Feedback3.5.1 What are the advantages and disadvantages of testing for TB infection?
Testing for TB infection will be beneficial for both individuals and programmes if it identifies people who will benefit most from TPT. For programmes, investments in the capacity to test for TB infection will be justified if this results in greater efficacy and efficiency in the use of resources to provide TPT, increased acceptance and enhanced coverage. Investments are needed to cover not only the cost of drugs but also the human resources for medical evaluation, TPT initiation and follow-up. Testing for TB infection will also reduce unnecessary expenditure on medication or adverse events experienced by those receiving unnecessary treatment. Hence, testing for TB infection before TPT is a valuable way to increase the TPT benefit–risk ratio.
The use of TPT reduces the risk of developing TB disease among people living with HIV, particularly in those who are TST positive. The updated systematic review undertaken during the development of the WHO guidelines on programmatic management of TPT in 2018 clearly demonstrated the benefits of systematic testing and treatment of TB infection among people living with HIV in terms of prevalence of TB infection, risk of progression to TB disease and incidence of TB disease when compared with the general population.
Household contacts were found to be at a substantially higher risk for progression to TB disease than the general population. The highest risk progression to active disease was among contacts who were aged below 5 years; hence, a strong recommendation to start TPT – irrespective of the availability of testing for TB infection – was issued. In addition, TPT was conditionally recommended for household contacts in other age groups, following assessment of harms versus benefits. Among household contacts aged above 5 years, testing for TB infection before TPT initiation may be desirable, although treatment was considered justifiable even without testing (59).
Among other risk groups, the evidence of benefits from systematic testing for TB infection and TPT varied. The benefits clearly exceeded the risks among people starting anti-TNF treatment, receiving dialysis, preparing for an organ or haematological transplant, or having silicosis. In other risk groups, the risk versus benefit was less clear. Therefore, prioritization of target groups for systematic testing and TPT based on individual risk and the local and national context was acceptable to people with TB infection and to key stakeholders, including clinicians, nurses and programme managers.
In summary, TPT will provide the greatest individual health benefits if given to people with clinical or epidemiological characteristics that increase the risk of TB disease and who also test positive for TB infection (not including contacts of TB patients who are aged <5 years and people living with HIV, for whom testing is not a prerequisite for TPT).
The most important disadvantage of testing for TB infection is the potential for significant delays between initial identification of someone at risk of developing TB disease and the initiation of TPT. In contacts, particularly young children (59) and people living with HIV, TB disease can develop rapidly after exposure and TB infection. In all contacts, the highest risk period for progression to TB disease is in the first 6 months after exposure (38,39). Hence, prompt initiation of TPT is crucial to prevent TB disease. Testing for TB infection may contribute to substantial delays, owing either to a lack of trained personnel to administer the test or read the skin test result, or to delays in laboratory processing and communication of IGRA test results. The results of IGRA testing should be available within 24–36 hours (although there may be additional delays due to sample transport and batch testing) and within 72 hours for TST or TBST; thus, testing for TB infection should not delay the initiation of TPT by more than 3 days after the initial identification.
The second potential challenge with testing is the greater burden on patients, including discomfort, fear of injections or blood collection, and the need for more visits before starting TPT (with associated potential patient costs, time, delays and resulting losses from the cascade of care). However, effective organization of health services can minimize cascade of care losses related to testing (42,60), both in high-income countries and in LMIC.
False negative and indeterminate TB infection tests are a third potential challenge (61). Such test outcomes are more frequent among immunocompromised individuals. However, the high relative risks of developing TB disease in people with positive TB infection tests compared with those with negative tests suggests that false negative results are not major determinants of outcomes that are important to patients. Additionally, some people at risk (e.g. older contacts) may test negative but become infected later, or show infection shortly after the test; in such cases, not giving TPT would be a missed opportunity to protect people.
3.5.2 When is testing for TB infection not advised?
This section sets out the various situations in which testing for TB infection is not advised.
Prior positive TB infection tests
If a prior positive test for TB infection or TB treatment is documented, then repeat testing for TB infection will not be useful and should not be done. Depending on the circumstances, the individual may be referred for further medical evaluation. However, if a prior positive result is self-reported and not documented, it is recommended to repeat the test, because studies have documented highly inaccurate self-reporting of prior skin test results (62).
Concomitant or recent vaccines or viral illnesses
Testing for TB infection may result in false negatives in individuals with certain viral illnesses (e.g. measles) or live virus vaccination (e.g. measles or mumps) within the preceding 30 days (63). This has been described with TST, but a similar effect with all TB infection tests is biologically plausible. Hence, it may be appropriate to delay the test for TB infection for 30 days after infection or vaccination. Alternatively, a negative test for TB infection may be repeated after 30 days.
A common question in recent years has been the impact of COVID-19 infection or vaccination on testing for TB infection. To date, no studies of TST or IGRA results after COVID-19 vaccination have been published. Given what is known about the immunological response to COVID-19 mRNA vaccination, such vaccination would not be expected to change TST or IGRA results (64). However, given that test results could (at least theoretically) be modified by immunization, it may be prudent to test before the vaccine or postpone testing for a few weeks after the vaccine where possible (65).
Clinical work-up of adults to diagnose TB disease or monitoring of the response to treatment
TB infection tests should not be used for the diagnosis of pulmonary or extrapulmonary TB, nor should they be used for the diagnostic work-up of adults (including people living with HIV) with presumed TB disease. TB infection tests should not be used for screening, or to monitor the response to treatment for TB disease or TB infection.
History of TST or TBST allergic reactions (but IGRAs may be used)
Skin testing is not advisable in people with a history of allergic reaction to TST or TBST. Allergic reactions to TST (PPD or equivalent), such as a generalized rash that occurs within the first 24 hours, are seen in less than 1% of recipients (46). If this has been well documented in the past, then it is best to avoid repeating the test with the same tuberculin material. Currently, it is unclear whether use of an alternative tuberculin material would be safe. Anaphylaxis in response to tuberculin skin testing is extremely rare (1 per million) (47); however, if there is well-documented anaphylaxis in response to TST, then TB infection skin testing should not be performed, even with TBST, until further safety information is available.
Loss of consciousness after TST administration due to a vasovagal reaction (simple fainting) is far more common than anaphylaxis.
Challenges with blood collection in young children when using IGRAs (but TBST may be used)
IGRA should not be used to test for TB infection in children aged 6 months to 2 years, because of insufficient data and the challenges of phlebotomy in this age group. Instead, TST or TBST may be used. Testing household contacts aged below 5 years is not a prerequisite for providing TPT.