Diagnosis and Medical Management of Latent Tuberculosis ... · Diagnosis and Medical Management of Latent Tuberculosis Infection . ... hemoptysis, decreasedfatigue ... Diagnosis and

TB Nurse Case Management Norman, Oklahoma October 8-10, 2008

Diagnosis and Medical Management of Latent Tuberculosis Infection

Phillip H. Lindsey, MD October 8, 2008

Diagnosis and Medical ManagementDiagnosis and Medical Management of Latent Tuberculosis Infectionof Latent Tuberculosis Infection

________________________________________________________________________ TB Nurse Case ManagementTB Nurse Case Management

Norman, OKNorman, OK October 8, 2008October 8, 2008

________________________________________________________________________ Phillip H. Lindsey, M.D.

Associate Tuberculosis Control Officer Oklahoma State Department of Health

Objectives/OverviewObjectives/Overview �� Discuss basic science of TB infectionDiscuss basic science of TB infection �� DiscussDiscuss ““targeted testingtargeted testing”” and risks for progressionand risks for progression

from infection to active diseasefrom infection to active disease �� Discuss tuberculin skin testing and interferonDiscuss tuberculin skin testing and interferon--gammagamma

release assayrelease assay �� Discuss recommendations for treatment of latent TBDiscuss recommendations for treatment of latent TB

infectioninfection �� Case studiesCase studies

MycobacteriaMycobacteria �� Over 120 speciesOver 120 species �� Named forNamed for mycomycolic acid in their celllic acid in their cell

wall. Unique to each specieswall. Unique to each species �� Most are nonMost are non--pathogenicpathogenic �� AcidAcid--fast: resistant to staining, acidfast: resistant to staining, acid

and alkaliand alkali �� Waxy cell wall: resistant toWaxy cell wall: resistant to

dehydrationdehydration �� Related to Nocardia andRelated to Nocardia and

ActinomycesActinomyces �� Very common in environment andVery common in environment and

““normal floranormal flora””

M. tuberculosis complexM. tuberculosis complex �� A group of seven pathogenic MycobacteriaA group of seven pathogenic Mycobacteria �� M. tuberculosis, M. africanum (humans)M. tuberculosis, M. africanum (humans) �� M. bovis (cattle, deer, many other mammals)M. bovis (cattle, deer, many other mammals) �� M. caprae (goats)M. caprae (goats) �� M. pinnipedii (seals)M. pinnipedii (seals) �� M. canetti (mice)M. canetti (mice) �� M. microti (lab)M. microti (lab) �� M. bovis, BCG vaccine strain (not reportable)M. bovis, BCG vaccine strain (not reportable)

M. tuberculosisM. tuberculosis �� Obligate aerobe: requires high O2Obligate aerobe: requires high O2

concentration for growthconcentration for growth �� Intracellular parasiteIntracellular parasite �� Very slow growing: 20 hour generationVery slow growing: 20 hour generation

time (E. coli: 20 min)time (E. coli: 20 min) �� Unique, very durable cell wall (majorUnique, very durable cell wall (major

factor in virulence)factor in virulence) �� 22--4 microns in length (RBC 64 microns in length (RBC 6--88

microns)microns) �� 10,000 organisms/ml required to show10,000 organisms/ml required to show

up asup as ““smear positivesmear positive””

Droplet NucleiDroplet Nuclei �� Basic infectious particle of TBBasic infectious particle of TB �� Aerosolized from source case.Aerosolized from source case.

Dry rapidly and floatDry rapidly and float �� 33--5 microns. Contain 15 microns. Contain 1--33

tubercle bacilli eachtubercle bacilli each �� Can float into the alveoliCan float into the alveoli �� From 5 to 200 viable bacilli mustFrom 5 to 200 viable bacilli must

impinge on an alveolus forimpinge on an alveolus for infection to possibly developinfection to possibly develop

Day 1Day 1--77 �� Droplet nuclei inhaled and impinge on alveolusDroplet nuclei inhaled and impinge on alveolus �� Ingested by nonIngested by non--activaactiv ted macrophageated macrophage �� Begins multiplying in macrophageBegins multiplying in macrophage �� Macrophage killed, cytokines released, attractingMacrophage killed, cytokines released, attracting

additional macrophages and lymphocytes from bloodadditional macrophages and lymphocytes from blood �� Or:Or: Organism is quickly killed if ingested by a previouslyOrganism is quickly killed if ingested by a previously

activated macrophageactivated macrophage (person has a prior +PPD)(person has a prior +PPD) �� This is why we are not as concerned about previouslyThis is why we are not as concerned about previously

infected contactsinfected contacts �� Having a + PPD is not all bad. It does offer someHaving a + PPD is not all bad. It does offer some

protection against reprotection against re--infectioninfection

Day 7Day 7--2121 �� ““Stage of logarithStage of logarit mic growthhmic growth”” �� NonNon--activated macrophages fill with organismsactivated macrophages fill with organisms

and burst. Many more cells attracted to site.and burst. Many more cells attracted to site. �� Macrophages and organisms move into localMacrophages and organisms move into local

lymphatics and eventually to thoracic ductlymphatics and eventually to thoracic duct �� Set up local foci of infection andSet up local foci of infection and disseminatedisseminate

throughout the bodythroughout the body via circulatory systemvia circulatory system.. �� Prefer sites of high O2 concentration (lung apices,Prefer sites of high O2 concentration (lung apices,

kidney, brain, growth centers of bone)kidney, brain, growth centers of bone)

