tb infection diagnosis · interferon-γ release assays and tuberculin skin testing for diagnosis of...

TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE May 8-11, 2018

Curry International Tuberculosis Center, UCSF

300 Frank H. Ogawa Plaza, Suite 520

Oakland, CA; Office (510) 238-5100

TB INFECTION DIAGNOSIS

LEARNING OBJECTIVES

Upon completion of this session, participants will be able to:

1. Understand the advantages and disadvantages of the TST and IGRA

2. Recognize CDC population preferences in the use of the TST and IGRA

3. Describe current regimens for the treatment of LTBI

INDEX OF MATERIALS PAGES

1. TB Infection Diagnosis – slide outline

Presented by: Lana Kay Tyer, RN, MSN

1-22

SUPPLEMENTAL MATERIAL

1. Centers for Disease Contol and Prevention. Division of Tuberculosis Elimination. Treatment Options for Latent Tuberculosis Infection.

2. JAMA. US Preventative Services Task Force. Screening for Latent Tuberculosis Infection in Adults. JAMA. 2016;316(9):962-969. doi:10.1001/jama.2016.11046.

TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE May 8-11, 2018

Curry International Tuberculosis Center, UCSF

300 Frank H. Ogawa Plaza, Suite 520

Oakland, CA; Office (510) 238-5100

ADDITIONAL REFERENCES

1. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children https://www.cdc.gov/tb/publications/guidelines/pdf/cid_ciw694_full.pdf

2. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf

3. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR 2011;60:1650-1653.

4. Centers for Disease Control and Prevention. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR 2003;52:735-739.

5. American Thoracic Society, CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–47.

6. CDC. Core Curriculum on Tuberculosis: What the Clinician Should Know. http://www.cdc.gov/tb/education/corecurr/index.htm

7. NTNC TB Nursing Manual: http://www.tbcontrollers.org/resources/tb-nursing-manual/#.WA-NDy0rJph

https://www.cdc.gov/tb/publications/guidelines/pdf/cid_ciw694_full.pdf

https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf

https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf

http://www.cdc.gov/tb/education/corecurr/index.htm

http://www.tbcontrollers.org/resources/tb-nursing-manual/#.WA-NDy0rJph

TB infection diagnosis

TB Case Management and Contact Investigation Intensive

Curry International Tuberculosis Center

May 8-11, 2018 1

TB INFECTION DIAGNOSIS

Lana Kay Tyer, RN MSN

Washington State Department of Health | 2

Objectives

• Apply risk assessment tools and determine TB risk

• Summarize the advantages and disadvantages of the TST and IGRA

• Identify the nurse role in LTBI diagnosis and treatment decisions




May 8-11, 2018 2


Terms and Definitions

TB Exposure Risk- risk factors are present that increase a patient’s risk of exposure to infectious TB disease

• high tb burden countries

• congregate settings

• identified contact

TB Progression Risk- Risk factors are present that increase a patient’s risk of developing TB disease once infected.

• Under 5 years old

• HIV infected

• Other Immunosuppression

Latent TB Infection- Evidence of cell-mediated immunity to TB (TST or IGRA) and NO evidence of active disease.

• Clinical

• Radiologic

• Microbiologic (usually not needed)


How will we reach TB elimination?




May 8-11, 2018 3

Section Two

MYCOBACTERIUM TUBERCULOSIS INFECTION


TB Progression

Exposure Infection Disease




May 8-11, 2018 4


TB Infection Diagnosis

Latent TB Infection- Evidence of cell-mediated immunity to TB (TST or IGRA) and NO evidence of active disease.

• Clinical

• Radiologic

• Microbiologic (usually not needed)


TB Exposure & Disease Risk

Approximately 30% of persons exposed to Mycobacterium tuberculosis will develop TB infection.

If untreated, approximately 5% to 10% of these persons will progress to active tuberculosis disease.

Highest risk of disease is in the first 2 years after exposure.

Overall risk increases with immunosuppressive conditions

o Uncontrolled Diabetes-30% lifetime risk

o HIV-10% additional risk per year




May 8-11, 2018 5


Tuberculosis Disease

Usually symptomatic and contagious.

o Cough

o Coughing up blood

o Weight loss

o Fever

o Night sweats

20% are asymptomatic

Abnormal X-ray, positive sputum culture (usually)

o Can be extrapulmonary


Assessment of TB Disease

Determine whether or not symptoms suggestive if TB disease are present

• Cough

• Coughing up blood

• Unexpected weight loss

• Fevers

• Night sweats

• Chest pain

• Hoarseness




May 8-11, 2018 6


Assessment of TB Disease

Chest Radiograph to look for evidence of disease

• Air space opacities

• Pleural effusions

• Cavities

• Changes on serial radiographs

If so, sampling (sputum collection, biopsy, etc) is needed for further evaluation.

• AFB Smear

• NAAT

• Culture identification

Section Two

ASSESSING RISK OF TB




May 8-11, 2018 7


Global TB Incidence

World Health Organization – Global Tuberculosis Report, 2017


CA Adult TB Risk Assessment




May 8-11, 2018 8


Testing Low Risk Individuals or Healthcare Workers

Low Risk

• TST low sensitivity, a subjective end point

• True conversion is 10mm or more increase in size during a 2 year period

Healthcare workers (Dorman)

• Baseline positive TST and negative IGRA was associated with BCG hx

• Conversions were not associated with TB exposure, and more than 90% of TST converters who were retested and 75% of IGRA converters were negative on testing 6 months later without treatment.

• Repeat testing in apparent converters in absence of know exposure is warranted to identify false positives.

TST VS IGRA




May 8-11, 2018 9


TST

Advantages Disadvantages

• Easy to perform

• Low cost

• Observation (reading) reflects a immune response

• Foundation of well controlled studies

• Well established definitions of TST conversion

• Trained person to place and interpret test

• Variability in interpretation

• 2 visits necessary

• Need 2 tests for baseline for serial testing

• False positives

• False negatives


IGRA

Advantages Disadvantages

• BCG-vaccinated population

• Screening hard to reach populations

o One patient visit

• No need for 2-step testing

• Requires blood draw

• Requires access to sophisticated lab

• Indeterminate rate may be higher in practice than in studies




May 8-11, 2018 10


IGRA Interpretation

QuantiFERON T-Spot TB

The QFT assay is considered positive if the difference between the IFN-γ concentration in response to the Mtb antigens and the IFN-γ response to the nil control is ≥0.35 IU

TB antigen response – Nil ≥0.35 IU/ml)

Source: http://www.quantiferon.com/wp-content/uploads/2017/05/PROM-10157_FAQs-Health-Professionals-Rev001v02.pdf

Results are interpreted by subtracting the spot count in the negative (NIL) control from the spot count in Panels A and B

Source: http://www.tspot.com/about-the-test/interpretation-t-spot-tb-results/


Recommendations for TB Infection Testing

ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children

• Recommend IGRA rather than TST in 5 years of older who

• Are likely to be infected with Mtb

• Have a low or intermediate risk of disease progression

• LTBI testing is warranted (risk assessment)

• Have a history of BCG

• Or are unlikely to return for TST read

• TST is acceptable alternative when limitations exist

• IGRA not available, too costly, too burdensome

• Recommend TST or IGRA in likely infected, high risk of progression.

http://www.quantiferon.com/wp-content/uploads/2017/05/PROM-10157_FAQs-Health-Professionals-Rev001v02.pdf

http://www.tspot.com/about-the-test/interpretation-t-spot-tb-results/




May 8-11, 2018 11


Recommendations for TB Infection Testing

ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of TB in Adults and Children

• Recommend that persons at low risk for Mtb infection and disease progression NOT be tested for Mtb infection.

