Five women were unable to produce sputum; the remaining 95 had sputum culture negative for M. tuberculosis. QFT was performed on all 100 participants, of which 34 were positive, 50 negative, and 16 indeterminate. Four participants did not have their TST read within 96 hours (Fig. 1). Of 96 women with TST results, 13.5% were positive (Fig. 2). The prevalence of LTBI in pregnancy, measured by either positive TST or QFT, was 37.0% (95% CI: 27.4 to 46.6). Of 96 women with both QFT and TST results in pregnancy, a significantly higher proportion were QFT+ compared with TST+ (35.4% vs. 13.5%, P = 0.001).
The sensitivity of QFT to identify LTBI was higher than TST, using a composite reference of either positive test (91.9% vs. 36.1%, P < 0.0001) (Supplemental Digital Content, Table 1, http://links.lww.com/QAI/A967). Ten women (10.4%) were concordant positive (QFT+/TST+), 47 (49.0%) were concordant negative (QFT−/TST−), and 14 (14.6%) had indeterminate QFT results because of low mitogen response (13 TST−, 1 TST+) (Supplemental Digital Content, Table 2, http://links.lww.com/QAI/A967). The most common pattern of discordance in pregnancy was QFT+/TST− (23/96, 24%). QFT and TST agreement was 56.9% (κ = 0.20, 95% CI: 0.16 to 0.24).
Postpartum, the sensitivity of QFT to identify LTBI remained higher than TST (94.4% vs. 61.1%, P = 0.003) (Supplemental Digital Content, Table 1, http://links.lww.com/QAI/A967). TST sensitivity improved significantly from pregnancy to postpartum (36.1%–61.1%, P = 0.02), whereas QFT sensitivity remained similarly high (91.9%–94.4%, P = 0.26). Among 81 women with both QFT/TST postpartum results, 12.4% were concordant positive (QFT+/TST+) and 67.9% were concordant negative (QFT−/TST−) (Supplemental Digital Content, Table 2, http://links.lww.com/QAI/A967). Comparable to pregnancy, the most common pattern of discordance was QFT+/TST− (17.3%, 14/81). Including 10 women initially QFT+/TST+ in pregnancy (not retested per protocol), IGRA/TST agreement improved to 82.4% postpartum (κ = 0.60, 95% CI: 0.42 to 0.77) (Supplemental Digital Content, Table 2, http://links.lww.com/QAI/A967).
In this study, QFT identified more than twice as many women with LTBI compared with TST in the peripartum period. These results are similar to recent studies of HIV-infected11 and -uninfected10 peripartum women in India and suggest that TST often fails to detect LTBI in peripartum women. Among previously TST-positive women in the United States, in vitro lymphocyte responses to PPD decreased in late pregnancy and delivery, returning to higher early pregnancy levels within 24 hours postpartum.26 We observed decreased likelihood of TST positivity later in pregnancy when the relative immune suppression of pregnancy may be greatest. The high proportion of postpartum TST− to TST+ conversion among consistently QFT+ women in our cohort may represent pregnancy-associated blunting of the PPD response in pregnancy with recovery early postpartum.
Our study had several limitations. We did not retest women with QFT+/TST+ results in pregnancy, though the low level of reversions among women with either QFT+ or TST+ tests suggest that re-testing QFT+/TST+ women would not have resulted in substantial reversions. Because there is no gold standard diagnostic test for LTBI, we assumed that either positive QFT or TST represented “true” LTBI in estimating sensitivity and are therefore unable to estimate specificity. Latent class analysis models could be used to estimate LTBI prevalence in the absence of a gold standard; however, additional data in this population are needed to strengthen these models, which require previous probability estimates.33 “Boosting” of an initially low pre-existing antigen response (false negative) with repeated TST testing may have contributed to increased TST positivity postpartum.34 Although QFT is considered less prone to “boosting,”6 Esmail et al35 recently reported that QFT conversion after TST placement may occur in HIV infection, associated with higher baseline median Mtb-Ag response in QFT converters vs. nonconverters (0.21 vs. 0.02 IU/mL, P = 0.002). In contrast, QFT converters in our study had baseline mean Mtb-Ag responses (0.01 IU/mL) well below the threshold for a positive QFT test (≥0.35 IU/mL). The magnitude of change in mean Mtb-Ag from baseline to postpartum (0.01–4.24 IU/mL) in our study suggests that these are truly new infections as opposed to “boosting” of borderline QFT-positive results.
Strengths of our study include formal screening for active TB through sputum culture, reducing misclassification of women with subclinical TB disease. Our relatively large sample size of longitudinally assessed women provided power to detect significant differences in test performance in both pregnancy and postpartum. Despite the known increased risk of progression from M. tuberculosis infection to disease in association with HIV36 and continued risk of TB even after ART initiation,37 there are few studies that serially assess LTBI status in HIV-infected individuals. Whether HIV increases Mtb acquisition risk as opposed to progression from infection to disease is unknown.5 Most studies in HIV-infected adults have assessed TST before and after initiation of ART.38–40 In this context, TST is unable to discriminate new Mtb infection from immune reconstitution of TST response after ART. The few longitudinal assessments of LTBI in HIV-infected individuals using IGRA have been primarily in low-burden settings.38,41 Longitudinal IGRA evaluation, such as our study, provides an opportunity to estimate incident Mtb infection in high-risk populations. Molecular fingerprinting studies indicate TB cases in HIV-infected individuals in sub-Saharan Africa are more likely because of new infection than to reactivation.42,43 We have previously described a high incidence of IGRA conversion (12.4% from 32 weeks gestation to 12 months postpartum) in a historical cohort of HIV-infected pregnant women before widespread availability of ART.31 The incidence of IGRA conversion (13.4/100 person-years) in this current study, with Mtb-Ag responses well above the threshold for positive QFT among converters, suggest that risk for Mtb infection in this cohort of HIV-infected peripartum women is similar to other well-described high-risk groups, including South African adolescents44,45 and household contacts of known TB cases.46–48 In our previous work in the same setting, we found 2.4% of HIV-infected pregnant women had culture-confirmed TB and women who reported household members with TB symptoms were more likely to have TB.18 This suggests the burden of undiagnosed TB in HIV-infected peripartum women, and within their households is high. In addition, mothers visit clinic and hospital in the peripartum period, both settings in which exposure to TB could occur given high HIV and TB prevalence in this region. Further studies are needed to investigate whether the increase in IGRA conversion postpartum is because of increased risk of Mtb acquisition in the peripartum period or diminished sensitivity of LTBI diagnostics by pregnancy.
The authors thank the staff at the Ahero Sub-district Hospital and Bondo District Hospital antenatal clinics, KEMRI/CDC laboratory personnel, and the study staff and participants.
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