Day 21Day 21--9090 �� Immune response (CMI) develops. TImmune response (CMI) develops. T--lymphocyteslymphocytes

and macrophages are able to destroy organismsand macrophages are able to destroy organisms �� Tubercles form, walling off and haltingTubercles form, walling off and halting

multiplication (although some organisms remainmultiplication (although some organisms remain viable in a dormant state).viable in a dormant state). ““TwoTwo--edged swordedged sword””

�� Skin test becomes positiveSkin test becomes positive. Microscopic dormant. Microscopic dormant tubercles can be found along lymphatic channels.tubercles can be found along lymphatic channels. Occasionally these are large enough to be seen on xOccasionally these are large enough to be seen on x-ray (primary complex). This is LTBIray (primary complex). This is LTBI

�� This is the end of the story for the majority ofThis is the end of the story for the majority of people.people.

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~

Basic algorithm followingBasic algorithm following exposureexposure

Exposure to TB Droplet Nuclei

No infection develops 80 90%

Infection develops 10-20%

LTBI 90%

Never develop disease Active TB 10%

5% in first 2 years

5% many years laterUntreated (from pre-antibiotic era data)

~33% die in first 2 years

~ 33% die later due to TB (Class4 Class 3)

33% spontaneously cured (Class 4)

Adequately treated

vast majority cured

small number re-activate

TB Pathogenesis:TB Pathogenesis: Progression from LTBI to DiseaseProgression from LTBI to Disease

5% First Year 2-3% Second Year

~0.1% per year thereafter

Latent TB Infection

Disease (10%)

No Disease (90%)

LTBI vs. Pulmonary TB DiseaseLTBI vs. Pulmonary TB Disease

Latent TB InfectionLatent TB Infection

�� TST or IGRA positiveTST or IGRA positive

�� Negative chest radiographNegative chest radiograph (may see calcified primary(may see calcified primary complex)complex)

�� No symptoms or physicalNo symptoms or physical findings suggestive of TBfindings suggestive of TB diseasedisease

Pulmonary TB DiseasePulmonary TB Disease

�� TST or IGRA usually positiveTST or IGRA usually positive

�� Chest radiograph usuallyChest radiograph usually abnormalabnormal

�� SymptomsSymptoms maymay include one orinclude one or more of the following: fever,more of the following: fever, cough, night sweats, weight loss,cough, night sweats, weight loss, fatigue, hemoptysis, decreasedfatigue, hemoptysis, decreased appetiteappetite

�� Respiratory specimensRespiratory specimens maymay bebe smear or culture positivesmear or culture positive

Targeted Tuberculin TestingTargeted Tuberculin Testing �� An essential TB prevention and control strategyAn essential TB prevention and control strategy �� Identify persons with LTBI who are at high riskIdentify persons with LTBI who are at high risk

of developing active diseaseof developing active disease �� Emphasizes treatment of those who wouldEmphasizes treatment of those who would

benefit mostbenefit most �� Once active disease is excluded, treatment isOnce active disease is excluded, treatment is

offered regardless of ageoffered regardless of age �� Testing discouraged for those at low riskTesting discouraged for those at low risk �� Reduces the waste of resources and preventsReduces the waste of resources and prevents

inappropriateinappropriate treatmenttreatment

Increased Risk for DevelopingIncreased Risk for Developing Active TB DiseaseActive TB Disease

�� Recent InfectionRecent Infection

��Medical ConditionsMedical Conditions

2 categories:

More likely to have been recently infected: �� Close contacts toClose contacts t infectious TB caseo infectious TB case

�� Skin test converters*Skin test converters*

�� Immigrants from TBImmigrants from TB--endemic regions of the worldendemic regions of the world (within 5 years of arrival to the U.S.)(within 5 years of arrival to the U.S.)

�� ChildrenChildren ≤≤ 5 years with a positive TST5 years with a positive TST �� Residents and employees of highResidents and employees of high--risk congregaterisk congregate

settings (correctional facilities, homeless shelters,settings (correctional facilities, homeless shelters, health care facilities)health care facilities)

**TST conversion is considered an increase of 10 mmTST conversion is considered an increase of 10 mm induration within a 2 year period, regardless of ageinduration within a 2 year period, regardless of age

More likely to progress from LTBI to TB disease:

�� HIVHIV--infected personsinfected persons

�� Those with a history of prior untreated TB or fibroticThose with a history of prior untreated TB or fibrotic lesions on chest radiographlesions on chest radiograph

�� Low body weight (> 10% below ideal body weight)Low body weight (> 10% below ideal body weight)

�� Injection drug usersInjection drug users

�� Conditions that require treatment withConditions that require treatment with TNFTNF--alphaalpha antagonistsantagonists,, prolonged corticosteroids or otherprolonged corticosteroids or other immunosuppressive agentsimmunosuppressive agents

More likely to progress from LTBI to TB disease:

Persons with certain medical conditionsPersons with certain medical conditions �� SilicosisSilicosis �� Diabetes mellitusDiabetes mellitus �� Chronic renal failure +/Chronic renal failure +/-- hemodialysishemodialysis �� Solid organ transplantationSolid organ transplantation �� Carcinoma of head or neckCarcinoma of head or neck �� Gastrectomy or jejunoilial bypassGastrectomy or jejunoilial bypass

