Why do HIV-positive inpatients with TB die?
In high-burden settings, between 11% and 32% of hospitalized patients with HIV-associated tuberculosis will die [1-7], but the reasons for this remain poorly understood. Charlotte Schutz and her CIDRI-Africa colleagues set out to address this critical public health problem by gaining a better understanding of the causes of death in HIV-positive people hospitalised with a new tuberculosis diagnosis.
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 [8-10]. But we cannot optimally treat what we do not fully understand.
To begin addressing this problem, the team collected clinical details, chest X-rays, sputum, urine, and blood samples from participants at Khayelitsha Hospital, Cape Town. The patients received standard in-hospital care and follow-up. The study team checked the vital status of the patients at 12 weeks.
One hundred and twenty four of the 576 participants (22%) died within twelve weeks and 37% of these deaths occurred within a week of study enrolment.
David Barr, a co-investigator previously developed a scoring system which enables assessment of the likelihood and degree of Mycobacterium tuberculosis spread beyond the lungs into the body (“dissemination”) . The scoring system assesses results of the: urine Xpert MTB/RIF assay, urine LAM test, and mycobacterial blood culture for M. tuberculosis.
Results of analysis of the biological samples were compared for patients who survived vs. those who died. The team identified several indicators of increased mortality risk:
- features of sepsis syndrome;
- rifampicin-resistant tuberculosis;
- an immune profile characterized by increased markers of the innate immune response and proteins that attract innate cells to tissue; and
- higher dissemination score.
These findings suggest new avenues for research and treatment of HIV-associated TB, targeting both the infecting organism and the host response. Higher-dose rifampicin and rapidly bactericidal fluoroquinolones could be considered as means to control disseminated M. tuberculosis, while adjunctive corticosteroids and recombinant IL-7 might be viable host-directed therapies to evaluate.
Charlotte is a clinician pursuing PhD studies at the University of Cape Town, and conducted this research as part of Prof. Graeme Meintjes team under his Wellcome Intermediate Fellowship. She previously practiced in the public sector, but developed an interest in clinical infectious diseases research and joined CIDRI-Africa in 2009. After her PhD is completed in 2019, she hopes to continue researching HIV-associated opportunistic infections to improve health outcomes for people living with HIV.
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. Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: a prospective cohort study. Hatherill M, editor. PLOS Medicine. (2019) 16(7):e1002840.
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