,bacilli arein the lungs)

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• Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli

• These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)


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TB Pathogenesis (8)TB Pathogenesis (8)TB DiseaseTB Disease

shell breaks down and tuberclebacilli escape

m ultip ly(in th is exam ple,TB d isease develops in the lungs)

and

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• If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease

• This process can occur in different places in the body


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LTBI vs. TB DiseaseLTBI vs. TB Disease

Latent TB Infection (LTBI)Latent TB Infection (LTBI) TB Disease (in the lungs)TB Disease (in the lungs)Inactive, contained tubercle bacilli in the body

Active, multiplying tubercle bacilli in the body

TST or blood test results usually positive

TST or blood test results usually positive

Chest x-ray usually normal Chest x-ray usually abnormal

Sputum smears and cultures negative

Sputum smears and cultures may be positive

No symptoms Symptoms such as cough, fever, weight loss

Not infectious Often infectious before treatment

Not a case of TB A case of TB

Signs and Symptoms of TBSigns and Symptoms of TB

► Cough for more than three weeksCough for more than three weeks► Coughing up bloodCoughing up blood► Unexplained weight lossUnexplained weight loss► Night sweatsNight sweats► FeverFever► Feeling tiredFeeling tired

Not everyone with TB looks really sick…Not everyone with TB looks really sick…

Systemic effctsSystemic effcts

► FeverFever

► MalaiseMalaise

► Weight lossWeight loss

► pancytopeniapancytopenia

► LeukocytosisLeukocytosis

► AnemiaAnemia

► LeukopeniaLeukopenia

► hyponatremiahyponatremia

Primary pulmonary tuberculosisPrimary pulmonary tuberculosis

► Often seen in childrenOften seen in children► Frequently localized to middle and lower Frequently localized to middle and lower

lung zonelung zone► Paratracheal or hilar lymphadenopathyParatracheal or hilar lymphadenopathy► Progressive primary tuberculosis (cavation)Progressive primary tuberculosis (cavation)► Pleural effusion, collapse lung, Pleural effusion, collapse lung,

BronchectasisBronchectasis► Dissemination ,may develop milliary Dissemination ,may develop milliary

tuberculosis and meningitistuberculosis and meningitis► Ghon lesion(healed lesion)Ghon lesion(healed lesion)

Secondary tuberculosisSecondary tuberculosis

► Symptom: Symptom: productive cough, hemoptysis, productive cough, hemoptysis, dyspnea, fever, night sweatdyspnea, fever, night sweat

► Signs: Signs: not specific,not specific, dullness with decreased fermitus (pleural dullness with decreased fermitus (pleural

effusion), effusion), rales, rales,

sign of consolidation, sign of consolidation, amphoric sound,clubbingamphoric sound,clubbing

Chest.x.rayChest.x.raysecondary tuberculosissecondary tuberculosis

► Apical and post. segments of the upper Apical and post. segments of the upper lobes(80-90%)lobes(80-90%)

► Superior segments of lower lobesSuperior segments of lower lobes► Infiltration and cavitary lesionInfiltration and cavitary lesion► Nodules and branching linear densities (tree in Nodules and branching linear densities (tree in

bud)bud)► Pleural effusionPleural effusion► Solitary nodule(atypical)Solitary nodule(atypical)

Other pulmonary presentationOther pulmonary presentation

► Endobronchial tuberculosisEndobronchial tuberculosis► ARDSARDS► Tuberculous pneumonitis (lower lobe)Tuberculous pneumonitis (lower lobe)► Lower lobe TB(elderly,diabetes,renal and Lower lobe TB(elderly,diabetes,renal and

hepatic dis. ,corticosteroid)hepatic dis. ,corticosteroid)► Tuberculoma (rounded mass lesion)Tuberculoma (rounded mass lesion)

Complication of pulmonary TBComplication of pulmonary TB

► Massive hemoptysis (rare)Massive hemoptysis (rare)► Spontaneous pneumothoraxSpontaneous pneumothorax► EmpyemaEmpyema► BronchectasisBronchectasis► Extensive pulmonary destructionExtensive pulmonary destruction► Tuberculosis of the upper airway(chronic Tuberculosis of the upper airway(chronic

productive cough, hoarseness,dysphagia)productive cough, hoarseness,dysphagia)

Pleural tuberculosisPleural tuberculosis

► Hypersensitivity reaction to mycobacterial Hypersensitivity reaction to mycobacterial antigens in pleural spaceantigens in pleural space

► Rupture or leakage from subpleural focus of Rupture or leakage from subpleural focus of diseasedisease