** All tuberculosis screening should be performed inAll tuberculosis screening should be performed in conjunction with risk assessmentconjunction with risk assessment

Tuberculosis Screening FlowchartTuberculosis Screening Flowchart

Evaluate for active TB

At-risk person

TST (or IGRA) + symptom review

Negative Positive

Chest x-ray

Normal Abnormal

Treatment not indicated

Potential candidate for Tx

of LTBI

Tuberculin SkinTuberculin Skin TestingTesting

Basic immunology, methodology andBasic immunology, methodology and pearlspearls

Classification of ImmunologicClassification of Immunologic ResponsesResponses

�� Immune responses provide specific protectiImmune responses pr on againstovide specific protection against infection with bacteria, viruses, fungi and parasitesinfection with bacteria, viruses, fungi and parasites

�� A twoA two--edged sword: Provides protection. Necessary foredged sword: Provides protection. Necessary for survival. Also the cause of mild to lifesurvival. Also the cause of mild to life--threatening reactionsthreatening reactions (hay fever to anaphylactic shock)(hay fever to anaphylactic shock)

�� Hypersensitivity: excessive or inappropriate immuneHypersensitivity: excessive or inappropriate immune response to antigenresponse to antigen

�� Coombs and Gell Classification of ImmunologicCoombs and Gell Classification of Immunologic Hypersensitivity Reactions (Type IHypersensitivity Reactions (Type I--IV)IV)

�� Useful guide to understanding immune reactionsUseful guide to understanding immune reactions

Type IType I Immediate HypersensitivityImmediate Hypersensitivity

• Mediated by IgE antibody to specific antigens • Mast cells stimulated and release histamine • Reaction within one hour of exposure

Examples 1. Urticaria (hives) 2. Angioedema 3. Anaphylaxis (e.g. penicillin allergy) 4. Atopic Allergy

Type IIType II Cytotoxic Antibody ReactionCytotoxic Antibody Reaction

_________________________________________________________ • Mediated by IgG and IgM to specific antigens • Antibodies directed against cell surface antigens • Damage is restricted to specific cells or tissues • B-lymphocytes (produce antibody). Have ~3 year memory

Examples 1. Transfusion Reaction 2. Rhesus Incompatibility (Rh Incompatibility) 3. Hashimoto’s Thyroiditis 4. Goodpasture’s Syndrome 5. Delayed transplant graft rejection

_________________________________________________________

Type IIIType III Immune Complex ReactionImmune Complex Reaction

_________________________________________________________ • Antigen-antibody complexes deposit in tissue • Most reactions within 1-3 weeks after exposure

Examples 1. Systemic Lupus Erythematosus 2. Erythema Nodosum 3. Polyarteritis nodosa 4. Arthus Reaction 5. Rheumatoid Arthritis 6. Elephantiasis (Wuchereria bancrofti reaction) 7. Jarisch-Herxheimer Reaction 8. Serum Sickness

_________________________________________________________

Type IVType IV DelayedDelayed--Type HypersensitivityType Hypersensitivity

_________________________________________________________ • Cell mediated immunity/Delayed-type hypersensitivity are 2 sides of

the same sword. Helpful and harmful at the same time. • Mediated mainly by T-lymphocytes sensitized to specific antigens • Involves major histocompatibility complex (MHC) • Reaction within 2-7 days after exposure • T-lymphocytes have ~15 year memory. Basis for the “booster” effect

Examples 1. Mantoux Test (PPD) 2. Cachexia and caseous necrosis due to tuberculosis 3. Allergic Contact Dermatitis (e.g. Nickel allergy)

__________________________________________________________

Tuberculin Skin TestTuberculin Skin Test

�� One of two primary methods of testing forOne of two primary methods of testing for M.M. tuberculosistuberculosis infectioninfection

�� TST is used for:TST is used for: �� Targeted testing for LTBITargeted testing for LTBI

�� Contact investigationContact investigation �� Evaluation of persons with signs andEvaluation of persons with signs and

symptoms of TBsymptoms of TB

Administering the TSTAdministering the TST

�� Inject 0.1 ml (5 TU) PPDInject 0.1 ml (5 TU) PPD tuberculin solutiontuberculin solution intradermally on volarintradermally on volar surface of forearm using asurface of forearm using a 2727--gauge needlegauge needle

�� Produce a wheal 6 to 10Produce a wheal 6 to 10 mm in diametermm in diameter

Reading the TSTReading the TST �� Measure reaction in 48 to 72 hoursMeasure reaction in 48 to 72 hours

�� Measure induration, not erythemaMeasure induration, not erythema

�� Record reaction in millimeters, nRecord reaction in millimeters, notot ““negativenegative”” oror ““positivepositive””

�� Ensure trained health careEnsure trained health care professional measures andprofessional measures and interprets tinterprets the TSThe TST

Reading the TSTReading the TST

�� Educate patient and family regardingEducate patient and family regarding significance of a positive TST resultsignificance of a positive TST result

�� Positive TST reactions can be measuredPositive TST reactions can be measured accurately for up to 7accurately for up to 7--10 days10 days

�� Negative reactions can be read accuratelyNegative reactions can be read accurately from 48 to 72 hours onlyfrom 48 to 72 hours only

TST InterpretationTST Interpretation 55--mm induration is interpreted as positive in:mm induration is interpreted as positive in:

�� HIVHIV--infected personsinfected persons

�� Close contacts to an infectious TBClose contacts to an infectious T caseB case

