Chapter 4. Testing for TB infection

Chapter 4 Cover

Decision point on role of TST or IGRA

What is the role of testing for TB infection before starting TPT among target populations prioritized by the ministry of health?

Just as excluding TB disease is a critical step before starting TPT, confirming TB infection before starting TPT may increase the certainty that individuals targeted for TPT would benefit from it. However, there is no gold standard test to diagnose TB infection. Currently available tests are indirect and require the person to mount an immune response in order to work properly. A positive test result by either method is not by itself a reliable indicator that the person will progress to TB disease. Conversely, a negative test result does not rule out TB infection, given the possibility of a false-negative test result among at-risk groups, such as young children or among those recently infected. National health authorities need to decide how to implement tests for TB infection within their PMTPT components, considering these uncertainties, the balance of benefit to harm to the individual of waiting for a test result before starting TPT, and logistic difficulties to procure and implement testing wherever it is needed most.

WHO recommendation:

16. Either a tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can be used to test for LTBI.


The currently recommended tests for TB infection are TST and IGRA. Both tests measure immune sensitization (type IV or delayed-type hypersensitivity) to mycobacterial protein antigens that occurs following infection by M. tuberculosis. While the TST measures delayed hypersensitivity reaction to exposure to purified protein derivative (PPD) of the mycobacterium, IGRAs measure the amount of interferon-gamma released in vitro by white blood cells when mixed with M. tuberculosis antigens(QuantiFERON-TB Gold In-Tube) or the number of T-lymphocytes producing interferon-gamma (T-SPOT.TB). A diagnosis of TB infection needs to be complemented by a negative test outcome for TB disease, through clinical evaluation, chest radiography and examination of sputum or another suitable specimen if symptomatic, as per national policy.

A meta-analysis conducted in 2015 found that the pooled prevalence of positive results to these tests among people eligible for testing to be 61% in LMICs versus 25% in high-income countries, implying that on an average every second person in target populations is likely to test positive (14). National programmes may consider such evidence to decide on the role of testing for TB infection.

Either a TST or IGRA can be used to test for TB infection. There is no strong evidence that one test should be preferred over the other in terms of predicting progression from TB infection to TB disease. Neither TSTs nor IGRAs should be used in persons having a low risk of TB infection and disease.

The choice of test for programmatic use depends on cost, availability, human resources and infrastructure to provide testing services in the country. Table 4.1 summarizes characteristic features of currently available TSTs and IGRAs. More details are provided in Annexes 5 and 6.

Role of testing for TB infection

The decision on whether to test for TB infection before TPT, is influenced by the expected prevalence of TB infection in the at-risk population, risk of progression to TB disease and the risk of harms due to unnecessary TPT (Fig. 4.1 summarizes the pathway to decision on choice of test). For individuals or populations with higher risk of harms due to TPT or (relatively) lower risk of progression to TB disease, confirmation of TB infection may be preferred. On the other hand, for individuals or populations that are more likely to be infected and at risk for progression to TB disease and adverse outcomes if TB disease develops, TPT without testing is justified.

People with HIV who are on ART benefit from TPT regardless of whether they test positive or negative for TB infection. However, People with HIV who are not on ART and who test positive for TB infection are shown to benefit more from TPT than those with a negative test (18). However, WHO recommends that testing for TB infection should not be a requirement for initiating TPT among People with HIV and child contacts below five years of age, particularly in countries with high TB incidence, given that benefits of treatment (even without testing) clearly outweigh the risks (40). Furthermore, these tests are insensitive and may provide a false-negative result, particularly among immunocompromised hosts who are at a greater risk for severe forms of disease and death if they develop TB. Immune response to TB antigens varies among people, and TST and IGRA could remain positive even after successful completion of TPT. Therefore, results of TST and IGRA should not be used to assess the efficacy of TPT. Overall, testing with TST or IGRA should not be considered a mandatory requirement for starting TPT (especially where access to testing services remains very limited) given that the benefits of treatment (without testing) still outweigh the risks.

Where national programmes recommend testing for TB infection before TPT, TST/IGRA should be employed only among at-risk groups (such as clinical risk groups, contacts above five years of age, prisoners, health care workers). Targeted testing helps identify, evaluate and treat persons who are at high risk for TB infection or at high risk for developing TB disease when infected with M. tuberculosis. Availability of a positive test for TB infection among HIV-negative contacts or individuals in other clinical risk groups (patients initiating anti-TNF treatment, receiving dialysis, preparing for organ or haematological transplantation) may reassure clinicians and health care workers that TB infection is likely and to start TPT.

Key point: It is desirable that governments and donors invest and build health system capacity (human resources, logistics and supply chain and monitoring and evaluation (M&E)) for TST and/or IGRAs to avoid unnecessary TPT and related harms and to improve acceptance. This will also enable rapid adoption of any new TB infection test endorsed for programmatic use in the future. However, testing for TB infection is not a mandatory requirement for TPT introduction and scale-up.


Implementation considerations for testing services for TB infection

General requirements

• Define the target population for testing and choice of test in the national guidelines.

