Contact Investigation Flagstaff, Arizona October 25, 2006

Tuberculosis Screening and Treatment of Latent TB Infection

L. Masae Kawamura, MD October 25, 2006

Tuberculosis Screening and Treatment of Latent TB Infection

2006

L. Masae Kawamura, M.D. Director, TB Control Section, San Francisco

Department of Public Health

Francis J. Curry National Tuberculosis Center University of California, San Francisco

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Diagnosing TB infection and disease is aDiagnosing TB infection and disease is a primary care issueprimary care issue …..

Overview

• Review the basis of TB screening and populationsmore likely to have been infected with Mycobacterium tuberculosis

• Review medical conditions and factors associated with higher TB disease progression

• To discuss recent developments in diagnosis andtreatment of latent tuberculosis infection

• Briefly discuss prioritizing patients for evaluation,treatment, and completion

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Transmission of Tuberculosis

CASE CONTACT

Site of TB Ventilation Closeness and Cough Filtration duration of contact Bacillary load U.V. light Immune status Treatment Previous infection

Active TB: Risk of Contagion Determined by bacillary load and sx’s � TB nodule: 100 - 1000 organisms � Cavity: millions to billions � Presence of cough � Positive sputum smears

Other factors Environment/site of exposure Respiratory protection On treatment Aerosolizing procedures (bronchoscopy)

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Transmission and Pathogenesis of TB

Children <5% and immunocompromised adults

Exposure

Continued containment (90%)

No infection (70%)

Adequate

Non-immunologic defenses

Inadequate

Infection (30%)

Inadequate

Immunologic defenses

Adequate

Containment (95%)

Early progression* (5%)

Late progression(5%)

Inadequate

Immunologic defenses

Adequate

*Risk of progression much higher in

Flowchart: Evaluation to Treatment of LTBI

At-risk person

Tuberculin test + symptom review

Negative Positive

Chest x-ray

Normal Abnormal

Treatment Candidate for Rx Evaluate for not indicated of latent TB active TB

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Symptoms and Signs of Active TB

Pulmonary Systemic • Chronic cough 40-80% • Fever – 65-80% • Sputum production • Chills/sweats • Pleuritic chest pain • Fatigue/malaise • Hemoptysis • Anorexia/weight loss

• No symptoms 10-20%

Goals of screening

� Identify active cases � Identify infected persons likely to benefit from

treatment of latent TB infection (LTBI) � Surveillance

1) Detect transmission: eg. evaluate efficacy of institutional control measures

2) Prevalence of TB infection in a population: surrogate marker of TB case rate

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Who should be screened NOT the general population. Screening should be targeted to those at higher risk of TB.

� Populations with increased rates of TB infection and documented cases of transmission

� Persons with increased risk of progression to active TB

if infected

Program prioritization should be based on local epidemiologic data and the number of risk factors present in a given population or individual (eg. Shelters with high HIV rate, etc)

TB Screening: Determining risk by your assessment

� Risk of infection -prior exposure TB -current/recent exposure to TB -ongoing/chronic exposure

� Risk of disease progression -Medical risk factors -history of prior TB

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Risk of infection

� Contacts of infectious TB cases

Risk associated with disease burden and presence of cough of the source case

� Foreign-born persons from TB endemic countries � Healthcare workers � Correctional facilities (inmates and staff) � Nursing homes � Long-term care facilities � Renal dialysis units

Risk of infection (2)

Medically underserved/low-income groups: � Homeless � Migrant workers � Low-cost hotel dwellers or crowded

impoverished living conditions

� Street drug users � Racial and ethnic minorities � Children with parents that have TB risk factors

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Risk of progression

� HIV infection and other medical conditions

� Individuals with abnormal chest x-ray compatible with past TB

� Infants and children <5 yrs of age (sentinels of transmission)

Risk of progression (2)

Recent infection (contacts and converters):

� 4-5% risk of developing active disease within the first 1-2 years

� Risk may double if contact is <4 years old

� 40% progression to disease in infants younger than 12 months

� HIV co-infected progression much higher than 7-10 per year%!!!!

