Jyoti S. Mathad

Tuberculosis in Pregnant and Postpartum Women: Epidemiology, Management, and Research Gaps

Tuberculosis is most common during a womans reproductive years and is a major cause of maternal-child mortality. National guidelines for screening and management vary widely owing to insufficient data. In this article, we review the available data on (1) the global burden of tuberculosis in women of reproductive age; (2) how pregnancy and the postpartum period affect the course of tuberculosis; (3) how to screen and diagnose pregnant and postpartum women for active and latent tuberculosis; (4) the management of active and latent tuberculosis in pregnancy and the postpartum period, including the safety of tuberculosis medications; and (5) infant outcomes. We also include data on HIV/tuberculosis coinfection and drug-resistant tuberculosis. Finally, we highlight research gaps in tuberculosis in pregnant and postpartum women.

Maternal pneumococcal capsular IgG antibodies and transplacental transfer are low in South Asian HIV-infected mother-infant pairs

BACKGROUND Our understanding of the mother-to-child transfer of serotype-specific pneumococcal antibodies is limited in non-immunized, HIV-positive women. METHODS We compared geometric mean antibody concentrations (GMCs), geometric mean transplacental cord:maternal ratios (GMRs) and proportions of samples with protective antibody concentration (≥0.35μg/ml) to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F between 74 HIV-infected and 98 HIV-uninfected mother-infant pairs who had not received pneumococcal immunization in South Asia. Multivariable analysis was performed to assess the influence of HIV on protective antibody concentrations. RESULTS HIV-infected mothers and their infants exhibited lower GMCs and GMRs than their uninfected counterparts. This was significant for all serotypes except maternal GMC to serotype 1 and GMR for serotype 6B. In multivariate analysis, HIV was significantly associated with reduced odds of having protective pneumococcal IgG levels; 56-73% reduction for 3 maternal serotypes (4, 5, 23F) and 62-90% reduction for all cord samples except serotype 6B. CONCLUSIONS Maternal HIV infection is associated with lower levels of maternal pneumococcal antibodies and disproportionately lower cord antibodies, relative to maternal antibodies, suggesting that HIV infection compromises transplacental transfer. Reassessment of maternal and/or infant pneumococcal immunization strategies is needed in HIV-infected women and their infants.

Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting.

Background Targeted screening for latent TB infection (LTBI) in vulnerable populations is a recommended TB control strategy. Pregnant women are at high risk for developing TB and likely to access healthcare, making pregnancy an important screening opportunity in developing countries. The sensitivity of the widely-used tuberculin skin test (TST), however, may be reduced during pregnancy. Methods We performed a cross-sectional study comparing the TST with the QuantiFERON Gold In-tube (QGIT) in 401 HIV-negative women presenting antepartum (n = 154), at delivery (n = 148), or postpartum (n = 99) to a government hospital in Pune, India. A subset of 60 women enrolled during pregnancy was followed longitudinally and received both tests at all three stages of pregnancy. Results The QGIT returned significantly more positive results than the TST. Of the 401 women in the cross-sectional study, 150 (37%) had a positive QGIT, compared to 59 (14%) for the TST (p<0.005). Forty-nine (12%) did not have their TST read. Of 356 who had both results available, 46 (13%) were concordant positive, 91 (25%) were discordant (12 (3%) TST+/QGIT-; 79 (22%) TST−/QGIT+), and 206 (57%) concordant negative. Comparison by stage of pregnancy revealed that QGIT percent positivity remained stable between antepartum and delivery, unlike TST results (QGIT 31–32% vs TST 11–17%). Median IFN-γ concentration was lower at delivery than in antepartum or postpartum (1.66 vs 2.65 vs 8.99 IU/mL, p = 0.001). During postpartum, both tests had significantly increased positives (QGIT 31% vs 32% vs 52%, p = 0.01; TST 17% vs 11% vs 25%, p<0.005). The same trends were observed in the longitudinal subset. Conclusions Timing and choice of LTBI test during pregnancy impact results. QGIT was more stable and more closely approximated the LTBI prevalence in India. But pregnancy stage clearly affects both tests, raising important questions about how the complex immune changes brought on by pregnancy may impact LTBI screening.