• Suggest IGRA instead of TST

• TST acceptable when limitations exist for performing IGRA

• Suggest second test (TST or IGRA) if initial test is positive

• Healthy children over 5 years old TST over IGRA

• Again yield to IGRA preference for BCG


Who to test?




May 8-11, 2018 12


What test to use?


TST and IGRA Gaps in Knowledge

Pick any from the following to review:

• TST Placement

• TST Reading

• False Positive

• False negative

• BCG & BCGatlas.org

• 2-step TST

• Boosting of IGRA with TST




May 8-11, 2018 13

Section

TREATMENT OF LTBI


TB Infection Treatments

Rifampin x 4 months

Isoniazid and Rifapentine x 12 weekly doses

Isoniazid 6-9 months




May 8-11, 2018 14

Section One

NURSING ROLE IN LTBI


Nursing role in TB infection

Major role in TB Elimination

Providing necessary tools to medical community especially primary care to support TB infection screening and treatment

• Risk assessment tools

• USPSTF recommendations (coverage)

• TSTin3D with stated limitations

• A decision to test is a decision to treat

• Discussing treatment options relative to patient’s unique picture




May 8-11, 2018 15


TSTin3D

Provides a positive predicative value for the tests completed in the context of the patient’s risk factors.

• Age limitations

• Hepatotoxicity risk is calculated by INH 9 months only

• False negative tests

• TB prevalence estimation and NTM prevalence

• TST 5-9mm, no estimate for PPV


Latent TB Cascade of Care

0




May 8-11, 2018 16


Nursing role in TB infection

Come back to 5 rights of medication administration

✓ Right patient- epi of patient to assess risk of exposure

✓ Right time- was exposure recent? Window, MMR? 48-72 hours later

✓ Right drug- TST or IGRA

✓ Right dose- If positive what treatments options considerations for this patient?

✓ Right route- will patient return for reading or will blood be more reliable?


References

Alsdurf, H. et al. The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis. The Lancet Infectious Diseases Volume 16, Issue 11, Pages 1269-1278 (November 2016) DOI: 10.1016/S1473-3099(16)30216-X

Dorman, SE et al (2014. Interferon-γ release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States.Am J Respir Crit Care Med. 2014 Jan 1;189(1):77-87. doi: 10.1164/rccm.201302-0365OC.

Lewinsohn, D.M. et al. (2016) Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clinical Infectious Diseases® 2016;00(0):1–33. DOI: 10.1093/cid/ciw694.

Menzies, D. et al. (2008) Thinking in three dimensions: a web-based algorithm to aid the interpretation of tuberculin skin test results. INT J Tuberc Lung Dis 12(5): 498-505. online: http://www.tstin3d.com/thinking3D_2008.pdf

US Preventive Services Task Force Screening for Latent Tuberculosis Infection in Adults US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316(9):962-969. doi:10.1001/jama.2016.11046.




May 8-11, 2018 17

Section 6

CASE STUDIES


TST or IGRA?

Answer either “TST”, “IGRA”, or “no preference” which for each situation.

• Contact investigation among US born church group in rural area

• Contact investigation in urban diverse countries of origin at a high school

• Multiple household members of three Marshallese families

• Home care worker from Ethiopia

• 21 year old International college student from Germany

• 30 year old 20 week pregnant patient originally from Mexico 10 years ago.




May 8-11, 2018 18


Case Study A

27 yo Native American woman underwent two-step testing for employment. The second TST was not read and thus additional TST was done which resulted in 14 mm of induration. QFT was indeterminate (mitogen 0.07, nil 0.04).


Case Study A

What do you need to know next?

Risk factors: no known TB contacts, but is unsure about her childhood exposure while living on a reservation. No other medical conditions.




May 8-11, 2018 19


Case Study A

TB Risk:

• A second (or a third) TST at least one week after the first TST should elicit the booster phenomenon and the induration of her TST is 14 mm.

• Does her childhood history make the TST cut-off 10 vs. 15 mm?

Indeterminate QFT could be due to a technical issue (e.g., shaking the QFT tubes to stimulate antigen exposure), rather than the patient’s immunologic issues.

• Recommend repeating QFT, which can be done sooner.


Case Study B

TB infection or TB disease?

• Probable diagnosis of latent TB infection

• With strong recommendation for adequate treatment completion due to patient risk factors.

• Consider shorter treatment due to timeline of starting treatment for other medical condition.




May 8-11, 2018 20


Case Study C

32 yo man, US-born, no risk factors for TB exposure / TB progression, no history of TB testing in the past, underwent two-step TST before volunteering. No symptoms reported.

1st TST 3 mm induration

2nd TST one week later 8 mm induration


Case Study C

• Per CDC guidelines, the interpretation of the test results is negative for TB infection. See TB Skin Test Cut Points guide.

• Although the main goal of pre-employment TB screening is to detect active TB and to have a baseline screening on record, a chest X-ray is not indicated as long as he is asymptomatic.

• If the patient requires further clarification, recommend an Interferon Gamma Release Assay (IGRA).




May 8-11, 2018 21


Case Study D

72 yo man from Guatemala with diabetes had positive IGRA. His TST had been “always” positive. He works as a home health aide. His CXR showed a RML nodule, unchanged compared to the previous studies.

Use the TSTin3D and determine this patients lifetime risk of developing TB Disease.


Case Study D

• LTBI treatment is recommended because of increased risk of progression to active TB (diabetes, abnormal CXR)

• Careful clinical monitoring and education of the patient regarding side effects

• Consider less lengthy regimen due to the risk of adverse events from INH likely outweighs the benefits.




May 8-11, 2018 22


Case Study E

• His lifetime risk of progression to active TB is approximately 1% if in fact his TST had been 15 mm or greater. If less than 15 mm, the risk is even lower.

• As the risk of adverse reactions due to LTBI treatment outweighs the benefit of preventing active TB, LTBI treatment is not recommended.

CS228419_E

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination

(Page 1 of 3)

TB EliminationTreatment Options for Latent Tuberculosis InfectionIntroductionTreatment of latent tuberculosis (TB) infection (LTBI) is essential to controlling and eliminating TB in the United States, because it substantially reduces the risk that TB infection will progress to TB disease. The Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force (USPSTF) recommend testing populations that are at increased risk for TB infection. Once the diagnosis of LTBI has been made, health care providers must choose the most appropriate and effective treatment regimen, and make every effort to ensure those persons complete the entire course of treatment for LTBI.