► Ph.E:dullness to percussion and absence of Ph.E:dullness to percussion and absence of breath soundbreath sound

Pleural fluid characteristicsPleural fluid characteristics

► Exudative (ppl / pserum >0/5)Exudative (ppl / pserum >0/5)► Normal or low glucoseNormal or low glucose► PH<7/2PH<7/2► Lymph dominantLymph dominant► Mesothelial cell rareMesothelial cell rare► AFB negative in smearAFB negative in smear► Fluid culture 30% positiveFluid culture 30% positive► Biopsy with culture 70-80% diagnosticBiopsy with culture 70-80% diagnostic► ADA, IFN gammaADA, IFN gamma

Miliary (disseminated) tuberculosisMiliary (disseminated) tuberculosis

► Hematogenous spread of tubercle bacilliHematogenous spread of tubercle bacilli► Recent infection or reactivationRecent infection or reactivation► Yellowish granuloma up to 2mmYellowish granuloma up to 2mm

Clinical manifestation (miliaryTBClinical manifestation (miliaryTB))

► HistoryHistory: fever, night sweat,anorexia, : fever, night sweat,anorexia, weakness,weight lossweakness,weight loss

► PH.EPH.E: Hepatomegaly,Splenomegaly, : Hepatomegaly,Splenomegaly, lymphadenopathy, choroidal tubercle, lymphadenopathy, choroidal tubercle, menangismusmenangismus

Diagnosis miliary TBDiagnosis miliary TB

► CXR :miliary reticonodular patternCXR :miliary reticonodular pattern► Sputum smear negative in 80%Sputum smear negative in 80%► Anemia,leukopenia,leukocytosisAnemia,leukopenia,leukocytosis► DICDIC► Elevated alk/ph, abnormal liver function testElevated alk/ph, abnormal liver function test► Negative PPD(50%)Negative PPD(50%)► BAL and biopsy more positiveBAL and biopsy more positive

Clinicopathologic patternsClinicopathologic patterns

► AcuteAcute miliary tuberculosis(typical miliary tuberculosis(typical caseating granuloma)caseating granuloma)

► CrypticCryptic miliary tuberculosis(more chronic, miliary tuberculosis(more chronic, non specific clinical presentation)non specific clinical presentation)

► Non reactiveNon reactive miliary TB(acute miliary TB(acute septicemic)septicemic)

Risk factorRisk factor:: Age, alcohol abuse, Age, alcohol abuse, malignancy, renal failure, CTD, diabetes, malignancy, renal failure, CTD, diabetes,

pregnancy, immunosuppresionpregnancy, immunosuppresion

HIV-associated TBHIV-associated TB

► Presentation varies with the stagePresentation varies with the stage

► Late stage: primary pattern with miliary Late stage: primary pattern with miliary infiltrate and lymphadenopathy , no infiltrate and lymphadenopathy , no cavitationcavitation

► Higher incidence of extrapulmonary and Higher incidence of extrapulmonary and pleural effusionpleural effusion

► Sputum smear frequently negativeSputum smear frequently negative

► Lack of classic granuloma formationLack of classic granuloma formation

Diagnosis TuberculosisDiagnosis Tuberculosis

► High index suspicionHigh index suspicion

► Chest.x.rayChest.x.ray

► AFB Microscopy:AFB Microscopy: three sputum specimens, collected in the three sputum specimens, collected in the

early morningearly morning Staining with ziehl neelsen or auramine-Staining with ziehl neelsen or auramine-

rhodaminerhodamine

DiagnosisDiagnosis► Culture:Culture:

Egg based (lowenstein-jensen), Egg based (lowenstein-jensen), agar based (middelbrook);agar based (middelbrook);

► 4-8 week may be requird for growth4-8 week may be requird for growth

► Liquid media with radiometric growth Liquid media with radiometric growth detection (bactec-460)detection (bactec-460)

► High pressure liquid chromatography of High pressure liquid chromatography of mycolic acid(2-3 week)mycolic acid(2-3 week)

► Nucleic acid amplificationNucleic acid amplification

BCG VACCINATIONBCG VACCINATION

► Derived from an attenuated strain of Derived from an attenuated strain of M.bovisM.bovis

