Kenneth Ssebambulidde

Background: Post-infectious inflammatory response syndrome (PIIRS) is an increasingly recognized complication of cryptococcal meningoencephalitis (CM) in non-HIV infected hosts with significant morbidity and mortality. Data describing long-term outcomes following immunomodulatory therapy are limited. Methods: We conducted a prospective observational study of 15 immunocompetent adults with CM-PIIRS treated with a pulse corticosteroid taper (PCT) regimen. Performance status, neurocognitive, ophthalmologic, audiologic, and radiologic assessments were performed at greater than one year following CM diagnosis. Results: After one year, performance status continued to improve from both baseline and the post-pulse periods. Neurocognitive testing revealed mild residual deficits, within the limits of normal, most prominently in information processing and psychomotor speed. Ocular abnormalities were frequent at baseline but showed substantial and sustained reductions following PCT, particularly in retinal nerve fiber layer thickness. Visual field deficits improved by 40% and remained stable thereafter. Evidence for changes in hearing sensitivity at post 1-year follow-up was mixed with 44.5% of ears meeting criteria for improvement, 11% for worsening, and 44.5% being stable. Radiologic abnormalities improved in 79% of patients, although intermittent inflammatory flares occurred during PCT but responded to dose escalation. A prolonged corticosteroid taper may be helpful, and MRI imaging can be used to evaluate response to taper. Conclusions: In immunocompetent patients with CM-PIIRS, adjunctive corticosteroid therapy was associated with sustained improvement in neurologic, visual, and radiologic outcomes with mixed improvement in hearing after a year of therapy, with mild residual deficits.

Female university students engaging in high-risk sexual behaviours, such as transactional sex or unprotected sex, are eligible for HIV pre- and post-exposure prophylaxis (PrEP/PEP). This study aimed to determine the uptake and correlates of PEP and PrEP use among female students at a public university in Uganda. We conducted an online survey among 483 female students at Makerere University and found that 53% had ever engaged in sexual intercourse, with a median debut of 20 years (interquartile range 18 to 22 years). Overall, 20% had sex with a person with HIV or of unknown status, and 9% experienced sexual assault. Despite 32% being eligible for PEP and 20% for PrEP, uptake remained low (9% and 2%, respectively). PEP use was associated with being married/cohabiting and perceived HIV risk. Low uptake of PrEP and PEP among eligible female students highlights the need for targeted awareness and accessibility efforts in academic institutions.

Background: Despite efforts to optimize therapy for HIV-associated cryptococcal meningitis (CM), survival outcomes remain poor. It is unclear how the cerebrospinal fluid (CSF) cellular immune phenotype and activation contribute to 2-week and 1-year survival following CM. Methods: We compared baseline CSF mononuclear cell phenotype and activation among adults with HIV-associated CM who died within 2 weeks of CM diagnosis to survivors who were alive at 1 year. The activated CSF T lymphocytes, CD14+ monocytes, and CD56+ natural killer cells were determined from freshly collected CSF using Cytek Aurora Spectroflo cytometry. Quantitative CSF soluble cryptococcal antigen (CrAg) titer from frozen CSF at baseline and 1 year was determined using CrAg lateral flow assay. Data were analyzed using STATA version 9. Results: Compared to survivors, participants who died within 2 weeks had significantly lower absolute CSF CD8+ T cells at baseline. For every 10% increase in PD-1 expression at baseline, the relative risk of 2-week mortality increased by 20%–60%. CSF CD14+ monocytes among those who died demonstrated low HLA-DR+ and high CD163+ expression compared to survivors. We noted a significant reduction in the median CSF CrAg titer from 1:2560 at baseline to 1:5 at 1 year (P < .0001) with 8 of 21 (38%) participants testing negative for CSF CrAg. Conclusions: Expression of CD163 on CD14+ macrophages and immune exhaustion of CSF mononuclear cells at baseline are associated with an increased risk of early mortality in CM. After 1 year of treatment, approximately 4 in 10 patients with CM have a negative CSF CrAg.