�� Persons with chest radiograph consistent withPersons with chest radiograph consistent with prior untreated TBprior untreated TB


��Organ transplant recipientsOrgan transplant recipients

��Other immunosuppressed patients (those takingOther immunosuppressed patients (those taking the equivalent of >15 mg/day of prednisone forthe equivalent of >15 mg/day of prednisone for >1 month or those taking TNF>1 month or those taking TNF--alphaalpha antagonistsantagonists))


��Recent immigrantsRecent immigrants �� Injection drug usersInjection drug users ��Residents or employees of congregateResidents or employees of congregate

settingssettings ��Mycobacteriology laboratory personnelMycobacteriology laboratory personnel


�� Persons with clinical conditions that place them atPersons with clinical conditions that place them at high riskhigh risk

�� Children < 4 yearsChildren < 4 years �� Infants, children, and adolescents exposed toInfants, children, and adolescents exposed to

adults at highadults at high--risk for TB diseaserisk for TB disease

TST InterpretationTST Interpretation

�� Persons with no known risk factors for TBPersons with no known risk factors for TB

Although skin testing programs should be conducted only in high-risk groups, certain low-risk persons do require testing for employment or school.

1515--mm induration is interpreted as positive in:mm induration is interpreted as positive in:

Tuberculin Skin TestTuberculin Skin Test �� False negative testsFalse negative tests �� Quality and stability of reagentsQuality and stability of reagents �� Poor techniquePoor technique �� Anergy (common with HIV infection)Anergy (common with HIV infection)

�� False positive testsFalse positive tests �� Reader errorReader error �� Presence of crossPresence of cross--reacting antigrea enscting antigens ��Nontuberculous mycobacteriaNontuberculous mycobacteria ��BCG vaccinationBCG vaccination

Factors That May Cause FalseFactors That May Cause False--Positive TST ReactionsPositive TST Reactions

�� Nontuberculous mycobacteriaNontuberculous mycobacteria �� Reactions caused by nontuberculousReactions caused by nontuberculous

mycobacteria are usuallymycobacteria are usually ≤≤ 10 mm of induration10 mm of induration

�� BCG vaccinationBCG vaccination �� Reactivity in BCG vaccine recipients wanes overReactivity in BCG vaccine recipients wanes over

time; positive TST result is likely due to TBtime; positive TST result is likely due to TB infection if risk factors are presentinfection if risk factors are present

Factors That May Cause FalseFactors That May Cause False--Negative TST ReactionsNegative TST Reactions

�� AnergyAnergy �� Inability to react to a TSInab T because of an alteredility to react to a TST because of an altered

immune responseimmune response �� Usefulness of anergy testing in TST negativeUsefulness of anergy testing in TST negative

persons who are HIV infected has not beenpersons who are HIV infected has not been demonstrateddemonstrated


�� Recent TB infectionRecent TB infection �� Defined as 2 to 10 weeks after exposureDefined as 2 to 10 weeks after exposure

�� Very young ageVery young age �� LiveLive--virus vaccinationvirus vaccination �� For example, MMR or varicellaFor example, MMR or varicella �� Can temporarily suppress TST reactivityCan temporarily suppress TST reactivity

�� Overwhelming TB diseaseOverwhelming TB disease


�� Poor TST administration techniquePoor TST administration technique �� Injection too shallow or deepInjection too shallow or deep ��Wheal too smallWheal too small

�� Reagent problemReagent problem �� Poor qualiPoor qual ty or degraded PPDity or degraded PPD ��Wrong substance injectedWrong substance injected

““Never has such a simple test been done so poorly by soNever has such a simple test been done so poorly by so manymany”” Harold Muchmore, M.D.Harold Muchmore, M.D.

Tuberculin Skin TestingTuberculin Skin Testing

�� A 100 yearA 100 year--old, very imperfect test. Poorly understood byold, very imperfect test. Poorly understood by many health care providers. Each reaction should bemany health care providers. Each reaction should be interpreted in context.interpreted in context.

�� A negative PPD does not rule out TBA negative PPD does not rule out TB. 15. 15--20% of active TB20% of active TB cases have a negative PPDcases have a negative PPD

�� In PPD reactors, TIn PPD reactors, T--lymphocytes recognize the antigen andlymphocytes recognize the antigen andstart to migrate to the PPD site 4 to 6 hours after injection.start to migrate to the PPD site 4 to 6 hours after injection.

�� The induration is caused by a dense accumulation of activatedThe induration is caused by a dense accumulation of activated TT--lymphocytes at the injection site.lymphocytes at the injection site.

Tuberculin skin testingTuberculin skin testing �� The only absolute contraindications to PPD application areThe only absolute contraindications to PPD application are

previous ulceronecroticprevious ulceronecroti reactionc reaction or aor a prior true anaphylacticprior true anaphylactic reaction to PPD.reaction to PPD.

�� Can safely be administered to newborns, pregnant women,Can safely be administered to newborns, pregnant women, AIDS patients, persons who have received BCG vaccinationAIDS patients, persons who have received BCG vaccination and to prior PPD reactors.and to prior PPD reactors.

�� Arthus ReactionArthus Reaction: rapid immune complex (Type III) reaction: rapid immune complex (Type III) reaction at PPD site. Redness and edema at site 12at PPD site. Redness and edema at site 12--24 hours after24 hours after injection. NOT a positive reaction.injection. NOT a positive reaction.