► Efficacy from 80% to nilEfficacy from 80% to nil

► Rarely complication: Rarely complication:

ulceration,ulceration,

regional lymphadenitis,regional lymphadenitis,

osteomyelitis,osteomyelitis,

disseminationdissemination

PPDPPD ► Purified protein derivativePurified protein derivative► PPD 5tu:0/1ml contain 0/0001mgPPD 5tu:0/1ml contain 0/0001mg► Mantoax method (interadermaly, volar Mantoax method (interadermaly, volar

surface)surface)► Wheal 6-10mmWheal 6-10mm► Reaction are read at 48 to72h(transverse Reaction are read at 48 to72h(transverse

diameter of induration in mm)diameter of induration in mm)► A second skin test administered 1week or A second skin test administered 1week or

more after the first(more after the first(two-step)two-step)

Measuring TSTMeasuring TST

► Record Record indurationinduration (bump) only (bump) only► Measure Measure transversetransverse (across arm) (across arm)► Record: Date given, date read, mmRecord: Date given, date read, mm


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TB Classification System (1)TB Classification System (1)

ClassClass TypeType DescriptionDescription

0 No TB exposure

Not infected

No history of TB exposure

Negative result to a TST or IGRA

1 TB exposure

No evidence of infection

History of TB exposure

Negative result to a TST (given at least 8-

10 weeks after exposure) or IGRA

2 TB infection

No TB disease

Positive result to a TST or IGRA

Negative smears and cultures (if done)

No clinical or x-ray evidence of active

TB disease

Based on pathogenesis of TB


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TB Classification System (2)TB Classification System (2)

ClassClass TypeType DescriptionDescription

3 TB, clinically active

Positive culture (if done) for M. tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease

4 Previous TB disease(not clinically active)

Medical history of TB disease

Abnormal but stable x-ray findings

Positive result to a TST or IGRA

Negative smears and cultures (if done)No clinical or x-ray evidence of active TB disease

5 TB suspected

Signs and symptoms of TB disease, but evaluation not complete

Based on pathogenesis of TB

TreatmentTreatment

► First line drugsFirst line drugs: Rifampin, Isoniazid, : Rifampin, Isoniazid, Ethambutol, Pyrazinamid, streptomycin Ethambutol, Pyrazinamid, streptomycin

► Short course treatment(6 month)Short course treatment(6 month) 2month initial phase (2month initial phase (bactericidalbactericidal): ):

rifampin, isoniazid, ethambutol, rifampin, isoniazid, ethambutol, pyrazinamidepyrazinamide

4month continuation (4month continuation (sterilizingsterilizing): rifampin ): rifampin and isoniazidand isoniazid

TreatmentTreatment

► Pyridoxin (vit B6) should be given to:Pyridoxin (vit B6) should be given to:

-ALCOHOLICS-ALCOHOLICS

-Malnurished-Malnurished

-pregnant and lactating woman-pregnant and lactating woman

-chronic renal failure-chronic renal failure

-diabetes-diabetes

-HIV infection -HIV infection

Hepatitis Hepatitis ► Most common adverse reactionMost common adverse reaction

► BaselineBaseline assessment of liver function in assessment of liver function in all adultall adult patientpatient

► monitoring monthly :monitoring monthly :

Older patientOlder patient

alcoholicsalcoholics

pregnancypregnancy

HIVHIV

history of hepatic diseasehistory of hepatic disease

► Treatment should be stopped: symptomatic hepatitis Treatment should be stopped: symptomatic hepatitis or three to five fold elevation LFTor three to five fold elevation LFT

First Line DrugsFirst Line Drugs

INH : INH : Raised LFT Raised LFT Hepatitis Hepatitis Peripheral-Peripheral-

neuropathy neuropathy Drug interactions Drug interactions Mild effect on CNS Mild effect on CNS drug induced lupusdrug induced lupus

RIFRIF:: GI-upset,DrugGI-upset,Drug InteractionsInteractions HepatitisHepatitis Thrombocytopenia Thrombocytopenia Rash Rash Interstitial nephritis Interstitial nephritis Flu like Flu like

PZAPZA:: Hepatitis, Rash Hepatitis, Rash GI upsetGI upset Arthralgia Arthralgia Hyperuricemia Hyperuricemia rarerly gout rarerly gout

EMB:EMB: Optic neuritisOptic neuritis

SMSM : : OtotoxicityOtotoxicity Nephrotoxicity Nephrotoxicity

Adjunctive corticosteroidAdjunctive corticosteroid

Meningitis Meningitis PericarditisPericarditis

Acute life threatening pulmonary Acute life threatening pulmonary tuberculosistuberculosis

Low serum albuminLow serum albumin Severe weight lossSevere weight loss Adenitis in childrenAdenitis in children

Monitoring response to treatmentMonitoring response to treatment► Sputum culture monthly until become negativeSputum culture monthly until become negative

► AFB smear conversion may follow culture conversionAFB smear conversion may follow culture conversion

► If culture not practical,AFB smear should be If culture not practical,AFB smear should be undertaken at 2,5and 6 monthsundertaken at 2,5and 6 months

► Culture/smear positive after 3month and smear Culture/smear positive after 3month and smear positive after 5months are indicative treatment failurepositive after 5months are indicative treatment failure

► Serial c.x.ray not recommended ,except at the end of Serial c.x.ray not recommended ,except at the end of treatmenttreatment

► results of susceptibility testing are expected to results of susceptibility testing are expected to become available within a few weeks become available within a few weeks changes in changes in the regimen can be postponed until that time. the regimen can be postponed until that time.

