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Effect of Pregnancy on Interferon Gamma Release Assay and Tuberculin Skin Test Detection of Latent TB Infection Among HIV-Infected Women in a High Burden Setting

LaCourse, Sylvia M. MD, MPH*; Cranmer, Lisa M. MD, MPH; Matemo, Daniel MPH; Kinuthia, John MBChB, MMed, MPH§,‖; Richardson, Barbra A. PhD‖,¶; Horne, David J. MD, MPH‖,#,**; John-Stewart, Grace MD, PhD*,‖,††,‡‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2017 - Volume 75 - Issue 1 - p 128–136
doi: 10.1097/QAI.0000000000001298
Translational Research
Free
SDC

Background: Peripartum immunologic changes may affect latent tuberculosis infection (LTBI) diagnostic performance among HIV-infected women.

Methods: HIV-infected women were serially tested with tuberculin skin test (TST) and interferon gamma release assay [QuantiFERON TB Gold In-tube (QFT)] in pregnancy and 6 weeks postpartum in Kenya. Prevalence, sensitivity and agreement, and correlates of QFT/TST positivity were assessed. Quantitative QFT mitogen and Mycobacterium tuberculosis antigen (Mtb-Ag) responses were compared by peripartum stage. Incidence of test conversion at 6 weeks postpartum was evaluated in baseline TST−/QFT− women.

Results: Among 100 HIV-infected women, median age was 26 years, median CD4 was 555 cells per cubic millimeter, and 88% were on antiretrovirals. More women were QFT+ than TST+ in both pregnancy (35.4% vs. 13.5%, P = 0.001) and postpartum (29.6% vs. 14.8%, P < 0.001). Among 18 consistently QFT+ women, 8 (44%) converted from TST− to TST+, with improved test agreement postpartum (56.9%, κ = 0.20 to 82.4%, κ = 0.60). Three initially QFT−/TST− women had test conversion (TST+ and/or QFT+), suggesting new infection (incidence 13.4/100 person-years). Mean QFT mitogen (4.46 vs. 7.64 IU/mL, P < 0.001) and Mtb-Ag (1.03 vs. 1.54 IU/mL, P = 0.03) responses were lower among all women retested in pregnancy vs. postpartum, and specifically among persistently QFT+ women (Mtb-Ag: 3.46 vs. 4.48 IU/mL, P = 0.007). QFT indeterminate rate was higher in pregnancy (16%) compared with postpartum (0%) because of lower mitogen response.

Conclusions: QFT identified >2-fold more women with LTBI compared with TST in pregnancy and postpartum. Lower QFT Mtb-Ag and mitogen responses in pregnancy compared with postpartum suggest that pregnancy-associated immunologic changes may influence LTBI test performance.

Supplemental Digital Content is Available in the Text.

*Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA;

Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA;

Departments of Research and Programs;

§Reproductive Health, Kenyatta National Hospital, Nairobi, Kenya;

Departments of Global Health;

Biostatistics, University of Washington, Seattle, WA;

#Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington Harborview Medical Center, Seattle, WA;

**Firland Northwest TB Center, Seattle, WA; and

Departments of ††Pediatrics;

‡‡Epidemiology, University of Washington, Seattle, WA.

Correspondence to: Sylvia M. LaCourse, MD, MPH, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 325 9th Avenue, Box 359931, Seattle, WA 98104 (e-mail: sylvial2@uw.edu).

Supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Child Health and Human Development at the National Institutes of Health (K23 AI 120793-01 and T32 AI07140 to S.M.L., K23 AI 85036-01 to D.J.H., K24 HD054314-06 to G.J.-S., K12 HD000850 to L.M.C.), University of Washington Center for AIDS Research (CFAR) P30AI027757 to S.M.L., UW INTERSECT-Ellison Fellowship to S.M.L., the National Center for Research Resources at the National Institutes of Health (UL1TR000423) and the Firland Foundation.

Preliminary study results were presented at the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19–22, 2015, Vancouver, BC, Canada; 46th International Union Against Tuberculosis and Lung Disease World Conference, December 2–6, 2015, Cape Town, South Africa; 21st International AIDS Conference, July 18–22, 2016, Durban, South Africa; and 47th International Union Against Tuberculosis and Lung Disease World Conference, October 26–29, 2016, Liverpool, United Kingdom.

