Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection

Abstract

Background: Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ vs. LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women.

Methods: We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFNβ, CRP, AGP, I-FABP, IFNγ, IL-1β, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression.

Results: Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1β, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors.

Conclusions: Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.

Keywords: LTBI; TB; cytokines; inflammation; latent tuberculosis infection; pregnancy; tuberculosis disease.

Figure 1

Levels of third trimester inflammation by LTBI status (N = 220). (A) Median and interquartile range (IQR) log₂ levels of markers, measured in the 3^rd trimester is shown for LTBI+ (n = 155) and LTBI− (n = 65) pregnant women. Wilcoxon rank-sum test was used to calculate p-values. *p < 0.05, **p < 0.01 and ***p < 0.001. (B) Relative fold-change is shown for each marker by LTBI status. Red bars indicate p-value <0.05.

Figure 2

Association of LTBI status with third trimester inflammation (N = 220). Using linear regression, the mean change in log₂ concentrations of each inflammation marker and 95% confidence intervals (95% CI) among LTBI+ individuals compared to LTBI−individuals are shown in the forest plot. Inflammation markers were measured in samples collected at the third trimester of pregnancy. Multivariate models adjusted for age, mid-upper arm circumference, HIV status, diet and gestational diabetes status. Only immune markers with a p-value <0.2 in the univariate model are shown.

Figure 3

Association of LTBI status with second trimester inflammation (N = 187). Using linear regression, the mean change in log₂ concentrations of each inflammation marker and 95% confidence intervals (95% CI) among LTBI+ individuals compared to LTBI− individuals are shown in the forest plot. Inflammation markers were measured in samples collected at the second trimester of pregnancy. Multivariate models adjusted for age, mid-upper arm circumference, HIV status, diet and gestational diabetes status. Only immune markers with a p-value <0.2 in the univariate model are shown.

Figure 4

Association of third trimester inflammation markers with TB progression (N = 155; nine progressors). Using logistic regression, the odds ratio and 95% confidence intervals (95% CI) of TB progression per log₂ increase in each inflammation marker among LTBI+ pregnant women are shown in the forest plot. Progressors were defined as those who developed TB either during the third trimester of pregnancy (n = 1) or up to one year post-partum (n = 8). Inflammation markers were measured in samples collected at the third trimester of pregnancy. Multivariable models adjusted for age, mid-upper arm circumference and HIV status. Only immune markers With a p-value <0.2 in the univariate model are shown.