Why do HIV-positive inpatients with TB die?

8 Jul 2019 - 08:15

A red door opens onto a hospital corridorIn high-burden settings, between 11% and 32% of hospitalised 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%), hospitalisation (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 on the paper, previously developed a scoring system which enables assessment of the likelihood and degree of Mycobacterium tuberculosis spread beyond the lungs into the body (“dissemination”) [11]. 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 characterised 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.

 

Read more

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. PLOS Medicine. (2019) 16(7):e1002840.

 

References

  1. Kyeyune R, den Boon S, Cattamanchi A, Davis JL, Worodria W, Yoo SD, et al. Causes of early mortality in HIV-infected TB suspects in an East African referral hospital. J Acquir Immune Defic Syndr. 2010; 55 (4):446–50. Epub 2010/11/26. PMID: 21105258; PubMed Central PMCID: PMC3249444.
  2. Bigna JJ, Noubiap JJ, Agbor AA, Plottel CS, Billong SC, Ayong AP, et al. Early Mortality during Initial Treatment of Tuberculosis in Patients Co-Infected with HIV at the Yaounde Central Hospital, Cameroon: An 8-Year Retrospective Cohort Study (2006–2013). PLoS ONE. 2015; 10(7):e0132394. https:// doi.org/10.1371/journal.pone.0132394 PMID: 26214516; PubMed Central PMCID: PMC4516239.
  3. Subbarao S, Wilkinson KA, van Halsema CL, Rao SS, Boyles T, Utay NS, et al. Raised Venous Lactate and Markers of Intestinal Translocation Are Associated With Mortality Among In-Patients With HIV Associated TB in Rural South Africa. J Acquir Immune Defic Syndr. 2015; 70(4):406–13. Epub 2015/07/18. https://doi.org/10.1097/QAI.0000000000000763 PMID: 26186506; PubMed Central PMCID: PMC4625603.
  4. Meintjes G, Kerkhoff AD, Burton R, Schutz C, Boulle A, Van Wyk G, et al. HIV-Related Medical Admissions to a South African District Hospital Remain Frequent Despite Effective Antiretroviral Therapy Scale-Up. Medicine (Baltimore). 2015; 94(50):e2269. https://doi.org/10.1097/MD.0000000000002269 PMID: 26683950.
  5. Griesel R, Stewart A, van der Plas H, Sikhondze W, Mendelson M, Maartens G. Prognostic indicators in the World Health Organization’s algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis. AIDS Res Ther. 2018; 15(1):5. https://doi.org/10.1186/s12981-018-0192-0 PMID: 29433509; PubMed Central PMCID: PMC5808414.
  6. Camara A, Sow MS, Toure A, Diallo OH, Kaba I, Bah B, et al. Treatment outcome, survival and their risk factors among new tuberculosis patients co-infected with HIV during the Ebola outbreak in Conakry. Rev Epidemiol Sante Publique. 2017; 65(6):419–26. https://doi.org/10.1016/j.respe.2017.05.011 PMID: 29066256.
  7. Saavedra A, Campinha-Bacote N, Hajjar M, Kenu E, Gillani FS, Obo-Akwa A, et al. Causes of death and factors associated with early mortality of HIV-infected adults admitted to Korle-Bu Teaching Hospital. Pan Afr Med J. 2017; 27:48. https://doi.org/10.11604/pamj.2017.27.48.8917 PMID: 28819470; PubMed Central PMCID: PMC5554638.
  8. Global tuberculosis report 2017. Geneva: World Health Organization, 2017 Contract No.: Licence: CC BY-NCSA 3.0 IGO.
  9. Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, et al. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and metaanalysis. J Int AIDS Soc. 2016; 19(1):20714. Epub 2016/01/15. https://doi.org/10.7448/IAS.19.1.20714 PMID: 26765347; PubMed Central PMCID: PMC4712323.
  10. Ford N, Shubber Z, Meintjes G, Grinsztejn B, Eholie S, Mills EJ, et al. Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis. Lancet HIV. 2015; 2 (10):e438–44. https://doi.org/10.1016/S2352-3018(15)00137-X PMID: 26423651.
  11. Kerkhoff AD, Barr DA, Schutz C, Burton R, Nicol MP, Lawn SD, et al. Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays. Sci Rep. 2017; 7(1):10931. Epub 2017/09/09. https://doi.org/10.1038/s41598-017-09895-7 PMID: 28883510; PubMed Central PMCID: PMC5589905.
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