The authors have no conflicts of interest to disclose.

S.M.L. and G.J.-S. designed the study and analyses. S.M.L., L.M.C., D.J.H., J.K., and D.M. conducted the study. S.M.L. and B.A.R. conducted statistical analysis. All co-authors contributed to manuscript writing.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Received October 04, 2016

Accepted January 17, 2017

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INTRODUCTION

Tuberculosis (TB) disease during pregnancy and the postpartum period is associated with poor maternal and infant outcomes.1,2 Pregnancy and HIV have both been associated with increased risk of progression to TB disease in women with Mycobacterium tuberculosis (Mtb) infection.3–5 Detecting latent tuberculosis infection (LTBI) is useful to identify individuals who may most benefit from TB prevention therapies.

LTBI diagnostics, including tuberculin skin tests (TSTs) and interferon gamma release assays (IGRAs), detect cell-mediated immune responses to Mtb infection.6 IGRAs measure interferon gamma (IFN-γ) released from T cells stimulated by Mtb-specific antigens in vitro, whereas TSTs assess the delayed-type hypersensitivity response to purified protein derivative (PPD), which triggers skin induration in vivo.7 In high-risk populations, IGRAs have higher specificity compared with TSTs because of less cross-reactivity with Bacillus Calmette-Guérin (BCG) vaccination and nontuberculous mycobacteria6 but are thought to generally have similar sensitivity.8

Cell-mediated immunity is altered in pregnancy9 and HIV,5 and there is evidence that both pregnancy10,11 and HIV8 effect LTBI diagnostic performance. Two studies in India have compared IGRAs with TSTs in peripartum women in a high TB burden setting,10,11 one of which focused on HIV-infected women.11 In both studies, IGRAs identified a higher proportion of women with LTBI compared with TSTs during pregnancy and postpartum. This pattern of discordance (IGRA+/TST−) differs from the predominant discordance pattern (TST+/IGRA−) observed in studies of HIV-negative pregnant women in low TB incidence settings.12–14 In settings with lower risk of TB transmission, a positive TST may reflect false positivity because of BCG vaccination rather than Mtb infection, leading to a higher proportion of TST+/IGRA−.15 Additionally, most studies have been cross-sectional and do not capture potential dynamic effects of peripartum stage on LTBI diagnostics.

There are no published prospective longitudinal studies evaluating LTBI diagnostics in HIV-infected peripartum women in Africa. In this study, we aimed to determine the effect of peripartum stage on the performance of TST and the QuantiFERON TB Gold In-tube (QFT) IGRA, for LTBI detection among HIV-infected women in Kenya.

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METHODS

Study Setting and Participants

This was a prospective cohort study of HIV-infected pregnant women at 2 antenatal care clinics in the Nyanza region of western Kenya. This region has the highest prevalence of HIV in Kenya (15%), and TB-HIV co-infection is common with ∼68% of TB cases occurring among those with HIV.16 Antenatal HIV prevalence estimates are 19%–26%,17 and the burden of culture-confirmed pulmonary TB among HIV-infected pregnant women in this setting is 2.4%–5.9%.18,19 In Kenya, BCG is administered once at birth, and BCG coverage is high (79%–99%).20 At the time of this study, pregnant HIV-infected women were not routinely offered isoniazid prophylaxis. HIV-infected pregnant women aged 16 years or older were eligible for study enrollment. Women were ineligible if they received treatment for TB disease or LTBI within the past year.

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Procedures

Enrollment in Pregnancy

HIV-infected pregnant women accessing prevention of maternal-to-child transmission services were consecutively recruited and screened. After informed consent, participants were interviewed regarding sociodemographic information, pregnancy, HIV, TB, and LTBI history. Participants were asked whether they or household members had TB symptoms using the World Health Organization 4-part symptom screen (fever, any cough, weight loss, and night sweats),21 as well as prolonged cough (>2 weeks), hemoptysis, and lymphadenopathy, or if they had known exposure to a TB case. Data extracted from clinic charts included medication history, CD4 cell count, and gestational age (estimated by last menstrual period).