However, if exposed to and infected by a person with multidrug-resistant TB (MDR TB) or extensively drug-resistant TB (XDR TB), preventive treatment may not be an option.

Pretreatment EvaluationTo decide whether an individual who has a positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) result is a candidate for treatment of LTBI

• Determine the benefits of treatment byevaluating the individual’s risk for developingTB disease

• Assess the person’s level of commitmentto completion of treatment and resourcesavailable to ensure adherence

Once the decision is made to treat an individual for LTBI, the health care provider must establish rapport with the patient and

• Discuss benefits and risks of treatment • Review possible medication side effects or

drug interactions • Emphasize importance of adherence • Identify potential barriers to adherence • Establish a plan to ensure adherence

Table1: Candidates for the Treatment of Latent TB Infection

Groups Who Should be Given High Priority for Latent TB Infection Treatment

People who have a positive IGRA result or a TST reaction of 5 or

more millimeters

People who have a positive IGRA result or a TST reaction of 10 or

more millimeters

• HIV-infected persons • Recent contacts of a

TB case • Persons with

fibrotic changes onchest radiographconsistent with oldTB

• Organ transplantrecipients

• Persons who areimmunosuppressedfor other reasons(e.g., taking theequivalent of>15 mg/day ofprednisone for 1month or longer,taking TNF-αantagonists)

• Recent immigrants(< 5 years) from high-prevalence countries

• Injection drug users • Residents and

employees of high-risk congregatesettings (e.g.,correctional facilities,nursing homes,homeless shelters,hospitals, and otherhealth care facilities)

• Mycobacteriologylaboratory personnel

• Children under4 years of age,or children andadolescents exposedto adults in high-riskcategories

Persons with no known risk factors for TB may be considered for treatment of LTBI if they have either a positive IGRA result or if their reaction to the TST is 15 mm or larger. However, targeted TB testing programs should only be conducted among high-risk groups. All testing activities should be accompanied by a plan for follow-up care for persons with TB infection or disease.

(Page 2 of 3)

Choosing the Most Effective RegimenTreatment of LTBI should be initiated after the possibility of TB disease has been excluded. Persons suspected of having TB disease should receive the recommended multidrug regimen for treatment of disease until the diagnosis is confirmed or ruled out.

Consultation with a TB expert is advised if the known source of TB infection has drug-resistant TB.

Table 2. Latent TB Infection Treatment Regimens

Drugs Duration Interval Minimum doses

Isoniazid 9 months

Daily 270

Twice weekly* 76

Isoniazid 6 monthsDaily 180

Twice weekly* 52

Isoniazid & Rifapentine 3 months Once

weekly* 12

Rifampin 4 months Daily 120

*Use Directly Observed Therapy (DOT).Note: Due to the reports of severe liver injury and deaths, CDC recommends that the combination of rifampin (RIF) and pyrazinamide (PZA) should generally not be offered for the treatment of latent TB infection.

Although regimens are broadly applicable, there are modifications that should be considered under special circumstances (e.g., HIV infection, suspected drug resistance, pregnancy, or treatment of children). Table 2 lists the current recommended regimens. Refer to Targeted Tuberculin Testing and Recommendations for Use of an Isoniazid–Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection for detailed information about the treatment of LTBI.

Isoniazid (INH)

The standard treatment regimen for LTBI is nine months of daily INH. This regimen is very effective and is the preferred regimen for HIV-infected people taking antiretroviral therapy, and children aged 2-11 years of age.

Isoniazid (INH) and Rifapentine (RPT) Regimen

The 12-dose regimen of INH and RPT does not replace other recommended LTBI treatment regimens; it is another effective regimen option for otherwise healthy patients aged ≥12 years who have predictive factor for greater likelihood of TB developing, which includes recent exposure to contagious TB, conversion from negative to positive on an indirect test for infection (i.e., interferon-γ release assay or tuberculin test), and radiographic findings of healed pulmonary TB.

This regimen is not recommended for

• Children younger than 2 years old,

• People with HIV/AIDS who are takingantiretroviral treatment,

• People presumed to be infected with INH orRIF-resistant M. tuberculosis, and

• Pregnant women or women expectingto become pregnant within the 12-weekregimen.

Adverse Drug ReactionsPatients on treatment for LTBI should be instructed to report any signs and symptoms of adverse drug reactions to their health care provider, including

• Unexplained anorexia, nausea or vomiting,dark urine*, or icterus

• Persistent paresthesia of hands or feet

• Persistent weakness, fatigue, fever, orabdominal tenderness

• Easy bruising or bleeding

(Page 3 of 3) August 2016

*Advise patients taking RIF or RPT that they willnotice a normal orange discoloration of body fluids, including urine and tears. Contact lenses may be permanently stained.

Obtain a list of patient’s current medications to avoid drug interactions. Some interactions to note:

• INH increases blood levels of phenytoin(Dilantin) and disulfiram (Antabuse)

• RIF and RPT decrease blood levels of manydrugs including oral contraceptives, warfarin,sulfonureas, and methadone

• RIF and RPT are contraindicated in HIV-infectedindividuals being treated with proteaseinhibitors (PIs) and most nonnucleoside reversetranscriptase inhibitors (NNRTIs)

Monitoring During TreatmentBaseline and routine laboratory monitoring during treatment of LTBI are indicated only when there is a history of liver disease, HIV infection, pregnancy (or within 3 months post delivery), or regular alcohol use. Baseline hepatic measurements of serum AST, ALT, and bilirubin are used in the situations mentioned above and to evaluate symptoms of hepatotoxicity. Laboratory testing should be performed to evaluate possible adverse reactions that occur during the treatment regimen.

Clinical monitoring, including a brief physical examination, should occur at monthly visits to assess adherence, rationale for treatment, and to identify signs or symptoms of adverse drug reactions.

CDC collects reports of all severe adverse events (e.g., liver injury, metabolic acidosis, anaphylaxis, seizure, severe dermatitis) leading to hospitalization or death of a person receiving treatment for LTBI. Report these adverse events to the Division of Tuberculosis Elimination by sending an email to [email protected].