�� In persons with atrophic skin (or diseased/damaged skin)In persons with atrophic skin (or diseased/damaged skin) on the arms and those who attempt to feign reactions (byon the arms and those who attempt to feign reactions (by scratching the site), place PPD between the shoulder blades.scratching the site), place PPD between the shoulder blades.

Tuberculin skin testingTuberculin skin testing �� For large, painful and/or ulcerating PPD reactions,For large, painful and/or ulcerating PPD reactions,

document the result and treat with a Medroldocument the result and treat with a Medrol DosePak and topical corticosteroids (extremelyDosePak and topical corticosteroids (extremely effective, rapideffective, rapid--acting therapy)acting therapy)

�� Most of the time,Most of the time, ““allergic reactionsallergic reactions”” to PPD areto PPD are actually misinterpretations of positive testsactually misinterpretations of positive tests

�� WhenWhen ““allergicallergic”” persons require documentation ofpersons require documentation of PPD status for employment, a screening chest xPPD status for employment, a screening chest x--rayray and symptom review are adequate most of the timeand symptom review are adequate most of the time

�� In these instances, IGRA testing will eventuallyIn these instances, IGRA testing will eventually become standardbecome standard

Boosting/AnamnesisBoosting/Anamnesis �� Some people with LTBI may have a negativeSome people with LTBI may have a negative

skin test reaction when tested years afterskin test reaction when tested years after infection because of a waning response.infection because of a waning response.

�� The initial skin test may stimulate (boost) theThe initial skin test may stimulate (boost) the ability to react to tuberculin.ability to react to tuberculin.

�� The booster effect is also known asThe booster effect is also known as ““anamnesisanamnesis”” (forgetting to forget).(forgetting to forget).

�� Without twoWithout two--step testing, a positive reaction withstep testing, a positive reaction with subsequent testing may be misinterpreted as newsubsequent testing may be misinterpreted as new infection rather than true old LTBI.infection rather than true old LTBI.

TwoTwo--Step TestingStep Testing ��A strategy to determine the differenceA strategy to determine the difference

between boosted reactions and reactionsbetween boosted reactions and reactions due to recent infection.due to recent infection. �� If first TST is positive, considIf first TST is positive, er the person infectedconsider the person infected �� If first TST is negative, give second TST 1If first TST is negative, give second TST 1––3 weeks3 weeks

laterlater �� If second TST is positive, consider the personIf second TST is positive, consider the person

infectedinfected �� If second TST is negative, consider the personIf second TST is negative, consider the person

uninfected at baselineuninfected at baseline

TwoTwo--Step TestingStep Testing

�� Use twoUse two--step test only for initial baseline skinstep test only for initial baseline skin testing of adults who will be retestedtesting of adults who will be retested periodically (health care workers, residents ofperiodically (health care workers, residents of long term care facilities, etc)long term care facilities, etc)

�� TwoTwo--step testing should not be used forstep testing should not be used for followfollow--up testingup testing

MMWR 2005: Vol. 54; RR-17

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Blood Assay for MTB (BAMT)Blood Assay for MTB (BAMT) InterferonInterferon--gamma release assay (IRGA)gamma release assay (IRGA) �� QuantiferonQuantiferon--TB Gold InTB Gold In--tube (QFTtube (QFT--GIT)GIT) �� Current test being used in the U.S.Current test being used in the U.S. �� A blood test to diagnose the presence or absence ofA blood test to diagnose the presence or absence of

tuberculosis infectiontuberculosis infection �� An inAn in--vitro enzymevitro enzyme--linked immunosorbent assaylinked immunosorbent assay

(ELISA) measuring release of IFN(ELISA) measuring release of IFN--γγ from sensitized Tfrom sensitized T-lymphocytes after stimulation with specific antigeniclymphocytes after stimulation with specific antigenic peptides from MTBpeptides from MTB

�� Advantages and disadvantages compared to theAdvantages and disadvantages compared to the tuberculin skin test. Can be used in all circumstances intuberculin skin test. Can be used in all circumstances in which the TST is currently used. Not a perfect testwhich the TST is currently used. Not a perfect test

MMWR December 16, 2005/54(RR15);49MMWR December 16, 2005/54(RR15);49-5555

TM

CDC Recommendations for QFTCDC Recommendations for QFT--GITGIT •CDC recommends that QFT-GIT may be used in all circumstances in which the TST is currently used, including:

- Contact investigations - Evaluation of recent immigrants - Sequential testing in surveillance programs for infection control

•Caution should be used in interpreting the results in selected populations such as:

- Young children - Immunocompromised persons

-

Advantages of IGRA over TSTAdvantages of IGRA over TST �� Increased specificitIncreased y and negative predictive value*specificity and negative predictive value* �� No cross reactivity with BCG and MAC antigensNo cross reactivity with BCG and MAC antigens

(and the majority of other non(and the majority of other non--tuberculoustuberculous mycobacterial antigens)mycobacterial antigens)‡‡

�� Prevalence of pulmonary disease and colonizationPrevalence of pulmonary disease and colonization with NTM is increasing**with NTM is increasing**

‡‡Does cross react with M. kansasii, M. marinum andDoes cross react with M. kansasii, M. marinum and M. szulgai antigensM. szulgai antigens

**Chest 2007;132(3) ** Thorax 2007;62:661Chest 2007;132(3) ** Thorax 2007;62:661-666666

Advantages of IGRA over TSTAdvantages of IGRA over TST �� Studies suggest possible improved sensitivity inStudies suggest possible improved sensitivity in

immunocompromised persons (including HIV)*immunocompromised persons (including HIV)*and better prediction of those more likely toand better prediction of those more likely toprogress to diseaseprogress to disease