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QuantiFERON TB Gold In-tube

Blood was collected in heparinized tubes and transported daily to an ISO 15189-accredited Kenya Medical Research Institute/U.S. Centers for Disease Control and Prevention (KEMRI/CDC) laboratory, where blood was transferred into QFT tubes per manufacturer's recommendations.22 An Mtb antigen (Mtb-Ag) response of ≥0.35 IU/mL (Mtb-Ag minus nil, with nil <8 IU/mL and positive mitogen control) was considered positive.

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Tuberculin Skin Test

After QFT blood collection, TSTs were placed using 5 tuberculin units (0.1 mL) of PPD (RT 23 solution; Sanofi Pasteur) and read by study nurses within 48–96 hours using the “ball-point” and ruler technique.23,24 A positive TST was defined as ≥5 mm of induration in this HIV-infected population.25

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Sputum Collection and Testing

Women provided one expectorated sputum specimen at enrollment. Sputum samples were refrigerated immediately after collection and transported on ice the same day to the KEMRI/CDC laboratory for processing with N-acetyl-L-cysteine and sodium hydroxide. Sputa were examined by acid-fast bacilli (AFB) smear microscopy using Ziehl–Neelsen technique. Mycobacterial culture was performed with MGIT Manual Mycobacterial Growth System (Becton-Dickinson, Franklin Lakes, NJ) and speciation using Capilia TB Test Kit (TAUNS, Numazu, Japan).

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Follow-up at 6 Weeks Postpartum

Participants were re-evaluated at 6 weeks postpartum. Women with either QFT−/TST− or discordant QFT/TST results on enrollment had repeat QFT and TST performed at follow-up. Women with both TST+/QFT+ in pregnancy were seen in follow-up but not retested postpartum per predefined protocol.

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Study Endpoints and Statistical Analysis

Participants with either positive TST or QFT, and negative sputum acid-fast bacilli (AFB) smear and culture were considered to have LTBI. Baseline characteristics were evaluated as potential correlates of LTBI and further stratified by TST or QFT positivity using univariate logistic regression or Fisher exact test as appropriate. The proportion of positive QFT and TST results were compared using χ2 tests. Given the lack of “gold standard,” we used a composite of either QFT+ or TST+ as a reference standard to indicate LTBI to calculate sensitivity. The effect of peripartum stage on sensitivity was assessed using McNemar test. QFT/TST agreement (proportion of QFT/TST tests both either positive or negative) was assessed and concordance measured using kappa (κ) statistics by peripartum stage. Mean quantitative mitogen (QFT mitogen minus nil) and Mtb antigen (QFT Mtb-Ag minus nil) responses were calculated per manufacturer's recommendations and compared by peripartum stage and QFT/TST result by paired or unpaired t tests as appropriate. Estimates were reported using 95% confidence intervals (CIs); all statistical tests were 2-sided with α = 0.05. Analyses were performed using Stata 13 (StataCorp, College Station, TX) and/or GraphPad Prism 6 (GraphPad Software, Inc., La Jolla, CA).

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Ethics Approval

This study was approved by the Kenyatta National Hospital—University of Nairobi Ethics and Research Committee and University of Washington Institutional Review Board.

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RESULTS

Between August 2014 and August 2015, 111 HIV-infected pregnant women were approached and all were eligible for study screening. Seven women declined screening, and 4 declined enrollment after screening. The remaining 100 women were enrolled (Fig. 1).

FIGURE 1

FIGURE 1

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Baseline Characteristics

Median maternal age was 26 years [interquartile range (IQR): 22–32 years), and median gestational age was 27 weeks (IQR: 20–32 weeks) (Table 1). Median CD4 cell count was 555 cells per cubic millimeter (IQR: 340–730 cells/mm3). Most women were on antiretroviral therapy at enrollment (92%), of whom 88 were on combination antiretroviral treatment (ART) and 4 were on nevirapine or zidovudine alone for prevention of maternal-to-child transmission. Although 74 (74%) knew their HIV seropositive status before this pregnancy, only 37 women had initiated ART before pregnancy. Six had a history of TB, and 23% reported TB contact exposure. None reported previous LTBI diagnosis or treatment.

TABLE 1-a

TABLE 1-a

TABLE 1-b

TABLE 1-b

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Enrollment Testing in Pregnancy

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).

FIGURE 2

FIGURE 2

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).