Sex-related differences in inflammatory and immune activation markers before and after combined antiretroviral therapy initiation

Background:Women progress to death at the same rate as men despite lower plasma HIV RNA (viral load). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. Methods:Inflammatory and immune activation markers [interferon &ggr;, tumor necrosis factor (TNF) &agr;, IL-6, IL-18, IFN-&ggr;–induced protein 10, C-reactive protein (CRP), lipopolysaccharide, and sCD14] were measured at weeks 0, 24, and 48 after combination antiretroviral therapy (cART) in a random subcohort (n = 215) who achieved virologic suppression in ACTG A5175 (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95% confidence intervals were estimated using multivariable models. Results:At baseline, women had lower median log10 viral load (4.93 vs 5.18 copies per milliliter, P = 0.01), CRP (2.32 vs 4.62 mg/L, P = 0.01), detectable lipopolysaccharide (39% vs 55%, P = 0.04), and sCD14 (1.9 vs 2.3 µg/mL, P = 0.06) vs men. By week 48, women had higher interferon &ggr; (22.4 vs 14.9 pg/mL, P = 0.05), TNF-&agr; (11.5 vs 9.5 pg/mL, P = 0.02), and CD4 (373 vs 323 cells per cubic millimeter, P = 0.02). In multivariate analysis, women had greater increases in CD4 and TNF-&agr; but less of a decrease in CRP and sCD14 compared with men. Conclusions:With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

Quantitative IFN-γ and IL-2 Response Associated with Latent Tuberculosis Test Discordance in HIV-infected Pregnant Women.

RATIONALE Pregnant women with latent tuberculosis infection (LTBI) are at high risk for development of TB, especially if infected with HIV. OBJECTIVES To assess the performance of LTBI tests in pregnant and postpartum women infected with HIV, investigate the immunology behind discordance in pregnancy, and explore the implications for the development of postpartum TB. METHODS We screened pregnant women in their second/third trimester and at delivery for LTBI using the tuberculin skin test (TST) and IFN-γ release assay (IGRA) (QuantiFERON Gold). A subset of antepartum women had longitudinal testing, with repeat testing at delivery and postpartum and additional cytokines measured from the IGRA supernatant. The kappa statistic and Wilcoxon rank sum test were used to determine agreement and comparison of cytokine concentrations, respectively. MEASUREMENTS AND MAIN RESULTS Of 252 enrolled, 71 (28%) women had a positive IGRA but only 27 (10%) had a positive TST (P < 0.005). There was 75% agreement (kappa, 0.25). When stratified by pregnancy versus delivery, 20% had IGRA(+)/TST(-) discordance at each time point. A positive IGRA was associated with known TB contact (odds ratio, 3.6; confidence interval, 1.2-11.1; P = 0.02). Compared with IGRA(+)/TST(+), women with IGRA(+)/TST(-) discordance had significantly less IFN-γ (1.85 vs. 3.48 IU/ml; P = 0.02) and IL-2 (46.17 vs. 84.03 pg/ml; P = 0.01). Five developed postpartum TB, of which three had IGRA(+)/TST(-) discordance during pregnancy. CONCLUSIONS Choice of LTBI test in pregnant women infected with HIV affects results. Pregnant women with IGRA(+)/TST(-) discordance had less IFN-γ and IL-2 than those with concordant-positive results and may represent an especially high-risk subset for the development of active TB postpartum.

Developing an Assessment Framework for Essential Internal Medicine Subspecialty Topics

Background Assessing residents by direct observation is the preferred assessment method for infrequently encountered subspecialty topics, but this is logistically challenging. Objective We developed an assessment framework for internal medicine (IM) residents in subspecialty topics, using tuberculosis diagnosis for proof of concept. Methods We used a 4-step process at 8 academic medical centers that entailed (1) creating a 10-item knowledge assessment tool; (2) pilot testing on a sample of 129 IM residents and infectious disease fellow volunteers to evaluate validity evidence; (3) implementing the final tool among 886 resident volunteers; and (4) assessing outcomes via retrospective chart review. Outcomes included tool score, item performance, and rates of obtaining recommended diagnostics. Results Following tool development, 10 infectious disease experts provided content validity. Pilot testing showed higher mean scores for fellows compared with residents (7 [SD = 1.8] versus 3.8 [SD = 1.7], respectively, P < .001) and a satisfactory Kuder-Richardson Formula 20 (0.72). Implementation of the tool revealed a 14-minute (SD = 2.0) mean completion time, 61% (541 of 886) response rate, 4.4 (SD = 1.6) mean score, and ≤ 57% correct response rate for 9 of 10 items. On chart review (n = 343), the rate of obtaining each recommended test was ≤ 43% (113 of 261), except for chest x-rays (96%, 328 of 343). Conclusions Our assessment framework revealed knowledge and practice gaps in tuberculosis diagnosis in IM residents. Adopting this approach may help ensure assessment is not limited to frequently encountered topics.