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Risk of progression (3)

Medical conditions: Immunosuppressive agents � Immunosuppression � Chronic steroids � Lymphoma, leukemia

� Cancer chemotherapy � Injection drug use

� Cyclosporine� Diabetes � Malnutrition � New: TNFα blockade � Renal failure -Etanercept (Enbrel®) � Silicosis -Infliximab (Remicade®) � Alcoholism -Adalimumab (HumiraTM)

� Gastrectomy/ Jejunoilealbypass � Head and neck cancer

Frequency of screening

� Retesting: dependent on ongoing risk of TB exposure � Frequency: dependent on degree of chronic TB

exposure (use local epidemiology) – Annual testing* : HCWs, long term-care residents,

shelter or homeless CBO or substance recovery program staff

– Q 6 month testing* : TB clinic frontline staff, ER workers, pulmonologists performing bronchoscopy

– Periodic testing * : extended travel to high risk area *Need to correlate with local epidemiologic data

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Diagnosis of tuberculosis infection

TB Skin Test (TST) QuantiFERON Blood Test

(QFT)

Mantoux Tuberculin Skin Test - Key Points

• TST should not be performed on someone with documented history of a positive test

• TST should be read and interpreted by a trained health care professional

• TB disease must be ruled out before initiating treatment for LTBI

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Administering the TST

• Inject 0.1 ml of 5 TU PPD tuberculin solution intradermally on volarsurface of lower arm using a 27 gauge needle

• Produce a wheal 6 to 10 mm in diameter

•

Reading the TST (1)

• Measure reaction in 48-72 hrs

• Measure induration, not erythema

• Record reaction in millimeters, not negative” or “positive”

• Ensure trained health care professional measures andinterprets the TST; no self-reading!!!!

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Reading the TST (2)

• Positive TST reactions can be measured accurately for up to 7 days

• Negative reactions can be read accurately for only 72 hours

Tuberculin Skin Test Interpretation: CDC/ATS/AAP Cut Points

> 5 mm > 10 mm

� HIV co-infection � Foreign-born from a HR country � Immune compromise � Drug –users � Recent contact to TB � Living in HR congregate setting � Suspected disease � Specific HR groups

� Children < 4 yrs old (AAP)

>15 mm

All others (low risk groups) Why did you test?

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Tuberculin skin test interpretation: tuberculin skin test conversion

� Signifies new infection

� CDC definition: >10 mm increase within 2 year period

� Problems with interpretation: conversions may actually represent BOOSTED reactions in some individuals

Tuberculin skin test interpretation: false-negative results

Host factors Technical factors � HIV

� The tuberculin used (i.e., � Recent TB infection (<3 improper storage,

months) contamination) � Infections (viral, fungal,

bacterial) � Improper method of administration, reading � Other illness affecting and/or recording of results lymphoid organs

� Live virus vaccination � Immunosuppressive drugs � Overwhelming TB

� Age (newborn, elderly)

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Tuberculin Skin Testing “Boosting”

14 mm 11 mm 12 mm

Years

0 5 10 15 20 30 31

Infection TST TST TST TST

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15

10

5

0

TST: False-positive Results

Causes

� Cross-reactions and boosted reactions from atypical mycobacterial infections and BCG

� Recent (<1 yr) or multiple BCG vaccination

� Misinterpretation of immediate hypersensitivity to tuberculin

� Switching tuberculin products (tubersol with applisol)

Indu

ratio

n(m

m)

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Tuberculin skin test interpretation: the booster phenomenon (2)

Who needs two-step testing for boosterresponse?

