A Parsimonious Host Inflammatory Biomarker Signature Predicts Incident Tuberculosis and Mortality in Advanced Human Immunodeficiency Virus

Abstract

Background People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death. Methods The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma. Results In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1β, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1β, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-β) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87–.94) and a specificity of 0.71(95% CI: .68–.75) with an area under the curve (AUC) of 0.81 (95% CI: .78–.83) for incident TB. Conclusion Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions. Clinical Trials Registration NCT01380080

Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection

“…Interestingly, in our exploratory analyses, LTBI+ TB progressors had a profile more similar to LTBI− women, with higher levels of IL-1 β , IL-6, IL-13 and IL17a and generally lower levels of IFN γ compared to LTBI+ non-progressors. These inflammatory markers have been recognized for their complex role in TB disease where while a deficiency is linked to reduced control of Mtb infection, excessive levels can result in tissue damage and immunopathology ( 1 , 28 – 33 ) as well as progression to active TB disease in non-pregnant adults ( 34 ). Given the small number of progressors in this study, these findings will need to be confirmed in other studies with a larger sample size.…”

Immunologic Biomarkers, Morbidity and Mortality Among HIV Patients Hospitalized in a Tertiary Care Hospital in the Brazilian Amazon

“…In the present study, no difference was observed in sCD14, IL-8 and Th1/Th2/Th17 cytokines between patients who died or were discharged. Biomarker concentrations are observable outcomes of complex biological processes that are only partially understood, and this may be the reason for a lack of consensus regarding immunological markers in prediction of mortality in HIV/AIDS patients [30][31][32][33][34] . Curiously, we observed much higher levels of in ammatory biomarkers sCD14, IL-8, and IL-6 than for other cytokines, which is consistent with the in ammatory status of the HIV/AIDS patients 35 .…”

Systemic Inflammation Associated with Immune Reconstitution Inflammatory Syndrome in Persons Living with HIV

“…Host-based markers are extensively being explored to improve predictive and diagnostic tools for IRIS in PLWH who have a concomitant OI [ 104 , 136 , 137 , 138 , 139 , 140 ]. In this context, several host factors have been studied as an IRIS predictive tool, including genetic markers, immune metabolomic and biomarkers of SI ( Table 1 ).…”