Background: In cryptococcal meningitis, increased intracranial pressure (ICP) is associated with worse outcomes and increased mortality. We sought to understand how changes in ICP and mean arterial pressure (MAP) affect cerebral perfusion pressure (CPP) and influence clinical outcomes. Methods: We performed a secondary data analysis of a prospective cohort of Ugandan adults with HIV-associated cryptococcal meningitis. We summarize demographic variables, clinical presentation, and 2-week survival by CPP and MAP groups. Results: Among 593 participants, 41% had low CPP 100 mm Hg. There was no association between baseline CPP and 2-week mortality. As a time-varying covariate, we observed a 39% increased risk of 2-week mortality with CPP levels 100 mm Hg (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.02–1.88, P = .04). Among 686 participants with baseline MAP measurements, there was an increased risk of 2-week mortality among people with low MAP 100 mm Hg (HR 1.47; 95% CI 1.08–1.99; P = .014) compared with normal MAP 70–100 mm Hg. We identified 4 clinical profiles based on MAP, CPP, and ICP measurements: (1) uncompensated intracranial hypertension (low CPP, elevated ICP, and low MAP), (2) compensated intracranial hypertension (normal CPP, elevated ICP, and MAP), (3) cerebral hypoperfusion (low CPP and low MAP), and (4) cerebral hyperperfusion (high CPP and high MAP). Conclusions: In cryptococcal meningitis, there is an intricate relationship between ICP, MAP, and CPP. We provide a concept framework using data from a clinical cohort and recommendations for clinical management.

Therapies to reduce neuroinflammation following resolution of acute central nervous system (CNS) infections are urgently needed, particularly for patients with non–HIV-associated cryptococcal meningoencephalitis complicated by a postinfectious inflammatory response syndrome (cPIIRS). To identify druggable targets in cPIIRS, patient cerebral spinal fluid samples underwent transcriptional analysis, revealing a Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dominance in neuroinflammatory gene signatures. MurinecPIIRS models recapitulated this pathway predominance and treatment with the JAK inhibitor ruxolitinib, confirmed a mechanistic requirement for this pathway in disease pathology. Ruxolitinib treatment improved markers of neuronal damage, reduced activated T cell and myeloid cells, and improved weight. On the basis of these findings, we conducted a first-in-human ruxolitinib treatment of patients with cPIIRS (NCT00001352). Ruxolitinib treatment of six patients led to demonstrated tolerability, reductions in inflammatory biomarkers and activated immune cells, and improved brain imaging. These results advocate for pathway-instructed therapeutics in neuroinflammatory diseases and endorse JAK inhibitors in further clinical studies of cPIIRS.

Background: Neurocognitive impairment in HIV-associated cryptococcal meningitis survivors remains poorly characterized. We sought to identify risk factors associated with sustained neurocognitive impairment. Methods: Cryptococcal meningitis survivors from the ASTRO-CM trial underwent neurocognitive assessment at 12 weeks. A composite quantitative neurocognitive performance score (QNPZ-8) was calculated as a mean of 8 independent z-scores. Participants were classified by QNPZ-8 score as having mild (QNPZ-8 ≥−1), moderate (−2 < QNPZ-8 < –1), or severe (QNPZ-8 ≤−2) impairment compared with the reference cohort of HIV-negative Ugandan adults. We compared differences in baseline demographics and clinical and laboratory variables by impairment categories. Results: One hundred fifty-two participants completed ≥5 of the 8 neuropsychological tests and were included in the analysis. Overall, 37% (57/152) exhibited mild (QNPZ-8 ≥−1), 37% (56/152) moderate (−2 < QNPZ-8 < –1), and 26% (39/152) severe impairment (QNPZ-8 ≤−2). The overall mean QNPZ-8 score (SD) of −1.4 (0.82) denoted moderate neurocognitive impairment at 12 weeks. At baseline, lower weight (P = .03), Glasgow Coma Scale score <15 (P = .03), and education ≤7 years (P < .001) were more frequently observed among those with severe neurocognitive impairment at 12 weeks. Education ≤7 years (odds ratio, 6.13; 95% CI, 2.96–12.68; P < .001) and Glasgow Coma Scale score <15 (odds ratio, 2.61; 95% CI, 1.23–5.57; P = .013) were associated with moderate or severe neurocognitive impairment. Conclusions: Neurocognitive impairment is prevalent at 12 weeks post-treatment in HIV-associated cryptococcal meningitis. Education level and Glasgow Coma Scale score <15 are associated with worse neurocognitive performance. Our findings underscore the need to further evaluate the impact of cryptococcal meningitis on neurocognitive outcomes.