Additional Information1. ATS/CDC. Targeted tuberculin testing and

treatment of latent TB infection. (PDF) MMWR2000;49(No. RR- 6). http://www.cdc.gov/MMWR/PDF/rr/rr4906.pdf

3. CDC. Recommendations for Use of anIsoniazid–Rifapentine Regimen with DirectObservation to Treat Latent Mycobacteriumtuberculosis Infection. MMWR 2011; 60:1650

–1653. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6048a3.htm?s_cid=mm6048a3_w

4. CDC. Update: Adverse Event Data andRevised American Thoracic Society/CDCRecommendations Against the Use ofRifampin and Pyrazinamide for Treatment ofLatent Tuberculosis Infection. MMWR 2003; 52(No. 31). http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm

5. Updated Guidelines for the Use of Rifamycinsfor the Treatment of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitorsor Nonnucleoside Reverse TranscriptaseInhibitors. MMWR 2004: 53 (No. 2). http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5302a6.htm

6. Latent Tuberculosis Infection: A Guide forPrimary Health Care Providers. http://www.cdc.gov/tb/publications/LTBI/default.htm

7. Targeted Tuberculosis (TB) Testing andTreatment of Latent TB Infection (slide set).http://www. cdc.gov/tb/publications/slidesets/LTBI/default. htm

8. Treatment of Latent Tuberculosis Infection:Maximizing Adherence. http://www.cdc.gov/tb/publications/factsheets/treatment/LTBIadherence.htm

9. CDC Division of Tuberculosis Eliminationwebsite http://www.cdc.gov/tbhttp://www.cdc.gov/tb

2. USPSTF. Latent Tuberculosis Infection:Screening Recommendation. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryDraft/latent-tuberculosis-infection-screening

http://www.cdc.gov/tb


http://www.cdc.gov/MMWR/PDF/rr/rr4906.pdf

http://www.cdc.gov/MMWR/PDF/rr/rr4906.pdf

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6048a3.htm?s_cid=mm6048a3_w



http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm





http://www.cdc.gov/tb/publications/LTBI/default.htm

http://www.cdc.gov/tb/publications/LTBI/default.htm

http://www.cdc.gov/tb/publications/slidesets/LTBI/default.htm



http://www.cdc.gov/tb/publications/factsheets/treatment/LTBIadherence.htm




http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryDraft/latent-tuberculosis-infection-screening




http://www.cdc.gov/tb/publications/ltbi/default.htm

http://www.cdc.gov/tb/publications/slidesets/ltbi/default.htm

http://www.cdc.gov/tb/publications/factsheets/treatment/ltbiadherence.htm

Copyright 2016 American Medical Association. All rights reserved.

Screening for Latent Tuberculosis Infection in AdultsUS Preventive Services Task Force Recommendation StatementUS Preventive Services Task Force

T he US Preventive Services Task Force (USPSTF) makes rec-ommendations about the effectiveness of specific preven-tive care services for patients without obvious related signs

or symptoms.It bases its recommendations on the evidence of both the benefits

andharmsoftheserviceandanassessmentofthebalance.TheUSPSTFdoes not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more con-siderations than evidence alone. Clinicians should understand theevidence but individualize decision making to the specific patientor situation. Similarly, the USPSTF notes that policy and coveragedecisions involve considerations in addition to the evidence of clini-cal benefits and harms.

Summary of Recommendation and EvidenceThe USPSTF recommends screening for latent tuberculosis infection(LTBI) in populations at increased risk (B recommendation) (Figure 1).

RationaleImportanceIn the United States, tuberculosis remains an important preventabledisease, including active tuberculosis infection, which may be infec-

tious, and latent infection (LTBI), which is asymptomatic and not in-fectious but can later reactivate and progress to active disease. Theprecise prevalence rate of LTBI in the United States is difficult to de-termine; however, based on 2011-2012 National Health and Nutri-tion Examination Survey data, estimated prevalence is 4.7% to 5.0%.1

Tuberculosis is spread through respiratory transmission. Approxi-mately 30% of persons exposed to Mycobacterium tuberculosis willdevelop LTBI and, if untreated, approximately 5% to 10% of these per-sons will progress to active tuberculosis disease or reactivation oftuberculosis.2-6 Rates of progression may be higher in persons withcertain risk factors or medical conditions. An effective strategy for re-ducing the transmission, morbidity, and mortality of active tubercu-losis disease is the identification and treatment of LTBI to prevent itsprogression to active disease. Traditionally, prevention of tuberculo-sis has relied on public health systems; however, more recently, screen-ing for LTBI has become a relevant primary care issue.

DetectionThe USPSTF found adequate evidence that accurate screening testsare available to detect LTBI. Screening tests include the Mantouxtuberculin skin test (TST) and interferon-gamma release assays(IGRAs); both are moderately sensitive and highly specific.

Benefits of Early Detection and TreatmentThe USPSTF found no studies that evaluated the direct benefits ofscreening for LTBI. The USPSTF found adequate evidence that treat-

IMPORTANCE Tuberculosis remains an important preventable disease in the United States. Aneffective strategy for reducing the transmission, morbidity, and mortality of active disease isthe identification and treatment of latent tuberculosis infection (LTBI) to prevent progressionto active disease.

OBJECTIVE To issue a current US Preventive Services Task Force (USPSTF) recommendationon screening for LTBI.

EVIDENCE REVIEW The USPSTF reviewed the evidence on screening for LTBI in asymptomaticadults seen in primary care, including evidence dating from the inception of searched databases.

FINDINGS The USPSTF found adequate evidence that accurate screening tests for LTBI are available,treatment of LTBI provides a moderate health benefit in preventing progression to active disease,and the harms of screening and treatment are small. The USPSTF has moderate certainty thatscreening for LTBI in persons at increased risk for infection provides a moderate net benefit.

CONCLUSIONS AND RECOMMENDATION The USPSTF recommends screening for LTBI inpopulations at increased risk. (B recommendation)

JAMA. 2016;316(9):962-969. doi:10.1001/jama.2016.11046

Editorial page 931

Author Audio Interview

Related article page 970

CME Quiz atjamanetworkcme.com andCME Questions page 988

Related article atjamainternalmedicine.com

Author/Group Information: TheUSPSTF members are listed at theend of this article.

Corresponding Author: KirstenBibbins-Domingo, PhD, MD, MAS([email protected])

Clinical Review & Education

JAMA | US Preventive Services Task Force | RECOMMENDATION STATEMENT

962 JAMA September 6, 2016 Volume 316, Number 9 (Reprinted) jama.com



ment of LTBI with regimens recommended by the Centers for Dis-ease Control and Prevention (CDC) decreases progression to ac-tive tuberculosis; the magnitude of this benefit is moderate.

Harms of Early Detection and TreatmentThe USPSTF found no direct evidence on the harms of screening forLTBI. The USPSTF found adequate evidence that the magnitude ofharms of treatment of LTBI with CDC-recommended regimens issmall. The primary harm of treatment is hepatotoxicity.

USPSTF AssessmentThe USPSTF concludes with moderate certainty that the net ben-efit of screening for LTBI in persons at increased risk for tuberculo-sis is moderate.

Clinical Considerations

Patient Population Under ConsiderationThis recommendation applies to asymptomatic adults 18 years andolder at increased risk for tuberculosis (see the “Assessment of Risk”section for more information). It does not apply to adults with symp-toms of tuberculosis or to children and adolescents (Figure 2).