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Six-Week Postpartum Follow-up

Of 100 women enrolled in pregnancy, 98 women were seen at 6-week postpartum follow-up and 2 were lost to follow-up (Fig. 1). Per protocol, 10 women with concordant positive QFT+/TST+ results in pregnancy were not retested. Of 88 women retested postpartum, the proportion of either positive QFT or TST was 34.1% (30/88, 95% CI: 23.9 to 44.1) (Fig. 2). Five had missing TST and 2 had missing QFT results. Among 81 with both postpartum QFT and TST results, a higher proportion of women were QFT+ compared with TST+ (29.6% vs. 14.8%, P < 0.001) (Fig. 2). There were no QFT indeterminates postpartum. Assuming 10 women initially QFT+/TST+ (not retested per protocol) remained positive, prevalence of LTBI at 6 weeks postpartum was estimated to be 39.6% (36/91, 95% CI: 29.3 to 49.8) (Supplemental Digital Content, Table 1, http://links.lww.com/QAI/A967).

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).

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Test Conversion/Reversion

Seventy-eight women underwent both QFT and TST testing in pregnancy and postpartum (Supplemental Digital Content, Table 3, http://links.lww.com/QAI/A967). The most common test conversion occurred among women with consistently positive QFT, who converted from TST− to TST+ by 6 weeks postpartum (10.3%, 8/78). Of 12 women with initially indeterminate QFT, the majority were QFT-negative postpartum (10/12). Three women with negative LTBI testing in pregnancy (QFT−/TST−) had at least 1 test conversion by 6 weeks postpartum (1 with both QFT+/TST+ conversion and 2 with QFT+ conversion but remaining TST−) for an estimated LTBI infection incidence of 13.4/100 person-years. Three women had test reversion to negative: 2 women reverted from QFT+ to QFT− without baseline TST change (1 TST+, 1 TST−), and 1 woman reverted from TST+ to TST− without baseline QFT− result change (Supplemental Digital Content, Table 3, http://links.lww.com/QAI/A967).

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Correlates of LTBI in Pregnancy and Postpartum

Both older age [odds ratio (OR): 1.1 (95% CI: 1.0 to 1.2) per year, P = 0.02] and ART before pregnancy [OR 4.1 (95% CI: 1.7 to 10.1), P = 0.002] were associated with LTBI (either positive TST or QFT) in pregnancy (Table 1). Women with earlier gestational age were less likely to be TST+ [OR 0.91 (95% CI: 0.83 to 0.99) per week gestation, P = 0.03] (Supplemental Digital Content, Table 4, http://links.lww.com/QAI/A967). Positive QFT or TST in the postpartum period were more strongly associated with reported household TB exposure than during pregnancy.

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Quantitative Mitogen and Mtb-Ag IFN-γ Response

Of 86 women QFT tested both in pregnancy and postpartum, mean mitogen (4.46 vs. 7.64 IU/mL, P < 0.001) (Fig. 3, panel A) and Mtb-Ag (1.03 vs. 1.54 IU/mL, P = 0.03) IFN-γ responses were lower in pregnancy compared with postpartum. This pattern of lower mean Mtb-Ag IFN-γ response in pregnancy was similar when restricted to women who remained QFT+ at both time points (3.46 vs. 4.48 IU/mL, P = 0.007) (Fig. 3, panel B). Most QFT−/TST− pregnant women remained QFT−/TST− postpartum (41/44), without change in Mtb-Ag IFN-γ (0.04 vs. 0.04 IU/mL, P = 0.93). Among women with initially negative testing (QFT−/TST−) in pregnancy, 1 converted to QFT+/TST+ (both test conversion) with corresponding increase in Mtb-Ag IFN-γ from 0.03 to 8.07 IU/mL, and 2 converted to QFT+/TST− (QFT+ conversion only) with mean Mtb-Ag IFN-γ increase from 0.0 to 2.33 IU/mL (Fig. 3C). Mean Mtb-Ag IFN-γ was higher (though not statistically significant) among QFT+/TST+ compared with those with discordant QFT+/TST− in pregnancy and postpartum (Figs. 3D,E).