Household food insecurity is associated with low interferongamma levels in pregnant Indian women

SETTING Over 20% of tuberculosis (TB) cases during pregnancy occur in India. OBJECTIVE To determine the association between household food insecurity and interferon-gamma (IFN-γ) levels in pregnancy. DESIGN Pregnant women in India were administered the Household Food Insecurity Access Scale (HFIAS) questionnaire and underwent an IFN-γ release assay. Logistic regression was used to identify factors associated with food insecurity. RESULTS Of 538 women, 60 (11%) had household food insecurity, 47 (78%) of which were moderate or severe food insecure. After mitogen stimulation, moderate or severe food insecure women had a median IFN-γ concentration of 4.2 IU/ml (IQR 2.2-9.8) vs. 8.4 IU/ml (IQR 3.0-10) in women with no or mild food insecurity (P = 0.03). In multivariate analysis, higher IFN-γ concentrations were associated with human immunodeficiency virus infection (OR 1.3, 95%CI 0.51-2.1, P = 0.001), and inversely associated with moderate or severe food insecurity (OR -1.6, 95%CI -2.9 to -0.27, P = 0.02) and the number of adults in the household (OR -0.08, 95%CI -0.16 to -0.01, P = 0.03). There was no association between food insecurity and IFN-γ response to Mycobacterium tuberculosis antigen. CONCLUSION Food insecurity in pregnancy is associated with low IFN-γ levels. There was no association between food insecurity and IFN-γ response to M. tuberculosis antigen, but our study was underpowered to detect this outcome.

Source Case Investigation for Children with TB Disease in Pune, India.

Setting. Contact tracing is broadly encouraged for tuberculosis (TB) control. In many high-burden countries, however, little effort is made to identify contacts of newly diagnosed TB patients. This failure puts children, many of whom live in poor crowded communities, at special risk. Objectives. To perform source-case investigations for 50 pediatric TB cases in Pune, India. Design. A descriptive cross-sectional observational study of pediatric TB cases < 5 years of age. Information was collected about the index case and household contacts. Results. In 15 (30%) of the 50 pediatric index cases, the household contained known TB contacts, 14 (86%) of whom were adults. Prior to their own diagnosis of TB, only one of the 15 pediatric index cases who met criteria for isoniazid preventive therapy received it. The index cases with known household TB contacts had a longer delay in initiating TB treatment than those without TB contacts (17.5 versus 2 days; P = 0.03). Use of contact tracing identified 14 additional household TB suspects, 8 (57%) of whom were children. Conclusions. This study identified missed opportunities for TB prevention, as contact tracing is poorly implemented in resource-limited countries, like India. Further strategies to improve the implementation of TB prevention, especially in young children, are urgently needed.

Internal medicine residents' knowledge and practice of pulmonary tuberculosis diagnosis

Abstract Background Internal medicine physicians are often the first providers to encounter patients with a new diagnosis of tuberculosis. Given the public health risks of missed tuberculosis cases, assessing internal medicine residents’ ability to diagnose tuberculosis is important. Methods Internal medicine resident knowledge and practice patterns in pulmonary tuberculosis diagnosis at 7 academic hospitals were assessed utilizing (a) a 10-item validated pulmonary tuberculosis diagnosis assessment tool and (b) a retrospective chart review of 343 patients who underwent a pulmonary tuberculosis evaluation while admitted to a resident-staffed internal medicine or infectious disease service. Our primary outcomes were the mean score and percentage of correct responses per assessment tool question, and the percentage of patients who had Centers for Disease Control and Prevention–recommended tuberculosis diagnostic tests obtained. Results Of the 886 residents who received the assessment, 541 responded, yielding a response rate of 61%. The mean score on the assessment tool (SD) was 4.4 (1.6), and the correct response rate was 57% (311/541) or less on 9 of 10 questions. On chart review, each recommended test was obtained for ≤43% (148/343) of patients, other than chest x-ray (328/343; 96%). A nucleic acid amplification test was obtained for 18% (62/343) of patients, whereas 24% (83/343) had only 1 respiratory sample obtained. Twenty patients were diagnosed with tuberculosis. Conclusions Significant knowledge and practice gaps exist in internal medicine residents’ abilities to diagnose tuberculosis. As residents represent the future providers who will be evaluating patients with possible tuberculosis, such deficiencies must be addressed.