�� Single patient encounter, result every timeSingle patient encounter, result every time �� No booster effect, application variables, reader biasNo booster effect, application variables, reader bias

or allegedor alleged ““allergic reactionsallergic reactions”” �� Automated lab reporting. Decreased lab entryAutomated lab reporting. Decreased lab entry

errors. Better analysis potentialerrors. Better analysis potential

*Am J Resp Crit Care Med 2008;*Am J Resp Crit Care Med 2008;177177

Disadvantages of IGRADisadvantages of IGRA �� Strict processing timetable/limited availabilityStrict processing timetable/limited availability

�� Must get specimen to reference lab or initiate incubation ofMust get specimen to reference lab or initiate incubation of specimen (at 37specimen (at 37°° C) within 16 hoursC) within 16 hours

�� Errors in collecting/transporting specimens and in interpretingErrors in collecting/transporting specimens and in interpreting results can decrease accuracyresults can decrease accuracy

�� No labs in Oklahoma are currently performing test commerciallyNo labs in Oklahoma are currently performing test commercially

�� Limited data on use in children, recent contacts andLimited data on use in children, recent contacts and immunocompromised personsimmunocompromised persons

�� ExpensiveExpensive �� Venipuncture on young children can be difficultVenipuncture on young children can be difficult

LTBI TreatmentLTBI Treatment RegimensRegimens

History of Treatment of LTBIHistory of Treatment of LTBI �� Preventive therapy/chemoprophylaxis/treatPreventive therapy/chemoproph ment of LTBIylaxis/treatment of LTBI

have been essential components of tuberculosis control inhave been essential components of tuberculosis control in the U.S. for 43 yearsthe U.S. for 43 years

�� 1965: ATS recommends preventive therapy for those with1965: ATS recommends preventive therapy for those with previously untreated TB, skin test converters, and youngpreviously untreated TB, skin test converters, and young childrenchildren

�� 1967: Recommendations expanded to include all TST1967: Recommendations expanded to include all TST positive reactors (positive reactors (≥≥10 mm).10 mm).

�� 1974: CDC and ATS guidelines recommend preventive1974: CDC and ATS guidelines recommend preventive therapy only for personstherapy only for persons ≤≤ 35 years of age in order to35 years of age in order to decrease risk of hepatitisdecrease risk of hepatitis

History of Treatment of LTBIHistory of Treatment of LTBI �� 1983: CDC recommends clinical and laboratory monitoring of1983: CDC recommends clinical and laboratory monitoring of

personspersons ≥≥ 35 who35 who require preventive therapyrequire preventive therapy

�� 1998: CDC recommends 2 months of RIF/PZA as an option1998: CDC recommends 2 months of RIF/PZA as an option for HIVfor HIV--infected patientsinfected patients

�� 2000: ATS/CDC updates recommendations for2000: ATS/CDC updates recommendations for ““treatment oftreatment of latent TB infectionlatent TB infection””

�� 20012001:: Due to cases of severe liver injury associated with 2Due to cases of severe liver injury associated with 2 month regimen of RIF/PZA, use of this option demonth regimen of RIF/PZA, use of this option de-emphasized in favor of other regimensemphasized in favor of other regimens

�� 2003: 22003: 2--month regimen of RIF/PZA not recommendedmonth regimen of RIF/PZA not recommended

Initiating TreatmentInitiating Treatment

Before initiating treatment for LTBI:Before initiating treatment for LTBI: �� Rule out TB disease!!Rule out TB disease!! �� Determine prior history of treatment forDetermine prior history of treatment for

LTBI or TB diseaseLTBI or TB disease �� Assess risks and benefits of treatmentAssess risks and benefits of treatment �� Determine current and previous drugDetermine current and previous drug

therapytherapy

Isoniazid RegimensIsoniazid Regimens �� 99--month regimen of isoniazid (INH) is themonth regimen of isoniazid (INH) is the

current CDCcurrent CDC ““preferredpreferred”” regimenregimen �� 66--month regimen is slightly less effectivemonth regimen is slightly less effective

but may be used if unable to complete 9but may be used if unable to complete 9 monthsmonths

�� May be given daily or intermittently (twiceMay be given daily or intermittently (twice weekly)weekly) �� Use directly observed therapy (DOT) forUse directly observed therapy (DOT) for

intermittent regimenintermittent regimen

Isoniazid RegimensIsoniazid Regimens ��INH daily for 9 monthsINH daily for 9 months

(270 doses within 12 months)(270 doses within 12 months) ��INH twice/week for 9 monthsINH twice/week for 9 months

(76 doses within 12 months)(76 doses within 12 months) ��INH daily for 6 monthsINH daily for 6 months

(180 doses within 9 months)(180 doses within 9 months) ��INH twice/week for 6 monthsINH twice/week for 6 months

(52 doses within 9 months)(52 doses within 9 months)

Rifampin RegimensRifampin Regimens �� Rifampin (RIF) given daily for 4 montRifampin (RIF) given daily for 4 mon hs is anths is an

acceptable alternative in HIVacceptable alternative in HIV –– andand HIVHIV ++ personspersons �� Shorter regimen leads to greater completion rates*Shorter regimen leads to greater completion rates* �� In situations where RIF cannot be usedIn situations where RIF cannot be used

(HIV(HIV--infected persons receiving proteaseinfected persons receiving protease inhibitors), rifabutin may be substituted.inhibitors), rifabutin may be substituted.