Assessment of RiskPopulations at increased risk for LTBI based on increased preva-lence of active disease and increased risk of exposure include per-sons who were born in, or are former residents of, countries with in-creased tuberculosis prevalence and persons who live in, or have

Figure 1. US Preventive Services Task Force Grades and Levels of Certainty

What the USPSTF Grades Mean and Suggestions for Practice

Grade Definition

A The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service.

Suggestions for Practice

B The USPSTF recommends the service. There is high certainty that the net benefit is moderate, orthere is moderate certainty that the net benefit is moderate to substantial.

Offer or provide this service.

CThe USPSTF recommends selectively offering or providing this service to individual patientsbased on professional judgment and patient preferences. There is at least moderate certaintythat the net benefit is small.

Offer or provide this service for selectedpatients depending on individualcircumstances.

D The USPSTF recommends against the service. There is moderate or high certainty that the servicehas no net benefit or that the harms outweigh the benefits.

Discourage the use of this service.

I statement

The USPSTF concludes that the current evidence is insufficient to assess the balance of benefitsand harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance ofbenefits and harms cannot be determined.

Read the Clinical Considerations sectionof the USPSTF RecommendationStatement. If the service is offered,patients should understand theuncertainty about the balance of benefitsand harms.

USPSTF Levels of Certainty Regarding Net Benefit

Level of Certainty Description

HighThe available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary carepopulations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to bestrongly affected by the results of future studies.

Moderate

The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimateis constrained by such factors as

the number, size, or quality of individual studies.inconsistency of findings across individual studies.limited generalizability of findings to routine primary care practice.lack of coherence in the chain of evidence.

As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be largeenough to alter the conclusion.

The USPSTF defines certainty as “likelihood that the USPSTF assessment of the net benefit of a preventive service is correct.” The net benefit is defined asbenefit minus harm of the preventive service as implemented in a general, primary care population. The USPSTF assigns a certainty level based on the natureof the overall evidence available to assess the net benefit of a preventive service.

Low

The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because ofthe limited number or size of studies.important flaws in study design or methods.inconsistency of findings across individual studies.gaps in the chain of evidence.findings not generalizable to routine primary care practice.lack of information on important health outcomes.

More information may allow estimation of effects on health outcomes.

USPSTF Recommendation: Screening for Latent Tuberculosis in Adults US Preventive Services Task Force Clinical Review & Education

jama.com (Reprinted) JAMA September 6, 2016 Volume 316, Number 9 963



lived in, high-risk congregate settings (eg, homeless shelters and cor-rectional facilities). Clinicians can consult their local or state healthdepartments for more information about populations at risk in theircommunity, because local demographic patterns may vary across theUnited States.

In 2015, among persons of known national origin, 66.2% of allactive tuberculosis cases in the United States were among foreign-born persons, and the case rate of active tuberculosis amongforeign-born persons was approximately 13 times higher thanamong US-born persons (15.1 vs 1.2 cases per 100 000 persons).7

More than half of all foreign-born persons in the United States withactive tuberculosis were from 5 countries: Mexico, the Philippines,Vietnam, India, and China.7 In addition, the CDC has identifiedforeign-born persons from Haiti and Guatemala as important con-tributors to active tuberculosis cases in the United States.8 TheWorld Health Organization (WHO) recently updated its list of coun-tries with a high burden of tuberculosis to include the top 20 coun-tries with the highest absolute numbers of cases and an additional10 countries with the most severe burden in terms of case rate percapita.9

Persons who live in, or have lived in, high-risk congregate set-tings also have a higher prevalence rate of active tuberculosis andincreased risk for exposure. Among persons 15 years and olderwith active tuberculosis, 5.6% were homeless within the pastyear, 2.2% were residents of a long-term care facility, and 4.2%were in a correctional facility at the time of diagnosis.10 Publishedprevalence rates of LTBI in these settings vary widely, dependingon the type of screening test used, the TST threshold used todefine the presence of LTBI, and the population studied. Esti-mates of LTBI prevalence range from 23.1% to 87.6% among

prisoners and from 18.6% to 79.8% among persons who arehomeless.2,11

Other populations at increased risk for LTBI or progressionto active disease include persons who are immunosuppressed (eg,persons living with human immunodeficiency virus [HIV], patientsreceiving immunosuppressive medications such as chemotherapyor tumor necrosis factor–alpha inhibitors, and patients who have re-ceived an organ transplant) and patients with silicosis (a lung dis-ease). However, given that screening in these populations may beconsidered standard care as part of disease management or indi-cated prior to the use of certain medications, the USPSTF did notreview evidence on screening in these populations. Some evi-dence from observational studies has explored the association be-tween poorly controlled diabetes and progression of LTBI to activedisease. However, there is insufficient evidence on screening for andtreatment of LTBI in persons with diabetes for the USPSTF to makea separate recommendation for this important subgroup.

Persons who are contacts of individuals with active tuberculo-sis, health care workers, and workers in high-risk congregate set-tings may also be at increased risk of exposure. Because screeningin these populations is conducted as part of public health12 or em-ployee health13,14 surveillance, the USPSTF did not review the evi-dence in these populations. Clinicians seeking further informationabout testing for tuberculosis in these populations can refer to the“Useful Resources” and “Recommendations of Others” sections.

Screening TestsTwo types of screening tests for LTBI are currently available in theUnited States: the TST and IGRA. The TST requires intradermal place-ment of purified protein derivative and interpretation of response

Figure 2. Screening for Latent Tuberculosis Infection in Adults: Clinical Summary

Population Asymptomatic adults at increased risk for infection

Recommendation Screen for latent tuberculosis infection (LTBI).

Grade: B

Risk Assessment

Screening Tests

Treatment andInterventions

Balance of Benefitsand Harms

For a summary of the evidence systematically reviewed in making this recommendation, the full recommendation statement, and supporting documents, pleasego to http://www.uspreventiveservicestaskforce.org.

Populations at increased risk for LTBI include persons who were born in, or are former residents of, countries with increasedtuberculosis prevalence and persons who live in, or have lived in, high-risk congregate settings (eg, homeless shelters and correctionalfacilities). Local demographic patterns may vary across the United States; clinicians can consult their local or state health departmentsfor more information about populations at risk in their community.

Screening tests include the Mantoux tuberculin skin test and interferon-gamma release assays; both are moderately sensitive andhighly specific for the detection of LTBI.

The CDC provides recommendations for the treatment of LTBI at http://www.cdc.gov/tb/topic/treatment/ltbi.htm.

The USPSTF concludes with moderate certainty that the net benefit of screening for LTBI in persons who are at increased risk fortuberculosis is moderate.

CDC indicates Centers for Disease Control and Prevention; USPSTF, US Preventive Services Task Force.

Clinical Review & Education US Preventive Services Task Force USPSTF Recommendation: Screening for Latent Tuberculosis in Adults




48 to 72 hours later. The skin test reaction is measured in millime-ters of the induration (a palpable, raised, hardened area or swell-ing). Interferon-gamma release assays require a single venous bloodsample and laboratory processing within 8 to 30 hours after collec-tion. Two types of IGRAs are currently approved by the US Food andDrug Administration: T-SPOT.TB (Oxford Immunotec Global) andQuantiFERON-TB Gold In-Tube (Qiagen).

