Tuberculosis - people.musc.edupeople.musc.edu/~selassie/IDclass/Lectures/Lec17_03-31-08.pdf · 713 Lecture XVII (Tuberculosis) March 31, 2008 Selassie AW (DBBE, MUSC) 2 The Organism

Infectious Disease Epidemiology BMTRY 713 Lecture XVII (Tuberculosis)

March 31, 2008

Selassie AW (DBBE, MUSC) 1

Infectious Disease EpidemiologyInfectious Disease EpidemiologyBMTRY 713 (A. Selassie, DrPH)BMTRY 713 (A. Selassie, DrPH)

Learning ObjectivesLearning Objectives1.1. Describe the biologic characteristics of the agent Describe the biologic characteristics of the agent 2.2. Determine the epidemiologic characteristics of TuberculosisDetermine the epidemiologic characteristics of Tuberculosis3.3. Identify the major risk factors of TuberculosisIdentify the major risk factors of Tuberculosis

March 31, 2008March 31, 2008Lecture XVII Lecture XVII TuberculosisTuberculosis

TuberculosisTuberculosis

Caused by Caused by Mycobacterium tuberculosisMycobacterium tuberculosisSuggestive identification in skeletons Suggestive identification in skeletons from 8,000from 8,000--5,000 BC5,000 BCAdditional evidence from Egyptian Additional evidence from Egyptian mummiesmummiesHypothesized it resulted from Hypothesized it resulted from domestication of cattledomestication of cattle

Impact of TBImpact of TB

1999, WHO identified TB as among the 1999, WHO identified TB as among the most serious threats to the worldmost serious threats to the world

1/3 of the population of the world are 1/3 of the population of the world are latently infectedlatently infected

77--8 million new cases annually8 million new cases annually

2 million deaths annually2 million deaths annually


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The Organism The Organism (see table 14(see table 14--1)1)

Four are usual human pathogensFour are usual human pathogens–– Mycobacterium tuberculosisMycobacterium tuberculosis–– M. M. africanumafricanum–– M. bovisM. bovis–– M. M. kansaiikansaii–– M.lepraeM.leprae——causes leprosycauses leprosy–– M. aviumM. avium——opportunistic infection in AIDSopportunistic infection in AIDS

Clinical manifestationsClinical manifestations

Initial latent infectionInitial latent infection–– AsymptomaticAsymptomatic

Clinical diseaseClinical disease–– Usually pulmonary (80%)Usually pulmonary (80%)–– ExtrapulmonaryExtrapulmonary

•• Can strike almost any organ systemCan strike almost any organ system–– Pericardium, spine, GI tract, skinPericardium, spine, GI tract, skin

•• More common in children and More common in children and immunocomprimisedimmunocomprimised

Clinical manifestations (2)Clinical manifestations (2)

Active diseaseActive disease–– Variable intensityVariable intensity–– NonNon--specific symptomsspecific symptoms

•• Cough, with or without bloody sputum, Cough, with or without bloody sputum, fatigue, anorexia and weight loss, fever, fatigue, anorexia and weight loss, fever, sweating and/or chills, chest painsweating and/or chills, chest pain

•• ExtrapulmonaryExtrapulmonary –– fatigue and night fatigue and night sweats, other symptoms specific to sweats, other symptoms specific to organsorgans


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Clinical manifestations (3)Clinical manifestations (3)

Systemic infectionSystemic infection–– Miliary tuberculosisMiliary tuberculosis

–– Spreads throughout the body, Spreads throughout the body, producing nodules of infection in producing nodules of infection in every organevery organ

–– More common in children and More common in children and immunocompromisedimmunocompromised

Chest XChest X--ray of Pulmonary TBray of Pulmonary TB

Tuberculous Pneumonia with consolidation

Miliary Tuberculosis with shadowing on both lungs

b

DiagnosisDiagnosisLatentLatent–– Asymptomatic, based on clinical testsAsymptomatic, based on clinical tests–– Tuberculin skin testTuberculin skin test——purified protein purified protein

derivative (PPD, derivative (PPD, MantouxMantoux test)test)•• IntracutaneousIntracutaneous injectioninjection•• Diagnosed by the size of the zone on Diagnosed by the size of the zone on

induration surrounding the injection site induration surrounding the injection site 4848--72 hours72 hours