� Individuals who will be tested on a regular basis (i.e., yearly)

� Elderly in high risk groups (>55 years)

The booster dose is usually administered 1-4 weeks after initial PPD and read in 48-72 hours

Screening individuals who are likely to have false negative TST results (young infants, HIV+s, immunosuppressed)

� Chest x-ray – look for evidence of TB infection (e.g., hilar calcification, upper lobe fibrosis, calcified granuloma)

� Symptom review

� Assess TB risk factors

� Decision to provide LTBI treatment in the absence of a positive TB test should be based on risk of true infection and public health implications

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A new blood test for TB: Interferon-γ Release Assays

1. QuantiFERON-TB Gold (Cellestis Ltd., Carnegie, Australia) approved for use by the FDA approved-12/04

2. T SPOT-TB (Oxford Immunotec, Oxford, UK)

� Measures T-cell reactivity to M.tb specific M.tb antigens ESAT-6 and CFP-10

� Improved specificity: able to distinguish between TB and NTM, BCG infection

� Studies in contacts, HIV infected and children promising

QFT-G CDC guidelines: MMWR. December 16, 2004 / Vol. 54 / No. 49

� Recommends use of the test in all situations where the skin test is currently being used

-includes contact investigation, immigrant

evaluation and serial testing of HCWs

� Use caution when interpreting negative QFT results in children, immunocompromised, and HIV infected adults because of limited data

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-

‘ ’

-

-

QFT-G CDC guidelines: MMWR. December 16, 2005 / Vol. 54 / No. 49

� Contact investigation: repeat test as you would the TST if initial QFT-G is negative at 8-10 wks

� If initial indeterminate results: repeat QFT-G or place TST or do nothing

� CDC guidelines for preventing the transmission of TB in health-care settings (MMWR 54 (No. RR-17, 1-141, 2005) also suggests that QFT-G can be used for surveillance and conversion: defined as change from negative to positive result

How QuantiFeron™ is performed

Culture overnight at 37Culture overnight at 37ooCC TB infected individuals respondTB infected individuals respond

by secreting IFNby secreting IFN-γγ

5 cc5 cc HeparinizedHeparinized whole bloodwhole blood

AntigensAntigens MitogenMitogen ControlControl

Transfer undiluted whole bloodTransfer undiluted whole blood into wells of a culture plateinto wells of a culture plate

and add antigensand add antigens

Harvest plasma from aboveHarvest plasma from above settled cells and incubate 60settled cells and incubate 60

min inmin in ‘SandwichSandwich’ ELISAELISA

Wash, add substrate,Wash, add substrate, incubate 30 minincubate 30 min

then stop reactionthen stop reaction

TMBTMB

COLORCOLOR

IFN-γ IU/mlOD

450

nmO

D 4

50nmStandard CurveStandard Curve

Measure OD,Measure OD, determine IFNdetermine IFN-γγ levelslevels

and interpret testand interpret test

Stage 2 IFNStage 2 IFN-gamma ELISAgamma ELISA

NilNil ControlControl

Stage 1 Blood CultureStage 1 Blood Culture

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QFT-gold Comparison with QFT-1g and TST

QFT-1g QFT-gold TST

89.0%* 82.1% 65.7%Sensitivity 105 / 118 92 / 112 +ve 50 / 76 > 5 mm+ve

98.1% 35.4%56.0%Specificity 213 / 216 – 40 / 113 < 10 108 / 192 -veve mm

Mori, et al. AJRCCM 2004; 170:59-64

Exposure group

QFT-gold: Contacts Brock et al, AJRCCM 2004; 170:65-69

TST+ n (%)

nBCG status

QFT n (%)

HIGH - 45 25 (56%) 24 (53%)

+ 8 Not done 4 (50%)

LOW - 40 4 (10%) 2 (5%)

+ 32 Not done 2(6%)

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QFT-gold: Contacts Brock et al, AJRCCM 2004; 170:65-69

• Study used recombinant ESAT-6 and CFP10 antigens (FDA approved QFT-G uses overlappingpeptides)

• Showed 94% agreement between TST and QFT-G in unvaccinated individuals

• QFT-G was not affected by BCG

Current IGRA studies on contacts: QFT-G and T-spot correlate better with exposure than TST

QFT-G vs TST QFT TST

Boosting No Yes Placement variability No Yes Reading variability No Yes Cross reactivity with BCG and NTMs No Yes Patient Visits > 1 > 2 Wait time for results (days) > 1 2-3

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QFT-G vs TST QFT TST

Potential conversions and reversions Yes No?

