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Oct 4, 2012

Shu-Hua Wang, MD, MPH &TM

Assistant Professor of Medicine

The Ohio State University2

Multidrug-resistant TB in the world

update October 2011

The Global TB SituationThe Global TB Situation

Estimated number

of cases, 2010

Estimated number

of deaths, 2010

1.1 million*

(0.9–1.2 million)

8.8 million

(8.5–9.2 million)

~ 650,000 out of 12 million (11-14 million)

prevalent TB cases

All forms of TB

Multidrug-

resistant TB

HIV-associated TB 1.1 million

(1.0–1.2 million)

350,000(320,000–390,000)

Source: WHO Global Tuberculosis Control Report 2011 (www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf)

* Excluding deaths attributed to HIV/TB

-•Every secondsomeone is newly infected with TB

•2 billion people, 1/3 of the world’s total population, are infected with TB

• 1 in 10 people infected with TB will develop TB

Slide courtesy of Ian Durrant, PhD

The Hidden Epidemic:

Latent TB Infection1999-2000 NHANES

� 4.2% = 11,213,000 persons infected� 1.8% in U.S.-born� 18.7% in foreign-born

� 25.5% reported prior history of TB/LTBI�Only 13.2% reported prior treatment (about half)

-

photo courtesy of Ian Durrant, PhD

Bennett DE. AJRCCM 2008 177:348

NHANE: National Health and Nutritional Examination

The Hidden Epidemic: LTBI in the US

Reported TB Cases United States, 1982–2010*

*Updated as of July 21, 2011

No. of Cases

Year

Targeted testing identifies high risk individuals who would benefit from treatment

of LTBI if it is detected

Definition of Targeted Testing

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�Tuberculin screening of general population is not recommended

� Screening should be targeted to those at higher risk of TB� Increased rates of TB infection

� Increased risk of progression to active TB if infected

� Persons or groups with increased risk of recent exposure to TB

Targeted TB Testing and treatment of LBI. Am J Respir Crit Med 2000:161

Who Should be Screened for TB?

�Close contacts to persons with infectious TB

�Residents and employees of high-risk

congregate setting (correctional facilities,

homeless shelters, health care facilities)

�Recent immigrants from TB-endemic regions

of the world (within 5 years of arrival to the

United States)

CDC: Target TB testing and treatment of LTBI Dec 2011

Increased Likelihood of Exposure

to Persons with TB Disease

Foreign-born Persons Who Entered the U.S.

Category Number

Immigrants

New Arrivals

Adjustment of status

1,042,625

358,411

619,913

Refugees/Asylees 73,293

Nonimmigrants/Temporary visa

Pleasure

Business

Workers and families

Students

159,700,000

235,131,310

5,205,980

2,816,525

1,595.078

U.S. Citizenship and Immigration Services 2010

TB

Scr

eenin

g

�HIV infected

�Those with history of prior untreated TB or fibrotic lesions on CXR

�Children ≤5 years with a positive TSTs

�Underweight or malnourished person

�Injection drug users

�Those receiving TNF-alpha antagonist for treatment of rheumatoid arthritis or Crohn’s disease

�Systemic glucocorticoids (>15mg/day for > 1 months)

CDC: Target TB testing and treatment of LTBI Dec 2011

Increased Likelihood of Exposure to

Persons with TB Disease - 1

�Diabetes mellitus

� Silicosis

�Chronic renal failure on hemodialysis

�Organ transplantation

�Carcinoma of head or neck

�Gastrectomy or jejunolilial bypass

�Cigarette smoker

CDC: Target TB testing and treatment of LTBI Dec 2011

Increased Likelihood of Exposure to

Persons with TB Disease - 2

Small & Fujiwara NEJM 2001 345:192

1-5µ

Transmission of TB and Progressionfrom Latent Infection to Reactivated Disease - 1

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Small & Fujiwara NEJM 2001 345:192

1-5µ

Transmission of TB and Progressionfrom Latent Infection to Reactivated Disease - 2

Hypertension

� Asymptomatic condition

� Very serious complications� Death

� Major disability

� Treatment = years� Expensive, potential SE, requires close monitoring

� NO debate about treatment

Latent TB Infection

� Asymptomatic condition

� Very serious complications� Death

� Major disability

� AND TRANSMISSION

� Treatment = 9 months� Cheap medication, potential serious SE, require close monitoring and follow up

�WHY the debate about treatment?

Menzies et al., Indian J Medical Research, 2011

Why Debate About Treating LTBI ?

�Gabriel

�20 years old

�TST = 5 mm, CXR = NAPD, No Symptoms

Question: True or False?

Gabriel’s tuberculin skin test is positive and

he should be started on treatment for latent TB infection.

Question 1

High-risk groups

�Recent contacts of a TB case

�HIV-infection

�Fibrotic changes on chest radiograph consistent

with old TB

�Organ transplant recipient

�Other immunosuppressed patients

� Equivalent >15 mg/day of prednisone for >1 month

� Anti-TNFα medication

August 2003 http://www.cdc.gov/tb (404) 639-8140 Document # 250110

TST ≥ 5mm

�Foreign born from countries with high TB

prevalence

� Injection drug users�Residents and employees of high-risk congregate settings

� correctional facilities , homeless shelters

� nursing homes, hospitals, health care facilities

�Mycobacteriology laboratory personnel�Chronic illness: DM, ESRD, Heme disorder, malignancy, loss > 10% IBW, Silicosis

August 2003 http://www.cdc.gov/tb (404) 639-8140 Document # 250110

TST > 15 mm – No Risk for TB

TST ≥ 5mm

Lee and Holzman CID 2002, 34:365

Distribution of TST Reactions

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� Diagnosis of latent TB relies on the 100-year old skin test

�Poor specificity: � antigenic cross-reactivity of PPD with BCG and environmental mycobacteria

�Poor sensitivity: � 75-90% in active disease

The skin test enters its 6th decade of use.