** ““The best preventive therapy is the one the patientThe best preventive therapy is the one the patient completescompletes”” Harold Muchmore, M.D.Harold Muchmore, M.D.

Rifampin RegimensRifampin Regimens

�� RIF daily for 4 monthsRIF daily for 4 months (120 doses within 6 months)(120 doses within 6 months)

�� RIF and PZA for 2 months shouldRIF and PZA for 2 months should generally not be offered due to risk ofgenerally not be offered due to risk of severe adverse events*severe adverse events*

* If 60 doses have been completed, can be* If 60 doses have been completed, can be considered adequate treatment for LTBIconsidered adequate treatment for LTBI

Other regimensOther regimens

�� INH and RMP for 4 months.INH and RMP for 4 months. �� Reassuring if subtle active disease has not beenReassuring if subtle active disease has not been

completely excludedcompletely excluded �� Rapid completion of fuRapid completion of f ll course (TNFull course (TNF--alpha, etc)alpha, etc)

�� INH and RMP for 3 monthsINH and RMP for 3 months �� Used in Great Britain and other countriesUsed in Great Britain and other countries

�� Rifapentine and INH once weeklyRifapentine and INH once weekly �� Currently being studiedCurrently being studied

Completion of TherapyCompletion of Therapy

Completion of therapy is based onCompletion of therapy is based on the total number of dosesthe total number of doses administered, not on duration alone.administered, not on duration alone.

Management of Interrupted TherapyManagement of Interrupted Therapy �� Extend or reExtend or re--start treatment if interruptions werestart treatment if interruptions were

frequent or prolonged enough to precludefrequent or prolonged enough to preclude completioncompletion

�� When treatment has been interrupted for more thanWhen treatment has been interrupted for more than 2 months, patient should be examined to rule out2 months, patient should be examined to rule out TB diseaseTB disease

�� Recommend and arrange for DOPT as neededRecommend and arrange for DOPT as needed �� Rule of ThumbRule of Thumb -- ““off for longer than on, start fromoff for longer than on, start from

scratch. On for longer than off, continue as if noscratch. On for longer than off, continue as if no break occurredbreak occurred””..

MonitoringMonitoring During TreatmentDuring Treatment

Clinical MonitoringClinical Monitoring

�� RashRash

�� Anorexia, nausea, vomiting, or abdominal pain inAnorexia, nausea, vomiting, or abdominal pain in right upper quadrantright upper quadrant

�� Fatigue or weaknessFatigue or weakness

�� Dark urineDark urine

�� Persistent numbness in hands or feetPersistent numbness in hands or feet

Instruct patient to report signs or symptoms of adverse drug reactions


�� Rationale for treatmentRationale for treatment �� Adherence with therapyAdherence with therapy �� Symptoms of adverse drug reactionsSymptoms of adverse drug reactions �� Plans to continue treatmentPlans to continue treatment

Monthly visits should include a review of


�� Incidence of hepatitis in persons takiIncidence of hepatitis in persons tak nging INH is lower than previously thought (0.1INH is lower than previously thought (0.1 to 0.15%)to 0.15%)

�� Hepatitis risk increases with ageHepatitis risk increases with age �� Uncommon in persons < 20 years oldUncommon in persons < 20 years old �� Nearly 2% in persons 50 to 64 years oldNearly 2% in persons 50 to 64 years old

�� Risk increased with underlying liver diseaseRisk increased with underlying liver disease or heavy alcohol consumptionor heavy alcohol consumption

Laboratory MonitoringLaboratory Monitoring Baseline liver function tests (AST, ALT, andBaseline liver function tests (AST, ALT, and bilirubin) are not necessary except for patientsbilirubin) are not necessary except for patients with the following risk factors:with the following risk factors:

• HIV infection

• History of liver disease

• Alcoholism

• Pregnancy or in early postpartum period

Laboratory MonitoringLaboratory Monitoring

Repeat laboratory monitoring if patient has:Repeat laboratory monitoring if patient has: �� Abnormal baseline resultsAbnormal baseline results �� Current or recent pregnancyCurrent or recent pregnancy �� High risk for adverse reactionsHigh risk for adverse reactions �� Symptoms of adverse reactionSymptoms of adverse reaction �� Liver enlargement or tenderness duringLiver enlargement or tenderness during

examinationexamination

Laboratory MonitoringLaboratory Monitoring •• Asymptomatic elevAsympto ation of hepatic enzymes seenmatic elevation of hepatic enzymes seen

in 10%in 10%--20% of people taking INH20% of people taking INH -- Levels usually return to normal after completion ofLevels usually return to normal after completion of

treatmenttreatment •• Some experts recommend withholding INH ifSome experts recommend withholding INH if

transaminase level exceeds 3 times the upper limittransaminase level exceeds 3 times the upper limit of normal (if symptomatic) and 5 times the upperof normal (if symptomatic) and 5 times the upper limit of normal if patient is asymptomaticlimit of normal if patient is asymptomatic

