Diagnosis of Latent Tuberculosis Infection: Too Soon to Pull the Plug on the Tuberculin Skin Test
Accurate identification of persons recently infected with Mycobacterium tuberculosis (MTB) is critical for tuberculosis (TB) control because they are at greatest risk for progression to active disease in 1 to 2 years. Two diagnostic methods exist for latent TB infection (LTBI) the historic and widely used tuberculin skin testing (TST) and the newer interferon release assays (IGRAs) Both tests measure host immunity to MTB antigens, representing an indirect immunologic footprint of past infection rather than direct microbial presence; however, neither predicts persons at high risk for progression (1) Current guidelines by the Centers for Disease Control and Prevention consider these tests equivalent for diagnosis of LTBI (2) but several discrepancies challenge whether they can indeed be used interchangeably. Tuberculin skin testing and IGRA results are not uniformly correlated, although the basis for this and the potential clinical implications are unknown. Recent observations suggest possible explanations. A prospective study of 357 Brazilian household contacts (HHCs) of persons with pulmonary TB found 21% discordance in TSTIGRA results measured 8 to 12 weeks after HHC enrollment82% of dissenting results were TST positiveIGRA negative (3) Discordance was more common (52% in newly MTB infected contacts, defined by TST conversion, and was associated with less exposure to the index case than in the concordant group (3) A prospective analysis of 152 HHCs of persons with TB in Spain showed that TSTIGRA concordance increased when assessed 2 months after baseline evaluation, as did correlation of each test with markers of risk for MTB infection, such as intensity of exposure (4) Eight weeksthe interval between acquisition of infection and a measurable immune responseis the generally accepted window period for TST reactions. The Brazilian and Spanish HHC studies suggest that an infectious doseresponse relationship may account for both discordance and the increase in concordance with time. A series of HHC studies in Uganda further supports that the window period for TST conversion may be greater than 8 weeks and that for IGRA conversion may be even longer (5) Overall, 41% of the 102 initially TST negative HHCs had TST conversion by 3 months, with an additional 10% of conversions occurring by 6 months or later (5) Compared with those who were TST positive at baseline, persons who converted 3 months after exposure had gradually increasing levels of interferon production that took 3 to 12 months to reach the magnitude of those with initially positive TST results (5) In a platoon of 32 South Korean soldiers exposed to a person with pulmonary TB, contact investigation 1 month after ascertainment of the source case revealed that 78% of soldiers tested TST positive, whereas 63% tested IGRA positive; in those with initially negative IGRA results, serial testing revealed that IGRA conversion occurred as late as 14 to 22 weeks after exposure (6) On the basis of these studies, we propose a hypothetical model (Figure) in which intensity of exposure modulates discordance by affecting the window period for TST and IGRA conversion. Less HHC exposure to a TB index case results in delayed TST conversion and even further delayed IGRA conversion. Figure. Timeline of TST and IGRA conversion for diagnosis of LTBI. It is recommended that screening for LTBI be performed within 2 wk after known exposure to a pulmonary TB case. According to the Centers for Disease Control and Prevention guidelines, screening with TST or IGRA is acceptable, and if the initial result is negative, repeated testing with the same method should be performed 810 wk later. Upon screening, some exposed contacts will be TST positive at baseline (A and B) whereas others may convert to TST positivity between testing periods (C and D) After the stated tuberculin window period of 810 wk, TST/IGRA concordance increases, as does the correlation of each test with measurements of exposure to the TB index case. We propose that conversion of IGRAs to positivity is delayed compared with that of TST and that less intense exposure to the TB index case may further delay conversion for both tests. IGRA interferon release assay; LTBI latent tuberculosis infection; TB tuberculosis; TST tuberculin skin testing. Interferon release assay testing offers better specificity than TST in distinguishing MTB infection from bacille CalmetteGurin (BCG) vaccination. However, this advantage is of little clinical significance if the vaccination is administered within the first year of life. Only 1% of children vaccinated before 1 year of age are TST positive after 10 years compared with 21% of those vaccinated later (7) These findings corroborate those from other studies showing that BCG vaccination may influence TSTIGRA discordance only in pediatric populations. The variable reproducibility of IGRA results also undermines its usefulness as an LTBI diagnostic tool. Intraindividual variability in the magnitude of interferon response has been observed in health care workers (HCWs) in high and low prevalence settings. A retrospective study performed in the United States reported that 64.8% of HCWs who had initially positive IGRA results reverted to IGRA negative results on repeated testing 6 weeks later (8) Cohort studies have shown that IGRA reversion is more common in persons who are TST negative, those from a low risk setting, or when the IGRA result barely surpasses the cutoff for positivity (9) Interpretation of IGRA may benefit from risk stratification that considers TB prevalence, exposure history, and risk for progression to disease, as is recommended for TST. In evaluation of HHCs for LTBI, TST is less costly than IGRA, even when 2 patient visits are accounted for. However, 50% of high risk populations may not return for the TST reading and be lost to follow up. Although routine use of IGRA confers the advantage of a single patient visit, limitations for the developing worldwhere TB burden is highestinclude higher cost and a lack of laboratory expertise and infrastructure for implementation. Targeted screening of HHCs has been endorsed for global TB control (10) Guidelines from the Centers for Disease Control and Prevention state that either TST or IGRA can be used for LTBI diagnosis and that the same screening method should be repeated at 8 to 10 weeks in close contacts with initially negative results (2) We believe that, when differences in testing characteristics, cost, implementation logistics, and timing and subpopulations of testing are being considered, TST and IGRA are not equivalent for LTBI diagnosis. The data and model we present indicate that the potential for a delayed IGRA response may not detect recently MTB infected HHCs who are at paramount risk for active TB. Thus, there are 3 strikes against adopting IGRAs as a replacement for TST in LTBI screening: decreased sensitivity for detecting newly infected persons at high risk for progression, diminished relevance of improved specificity in BCG immunized populations, and instability of IGRA results in annual retesting of HCWs. Our recommendation is to choose testing on the basis of an a priori risk for MTB infection and risk for progression from LTBI to active disease. If both risks are low, either test can be used initially, with IGRA being preferred if BCG was administered after 1 year of age. If the initial test was IGRA and the result was positive, then repeating or performing TST as confirmation before treating for LTBI can be considered. If the initial test was TST and the result was positive, then treating for LTBI is reasonable given that interpretation of TST is risk stratified. Conversely, if risk is high or the patient is immunocompromised, both tests should be used and the patient should be treated for LTBI if the result of either test is positive. In conclusion, it is too soon to abandon TST.
Annals of Internal Medicine