Date Published: July 5, 2019
Publisher: Public Library of Science
Author(s): Charlotte Schutz, David Barr, Bruno B. Andrade, Muki Shey, Amy Ward, Saskia Janssen, Rosie Burton, Katalin A. Wilkinson, Bianca Sossen, Kiyoshi F. Fukutani, Mark Nicol, Gary Maartens, Robert J. Wilkinson, Graeme Meintjes, Mark Hatherill
Abstract: BackgroundIn high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis.Methods and findingsAdult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31–43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21–120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3–5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1β]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9–2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death.ConclusionsIn this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.
Partial Text: HIV-associated tuberculosis comprises 10% of global tuberculosis cases but contributes a disproportionate 22% of tuberculosis deaths . Despite advances in diagnostics and widespread availability of treatment, tuberculosis remains the leading cause of death (40%), hospitalization (18%) and in-hospital death (25%) in patients with HIV worldwide [1–3]. In high-burden settings, hospitalized patients with HIV-associated tuberculosis have case fatality rates between 11% and 32% [4–10]. 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) , and failure to recover cellular immune responses to Mycobacterium tuberculosis . In Africa, disseminated tuberculosis is found in 88% of autopsies of patients dying with HIV-associated tuberculosis . M. tuberculosis bloodstream infection (MTB BSI or mycobacteremia) is the most common microbiologic diagnosis in patients with HIV admitted with a clinical sepsis syndrome in Africa [15,16] and is associated with higher mortality [16–19]. Patients with MTB BSI may present with sepsis syndrome [19,20] and with septic shock, which has high mortality, especially if antituberculosis treatment is delayed .
We enrolled 576 hospitalized patients with HIV and newly diagnosed tuberculosis at presentation to hospital, collected samples at baseline, and followed patients for 12 weeks to ascertain vital status. We performed comprehensive tuberculosis investigations, measured host soluble inflammatory mediators, and compared patients who died with those who survived. We found high mortality (21.5%) despite timely initiation of antituberculous therapy. Clinician-attributed causes of death identified tuberculosis as the major contributor or one of the major contributors to death in 89.5% of cases. We observed disseminated tuberculosis in 64.6%, which was associated with mortality. One third of participants (33.9%) presented with features of sepsis syndrome, as indicated by elevated lactate, and amongst the patients in whom the clinician-attributed cause of death included tuberculosis as a major cause, 15.3% had rifampicin-resistant tuberculosis. We describe an immune profile identified by non-supervised hierarchical cluster analysis and principal components analysis that was associated with mortality in Cox proportional hazards analysis and was also associated with a higher tuberculosis dissemination score. The immune profile was dominated by soluble inflammatory mediators associated with the innate immune system and chemotactic signaling.