•• > 10 mm of induration> 10 mm of induration•• Identifies disease in 98% of positives, Identifies disease in 98% of positives,

only 5% of negativesonly 5% of negatives•• BCG vaccine can produce false positiveBCG vaccine can produce false positive


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False negative testsFalse negative tests

Individuals with HIV or cancerIndividuals with HIV or cancer

MalnutritionMalnutrition

Viral infection, such as measlesViral infection, such as measles

Actively infected may have neg testActively infected may have neg test

Cut points for positive testCut points for positive test

Dependent upon the size of induration, Dependent upon the size of induration, prior probability of infection, and clinical prior probability of infection, and clinical consequences of misreading the result.consequences of misreading the result.>=5>=5 HIV+, close contact with known HIV+, close contact with known

casecase>=10>=10 Medical factors increase risk, Medical factors increase risk,

high prevalence areahigh prevalence area>=15>=15 Low riskLow risk

Active diseaseActive disease

55--10% with latent infection develop 10% with latent infection develop active diseaseactive diseaseDiagnosis is based upon assessment of Diagnosis is based upon assessment of risk, clinical findings and symptoms, risk, clinical findings and symptoms, PPD test, chest XPPD test, chest X--ray, sputum cultureray, sputum cultureWhere medical tests are unavailable, Where medical tests are unavailable, diagnosis depends upon clinical diagnosis depends upon clinical symptoms and examination of sputumsymptoms and examination of sputum


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TherapyTherapyThree erasThree eras–– PrePre--sanatoriumsanatorium

•• Tumors cause by ill airs, tx living in a mild, Tumors cause by ill airs, tx living in a mild, seaside climate, bloodletting, restseaside climate, bloodletting, rest

–– SanatoriumSanatorium•• 18501850’’s, rest, decreased transmissions, rest, decreased transmission

–– ChemotherapeuticChemotherapeutic•• PAS, INH, streptomycinPAS, INH, streptomycin

Early clinical trialEarly clinical trial

1940 England, multicenter, 1940 England, multicenter, randomized, control trial randomized, control trial

Streptomycin vs. placeboStreptomycin vs. placebo

Current treatmentCurrent treatment

Slowly progressive diseaseSlowly progressive diseaseSome drugs only kill actively growing Some drugs only kill actively growing bacteriabacteriaNeed to be taken for 6 monthsNeed to be taken for 6 monthsRisk of mutation with single drug Risk of mutation with single drug therapytherapyUsual treatment 2 or more drugsUsual treatment 2 or more drugs


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Patient adherencePatient adherence

If nonIf non--adherent there is a risk of a adherent there is a risk of a antibiotic resistant strain developingantibiotic resistant strain developing

Directly observed therapy (DOT)Directly observed therapy (DOT)

6 month treatment, relapse 5%or less6 month treatment, relapse 5%or less

EpidemiologyEpidemiology

PandemicPandemicSeventh leading cause of death in the Seventh leading cause of death in the worldworldSecond leading infectious cause of Second leading infectious cause of deathdeath95% of all cases are in the developing 95% of all cases are in the developing world, most victims between 15 and 55world, most victims between 15 and 55

Global variation in diseaseGlobal variation in diseaseUS and EuropeUS and Europe–– Low prevalenceLow prevalence–– Lowest in infancy, increasing with ageLowest in infancy, increasing with age

Latin America and CaribbeanLatin America and Caribbean–– Higher prevalence, incidence, and Higher prevalence, incidence, and

mortalitymortality–– Two peaks in incidence and mortalityTwo peaks in incidence and mortality

•• Infancy TB> males, Early adult TB>femalesInfancy TB> males, Early adult TB>females•• Age 35 TB > malesAge 35 TB > males


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Global variation in disease (2)Global variation in disease (2)

Asia and AfricaAsia and Africa–– 6060--70% adults have latent infection70% adults have latent infection

–– Two peaks in incidenceTwo peaks in incidence•• Infancy TB > malesInfancy TB > males