Given extensive improvements in access to antiretroviral therapy (ART) over the past 12 years, the HIV and cryptococcal meningitis landscapes have dramatically changed since 2010. We sought to evaluate changes in clinical presentation and clinical outcomes of people presenting with HIV-associated cryptococcal meningitis between 2010 and 2022 in Uganda. We analyzed three prospective cohorts of HIV-infected Ugandans with cryptococcal meningitis during 2010–2012, 2013–2017, and 2018–2022. We summarized baseline demographics, clinical characteristics at presentation, and 2-week and 16-week mortality. Overall, 2022 persons had confirmed cryptococcal meningitis between 2010 and 2022. In the most recent 2018–2022 cohort, 48% presented as ART-naïve, and the median CD4 cell count was 26 cells/µl. Participants in the 2018–2022 cohort had the lowest cerebrospinal fluid (CSF) opening pressure (median 22 cmH2O) and the highest percentage with sterile CSF quantitative cultures (21%) compared with earlier cohorts (P < .001 for both), signifying a less severely ill population presenting with cryptococcal meningitis. Two-week mortality was lowest among participants with cryptococcal meningitis enrolled in a clinical trial in the 2018–2022 cohort at 13% compared to 26% in both 2010–2012 and 2013–2017 (P < .001). While AIDS-related deaths have dramatically declined over the past 12 years, cryptococcosis persists, presenting challenges to HIV program implementation. Two-week mortality has improved in the most recent cohort, likely due to the establishment of cryptococcal screening programs, better supportive care including scheduled lumbar punctures, and the availability of flucytosine—an essential component of antifungal therapy.

Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis; however, its clinical implications remain unclear. We analyzed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into < 100 mg/dl (72%, n = 641) and ≥ 100 mg/dl (28%, n = 249). We described baseline clinical variables and 18-week mortality by CSF protein groups. Those with CSF protein ≥ 100 mg/dl were more likely to present with Glasgow coma scale score < 15 (P < .01), self-reported seizures at baseline (P = .02), higher CD4 T-cell count (P < .001), and higher CSF white blood cells (P < .001). Moreover, those with a baseline CSF protein ≥ 100 mg/dl also had a lower baseline CSF fungal burden (P < .001) and a higher percentage of sterile CSF cultures at day 14 (P = .02). Individuals with CSF protein ≥ 100 mg/dl demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules, pro-inflammatory cytokines, T-helper cell type 1 and 17 cytokines, and immune-exhaustion marker (P < .05). 18-week mortality risk in individuals with a CSF protein < 100 mg/dl was 34% higher (unadjusted Hazard Ratio 1.34; 95% Confidence Interval, 1.05–1.70; P = .02) than those with CSF protein ≥ 100 mg/dl. In HIV-associated cryptococcal meningitis, individuals with baseline CSF protein ≥ 100 mg/dl more frequently presented with neurological symptoms, higher CSF inflammatory cytokines, reduced fungal burden, and lower mortality risk. The findings underscore the prognostic significance of baseline CSF protein levels in predicting disease severity and mortality risk in cryptococcal meningitis.

: No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to analyze eligible datasets with individual-level participant data (IPD). We imputed missing data and explored three approaches: stepwise logistic regression, classification and regression tree (CART), and random forest regression. We evaluated performance using calibration plots and C-statistics via internal–external cross-validation. We included 3,761 individual participants from 14 studies and nine countries. A total of 1,240 (33%) participants had “definite” (30%) or “probable” (3%) TBM by case definition. Important predictive variables included cerebrospinal fluid (CSF) glucose, blood glucose, CSF white cell count, CSF differential, cryptococcal antigen, HIV status, and fever presence. Internal validation showed that performance varied considerably between IPD datasets with C-statistic values between 0.60 and 0.89. In external validation, CART performed the worst (C = 0.82), and logistic regression and random forest had the same accuracy (C = 0.91). We developed a mobile app for TBM clinical prediction that accounted for heterogeneity and improved diagnostic performance (https://tbmcalc.github.io/tbmcalc). Further external validation is needed.