Numerous patient and systems factors may influence the se-lection of a screening test.15 Generally, the CDC recommends screen-ing with either the TST or IGRA but not both. Testing with IGRAs maybe preferable for persons who have received a BCG vaccination orpersons who may be unlikely to return for TST interpretation. Ad-ditional information on the use and interpretation of the TST andIGRA is available from the CDC.16

Screening IntervalsThe USPSTF found no evidence on the optimal frequency of screen-ing for LTBI. Depending on specific risk factors, screening fre-quency could range from 1-time only screening among persons whoare at low risk for future tuberculosis exposure to annual screeningamong those who are at continued risk of exposure.

TreatmentRecommendations for the treatment of LTBI are available fromthe CDC.17

Additional Approaches to PreventionThe public health system has an essential role in the control and elimi-nation of tuberculosis. Clinicians are required to report cases of ac-tive tuberculosis to their local health department. As outlined by lo-cal and state public health laws, local health departments investigateand ensure treatment of active tuberculosis cases and perform con-tact tracing and medical surveillance of contacts.

Occupational health services also have an important role in theprevention and control of tuberculosis. Certain work settings (healthcare settings, correctional facilities, and other high-risk congregatehousing settings) may pose a higher risk of tuberculosis exposure,and employers often have an important role in preventing tubercu-losis exposure among employees and performing medical surveil-lance of employees for exposure.

Useful ResourcesClinicians seeking guidance on tuberculosis management among per-sons living with HIV can obtain additional information from the Na-tional Institutes of Health.18 Clinicians seeking information on medi-cal surveillance of contacts of persons with active tuberculosis cancontact their local health department, review their local public healthlaw, or review guidance from the CDC.19 The CDC also provides in-formation for public health tuberculosis programs.20

Clinicians seeking information on medical surveillance of healthcare workers or employees working in high-risk settings can con-sult resources from the CDC and the Occupational Safety and HealthAdministration.21-23 Clinicians seeking guidance on screening for LTBIin children can find more information on the American Academy ofPediatrics’ Bright Futures website.24 Clinicians seeking guidance ontuberculosis and pregnancy can obtain information from the CDC.25

Other Considerations

ImplementationScreening with the TST requires that patients return 48 to 72 hoursafter administration of the skin test for interpretation of results. Whenplacing a TST, clinicians should plan with patients accordingly to en-sure they can return in time and that the facility is able to interpretthe test results within the proper time frame.26 Screening with anIGRA requires obtaining a single venous blood sample, and pa-tients do not need to return for interpretation of results. However,clinicians should be aware of processing requirements for bloodsamples and ensure that venous blood samples are drawn and canreach the laboratory for processing within the appropriate time frame(8-30 hours, depending on the test).27

Research Needs and GapsFurther research is needed that evaluates risk assessment tools todetermine efficient ways of identifying candidates for LTBI testingand treatment. Additional research on how often LTBI screeningshould be performed in different subpopulations is also needed. TheUSPSTF identified no studies on LTBI screening or treatment in preg-nant women and the potential effects on the fetus; this representsan important gap in the literature that needs further research. In ad-dition, more studies are needed to clarify whether certain screen-ing methods are preferable for certain risk groups.

DiscussionBurden of DiseaseTuberculosis causes a substantial health burden globally. Approxi-mately one-third of the world’s population is infected with tuber-culosis; in 2014, 9.6 million persons were estimated to have con-tracted tuberculosis, and an estimated 1.5 million deaths related totuberculosis infection occurred worldwide.9 In the United States,9563 new active cases of tuberculosis were reported in 2015, whichcorresponds to an incidence rate of 3.0 cases per 100 000 persons.7

In 2013, 555 deaths from tuberculosis were reported in the UnitedStates.28 In 2015, half of all tuberculosis cases occurred in 4 states:California, Texas, New York, and Florida. Asians represented the larg-est percentage of total cases (33%), followed by Hispanics (28%),African Americans (21%), and whites (13%); American Indian orAlaska Natives and Native Hawaiian or other Pacific Islanders eachrepresented approximately 1% of cases.7 Incidence rates of activetuberculosis may be higher in populations at increased risk, owingto greater likelihood of exposure (eg, persons who have lived in coun-tries with a high tuberculosis burden) or greater likelihood of pro-gression from LTBI to active disease (eg, persons who are immuno-suppressed). Although LTBI is asymptomatic, signs and symptomsof active tuberculosis disease may include cough, hemoptysis(coughing up blood), unexplained weight loss, night sweats, fe-vers, chills, and fatigue.

Scope of ReviewThe USPSTF commissioned a systematic review of the evidence onscreening for LTBI.2,3 Evidence dating from the inception of searcheddatabases until August 3, 2015, was included. The review focused





on evidence about screening for LTBI in asymptomatic adults seenin primary care settings. It did not include evidence on screening inpersons for whom LTBI screening would be considered manage-ment of a specific condition (eg, persons living with HIV), publichealth surveillance (ie, tracing contacts of persons with active tu-berculosis disease), surveillance of employees working in high-risksettings, or screening indicated prior to the use of specific immu-nosuppressive medications.

Accuracy of Screening TestsThere is no direct test for the diagnosis of latent infection withM tuberculosis. Following screening, diagnosis of LTBI is based onmedical history, physical examination, and exclusion of activetuberculosis disease. In the absence of a reference standard fordetection of LTBI, screening test performance is based on detec-tion of disease in persons with known active tuberculosis andnondetection of disease in populations at low risk for the diseaseand presumed not to have LTBI or active tuberculosis.

The USPSTF identified 67 good- or fair-quality studies that pro-vided information on the accuracy and reliability of screening testsfor LTBI.2 For studies reporting on sensitivity, 8 were conducted incountries with a high burden of tuberculosis, 29 were conducted incountries with an intermediate burden, 10 were conducted in coun-tries with a low burden, and 3 were conducted in countries with amix of low to intermediate burden. For studies reporting on speci-ficity, 3 were conducted in countries with an intermediate burden;14 were conducted in countries with a low burden; and 1 was con-ducted in 2 countries: 1 with an intermediate burden and 1 witha low burden.

When using a positive threshold of 10 mm of induration, theTST has moderate sensitivity and high specificity for detection ofLTBI. Based on pooled analyses of studies reviewed by theUSPSTF, when using a positive threshold of 10 mm, the TST hassensitivity of 79% (11 studies; n = 988) and specificity of 97% (9studies; n = 9651).2

Pooled analyses of the T-SPOT.TB test (a type of IGRA) indicatesensitivity of 90% (16 studies; n = 984) and specificity of 95%(5 studies; n = 1810). Pooled analyses of the QuantiFERON-TB GoldIn-Tube test (another type of IGRA) indicate sensitivity of 80%(24 studies; n = 2321) and specificity of 97% (4 studies; n = 2053).The USPSTF identified no studies that evaluated the accuracy andreliability of sequential screening strategies.

