Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis
| dc.contributor.advisor | Meintjes, Graeme | |
| dc.contributor.advisor | Wilkinson, Robert J | |
| dc.contributor.advisor | Shey, Muki | |
| dc.contributor.author | Schutz,Charlotte | |
| dc.date.accessioned | 2023-03-14T11:07:59Z | |
| dc.date.available | 2023-03-14T11:07:59Z | |
| dc.date.issued | 2021 | |
| dc.date.updated | 2022-11-23T09:11:02Z | |
| dc.description.abstract | Background: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in hospitalized patients ranging between 13% and 32%. Underlying causes of mortality remain poorly characterized and better characterization of causes could inform development of novel management strategies to improve survival. This study aimed to assess determinants of mortality in hospitalized HIV-TB patients. I assessed the association of clinical, microbiologic and treatment factors, host soluble inflammatory mediators, markers of tuberculosis dissemination, antituberculosis drug concentrations and markers of microbial translocation with 12-week mortality in hospitalized HIV-TB patients. Methods: We conducted a prospective observational cohort study and enrolled adult HIV-positive patients hospitalized with a new diagnosis of HIV-TB in Khayelitsha Hospital in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed (including urine Xpert testing) and we collected clinical samples for analysis at baseline. We performed intensive pharmacokinetic studies in a subset of patients on the third day of antituberculosis therapy. Patients were followed up for 12 weeks to ascertain vital status. Results: We enrolled 682 participants and included 576 patients with tuberculosis in the cohort analyses. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Determinants of mortality included tuberculosis dissemination, rifampicin resistance and having features of sepsis syndrome. Using principal components analysis, we characterised an innate immune profile which was associated with mortality and with biomarkers of disseminated tuberculosis. A large proportion of patients had sub-optimal concentrations of rifampicin and isoniazid. Patients who presented with elevated lactate concentrations had higher rifampicin concentration and exposure. Opportunistic infections other than tuberculosis and microbial translocation did not have a significant association with mortality. Conclusions: There was high early mortality in hospitalized HIV-TB patients. An innate immune profile was associated with tuberculosis dissemination and mortality. Rifampicin and isoniazid concentrations and exposure were sub-optimal. These findings provide novel pathophysiologic insight and provide rationale to test high dose rifampicin and immune modulatory therapy for safety and efficacy to improve survival in this patient population. | |
| dc.identifier.apacitation | (2021). <i>Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis</i>. (). ,Faculty of Health Sciences ,Department of Medicine. Retrieved from http://hdl.handle.net/11427/37439 | en_ZA |
| dc.identifier.chicagocitation | . <i>"Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis."</i> ., ,Faculty of Health Sciences ,Department of Medicine, 2021. http://hdl.handle.net/11427/37439 | en_ZA |
| dc.identifier.citation | 2021. Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis. . ,Faculty of Health Sciences ,Department of Medicine. http://hdl.handle.net/11427/37439 | en_ZA |
| dc.identifier.ris | TY - Doctoral Thesis AU - Schutz,Charlotte AB - Background: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in hospitalized patients ranging between 13% and 32%. Underlying causes of mortality remain poorly characterized and better characterization of causes could inform development of novel management strategies to improve survival. This study aimed to assess determinants of mortality in hospitalized HIV-TB patients. I assessed the association of clinical, microbiologic and treatment factors, host soluble inflammatory mediators, markers of tuberculosis dissemination, antituberculosis drug concentrations and markers of microbial translocation with 12-week mortality in hospitalized HIV-TB patients. Methods: We conducted a prospective observational cohort study and enrolled adult HIV-positive patients hospitalized with a new diagnosis of HIV-TB in Khayelitsha Hospital in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed (including urine Xpert testing) and we collected clinical samples for analysis at baseline. We performed intensive pharmacokinetic studies in a subset of patients on the third day of antituberculosis therapy. Patients were followed up for 12 weeks to ascertain vital status. Results: We enrolled 682 participants and included 576 patients with tuberculosis in the cohort analyses. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Determinants of mortality included tuberculosis dissemination, rifampicin resistance and having features of sepsis syndrome. Using principal components analysis, we characterised an innate immune profile which was associated with mortality and with biomarkers of disseminated tuberculosis. A large proportion of patients had sub-optimal concentrations of rifampicin and isoniazid. Patients who presented with elevated lactate concentrations had higher rifampicin concentration and exposure. Opportunistic infections other than tuberculosis and microbial translocation did not have a significant association with mortality. Conclusions: There was high early mortality in hospitalized HIV-TB patients. An innate immune profile was associated with tuberculosis dissemination and mortality. Rifampicin and isoniazid concentrations and exposure were sub-optimal. These findings provide novel pathophysiologic insight and provide rationale to test high dose rifampicin and immune modulatory therapy for safety and efficacy to improve survival in this patient population. DA - 2021_ DB - OpenUCT DP - University of Cape Town KW - Medicine LK - https://open.uct.ac.za PY - 2021 T1 - Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis TI - Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis UR - http://hdl.handle.net/11427/37439 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/37439 | |
| dc.identifier.vancouvercitation | . Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis. []. ,Faculty of Health Sciences ,Department of Medicine, 2021 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/37439 | en_ZA |
| dc.language.rfc3066 | eng | |
| dc.publisher.department | Department of Medicine | |
| dc.publisher.faculty | Faculty of Health Sciences | |
| dc.subject | Medicine | |
| dc.title | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis | |
| dc.type | Doctoral Thesis | |
| dc.type.qualificationlevel | Doctoral | |
| dc.type.qualificationlevel | PhD |