•• Late adolescence TB > femalesLate adolescence TB > females

•• Rates of women exceed men until age Rates of women exceed men until age 6060

Natural History & BacteriologyNatural History & Bacteriology

Moderately infectiousModerately infectious–– 20%20%--30% of exposed become infected30% of exposed become infected–– Can remain dormant for 20Can remain dormant for 20--30 years30 years–– 5%5%--10% develop active disease, the rest 10% develop active disease, the rest

have latent diseasehave latent disease–– 5%5%--10% of those with latent disease 10% of those with latent disease

develop active disease (reactivation TB)develop active disease (reactivation TB)•• Facilitated by malnutrition, HIV, other medical Facilitated by malnutrition, HIV, other medical


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Impact of natural history on Impact of natural history on populationpopulation

Reservoir of latent infection (stage1)Reservoir of latent infection (stage1)Development of active infection (stage 2)Development of active infection (stage 2)People with active infection or People with active infection or reactivation transmit disease to others reactivation transmit disease to others (stage 3)(stage 3)–– Impacted by prevalence of HIVImpacted by prevalence of HIV–– Average of 10 contacts infected before case Average of 10 contacts infected before case

is treatedis treated–– 55--10% will develop TB in 12 months10% will develop TB in 12 months–– Transmit disease to their contactsTransmit disease to their contacts


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The outer cover ofThe outer cover ofM. TuberculosisM. Tuberculosis is a is a waxy layer (mycolic waxy layer (mycolic acid, phosphoacid, phospho-- and and sulfolipids) that sulfolipids) that allows some of the allows some of the bacilli not to fuse bacilli not to fuse with lysosome. This with lysosome. This allows some of the allows some of the bacilli to remain bacilli to remain alive indefinitely. alive indefinitely.

Transmission of TBTransmission of TB

Airborne via respiratory tractAirborne via respiratory tract

People with active disease discharge People with active disease discharge minute particles of sputum when minute particles of sputum when coughing, talking, sneezing, singingcoughing, talking, sneezing, singing

Smaller droplets are suspended in the Smaller droplets are suspended in the air for long time periodsair for long time periods

Inhaled by uninfected peopleInhaled by uninfected people

Infectivity of pulmonary TBInfectivity of pulmonary TB

Function ofFunction of–– Virulence of the bacteriaVirulence of the bacteria

–– Frequency of coughFrequency of cough

–– Degree of pulmonary infiltrationDegree of pulmonary infiltration

–– Bacterial load in the sputumBacterial load in the sputum


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Extrapulmonary TBExtrapulmonary TB

Enters the body through mucous Enters the body through mucous membranes in GI tract, genitourinary membranes in GI tract, genitourinary tract, conjunctiva, breaks in the skintract, conjunctiva, breaks in the skin

Causes infection at the site of entry Causes infection at the site of entry which can remain localized or spread to which can remain localized or spread to other organsother organs

Rarer transmission, esp. in developed Rarer transmission, esp. in developed countriescountries

Various sites of TuberculosisVarious sites of Tuberculosis

Choroidal tuberculosisChoroidal tuberculosis Vertebral tuberculosisVertebral tuberculosis

Risk factors associated with Risk factors associated with infectioninfection

Severity of disease in the index case is Severity of disease in the index case is the most important factorthe most important factor

Social factorsSocial factors–– Crowding and povertyCrowding and poverty–– May be related to probability of exposureMay be related to probability of exposure

Risk is a function of exposureRisk is a function of exposure


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Risk factors associated with Risk factors associated with development of diseasedevelopment of disease

5%5%--10% of infected become diseased, 10% of infected become diseased, usually within the first 2 yearsusually within the first 2 years–– 1% in the first year1% in the first year–– 0.07% 80.07% 8--10 years later10 years later

Age, cohort effectAge, cohort effectGenderGender–– Peak in women during reproductive years maybe Peak in women during reproductive years maybe

hormonalhormonal–– Peak in men at older ages a function of decrease Peak in men at older ages a function of decrease

immunity due to smoking and drinkingimmunity due to smoking and drinking

Risk factors associated with Risk factors associated with development of disease (2)development of disease (2)

GeneticsGenetics–– Twin studies Twin studies –– infection of second twin infection of second twin

more likely if monozygoticmore likely if monozygotic–– Some correlation of TB response and Some correlation of TB response and

blood typeblood type•• OR for Types AB and B vs. O and A =3OR for Types AB and B vs. O and A =3

–– Lean body buildLean body build–– SES, but may reflect different exposureSES, but may reflect different exposure