(Canada 1957)

Current Diagnostic Test for TB

Administering TST

� Inject 0.1 ml of 5 TU PPD tuberculin solution intradermally on volar surface of lower arm

� Produce a wheal 6 to 10 mm in diameter

No Tape or band aids

Tuberculin Skin Test (TST)

Needle Too Shallow

Reading TST

�Measure 48 to 72

hours

� Induration, not

erythema

�Record reaction in

mm, not “negative”

or “positive”

Tuberculin Skin Test (TST)

�Andrea�40 years old, HIV (+), pregnant 2 months�Boyfriend just diagnosed with active pulmonary TB

�She does not have any symptoms of active TB

�A. Can you place TST on a pregnant woman?

�B. Should we place an anergy panel? �C. Should you get a CXR in a pregnant woman if she has no symptoms?

�D. Should she be treated for LTBI or active TB?

Question 2

�A. Placing TST on pregnant or nursing mother is safe

�B. Anergy skin testing no longer routinely recommended

� C. CXR - Shielding consistent with safety guidelines even during first trimester of pregnancy

� D. HIV infected persons and children <4 years old exposed to an infectious case of TB, should be treated for LTBI after r/o for active TB

Answer

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Menzies D AJRCCM 1999. 159:15

Interval from Primary Infection

to TST Conversion

Rosa

�40 year old nurse from the Philippines

�No significant past medical history

�Needs tuberculin skin test (TST) for work

� She states that she has been vaccinated with BCGwhich will cause her TST result positive, so she should be exempt from getting a TST

�True or False?

Testing in BCG Vaccinated

Individuals

�Live vaccines derived from a strain of Mycobacterium bovis that was attenuated by Calmette and Guérin at the Pasteur Institute

�First administered to human in 1921

�Many different BCG vaccines are available worldwide

�BCG protective efficacy TB in children is high (>80%) against TB meningitis and miliary TB

Grange et al., What is BCG? Tubercle 1983;64:129-39

Clemens The BCG controversy JAMA 1983;249:2362-9

What is BCG?

�BCG might cause a false positive result initially

�Tuberculin reactivity wanes after 5 years but can be boosted by subsequent TST

�TST reactions of > 20mm of indurations are not usually caused by BCG

�No reliable skin test method to differentiate TST reaction from BCG vs mycobacterial infection

�U.S. guidelines: Positive TST in person who receive BCG should be interpreted as indicating LTBI

MMWR 2005, Vol 54 RR17p83

Does BCG Affect TST Results and

Interpretation?

BCG Vaccination Program

�Rosa’s baseline first TST result is 6 mm, does a second step TST need to be placed?

� If baseline TST is <10mm, a second-step should be applied 1-3 weeks after the first TST result was read

TST “Boosting”

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�Reactivity can be accentuated with repeated testing• Initial skin test may stimulate (boost) ability to react to tuberculin

�Positive reactions to subsequent tests may be misinterpreted as a new infection

Menzies D AJRCCM 1999. 159:15

TST Boosting

False Negatives� Anergy � Recent Exposure (less than 10 weeks after exposure)

� Very young age (newborns < 6 months)

� Live-virus vaccination (TST placed < 4 weeks after MMR)

� Overwhelming active TB Disease

� Other active infection� Poor administration technique for TST

False Positive

�Non-tuberculosis mycobacteria (NTM)

� BCG vaccination

False Positive or False Negative TST

Is there another test besides TST?

Anderson et al., Lancet

Interferon Gamma Release Assays

TB naive

X

XX

Interferon Gamma Release Assays

TB exposedPositive Test!

Interferon Gamma Release Assays

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Species specificity of

ESAT-6 and CFP-10

Tuberculosis Complex ESAT CFP 10

M tuberculosis + +

M africanum + +

M bovis + +

BCG substrains - -

Environmental strains ESAT CFP 10

M kansasii + +

M marinum + +

M szulgai + +

http://www.tbevidence.org/documents/guidelines/ECDC_IGRA_Guideline_2011.pdf

�Use TST or IGRAs as aids to diagnose

M. tuberculosis infection

�May use IGRAs in place of TST in all situations in which CDC recommends TST

� IGRA is preferred

� poor rates of return for TST reading

� who have received BCG

�TST is preferred

� for testing children < 5 years of age

2010 IGRA Recommendations

IGRA TSTin vitro test in vivo test

Specific antigens

Not affected by prior BCG Less specific PPD

No boosting Boosting

single patient visit 2 patient visits

Results possible in 1 day Results in 2-3 days

Requires phlebotomy TST placement skills

Error in collecting, transporting, lab

Inter-reader variability

IGRA = interferon gamma release assay, blood test for TBTST = tuberculin skin test or PPD

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NO Test Can “RULE OUT” TB

LTBI

�TST or IGRA

positive

�CXR Negative

�No symptoms or

physical findings

suggestive of TB

disease

Pulmonary TB Disease�TST or IGRA may be positive

�CXR may be abnormal� Symptoms may include one or more of the following: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite

�Respiratory specimens may be smear or culture positive

�NAAT may be positive

NAAT= nucleic acid amplification tests

Summary

� Finding and treating LTBI is essential for TB

prevention and control

�New tools for dx and tx of LTBI can improve

effectiveness of TB control

� In some groups, use of IGRAs can be cost

effective compared to TST

A Decision to Test is a Decision to Treat