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Cited by 367Fungal Infections and StudiesInfectious Diseases and TuberculosisBacterial Infections and Vaccines

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Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes

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Jarvis, Joseph N., Bicanic, Tihana, Loyse, Angela, Namarika, Daniel, Jackson, Arthur, Nussbaum, Jesse C., Longley, Nicky, Muzoora, Conrad, Phulusa, Jacob, Taseera, Kabanda, Kanyembe, Creto, Wilson, Douglas, Hosseinipour, Mina C., Brouwer, Annemarie E., Limmathurotsakul, Direk, White, Nicholas, van der Horst, Charles, Wood, Robin, Meintjes, Graeme, Bradley, John, Jaffar, Shabbar, Harrison, Thomas·2014·Clinical Infectious Diseases
DOI 10.1093/cid/cit794PMC PMC3922213
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Abstract

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes. METHODS: Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality. RESULTS: Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART). CONCLUSIONS: CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.

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Figure 1. Associations between cerebrospinal fluid (CSF) interferon gamma (IFN-γ) concentrations and baseline fungal burden, rate of clearance of infection (EFA), and 2-week mortality in the 243 Thai and South African patients with CSF cytokine measurements. CSF IFN-γ concentration was strongly associated with rate of clearance of infection, with a 0.10 log10 CFU/mL/day (95% confidence interval, .06–.15) increase in EFA for every log10 picogram increment in IFN-γ concentration. Abbreviations: CFU, colony-forming units; EFA, early fungicidal activity; IFN, interferon; QCC, quantitative cryptococcal culture.
Figure 1. Associations between cerebrospinal fluid (CSF) interferon gamma (IFN-γ) concentrations and baseline fungal burden, rate of clearance of infection (EFA), and 2-week mortality in the 243 Thai and South African patients with CSF cytokine measurements. CSF IFN-γ concentration was strongly associated with rate of clearance of infection, with a 0.10 log10 CFU/mL/day (95% confidence interval, .06–.15) increase in EFA for every log10 picogram increment in IFN-γ concentration. Abbreviations: CFU, colony-forming units; EFA, early fungicidal activity; IFN, interferon; QCC, quantitative cryptococcal culture.CC BY · PubMed Central
Figure 2. Kaplan-Meier survival curves. A, Survival in the 263 South African amphotericin B (AmB)–treated patients followed up for 1 year. B, Survival from enrollment in the subset of patients who started antiretroviral therapy (ART), stratified by ART timing (before and after the median of 31 days; P = .15). Only patients surviving to ART initiation are shown. C, Cause of death data (as determined by study clinicians) in the cohort of 263 South African AmB-treated patients followed up for 1 year, split by time from diagnosis. “Other” included tuberculosis (n = 11), bacterial sepsis (n = 8), bacterial pneumonia (n = 7), nonspecified infections (n = 9), Kaposi sarcoma (n = 2), lymphoma (n = 1), non–cryptococcal meningitis immune reconstitution inflammatory syndrome (n = 3), ART toxicity (n = 2), diarrhea/wasting syndrome (n = 4), and decompensation of chronic liver disease (n = 1). Abbreviations: ART, antiretroviral therapy; CM, cryptococcal meningitis; IRIS, immune reconstitution inflammatory syndrome.
Figure 2. Kaplan-Meier survival curves. A, Survival in the 263 South African amphotericin B (AmB)–treated patients followed up for 1 year. B, Survival from enrollment in the subset of patients who started antiretroviral therapy (ART), stratified by ART timing (before and after the median of 31 days; P = .15). Only patients surviving to ART initiation are shown. C, Cause of death data (as determined by study clinicians) in the cohort of 263 South African AmB-treated patients followed up for 1 year, split by time from diagnosis. “Other” included tuberculosis (n = 11), bacterial sepsis (n = 8), bacterial pneumonia (n = 7), nonspecified infections (n = 9), Kaposi sarcoma (n = 2), lymphoma (n = 1), non–cryptococcal meningitis immune reconstitution inflammatory syndrome (n = 3), ART toxicity (n = 2), diarrhea/wasting syndrome (n = 4), and decompensation of chronic liver disease (n = 1). Abbreviations: ART, antiretroviral therapy; CM, cryptococcal meningitis; IRIS, immune reconstitution inflammatory syndrome.CC BY · PubMed Central

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Authors
Jarvis, J. N., Bicanic, T., Loyse, A., Namarika, D., Jackson, A., Nussbaum, J. C., Longley, N., Muzoora, C., Phulusa, J., Taseera, K., Kanyembe, C., Wilson, D., Hosseinipour, M. C., Brouwer, A. E., Limmathurotsakul, D., White, N., van der Horst, C., Wood, R., Meintjes, G., Bradley, J., Jaffar, S., & Harrison, T.
Affiliations
  • University of Cape Town (ZA)
  • St George's, University of London (GB)
  • University of California, San Francisco (US)
  • Mbarara University of Science and Technology (UG)
  • Edendale Hospital (ZA)
  • Radboud University Medical Center (NL)
  • Mahidol University (TH)
  • London School of Hygiene & Tropical Medicine (GB)
Corresponding author
Jarvis, Joseph N.
ORCID
Venue
Clinical Infectious Diseases
Publisher
Oxford University Press (OUP)
Published
2013-12-06
Volume
58
Issue
5
Pages
736-745
ISSN
  • 1058-4838 (ISSN-L)
  • 1537-6591
DOI
10.1093/cid/cit794
PMC
PMC3922213
OpenAlex
W2101195119
Cited by
367
References
30
Citations by year
2026: 19 · 2025: 22 · 2024: 30 · 2023: 22 · 2022: 24 · 2021: 28 · 2020: 31 · 2019: 39 · 2018: 39 · 2017: 37 · 2016: 28 · 2015: 29 · 2014: 19
FWCI
18.28
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Clinical Infectious Diseases (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • Greater South Information System
Funders
  • Wellcome Trust (84323)
  • National Institute for Health and Care Research (CL-2012-20-001)
  • Medical Research Council (MR/K012126/1)
  • National Institute of Allergy and Infectious Diseases (P30AI045008, P30AI050410)
  • Fogarty International Center (D43TW001039)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
  • Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
cryptococcal meningitis, HIV, mortality determinants, altered mental status, immune reconstitution inflammatory syndrome, amphotericin B, fluconazole, antiretroviral therapy, anemia, CSF opening pressure, age, white blood cell count
MeSH terms
Adult, Africa, Mental Disorders, Cerebrospinal Fluid, Female, Humans, Longitudinal Studies, Male, Prospective Studies, Risk Factors, Thailand, Colony Count, Microbial, Cohort Studies, HIV Infections, Meningitis, Cryptococcal, AIDS-Related Opportunistic Infections

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