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

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

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Abstract

BACKGROUND: In 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 FINDINGS: Adult 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.

CONCLUSIONS: In 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.

Original languageEnglish
Pages (from-to)e1002840
JournalPLoS Medicine
Volume16
Issue number7
DOIs
Publication statusPublished - Jul 2019
Externally publishedYes

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Tuberculosis
Cohort Studies
HIV
Prospective Studies
Mortality
Chemokine CCL4
Survivors
Cause of Death
Systemic Inflammatory Response Syndrome
Biomarkers
Rifampin
Immune System
Urine
Ligands
Chemokine CCL3
CXC Chemokines
CC Chemokines
Interleukin-1 Receptors
Protein C
Principal Component Analysis

Cite this

Schutz, Charlotte ; Barr, David ; Andrade, Bruno B ; Shey, Muki ; Ward, Amy ; Janssen, Saskia ; Burton, Rosie ; Wilkinson, Katalin A ; Sossen, Bianca ; Fukutani, Kiyoshi F ; Nicol, Mark ; Maartens, Gary ; Wilkinson, Robert J ; Meintjes, Graeme. / Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis : A prospective cohort study. In: PLoS Medicine. 2019 ; Vol. 16, No. 7. pp. e1002840.
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title = "Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study",
abstract = "BACKGROUND: In 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 FINDINGS: Adult 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.CONCLUSIONS: In 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.",
author = "Charlotte Schutz and David Barr and Andrade, {Bruno B} and Muki Shey and Amy Ward and Saskia Janssen and Rosie Burton and Wilkinson, {Katalin A} and Bianca Sossen and Fukutani, {Kiyoshi F} and Mark Nicol and Gary Maartens and Wilkinson, {Robert J} and Graeme Meintjes",
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Schutz, C, Barr, D, Andrade, BB, Shey, M, Ward, A, Janssen, S, Burton, R, Wilkinson, KA, Sossen, B, Fukutani, KF, Nicol, M, Maartens, G, Wilkinson, RJ & Meintjes, G 2019, 'Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study' PLoS Medicine, vol. 16, no. 7, pp. e1002840. https://doi.org/10.1371/journal.pmed.1002840

Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis : A prospective cohort study. / Schutz, Charlotte; Barr, David; Andrade, Bruno B; Shey, Muki; Ward, Amy; Janssen, Saskia; Burton, Rosie; Wilkinson, Katalin A; Sossen, Bianca; Fukutani, Kiyoshi F; Nicol, Mark; Maartens, Gary; Wilkinson, Robert J; Meintjes, Graeme.

In: PLoS Medicine, Vol. 16, No. 7, 07.2019, p. e1002840.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis

T2 - A prospective cohort study

AU - Schutz, Charlotte

AU - Barr, David

AU - Andrade, Bruno B

AU - Shey, Muki

AU - Ward, Amy

AU - Janssen, Saskia

AU - Burton, Rosie

AU - Wilkinson, Katalin A

AU - Sossen, Bianca

AU - Fukutani, Kiyoshi F

AU - Nicol, Mark

AU - Maartens, Gary

AU - Wilkinson, Robert J

AU - Meintjes, Graeme

PY - 2019/7

Y1 - 2019/7

N2 - BACKGROUND: In 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 FINDINGS: Adult 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.CONCLUSIONS: In 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.

AB - BACKGROUND: In 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 FINDINGS: Adult 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.CONCLUSIONS: In 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.

U2 - 10.1371/journal.pmed.1002840

DO - 10.1371/journal.pmed.1002840

M3 - Article

VL - 16

SP - e1002840

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 7

ER -