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

Detalhes bibliográficos
Autor(a) principal: Schutz, Charlotte
Data de Publicação: 2019
Outros Autores: Barr, David, Andrade, Bruno de Bezerril, Shey, Muki, Ward, Amy, Janssen, Saskia, Burton, Rosie, Wilkinson, Katalin A., Sossen, Bianca, Fukutani, Kiyoshi Ferreira, Nicol, Mark, Maartens, Gary, Wilkinson, Robert J., Meintjes, Graeme
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/34767
Resumo: Wellcome Trust (FC00110218), Cancer Research UK (FC00110218), and the UK Medical Research Council (FC00110218). RJW also receives support from Wellcome (104803, 203135) and the National Institutes of Health (U01AI115940).
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spelling Schutz, CharlotteBarr, DavidAndrade, Bruno de BezerrilShey, MukiWard, AmyJanssen, SaskiaBurton, RosieWilkinson, Katalin A.Sossen, BiancaFukutani, Kiyoshi FerreiraNicol, MarkMaartens, GaryWilkinson, Robert J.Meintjes, Graeme2019-08-13T13:50:30Z2019-08-13T13:50:30Z2019SCHUTZ, Charlotte et al. Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. PLoS Medicine, v. 16, n. 7, p. 1-30, 2019.1549-1277https://www.arca.fiocruz.br/handle/icict/3476710.1371/journal.pmed.10028401549-1676Wellcome Trust (FC00110218), Cancer Research UK (FC00110218), and the UK Medical Research Council (FC00110218). RJW also receives support from Wellcome (104803, 203135) and the National Institutes of Health (U01AI115940).University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa.University of Liverpool. Wellcome Trust Liverpool Glasgow Centre for Global Health Research. Liverpool, United Kingdom.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil / Vanderbilt University. School of Medicine. Department of Medicine. Division of Infectious Diseases. Nashville, Tennessee, USA / Universidade Salvador. Laureate Universities. Salvador, BA, Brasil.University of Amsterdam. Amsterdam University Medical Center. Amsterdam, the Netherlands.Khayelitsha Hospital. Department of Medicine. Cape Town, South Africa.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa / The Francis Crick Institute. London, United Kingdom.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative. Salvador, BA, Brazil / Faculdade de Tecnologia e Ciências. Salvador, BA, BrasilUniversity of Cape Town and National Health Laboratory Services. Division of Medical Microbiology. Cape Town, South Africa.University of Cape Town. Department of Medicine. Division of Clinical Pharmacology. Cape Town, South Africa.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa / The Francis Crick Institute. London, United Kingdom / Imperial College. Department of Medicine. London, United Kingdom.University of Cape Town. Institute of Infectious Disease and Molecular Medicine. Wellcome Centre for Infectious Diseases Research in Africa. Cape Town, South Africa / University of Cape Town. Department of Medicine. Cape Town, South Africa.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.engPublic Library of ScienceTuberculoseHIVMortalidadeBiomarcadoresEstudo de CoortesHumanosTuberculosisHIVMortalityBiomarkersCohort StudiesHumansClinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort studyinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/34767/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALSchutz, Charlotte Clinical, microbiologic.pdfSchutz, Charlotte Clinical, microbiologic.pdfapplication/pdf3941233https://www.arca.fiocruz.br/bitstream/icict/34767/2/Schutz%2c%20Charlotte%20Clinical%2c%20microbiologic.pdfd17518efa8e2529a9ff58bb9983f7f1aMD52TEXTSchutz, 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dc.title.pt_BR.fl_str_mv Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
title Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
spellingShingle Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
Schutz, Charlotte
Tuberculose
HIV
Mortalidade
Biomarcadores
Estudo de Coortes
Humanos
Tuberculosis
HIV
Mortality
Biomarkers
Cohort Studies
Humans
title_short Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
title_full Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
title_fullStr Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
title_full_unstemmed Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
title_sort Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study
author Schutz, Charlotte
author_facet Schutz, Charlotte
Barr, David
Andrade, Bruno de Bezerril
Shey, Muki
Ward, Amy
Janssen, Saskia
Burton, Rosie
Wilkinson, Katalin A.
Sossen, Bianca
Fukutani, Kiyoshi Ferreira
Nicol, Mark
Maartens, Gary
Wilkinson, Robert J.
Meintjes, Graeme
author_role author
author2 Barr, David
Andrade, Bruno de Bezerril
Shey, Muki
Ward, Amy
Janssen, Saskia
Burton, Rosie
Wilkinson, Katalin A.
Sossen, Bianca
Fukutani, Kiyoshi Ferreira
Nicol, Mark
Maartens, Gary
Wilkinson, Robert J.
Meintjes, Graeme
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Schutz, Charlotte
Barr, David
Andrade, Bruno de Bezerril
Shey, Muki
Ward, Amy
Janssen, Saskia
Burton, Rosie
Wilkinson, Katalin A.
Sossen, Bianca
Fukutani, Kiyoshi Ferreira
Nicol, Mark
Maartens, Gary
Wilkinson, Robert J.
Meintjes, Graeme
dc.subject.other.pt_BR.fl_str_mv Tuberculose
HIV
Mortalidade
Biomarcadores
Estudo de Coortes
Humanos
topic Tuberculose
HIV
Mortalidade
Biomarcadores
Estudo de Coortes
Humanos
Tuberculosis
HIV
Mortality
Biomarkers
Cohort Studies
Humans
dc.subject.en.pt_BR.fl_str_mv Tuberculosis
HIV
Mortality
Biomarkers
Cohort Studies
Humans
description Wellcome Trust (FC00110218), Cancer Research UK (FC00110218), and the UK Medical Research Council (FC00110218). RJW also receives support from Wellcome (104803, 203135) and the National Institutes of Health (U01AI115940).
publishDate 2019
dc.date.accessioned.fl_str_mv 2019-08-13T13:50:30Z
dc.date.available.fl_str_mv 2019-08-13T13:50:30Z
dc.date.issued.fl_str_mv 2019
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv SCHUTZ, Charlotte et al. Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. PLoS Medicine, v. 16, n. 7, p. 1-30, 2019.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/34767
dc.identifier.issn.pt_BR.fl_str_mv 1549-1277
dc.identifier.doi.pt_BR.fl_str_mv 10.1371/journal.pmed.1002840
dc.identifier.eissn.pt_BR.fl_str_mv 1549-1676
identifier_str_mv SCHUTZ, Charlotte et al. Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. PLoS Medicine, v. 16, n. 7, p. 1-30, 2019.
1549-1277
10.1371/journal.pmed.1002840
1549-1676
url https://www.arca.fiocruz.br/handle/icict/34767
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
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instacron_str FIOCRUZ
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reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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