MMWR June 9, 2000; 49(No. RR-6): 39

Meeting the Challenge ofMeeting the Challenge of TB PreventionTB Prevention

For every patient:For every patient: �� Assess TB risk factorsAssess TB risk factors �� If risk is present, perform TST or IGRAIf risk is present, perform TST or IGRA �� If TST or IGRA is positive, rule out active TBIf TST or IGRA is positive, rule out active TB

diseasedisease �� If active TB disease is ruled out, initiateIf active TB disease is ruled out, initiate

treatment for LTBItreatment for LTBI �� If treatment is initiated, ensure completionIf treatment is initiated, ensure completion

Case StudiesCase Studies

Case Study #1Case Study #1 Patient historyPatient history

�� 36 year36 year--old Native American femaleold Native American female

�� History of diabetesHistory of diabetes

�� 35 weeks pregnant35 weeks pregnant

�� TST = 18 mm indurationTST = 18 mm induration

�� No symptoms of TB diseaseNo symptoms of TB disease

�� CXR, CBC, LFTs normalCXR, CBC, LFTs normal

�� No known contact to active caseNo known contact to active case

Case Study #1Case Study #1 QuestionsQuestions 1.1. What are this patientWhat are this patient’’s risk factors fors risk factors for

TB infection or disease?TB infection or disease?

2.2. What is the appropriate managementWhat is the appropriate management for this patient?for this patient?

Case Study #1Case Study #1

•• Persons withPersons with diabetes mellitusdiabetes mellitus are 2 to 4are 2 to 4 times more likely to develop TB diseasetimes more likely to develop TB disease than those withoutthan those without diabetesdiabetes

•• Risk may be higher in insulinRisk may be higher in insulin--dependentdependent diabetics and those with poorlydiabetics and those with poorly controlled diabetescontrolled diabetes


•• Pregnancy has minimal influence on thePregnancy has minimal influence on the pathogenesis of TB or the likelihood of LTBIpathogenesis of TB or the likelihood of LTBI progressing to diseaseprogressing to disease

•• Pregnant women should be targeted for TBPregnant women should be targeted for TB testing only if they have specific risk factorstesting only if they have specific risk factors for LTBI or progression to diseasefor LTBI or progression to disease


�� In the absence of risk factors, wait untilIn the absence of risk factors, wait until after delivery to start therapy (to avoidafter delivery to start therapy (to avoid unnecessary medication during pregnancy)unnecessary medication during pregnancy)

�� Consider immediate treatment for LTBI ifConsider immediate treatment for LTBI if HIV+ or recent contactHIV+ or recent contact

Case Study #2Case Study #2 Patient historyPatient history

�� 41 year41 year--old Hispanic maleold Hispanic male

�� Moved to U.S. from Mexico 4 years agoMoved to U.S. from Mexico 4 years ago

�� Known contact of infectious TB caseKnown contact of infectious TB case

�� TST = 5 mm of indurationTST = 5 mm of induration

�� 3 months later TST = 23 mm of induration3 months later TST = 23 mm of induration

�� No symptoms of TB diseaseNo symptoms of TB disease

�� Normal CXR, CBC, AST, and bilirubinNormal CXR, CBC, AST, and bilirubin


QuestionsQuestions

1.1. What are the patientWhat are the patient’’s risk factors for TBs risk factors for TB infection or disease?infection or disease?

2.2. Has the management of this patient toHas the management of this patient to date been appropriate?date been appropriate?


Risk factorsRisk factors

•• Patient is aPatient is a contact of an infectious TBcontact of an infectious TB casecase

•• Recent immigrantRecent immigrant to the U.S. from ato the U.S. from a country with a high prevalence of TBcountry with a high prevalence of TB

Case Study #2Case Study #2 Discussion of risk factorsDiscussion of risk factors •• If the patient had not been a contact, theIf the patient had not been a contact, the

recent immigration (less than 4 years) wouldrecent immigration (less than 4 years) would have made him a candidate for TB testing,have made him a candidate for TB testing, but the 5but the 5--mm reaction would not bemm reaction would not be considered positiveconsidered positive

•• Persons who immigrate from TBPersons who immigrate from TB--endemicendemic countries have increased rates of TBcountries have increased rates of TB


Discussion of managementDiscussion of management •• Recent immigrants should be treated forRecent immigrants should be treated for

LTBI if TSTLTBI if TST ≥≥ 10 mm of induration10 mm of induration •• As a contact of an active TB case, 5 mmAs a contact of an active TB case, 5 mm

of induration is considered positiveof induration is considered positive •• This patient should have been treated forThis patient should have been treated for

LTBI immediately after the first TSTLTBI immediately after the first TST

Case Study #3Case Study #3 Patient historyPatient history �� 56 year56 year--old White maleold White male �� Works in a mycobacteriology labWorks in a mycobacteriology lab �� TST (1 year ago) = 0mmTST (1 year ago) = 0mm �� M.M. marinummarinum infection in his hand 8 months agoinfection in his hand 8 months ago �� TST (current) = 5 mm indurationTST (current) = 5 mm induration �� IGRA (QFTIGRA (QFT--GIT) testGIT) test ““positivepositive”” �� No symptoms of TB disease, CXR normalNo symptoms of TB disease, CXR normal �� No contact to TB case and no spills / accidents in theNo contact to TB case and no spills / accidents in the

lablab


Questions:Questions: �� Is treatment of LTBI indicated?Is treatment of LTBI indicated? �� What about positive QFT test?What about positive QFT test? �� Current skin test positive?Current skin test positive? �� What if TST one year from today measuresWhat if TST one year from today measures

15 mm induration?15 mm induration?

Documents

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