Results without patient return Yes No

CI: correlation to exposure Yes variable

Risk of progression known No Yes

Laboratory logistical issues Yes No

Current GUIDELINES FOR TB PREVENTION: CHANGES FROM THE

PAST

• DECISION TO TEST IS DECISION TO TREAT!

• No 35-year-old cut-off

• 9 months of INH preferred over 6 months

• Baseline laboratory monitoring not routinely indicated

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TREATMENT OF LATENT TB INFECTION How long is enough?

0 6 12 18 24

Months of Treatment

Cases per 100

5

4

3

2

1

0

Observed values

Calculated curve Calculated values

Comstock Int J Tuberc Lung Dis. 1999;10:847

• Lower TB rates among those who took 0-9 mo

• No extra increase among those who took >9 mo

NEW TB GUIDELINES FOR INH A Numbers Game

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HIV Co-Infection Children

Prior TB on CXR (TB-4) Regular Folks

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CURRENT OPTIONS FOR TREATMENT OF LATENT TB INFECTION

• Isoniazid for 9 months – either daily or twice weekly (6 months acceptable for programmaticreasons)

• Rifampin for 4 months (+/- INH) ATS/CDC AFRCCM 2000;161:s221

NOTE: Rifampin/pyrazinamide 2 months regimen isno longer recommended due to severe liverinjury and deaths (CDC revision 8/03)

Window Prophylaxis: LTBI treatment of TB exposed individuals with negative TB test results

Who should get window prophylaxis? • High risk TB contacts (young children and

immunocompromised/HIV+) who have initial negative TB test results AND significant TB exposure

When can window treatment be discontinued? • HIV-negative children: 8-10 weeks after contact broken to

untreated case and repeat TB test negative • Immunocompromised/HIV: Repeat testing may not be helpful

because of false negative results Use discretion of your TB program (some programs will treat for 9 months, while others may use CD-4 counts, hours of exposure, bacillary burden of index case and environmental factors)

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TREATMENT OF LATENT TUBERCULOSIS IN SPECIAL SITUATIONS

• HIV-infected patients: Use rifabutin when rifampin is contraindicated with concurrent use of certain anti­retroviral agents

• For persons intolerant of INH, use 4 months of rifampin

• Pregnancy is not a contraindication to LTBI treatment unless the source case is MDR Balance likelihood of true MDR infection, risk of progression, maternal resistance to taking meds with waiting until after delivery

What About LTBI and Drug-Resistance?

• Contacts of INH-resistant TB: 4-6 months of rifampin (longer for children and immunocompromised)

• Contacts of MDR-TB: consult an expert

If treatment is not available, refused or not tolerated: • Thorough patient education of TB signs and sxs • Close clinical monitoring for 2 years is recommended

for contacts and converters

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Initiating Treatment

Before initiating treatment for LTBI • Rule out TB disease (CXR; sputum

samples; wait for culture result if sputum samples obtained)

• Determine prior history of treatment for LTBI or TB disease

• Assess risks and benefits of treatment

Isoniazid Regimens (1)

• 9-month regimen of isoniazid (INH) is the preferred regimen

• 6-month regimen is less effective but may be used if unable to complete 9 months

• May be given daily or intermittently (twice weekly) – Use directly observed therapy (DOT) for

intermittent regimen

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Isoniazid Regimens (2)

• INH daily for 9 months (270 doses within 12 months)

• INH twice/week for 9 months (76 doses within 12 months)

• INH daily for 6 months (180 doses within 9 months)

• INH twice/week for 6 months (52 doses within 9 months)

Adverse Reactions - INH

Possible adverse effects – • Asymptomatic elevation of serum liver

enzymes • Clinical hepatitis • Peripheral neuropathy • Allergic rash

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INH and Peripheral Neuropathy

• Occurs in < 0.2% of people taking INH at conventional doses

• More likely in diabetes, HIV, renal failure, and alcoholism

• Give pyridoxine supplementation (B6) 25-50 mg daily with above conditions

• B6 also recommended for pregnant and breastfeeding women (50 mg)