Effectiveness of Early Detection and TreatmentThe USPSTF identified no randomized clinical trials that com-pared screening with no screening to provide direct evidence ofthe benefit of screening for LTBI on health outcomes, such asrates of active tuberculosis disease, disease-specific or all-causemortality, or tuberculosis transmission. Three good- or fair-qualitytrials (n = 35 563) conducted in Canada, Brazil, Saudi Arabia,Spain, Czechoslovakia, Finland, Germany, Hungary, Poland,Romania, and Yugoslavia provided evidence on the benefits oftreatment of LTBI.2 Trials evaluated treatment with isoniazid,29

rifampin,30 and rifapentine plus isoniazid.31

The best evidence on the effectiveness of treatment wasfrom the International Union Against Tuberculosis (IUAT) trial.This good-quality randomized clinical trial was conducted in 7European countries (Czechoslovakia, Finland, Germany, Hungary,

Poland, Romania, and Yugoslavia) among participants withfibrotic pulmonary lesions but not active tuberculosis. The trial,published in 1982, included 27 830 participants and evaluatedtreatment with daily isoniazid. It found that at 5 years, the relativerisk (RR) of progression to active tuberculosis was 0.35 (95% CI,0.24-0.52) for treatment with isoniazid (300 mg daily for 24weeks) compared with placebo. The trial reported fewer deathsattributable to tuberculosis among participants receiving treat-ment with isoniazid (0 vs 3 deaths in the placebo group; RR, 0.14[95% CI, 0.01-2.78]), although this difference was not statisticallysignificant.

The other 2 treatment trials compared either rifampin withisoniazid and found zero deaths in either group or rifapentine plusisoniazid with isoniazid alone and found that the combinationtherapy was noninferior in preventing progression to activetuberculosis. None of the treatment studies reported on trans-mission rates of tuberculosis.

Potential Harms of Screening and TreatmentThe USPSTF identified no studies that directly reported on theharms of screening. Potential harms include stigma associated withscreening and diagnostic workup and treatment of false-positiveresults. Five good- or fair-quality studies (n = 36 043) conducted inthe United States, Canada, Saudi Arabia, Brazil, Spain, Czechoslova-kia, Finland, Germany, Hungary, Poland, Romania, and Yugoslaviareported on the harms of treatment.2,29-33 Interventions evaluatedincluded isoniazid, rifampin, and rifapentine plus isoniazid. Themost consistently reported harm was hepatotoxicity. The onlystudy that assessed harms of treatment vs placebo was the IUATtrial,30 which found an RR of 4.59 (95% CI, 2.03-10.39) for hepato-toxicity at 5 years among participants being treated with isoniazid(300 mg for 24 weeks) vs placebo. The IUAT trial also reportedmore deaths from hepatotoxicity among participants being treatedwith isoniazid than with placebo, although this finding was not sta-tistically significant (0.14 vs 0 deaths per 1000 persons; RR calcu-lated from published data, 2.35 [95% CI, 0.12-45.46]).

The other trials compared either rifampin30,32,33 or rifapentineplus isoniazid31 with isoniazid. Meta-analysis of 3 trials of rifampincompared with isoniazid found a higher RR for hepatoxicity amongparticipants being treated with isoniazid (RR, 3.29 [95% CI,1.72-6.28]).2 None of these trials, which were more recent than theIUAT trial, reported any deaths from hepatotoxicity. The 1 study thatreported on hepatotoxicity of rifapentine plus isoniazid vs isonia-zid alone found a nonsignificant reduced RR of 0.90 (95% CI, 0.75-1.08) for grade 3 or 4 hepatotoxicity among participants beingtreated with rifapentine plus isoniazid. There also was a nonsignifi-cant reduced RR of death from hepatotoxicity among participantsbeing treated with rifapentine plus isoniazid vs isoniazid alone (RR,0.83 [95% CI, 0.51-1.35]).

A few studies also reported on gastrointestinal adverseevents. Compared with placebo, participants treated with isonia-zid had a higher risk of medication discontinuation because ofgastrointestinal adverse events (RR, 1.33 [95% CI, 1.01-1.75]).29

Compared with rifampin, treatment with isoniazid had a nonsig-nificant increased RR of gastrointestinal adverse events (RR, 1.60[95% CI, 0.76-3.40]) in 2 studies.2 All 5 studies also reported ondiscontinuation of treatment because of adverse events. Com-pared with placebo, treatment with isoniazid had an RR of medi-





cation discontinuation of 1.50 (95% CI, 1.18-1.89).29 Poolingresults from the 3 studies of isoniazid vs rifampin found a nonsig-nificant increased risk of discontinuation with isoniazid (RR, 1.61[95% CI, 0.57-4.57]).2 The study of rifapentine plus isoniazid vsisoniazid alone found an increased risk of discontinuation withrifapentine plus isoniazid (RR, 1.28 [95% CI, 1.03-1.59]).31

Estimate of Magnitude of Net BenefitOverall, the USPSTF found adequate evidence that accuratescreening tests for LTBI are available, treatment of LTBI provides amoderate health benefit in preventing progression to active dis-ease, and the harms of screening and treatment are small. TheUSPSTF has moderate certainty that screening for LTBI in personsat increased risk for infection provides a moderate net benefit. TheUSPSTF estimated that if a hypothetical cohort of 100 000 asymp-tomatic adults at increased risk for tuberculosis (eg, persons bornin, or former residents of, high-prevalence countries) werescreened, 52 to 146 active tuberculosis cases would be prevented,7 to 67 cases of hepatotoxicity would occur (depending on type oftreatment), and 111 persons would discontinue treatment becauseof adverse events. The number needed to treat to prevent 1 case ofLTBI from progressing to active tuberculosis would range from 111to 314 (depending on the patient’s risk for progression), and thenumber needed to harm to cause 1 case of hepatotoxicity fromtreatment would range from 279 to 2531 (depending on type oftreatment). These estimates are based on prevalence data fromthe 2011-2012 National Health and Nutrition Examination Survey1

and numerous assumptions about screening sensitivity and speci-ficity (eg, using the TST with a 10-mm threshold for a positive diag-nosis) and potential benefits of treatment (eg, estimated efficacyof treatment for 24 weeks of isoniazid, based on IUAT trial find-ings). Further information on the assumptions used is available inthe corresponding evidence review.2

How Does Evidence Fit With Biological Understanding?Tuberculosis disease is caused by M tuberculosis, which is spreadthrough airborne transmission when a person with active pulmo-nary tuberculosis coughs or sneezes. When the tuberculosis bacil-lus is inhaled, a person can either clear M tuberculosis; developactive disease (primary tuberculosis disease), which may be infec-tious; or develop latent infection (LTBI), which is asymptomatic andnot infectious. Latent infection can later reactivate and progress toactive tuberculosis disease. Approximately 30% of personsexposed to active M tuberculosis will develop LTBI.2 Approximately5% to 10% of persons with a positive TST result will experiencereactivation of LTBI and progress to active tuberculosis disease.2-6

