Role of CSF budding yeast cells in predicting culture-positive cryptococcal meningitis relapse and mortality in patients with recurrence of meningitis symptoms at three tertiary hospitals in Uganda

Abstract

Introduction: The presence of cerebrospinal fluid (CSF) budding yeast cells as a predictive biomarker for culture-positive cryptococcal meningitis (CM) relapse could be a cost-effective and timely diagnostic tool, particularly in resource-limited settings such as Uganda. Objective: This study aimed to investigate the role of CSF budding yeast cells in predicting culture-positive relapse and mortality in patients with recurrence of meningitis symptoms at three tertiary hospitals in Uganda. Methods: This retrospective multi-methods study was conducted at the Infectious Diseases Institute (IDI), Makerere University, as part of two existing meningitis studies. Participants aged 18 years or older with a prior history of human immunodeficiency virus (HIV)-associated CM who had experienced a recurrence of meningitis symptoms and received care at Mulago Hospital, Kiruddu Hospital, and Mbarara Regional Referral Hospital between March 2015 and December 2023 were included in the study. A total of 219 participants were enrolled in this study. An abstraction tool was utilized to collect data on demographics, disease-related factors, CSF parameters, and treatment factors from the parent studies databases. Data were analyzed with modified Poisson regression model using clustered robust standard errors to adjust for clustering to determine associations, and validity parameters were reported as percentages. Kaplan-Meier analysis plots were used to compare the mortality between the two patient groups with and without CSF budding yeast cells. Results: Among 219 patients with recurrence of symptoms after initial CM therapy, having CSF yeast cells (adjusted prevalence ratio (aPR) = 0.29, 95% CI: 0.098, 0.876) was significantly associated with positive CSF culture relapse. CSF budding yeast cells showed 75.0% sensitivity, 75.8% specificity and an area under the receiver operator characteristic (ROC) curve of 0.75 (95% CI: 0.70, 0.81). The positive predictive value of 81.4% (95% CI: 73.1%, 87.9%), a negative predictive value of 68.3% (95% CI: 58.3%, 77.2%), and a positive likelihood ratio (LR+) and negative likelihood ratio (LR-) of 3.10 (95% CI: 2.13, 4.52) and 0.33 (95% CI: 0.24, 0.45), respectively. Furthermore, CSF yeast cells (aHR = 1.28, 95% CI: 1.190, 1.380) was significantly associated with day 14 mortality among patients with recurrence of meningitis symptoms. Conclusions: CSF budding yeast cells were associated with culture-positive relapse among patients with recurrence of symptoms after treatment for the initial CM episode especially with low CD4 count. This study highlights the validity of microscopic CSF budding yeast cells in predicting microbiological culture-positive relapse. Patients with CSF yeast cells absent exhibited higher mortality, a surprising finding considering their higher CD4 cell count and lower CSF opening pressure.