Rifampin Regimens (1)

• Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible

• RIF daily for 6 months is recommended for children and HIV infected patients

• In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted

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Rifampin Regimens (2)

• RIF daily for 4 months (120 doses within 6 months)

• RIF and PZA for 2 months should generally not be given due to risk of severe liver injury and deaths*

*MMWR August 8, 2003; 52 (31): 735-739

Rifampin: Adverse Reactions

• Hepatotoxicity • Drug rash • Many drug-drug interactions • Contraindicated in HIV-infected individuals

taking certain protease inhibitors or non­nucleoside reverse transcriptase inhibitors

Don’t forget to warn patients about orangediscoloration of body fluids!

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Management of Patient Who Missed Doses

• Extend or re-start treatment if interruptions were frequent or prolonged enough to preclude completion

• When treatment has been interrupted for > 2 months, patient should be examined to rule out TB disease

• Recommend and arrange for DOT as needed

MONITORING PATIENTS

• Baseline laboratory testing not needed except for: 1) HIV infection 2) pregnancy 3) Hx of liver disease/heavy EtOH use 4) Patient on other liver toxic medication

• Monthly clinical monitoring : 1) adherence 2) side effects

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INH HEPATOTOXICITY IN THE MODERN ERA

• 11,141 patients treated with INH from 1989-1995

• 11 had hepatitis (defined by symptoms, ↑ AST, resolution after stopping INH), no deaths

• Overall rate was 1 per 1,000!

Nolan JAMA 1999;281:1014

Asymptomatic Elevation of Serum Liver Enzymes

• Seen in 10%-20% of people taking INH – Levels usually return to normal after completion of

treatment

• Withhold INH if SGOT (AST) or SGPT (ALT) level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity and 5 times the upper limit of normal if patient is asymptomatic

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

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Clinical Monitoring (1)

Instruct patient to report signs or symptoms of adverse drug reactions

• Rash

• Anorexia, nausea, vomiting, or abdominal pain in right upper quadrant

• Fatigue or weakness

• Dark urine

• Persistent numbness in hands or feet

Clinical Monitoring (2)

Monthly face-to-face visits should include a review of the following:

• Rationale for treatment • Adherence with therapy • Symptoms of adverse drug reactions • Plans to continue treatment

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RE-TREATMENT OF LATENT TB INFECTION

• Re-infection can occur • Serious issue for immunocompromised

individuals

• Recommended for those who have HIV infection, other diseases causing chronicimmune suppression, and <21-years-old whohave been in contact with a smear-positive case

Counseling A Patient With LTBI

NEVER SAY: You’ve been “exposed” so you need to be treated.

INSTEAD: You have been exposed AND infected with the TB bacteria. But don’t worry…

Good news: you do not have the disease and you are not contagious to anyone.

Bad news: It is sleeping in your body and can wake up later, make you very ill and contagious to others

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Counseling A Patient With LTBI (2)

Why get treated? Treatment will prevent future disease and protect you and those close to you.

Warning: • Taking medication for 6-9 months is a long time but

it takes that long to kill all or most of the TB germs. • “TOUGH bugs”… so take your medicine correctly

and completely

Summary

For every patient • Assess TB risk factors • If risk is present, perform TST or

QFT-G • If TST or QFT-G is positive, rule out

active TB disease • If active TB disease is ruled out,

initiate treatment for LTBI • If treatment is initiated, ensure

completion!

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Resources for TB Medical Consultation

� Francis J Curry National TB Center: TB Warmline (415) 502-4700 � Your local TB program

Acknowledgement: Karen Steingart MD

3 kinds of infected contacts: 20 y/o immigrant from China, an HIV+ US-born homeless man,

and a 3 y/o US-born Hispanic child • Each with 20 hours of exposure to smear positive

cases in similar indoor environments

• All 3 have 1st time positive TSTs –12 mm 1. Which most likely represents recent transmission? 2. Who will most likely to develop disease? 3. Who needs to be evaluated most urgently? 4. What other factors will influence your decision? 5. Will you use DOT?

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Thank you!