Biomarkers Associated with Death After Initiating Treatment for Tuberculosis and HIV in Patients with Very Low CD4 Cells

Abstract

BackgroundThe risk of short-term death for treatment naive patients dually infected with Mycobacterium tuberculosis and HIV may be reduced by early anti-retroviral therapy. Of those dying, mechanisms responsible for fatal outcomes are unclear. We hypothesized that greater malnutrition and/or inflammation when initiating treatment are associated with an increased risk for death.MethodsWe utilized a retrospective case-cohort design among participants of the ACTG A5221 study who had baseline CD4 < 50 cells/mm3. The case-cohort sample consisted of 51 randomly selected participants, whose stored plasma was tested for C-reactive protein, cytokines, chemokines, and nutritional markers. Cox proportional hazards models were used to assess the association of nutritional, inflammatory, and immunomodulatory markers for survival.ResultsThe case-cohort sample was similar to the 282 participants within the parent cohort with CD4 <50 cells/mm3. In the case cohort, 7 (14%) had BMI < 16.5 (kg/m2) and 17 (33%) had BMI 16.5-18.5(kg/m2). Risk of death was increased per 1 IQR width higher of log10 transformed level of C-reactive protein (adjusted hazard ratio (aHR) = 3.42 [95% CI = 1.33-8.80], P = 0.011), interferon gamma (aHR = 2.46 [CI = 1.02-5.90], P = 0.044), MCP-3 (3.67 [CI = 1.08-12.42], P = 0.037), and with IL-15 (aHR = 2.75 [CI = 1.08-6.98], P = 0.033) and IL-17 (aHR = 3.99 [CI = −1.06-15.07], P = 0.041). BMI, albumin, hemoglobin, and leptin levels were not associated with risk of death.ConclusionsUnlike patients only infected with M. tuberculosis for whom malnutrition and low BMI increase the risk of death, this relationship was not evident in our dually infected patients. Risk of death was associated with significant increases in markers of global inflammation along with soluble biomarkers of innate and adaptive immunity.

Immunologic biomarkers, morbidity and mortality among HIV patients hospitalised in a Tertiary Care Hospital in the Brazilian Amazon

“…During the last decade, TB has been highly prevalent among HIV/AIDS patients who died [ 5 , 10 , 11 , 18 ]. Additionally, we found weight loss associated to death through the univariate analysis, in agreement with early mortality in TB-HIV coinfected patients presenting malnutrition or low body mass index [ 19 , 20 ]. It is worth mentioning that weight loss and gastrointestinal disorders can be correlated variables [ 20 ].…”

“…It is worth mentioning that weight loss and gastrointestinal disorders can be correlated variables [ 20 ]. Our multivariate analysis corroborated greater risk of death among those TB-HIV coinfected patients, similar with those coming from low-income regions, whose poverty, schooling, and social vulnerability index decrease the odds of access ART [ 6 , 19 , 21 – 26 ]. We observed an augmented risk of death among those patients presenting gastrointestinal disorders, especially oropharyngeal–esophageal candidiasis, which is recognized as an indicator of advanced immunosuppression [ 27 ].…”

Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study

“…Immune activation at baseline [11,49] and failure to resolve or increased immune activation after ART initiation have been described as risk factors for mortality in HIV-associated tuberculosis cohorts [12, 13, 50]. One of these studies was an outpatient cohort study that followed participants with HIV-associated tuberculosis and showed that higher pre-ART levels of MCP-1/CCL2, eotaxin, IL-10, TNF-α, and IL-6 were associated with 6-month mortality.…”

“…The underlying causes of mortality remain poorly characterized. In outpatient cohorts with HIV-associated tuberculosis, early mortality has been associated with high baseline immune activation [11,12], persistent or increased immune activation on antiretroviral therapy (ART) [12], and failure to recover cellular immune responses to Mycobacterium tuberculosis [13]. In Africa, disseminated tuberculosis is found in 88% of autopsies of patients dying with HIV-associated tuberculosis [14].…”

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 .…”