Response to Public CommentA draft version of this recommendation statement was posted forpublic comment on the USPSTF website from March 8 to April 4,2016. Many comments sought clarification around risk assessmentof populations who should receive screening. The USPSTF clarifiedthat given regional variations in the local populations considered atrisk for tuberculosis, clinicians may consult their local or state publichealth agency for additional details on specific populations at risk intheir community. Furthermore, the USPSTF clarified that althoughpersons with diabetes and pregnant women are not addressedseparately in this recommendation statement, they are also not

excluded from the recommendation. A few public commentssought clarification on the recommended frequency of screening.Although the USPSTF sought evidence on screening frequency,there was not enough evidence available to determine an optimalscreening interval. Several comments requested that the recom-mendation include treatment of LTBI. While the USPSTF acknowl-edges that treatment of LTBI contributes to the success of LTBIscreening, it is beyond the scope of the USPSTF to make any spe-cific recommendations on treatment. The CDC provides treatmentguidelines for LTBI.17

Update of Previous USPSTF RecommendationThe USPSTF last issued a recommendation on screening for tuber-culosis in 1996. At that time, the USPSTF recommended screeningfor tuberculosis infection with the TST in asymptomatic, high-riskpersons (A recommendation) and consideration of BCG vaccina-tion for selected high-risk individuals only (B recommendation).Given the changes in the epidemiology of the disease, the develop-ment of newer screening technologies, and newer methods for de-veloping evidence-based recommendations, the USPSTF decidedto update the topic and issue a recommendation using its currentmethodology and considering all of the available evidence, includ-ing studies published prior to 1996.

Recommendations of OthersThe American Academy of Family Physicians recommends screen-ing for LTBI in populations at increased risk.34 In 2005, the CDC,the American Thoracic Society, and the Infectious Diseases Societyof America issued joint guidelines recommending that cliniciansscreen for LTBI only among high-risk populations and when treat-ment is feasible.35 In its 2013 “Guide for Primary Health Care Pro-viders,” the CDC recommended targeted testing for tuberculosisamong high-risk populations only.8 The CDC identifies persons atrisk for developing tuberculosis as those who have an increasedlikelihood of exposure to persons with tuberculosis disease (knownclose contacts of a person with infectious tuberculosis disease, per-sons who have immigrated from tuberculosis-endemic regions ofthe world, and persons who work or reside in facilities or institu-tions with those at high risk for tuberculosis) or persons with clini-cal conditions or other factors associated with an increased risk ofprogression from LTBI to tuberculosis disease (HIV infection, injec-tion drug use, radiographic evidence of prior healed tuberculosis,low body weight, or other medical conditions). Further informationon targeted testing is available from the CDC.36

The WHO also recently issued guidelines on the managementof LTBI. For high-income countries with an estimated tuberculosisincidence of less than 100 cases per 100 000 persons (such asthe United States), the WHO recommends systematic testingfor and treatment of LTBI among persons living with HIV, adultand child contacts of persons with pulmonary tuberculosis,patients initiating anti–tumor necrosis factor treatment, patientsreceiving dialysis, patients preparing for an organ or hematologictransplant, and patients with silicosis. Either an IGRA or theTST should be used. The WHO also recommends considering





systematic testing and treatment among prisoners, health careworkers, immigrants from high-burden countries, homeless per-sons, and illicit drug users. Either an IGRA or the TST should beused. It does not recommend systematic testing for LTBI among

persons who have diabetes, engage in harmful alcohol use, smoketobacco, or are underweight, unless they are already included inthe above recommendations.37 Further information is availablefrom the WHO.38

ARTICLE INFORMATION

Authors/US Preventive Services Task Force(USPSTF) members: Kirsten Bibbins-Domingo, PhD,MD, MAS; David C. Grossman, MD, MPH; Susan J.Curry, PhD; Linda Bauman, PhD, RN, APRN;Karina W. Davidson, PhD, MASc; John W.Epling Jr, MD, MSEd; Francisco A.R. García, MD,MPH; Jessica Herzstein, MD, MPH; Alex R.Kemper, MD, MPH, MS; Alex H. Krist, MD, MPH;Ann E. Kurth, PhD, RN, MSN, MPH; C. SethLandefeld, MD; Carol M. Mangione, MD, MSPH;William R. Phillips, MD, MPH; Maureen G. Phipps,MD, MPH; Michael P. Pignone, MD, MPH.

Affiliations of Authors/US Preventive ServicesTask Force (USPSTF) members: University ofCalifornia, San Francisco (Bibbins-Domingo); GroupHealth Research Institute, Seattle, Washington(Grossman); University of Iowa, Iowa City (Curry);University of Wisconsin-Madison (Bauman);Columbia University, New York, New York(Davidson); State University of New York UpstateMedical University, Syracuse (Epling); Pima CountyDepartment of Health, Tucson, Arizona (García);Independent consultant, Washington, DC(Herzstein); Duke University, Durham, NorthCarolina (Kemper); Fairfax Family PracticeResidency, Fairfax, Virginia (Krist); VirginiaCommonwealth University, Richmond (Krist); YaleUniversity, New Haven, Connecticut (Kurth);University of Alabama at Birmingham (Landefeld);University of California, Los Angeles (Mangione);University of Washington, Seattle (Phillips); BrownUniversity, Providence, Rhode Island (Phipps);University of Texas at Austin (Pignone).

Author Contributions: Dr Bibbins-Domingo hadfull access to all of the data in the study and takesresponsibility for the integrity of the data and theaccuracy of the data analysis. The USPSTFmembers contributed equally to therecommendation statement.

Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest andnone were reported. Authors followed the policyregarding conflicts of interest described athttp://www.uspreventiveservicestaskforce.org/Page/Name/conflict-of-interest-disclosures.All members of the USPSTF receive travelreimbursement and an honorarium for participatingin USPSTF meetings.

Funding/Support: The USPSTF is an independent,voluntary body. The US Congress mandates thatthe Agency for Healthcare Research and Quality(AHRQ) support the operations of the USPSTF.

Role of the Funder/Sponsor: AHRQ staff assistedin the following: development and review of theresearch plan, commission of the systematicevidence review from an Evidence-based PracticeCenter, coordination of expert review and publiccomment of the draft evidence report and draftrecommendation statement, and the writing andpreparation of the final recommendation statementand its submission for publication. AHRQ staff had

no role in the approval of the final recommendationstatement or the decision to submit for publication.

Disclaimer: Recommendations made by theUSPSTF are independent of the US government.They should not be construed as an official positionof AHRQ or the US Department of Health andHuman Services.

Additional Contributions: We thank Tina Fan, MD,MPH (AHRQ), who contributed to the writing of themanuscript, and Lisa Nicolella, MA (AHRQ), whoassisted with coordination and editing.

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