FIGURE 3

FIGURE 3

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DISCUSSION

In this longitudinal study of HIV-infected women in western Kenya, a higher proportion was identified as having LTBI by QFT compared with TST in both pregnancy and early postpartum. Our findings of lower likelihood of TST+ at later gestational age (when immunosuppression peaks just before delivery) and lower proportion of positive TST in pregnancy and postpartum compared with QFT suggest that TST is more influenced by peripartum stage than QFT. TST conversion from negative in pregnancy to positive postpartum among women who remained QFT positive at both time points, supports this hypothesis. In addition, lower mean QFT Mtb-Ag and mitogen responses and higher indeterminate rates (because of low mitogen levels) in pregnancy compared with postpartum suggest that IGRAs are also effected by pregnancy-related immunologic changes. The relatively high incidence of postpartum test conversion may indicate that the peripartum period is a time of increased risk for Mtb infection.

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.

QFT responses were also affected by pregnancy. In the HIV-infected Indian cohort described by Mathad et al,11 median mitogen and Mtb-Ag IFN-γ responses decreased from pregnancy to delivery, with postpartum increases. Similarly in our cohort, mean mitogen and Mtb-Ag IFN-γ responses were significantly lower in pregnancy compared with postpartum. We noted higher rates of indeterminates in pregnancy compared with postpartum, all because of low mitogen response. Both IGRA and TST measure Th-1 immune responses. Increasing levels of progesterone throughout pregnancy favor transition from Th-1 to Th-2 T-cell responses.9 Th-1 responses reach a nadir late in the third trimester, with decreased cellular expression of IFN-γ in later pregnancy with postpartum rebound.27,28

Similar mechanisms responsible for the blunted response of LTBI diagnostics in pregnancy may contribute to the observed increase in active TB noted in the postpartum period. Decreased Th-1 responses in pregnancy have been speculated to increase risk of influenza9,29 and potentially TB.1 Early postpartum Th-1 response rebound has been described as analogous to immune reconstitution inflammatory syndrome30 and may account for the increased incidence of both IGRA conversion and active TB disease observed in the early postpartum period.3,4,31 In a large cohort in the United Kingdom, there was a nearly 2-fold increased incidence of active TB in the early postpartum period.3 Given difficulties with TB screening and diagnoses in pregnancy,18,19 this early postpartum risk could reflect TB during pregnancy not detected until postpartum3 or pregnancy-related risk of progression from infection to disease. In a cohort of HIV-infected women in Kenya, positive IGRA results in pregnancy were associated with increased postpartum active TB and mortality among mothers and their infants.32 Mathad et al11 found a similar increase in postpartum TB among IGRA-positive HIV-infected pregnant women and noted greater decreases in mitogen and Mtb-Ag IFN-γ and IL-2 responses from pregnancy to delivery compared with IGRA+ women who did not develop TB, suggesting a potential mechanism for this observation.

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.

TB contributes significant morbidity and mortality to HIV-infected pregnant women and their children1 and is the third leading cause of death among women of child-bearing age in high burden areas.1 Our study provides evidence that pregnancy influences the performance of LTBI diagnostics. We found that QFT was superior to TST in identifying LTBI in HIV-infected pregnant women. The shortcomings of both tests to identify individuals who are most likely to progress to active TB has led to ongoing efforts to develop improved diagnostics that better predict for active TB disease.49 Our findings suggest that peripartum women and their infants should be included in these evaluations. The development of improved, lower cost, clinic-based testing for LTBI could inform use of isoniazid preventive therapy to potentially impact TB-related morbidity and mortality in HIV-infected peripartum women and their infants in high-burden settings.

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ACKNOWLEDGMENTS

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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REFERENCES

1. Mathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect Dis. 2012;55:1532–1549.
2. Getahun H, Sculier D, Sismanidis C, et al. Prevention, diagnosis, and treatment of tuberculosis in children and mothers: evidence for action for maternal, neonatal, and child health services. J Infect Dis. 2012;205(suppl 2):S216–S227.
3. Zenner D, Kruijshaar ME, Andrews N, et al. Risk of tuberculosis in pregnancy: a national, primary care-based cohort and self-controlled case series study. Am J Respir Crit Care Med. 2012;185:779–784.
4. Gupta A, Nayak U, Ram M, et al. Postpartum tuberculosis incidence and mortality among HIV-infected women and their infants in Pune, India, 2002–2005. Clin Infect Dis. 2007;45:241–249.
5. Lawn SD, Wood R, Wilkinson RJ. Changing concepts of “latent tuberculosis infection” in patients living with HIV infection. Clin Dev Immunol. 2011;2011.
6. Pai M, Denkinger CM, Kik SV, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014;27:3–20.
7. Andersen P, Munk ME, Pollock JM, et al. Specific immune-based diagnosis of tuberculosis. Lancet. 2000;356:1099–1104.
8. Cattamanchi A, Smith R, Steingart KR, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2011;56:230–238.
9. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med. 2014;370:2211–2218.
10. Mathad JS, Bhosale R, Sangar V, et al. Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting. PLoS One. 2014;9:e92308.
11. Mathad JS, Bhosale R, Balasubramanian U, et al. Quantitative IFN-gamma and IL-2 response associated with latent tuberculosis test discordance in HIV-infected pregnant women. Am J Respir Crit Care Med. 2016;193:1421–1428.
12. Lighter-Fisher J, Surette AM. Performance of an interferon-gamma release assay to diagnose latent tuberculosis infection during pregnancy. Obstet Gynecol. 2012;119:1088–1095.
13. Worjoloh A, Kato-Maeda M, Osmond D, et al. Interferon gamma release assay compared with the tuberculin skin test for latent tuberculosis detection in pregnancy. Obstet Gynecol. 2011;118:1363–1370.
14. Chehab BM, Kallail JK, ElFakih R, et al. Use of the QuantiFERON-TB Gold assay in pregnant patients. Kans J Med. 2010;3:24–30.
15. Malhame I, Cormier M, Sugarman J, et al. Latent tuberculosis in pregnancy: a systematic review. PLoS One. 2016;11:e0154825.
16. Kenya Ministry of Health (MOH) National Tuberculosis; Leprosy and Lung Disease Unit (NTLD). Kenya NTLD Unit Annual Report 2014. 2014. Available at: http://nltp.co.ke/annual-reports/. Accessed September 1, 2015.
17. Kenya National AIDS and STI Control Programme (NASCOP). Kenya AIDS Indicator Survey 2012: Final Report. 2014. Available at: http://http://www.nacc.or.ke/images/documents/KAIS-2012.pdf. Accessed September 1, 2015.
18. LaCourse SM, Cranmer LM, Matemo D, et al. Tuberculosis case finding in HIV-infected pregnant women in Kenya reveals poor performance of symptom screening and rapid diagnostic tests. J Acquir Immune Defic Syndr. 2016;71:219–227.
19. Modi S, Cavanaugh JS, Shiraishi RW, et al. Performance of clinical screening algorithms for tuberculosis intensified case finding among people living with HIV in Western Kenya. PLoS One. 2016;11:e0167685.
20. World Health Organization. Kenya—WHO and UNICEF Estimates of National Immunization Coverage. 2015. Available at: http://http://www.who.int/immunization/monitoring_surveillance/data/ken.pdf. Accessed September 1, 2015.
21. World Health Organization. Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living With HIV in Resource-Constrained Settings. 2011. Available at: http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf. Accessed September 1, 2015.
22. Qiagen. QuantiFERONï TB Gold in Tube package insert. 2015. Available at http://http://www.quantiferon.com/irm/content/PI/QFT/2PK/US.pdf. Accessed September 1, 2015.
23. Cobelens F, Van Deutekom H, Draayer-Jansen I, et al. Tuberculin skin test reactions by time of reading among Dutch travellers. Int J Tuberc Lung Dis. 2003;7:758–763.
24. Tuberculin reaction size on five consecutive days. Bull World Health Organ. 1955;12:189–196.
25. Targeted tuberculin testing and treatment of latent tuberculosis infection: joint statement of the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Am J Respir Crit Care Med. 2000;161:S221–S247.
26. Covelli HD, Wilson RT. Immunologic and medical considerations in tuberculin-sensitized pregnant patients. Am J Obstet Gynecol. 1978;132:256–259.