► If the patient's clinical condition is deteriorating, an If the patient's clinical condition is deteriorating, an earlier change in regimen may be indicated. earlier change in regimen may be indicated.

A cardinal rule in the latter situationA cardinal rule in the latter situation

always add more than one drug at a time to a always add more than one drug at a time to a failing regimen: failing regimen:

at least at least twotwo and preferably and preferably three drugs that have three drugs that have never been used never been used and to which theand to which the bacilli are likely bacilli are likely to be susceptible to be susceptible

The patient may continue to take isoniazid and The patient may continue to take isoniazid and rifampin along with these new agents pending the rifampin along with these new agents pending the results of susceptibility tests.results of susceptibility tests.

► Patients who experience a Patients who experience a recurrence recurrence after after apparently successful treatment (apparently successful treatment (relapsesrelapses) are ) are less likelyless likely to harbor to harbor drug-resistant strainsdrug-resistant strains than are than are patients in whom treatment has failed. patients in whom treatment has failed.

► If the regimen administered initially If the regimen administered initially does notdoes not contain contain rifampinrifampin, the probability of , the probability of isoniazid isoniazid resistance is high. resistance is high.

► begin the treatment of all patients who have begin the treatment of all patients who have relapsed with relapsed with all four first-lineall four first-line drugs plus drugs plus streptomycinstreptomycin, pending the results of susceptibility , pending the results of susceptibility testing.testing.

Drug-Resistant TBDrug-Resistant TB

M. tuberculosisM. tuberculosis resistant to individual drugs resistant to individual drugs spontaneous point mutations in the mycobacterial spontaneous point mutations in the mycobacterial

genomegenome there is no cross-resistance among the commonly there is no cross-resistance among the commonly

used drugs used drugs ► probability that a strain will be resistant to two probability that a strain will be resistant to two

drugs : drugs : product of the probabilitiesproduct of the probabilities of resistance of resistance to each drugto each drug

► drug-resistant TB is invariably the result of drug-resistant TB is invariably the result of Monotherapy Monotherapy —i.e., the failure of the health care —i.e., the failure of the health care

provider to prescribe at least two drugs to which provider to prescribe at least two drugs to which tubercle bacilli are susceptible tubercle bacilli are susceptible

the the patient to take properlypatient to take properly prescribed therapy prescribed therapy

► Drug-resistant TB may be either primary or Drug-resistant TB may be either primary or acquiredacquired

PrimaryPrimary : develops in a strain infecting a patient : develops in a strain infecting a patient who has not previously been treatedwho has not previously been treated

Acquired Acquired : during treatment with an inappropriate : during treatment with an inappropriate regimenregimen

Multidrug-resistant tuberculosis (Multidrug-resistant tuberculosis (MDR-TBMDR-TB)) defined as resistance to at least isoniazid and defined as resistance to at least isoniazid and

rifampin (also known as rifampicin in many rifampin (also known as rifampicin in many countries), countries),


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Mono-resistant Resistant to any one TB treatment drug

Poly-resistant Resistant 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 drugs

Extensively 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)

Drug-Resistant TB (3)Drug-Resistant TB (3)

XDR-TBXDR-TB

► MDR strains that are resistant to :MDR strains that are resistant to : allall fluoroquinolones fluoroquinolones andand

at least at least one one of three second-line of three second-line injectableinjectable agents agents (amikacin, kanamycin, and capreomycin). (amikacin, kanamycin, and capreomycin).

► Drug-resistant TB can be prevented by Drug-resistant TB can be prevented by adherence :adherence :

the inclusion of at least two bactericidal drugs to the inclusion of at least two bactericidal drugs to which the organism is susceptiblewhich the organism is susceptible

the use of fixed-drug-combination productsthe use of fixed-drug-combination products the verification that patients complete the the verification that patients complete the

prescribed course.prescribed course.

Tuberculosis. A Small Disclaimer… This presentation will NOT teach you everything there is to know about tuberculosis.

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