• Build capacity of health care workers responsible for different components of testing services for TB infection (such as administration of TST and test reading, collection and processing of blood specimen for IGRAs, specimen collection and transport).

• Develop SOPs for administration of TST, collection and processing of a blood specimen for IGRA and interpretation of test results.

• Develop SOPs for appropriate follow-up after testing including access to clinical evaluation, chest radiography and other TB investigations to decide the eligibility of individuals for TPT.

• Develop job-aids to assist providers in educating the test recipient and to respond to frequently asked questions regarding utility and procedure of TST or IGRA.

• Develop tools for systematic recording and reporting of test results and linkage to care and treatment (such as WHO Prevent TB mobile application (39)).

• Strengthen mechanisms for supportive supervision and monitoring of accurate implementation.


• Ensure availability and supply of tuberculin in cold chain as well as syringes, needles and consumables.

• Train personnel in intradermal injections as well as reading and interpretation and provide ongoing capacity building and supportive supervision to maintain skill levels.

• Develop mechanisms to ensure standardized application of test procedures, mentoring and supervision and periodic standardized reliability testing for quality assurance.

• Develop and provide job-aids for health care workers showing the correct technique for TST administration and measurement of induration.

• Establish mechanisms to call people who have been tested to return for the test reading within 48–72 hours of tuberculin administration, or alternatively ensure test reading at the person’s residence.

• Provide funding support for people to travel for testing or for health care workers to administer and read test results.

• Develop and supply TST request forms and update the HMIS to enable documentation and reporting of TST results.


• Develop capacity of the laboratory system to conduct IGRA (phlebotomy, processing of blood specimen, incubation and enzyme-linked immunosorbent assay (ELISA) reading). National programmes may leverage collaboration with other, non-TB-specific laboratories, having capacity for blood draws and ELISA testing or private institutions and laboratories through MoUs or free vouchers for individuals requiring testing.

• Ensure availability of trained laboratory technicians in laboratories performing IGRA tests.

• Establish mechanisms to ensure rapid transportation of blood specimens from peripheral centres to the IGRA testing laboratory (within 8–30 hours to allow incubation depending on type of IGRA).

• Ensure functioning of laboratory equipment and establish a mechanism for regular equipment maintenance for optimal functioning of the laboratory.

• Ensure supply of appropriate reagents and testing tubes for IGRA, suitable for use at different altitudes (e.g. Johannesburg, South Africa which is close to 1700 m from sea level needs different reagents or tubes than a place closer to sea level).³

• Ensure supply of updated laboratory request forms, registers and update laboratory information systems to document and report IGRA test results.

Additional funding considerations for implementation of testing programmes

• Cost per test and estimated number of target populations for testing.

• Travel support to individuals considered for TPT and health care workers to access TST and IGRA testing and TST reading.

• Incentive for health care workers or laboratory technicians.

• Maintenance of cold chain for tuberculin.

• Training, capacity building and ongoing supportive supervision.

• Maintenance of laboratory services for IGRA and specimen collection and transport.

• Hiring of laboratory technicians or laboratory services as required, including from the private sector.

• Strengthening supply chain management to ensure uninterrupted supply of tuberculin or IGRA blood collection tubes and reagents.

• Tools for routine data capture, preferably electronic.

Also refer to Annex 3.

Characteristic features of TST and IGRA


Algorithm for TB screening and TPT

² One of the IGRAs assessed and endorsed by WHO was QuantiFERON-TB Gold In-tube (QFT-GIT) test. Manufacturers of this test plan to phase it out and substitute it with the QuantiFERON-TB Gold Plus, 4-Tube test.

³, accessed 12 March 2020.

ᵃ. If < 10 years, any one of current cough or fever or history of contact with TB or reported weight loss or confirmed weight loss > 5% since last visit or growth curve flattening or weight for age <-2 Z-scores. Asymptomatic infants < 1 year with HIV are only treated for LTBI if they are household contacts of TB. TST or IGRA may identify People with HIV who will benefit most from preventive treatment. Chest radiography (CXR) may be used in People with HIV on ART, before starting LTBI treatment.

ᵇ. Any one of cough or fever or night sweats or haemoptysis or weight loss or chest pain or shortness of breath or fatigue. In children < 5 years, they should also be free of anorexia, failure to thrive, not eating well, decreased activity or playfulness to be considered asymptomatic.

ᶜ. Including silicosis, dialysis, anti-TNF agent treatment, preparation for transplantation or other risks in national guidelines. People in this category should also have TB disease ruled out if they have suggestive clinical manifestations.

ᵈ. Including acute or chronic hepatitis; peripheral neuropathy (if isoniazid is used); regular and heavy alcohol consumption. Pregnancy or a previous history of TB are not contraindications.

ᵉ. Regimen chosen based on considerations of age, strain (drug susceptible or otherwise), risk of toxicity, availability and preferences.

ᶠ. Chest radiography may have been carried out earlier or as part of intensified case finding.

Book navigation