27. Kraus TA, Sperling RS, Engel SM, et al. Peripheral blood cytokine profiling during pregnancy and post-partum periods. Am J Reprod Immunol. 2010;64:411–426.
28. Kraus TA, Engel SM, Sperling RS, et al. Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study. J Clin Immunol. 2012;32:300–311.
29. Raj RS, Bonney EA, Phillippe M. Influenza, immune system, and pregnancy. Reprod Sci. 2014;21:1434–1451.
30. Singh N, Perfect JR. Immune reconstitution syndrome and exacerbation of infections after pregnancy. Clin Infect Dis. 2007;45:1192–1199.
31. Jonnalagadda S, LaCourse SM, Otieno P, et al. Incidence and correlates of tuberculosis IGRA conversion among HIV-infected postpartum women. Int J Tuberc Lung Dis. 2015;19:792–798.
32. Jonnalagadda S, Lohman Payne B, Brown E, et al. Latent tuberculosis detection by interferon gamma release assay during pregnancy predicts active tuberculosis and mortality in human immunodeficiency virus type 1-infected women and their children. J Infect Dis. 2010;202:1826–1835.
33. Pai M, Dendukuri N, Wang L, et al. Improving the estimation of tuberculosis infection prevalence using T-cell-based assay and mixture models. Int J Tuberc Lung Dis. 2008;12:895–902.
34. Hecker MT, Johnson JL, Whalen CC, et al. Two-step tuberculin skin testing in HIV-infected persons in Uganda. Am J Respir Crit Care Med. 1997;155:81–86.
35. Esmail H, Thienemann F, Oni T, et al. QuantiFERON conversion following tuberculin administration is common in HIV infection and relates to baseline response. BMC Infect Dis. 2016;16:545.
36. Markowitz N, Hansen NI, Hopewell PC, et al. Incidence of tuberculosis in the United States among HIV-infected persons. The Pulmonary Complications of HIV Infection Study Group. Ann Intern Med. 1997;126:123–132.
37. Kufa T, Mabuto T, Muchiri E, et al. Incidence of HIV-associated tuberculosis among individuals taking combination antiretroviral therapy: a systematic review and meta-analysis. PLoS One. 2014;9:e111209.
38. Pullar N, Steinum H, Bruun J, et al. HIV patients with latent tuberculosis living in a low-endemic country do not develop active disease during a 2 year follow-up: a Norwegian prospective multicenter study. BMC Infect Dis. 2014;14:667.
39. French AL, Evans CT, Anastos K, et al. Incidence of tuberculin skin test conversion among HIV-infected and -uninfected women: results of a 6-year study. J Acquir Immune Defic Syndr. 2006;42:592–596.
40. Girardi E, Palmieri F, Zaccarelli M, et al. High incidence of tuberculin skin test conversion among HIV-infected individuals who have a favourable immunological response to highly active antiretroviral therapy. AIDS. 2002;16:1976–1979.
41. Aichelburg MC, Reiberger T, Breitenecker F, et al. Reversion and conversion of interferon-gamma release assay results in HIV-1-infected individuals. J Infect Dis. 2014;209:729–733.
42. Houben RM, Crampin AC, Ndhlovu R, et al. Human immunodeficiency virus associated tuberculosis more often due to recent infection than reactivation of latent infection. Int J Tuberc Lung Dis. 2011;15:24–31.
43. Middelkoop K, Mathema B, Myer L, et al. Transmission of tuberculosis in a South African community with a high prevalence of HIV infection. J Infect Dis. 2015;211:53–61.
44. Middelkoop K, Bekker LG, Liang H, et al. Force of tuberculosis infection among adolescents in a high HIV and TB prevalence community: a cross-sectional observation study. BMC Infect Dis. 2011;11:156.
45. Andrews JR, Hatherill M, Mahomed H, et al. The dynamics of QuantiFERON-TB gold in-tube conversion and reversion in a cohort of South African adolescents. Am J Respir Crit Care Med. 2015;191:584–591.
46. Hill PC, Brookes RH, Fox A, et al. Longitudinal assessment of an ELISPOT test for Mycobacterium tuberculosis infection. PLoS Med. 2007;4:e192.
47. Pai M, Joshi R, Dogra S, et al. T-cell assay conversions and reversions among household contacts of tuberculosis patients in rural India. Int J Tuberc Lung Dis. 2009;13:84–92.
48. Shah M, Kasambira TS, Adrian PV, et al. Longitudinal analysis of QuantiFERON-TB Gold In-Tube in children with adult household tuberculosis contact in South Africa: a prospective cohort study. PLoS One. 2011;6:e26787.
49. Petruccioli E, Scriba TJ, Petrone L, et al. Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis. Eur Respir J. 2016;48:1751–1763.
Keywords:

latent tuberculosis infection; HIV; pregnancy; tuberculin skin testing; interferon gamma release assay; QuantiFERON TB Gold In-tube; diagnostics

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