Background The mortality from cryptococcal meningitis remains high, despite the availability of antiretroviral therapy (ART) and amphotericin-based fungal regimens. The role of neutrophils in cryptococcosis is controversial. Our objective was to examine the association between blood neutrophil counts and outcomes in terms of mortality, the incidence of bacterial infections (including Mycobacterium tuberculosis) and hospitalization among HIV-infected patients presenting with cryptococcal meningitis. Methods We used data from participants from the Cryptococcal Optimal ART Timing (COAT) trial (2010–2012; Uganda and South Africa) and the Adjunctive Sertraline for Treatment of Cryptococcal Meningitis (ASTRO-CM) trial (2013–2017; Uganda). We estimated 30-day mortality risk with Cox proportional hazards models by baseline neutrophil counts (a) on a continuous scale and (b) with indicators for both relatively high (> 3,500 cells/mm 3 ) and low ( 1,000 cells/mm 3 ) counts. Follow-up neutrophil counts from the COAT trial were used to examine the time-dependent association of neutrophil counts with 12-month mortality and rehospitalization. Results 801 participants had an absolute neutrophil value at meningitis diagnosis. The median baseline absolute neutrophil count was 2100 cells/mm 3 (IQR, 1400 to 3300 cells/mm 3 ). Baseline neutrophil count was positively associated with 30-day mortality (adjusted hazard ratio = 1.09, 95%CI, 1.04–1.13, per 1000 cells/mm 3 increase; p<0.001). Baseline absolute neutrophil counts 1000 cells/mm 3 did not have increased risk of 30-day mortality compared to those with baseline neutrophils of 1001–3500 cells/mm 3 ; however, baseline >3500 cells/ mm 3 had significantly increased risk, with an adjusted hazard ratio of 1.85(95%CI, 1.40–2.44; p<0.001). Among the COAT participants with follow-up neutrophil data, there was a strong association between time-updated neutrophil count and 12-month mortality (adjusted hazard ratio = 1.16, 95% CI 1.09–1.24; p<0.001. Conclusion Higher blood neutrophil counts in HIV-infected patients with cryptococcal meningitis were associated with mortality. Neutrophils role requires further investigation as to whether this may be a mediator directly contributing to mortality or merely a marker of underlying pathologies that increase mortality risk.
Bibliographical noteFunding Information:
This work was supported by Fogarty International Center, R25TW009345, Dr. Abdu Kisekka Musubire; U.S. National Institute of Neurologic Diseases and Stroke (NINDS), R01NS086312, David R Boulware; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (US), U01AI089244, David R Boulware; National Institute of Allergy and Infectious Diseases, T32AI055433, David R Boulware; United Kingdom Medical Research Council/Wellcome Trust Global Health Trials, MR/ M007413/1, David B Meya; Wellcome Trust, 098316, Graeme Meintjes; South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa, 64787, Graeme Meintjes; Fogarty International Center, 5K43TW010718-02, Dr. Abdu Kisekka Musubire. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All the ASTRO and COAT Team members: Reuben Kiggundu, Charlotte Schutz, Lillian Tugume, Henry W Nabeta, Andrew Akampurira, Darlisha A Williams, Mahsa Abassi, Kabanda Taseera, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Tadeo Kiiza Kandole, Tony Luggya, Katelyn Pastick, Julian Kaboggoza, Eva Laker, Radha Rajasingham, Nathan C Bahr, Bozena M Morawski, Sarah Bridge, Elissa K Butler, Jonathan Dyal, A. Wendy Fujita, Nathan Yueh, Sarah C Bridge, Alice Namudde, Sruti S Velama-kanni, Bilal Jawed, Priya Vedula, Kirsten Nielsen, Andrew Kambugu.
© 2018 Musubire et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.