Stress (Danish study)Stress (Danish study)–– Lowest in married menLowest in married men–– Intermediate in single and widowed menIntermediate in single and widowed men–– Highest in divorced menHighest in divorced men–– Similar results but less dramatic for womenSimilar results but less dramatic for women–– Married people developed less severe Married people developed less severe

diseasedisease–– PovertyPoverty


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Risk factors associated with development of disease (4)

NutritionNutrition–– Specific micronutrientsSpecific micronutrients

•• Low vitamin A and selenium associated with Low vitamin A and selenium associated with increased risk of developing diseaseincreased risk of developing disease

–– MalnutritionMalnutrition•• Higher among malnourished, thinner peopleHigher among malnourished, thinner people

OccupationOccupation–– Silica in the work site, health care workersSilica in the work site, health care workers


HIV infection and AIDSHIV infection and AIDS–– Most potent biologic risk factor for Most potent biologic risk factor for

developing TBdeveloping TB•• Reactivation is 3%Reactivation is 3%--14%14%•• New infection 40% of HIV + develop Tb within New infection 40% of HIV + develop Tb within

several yearsseveral years•• Can occur even with relatively high CD4 countsCan occur even with relatively high CD4 counts

–– HIV epidemic severely undermines TB HIV epidemic severely undermines TB control, especially in developing countriescontrol, especially in developing countries


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BCG vaccinationBCG vaccination

Developed in 1921Developed in 1921

Common in Europe until Common in Europe until LubeckLubeck disasterdisaster–– In 1930, 251/412 German children vaccinated In 1930, 251/412 German children vaccinated

contracted TBcontracted TB–– Accidentally vaccinated with live, virulent cultureAccidentally vaccinated with live, virulent culture–– Decreased usage followed by increase in TBDecreased usage followed by increase in TB–– Safe vaccine, efficacy range 22% to 85%Safe vaccine, efficacy range 22% to 85%–– WHO standard vaccine, except US and WHO standard vaccine, except US and

NetherlandsNetherlands

BCG response at 6 weeks: Clinical evidence of BCG response at 6 weeks: Clinical evidence of a cella cell--mediated immune responsemediated immune response

Control strategiesControl strategies

Case finding and treatmentCase finding and treatment–– Strong surveillance system, sufficient Strong surveillance system, sufficient

laboratory components, effective laboratory components, effective treatments (DOT), reliable supply of drugstreatments (DOT), reliable supply of drugs

–– Goal is to identify 70% of smear positive Goal is to identify 70% of smear positive patients and to treat 85% successfullypatients and to treat 85% successfully

–– Current estimate is 1/3 of cases identified Current estimate is 1/3 of cases identified and treatedand treated


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Epidemiologic basis of controlEpidemiologic basis of controlReproductive rate to be <1Reproductive rate to be <1

Developing countriesDeveloping countries–– BCG vaccinationBCG vaccination–– Case detection and treatmentCase detection and treatment

Preventive therapyPreventive therapy–– Treatment of latent disease reduces the Treatment of latent disease reduces the

risk by 60%risk by 60%--90%90%–– Offering preventive treatment o high risk Offering preventive treatment o high risk

patientspatients•• Close contacts, HIV, recent convertersClose contacts, HIV, recent converters

Increasing prevalence of drugIncreasing prevalence of drug--resistant TBresistant TB

19941994--19971997–– Patients without prior therapy 9.9%Patients without prior therapy 9.9%–– History of therapy 35.6%History of therapy 35.6%MultiMulti--drug resistancedrug resistance–– Treatment is more toxic and Treatment is more toxic and

expensiveexpensive–– Hot spotsHot spots

•• Russia, Dominican Republic, ChinaRussia, Dominican Republic, China

Various lesions of TuberculosisVarious lesions of Tuberculosis

Cavitary Tuberculosis fromCavitary Tuberculosis fromMycobacterium aviumMycobacterium avium6060--yearyear--old male smokerold male smoker

Bilateral Tuberculosis fromBilateral Tuberculosis fromMycobacterium Mycobacterium kansaiikansaii4242--yearyear--old male smokerold male smoker

Documents

Tuberculosis - people.musc.edupeople.musc.edu/~selassie/IDclass/Lectures/Lec17_03-31-08.pdf · 713 Lecture XVII (Tuberculosis) March 31, 2008 Selassie AW (DBBE, MUSC) 2 The Organism