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Background It is unknown whether persons with symptomatic cryptococcal meningitis detected during routine blood cryptococcal antigen (CrAg) screening have better survival than persons presenting with overt meningitis. Methods We prospectively enrolled Ugandans with HIV and cryptocococcal meningitis from December 2018 to December 2021. Participants were treated with amphotericin-based combination therapy. We compared outcomes between persons who were CrAg screened then referred to hospital with those presenting directly to the hospital with symptomatic meningitis. Results Among 489 participants with cryptococcal meningitis, 40% (194/489) received blood CrAg screening and were referred to hospital (median time to referral 2 days; interquartile range [IQR], 1–6). CrAg-screened persons referred to hospital had lower 14-day mortality than non–CrAg-screened persons who presented directly to hospital with symptomatic meningitis (12% vs 21%; hazard ratio,.51; 95% confidence interval,.32–.83; P =.006). Fewer CrAg-screened participants had altered mental status versus non–CrAg-screened participants (29% vs 41%; P =.03). CrAg-screened persons had lower quantitative cerebrospinal fluid (CSF) culture burden (median [IQR], 4570 [11–100 000] vs 26 900 [182–324 000] CFU/mL; P =.01) and lower CSF opening pressures (median [IQR], 190 [120–270] vs 225 [140–340] mmH2O; P =.004) compared with non–CrAg-screened persons. Conclusions Survival from cryptococcal meningitis was higher in persons with prior CrAg screening than those without CrAg screening. Altered mental status was the most potent predictor for mortality in a multivariate model. We suggest that CrAg screening detects cryptococcal meningitis at an earlier stage, as evidenced by a favorable baseline risk profile and notably fewer persons with altered mental status. [ABSTRACT FROM AUTHOR]

Background Cerebrospinal fluid (CSF) lactate levels can be used to differentiate between bacterial and viral meningitis. We measured CSF lactate in individuals with cryptococcal meningitis to determine its clinical significance. Methods We measured point-of-care CSF lactate at the bedside of 319 Ugandan adults living with human immunodeficiency virus at diagnosis of cryptococcal meningitis. We summarized demographic variables and clinical characteristics by CSF lactate tertiles. We evaluated the association of CSF lactate with clinical characteristics and survival. Results Individuals with high CSF lactate >5 mmol/L at cryptococcal diagnosis more likely presented with altered mental status (P  < .0001), seizures (P  = .0005), elevated intracranial opening pressure (P  = .03), higher CSF white cells (P  = .007), and lower CSF glucose (P  = .0003) compared with those with mid-range (3.1 to 5 mmol/L) or low (≤3 mmol/L) CSF lactate levels. Two-week mortality was higher among individuals with high baseline CSF lactate >5 mmol/L (35%; 38 of 109) compared with individuals with mid-range (22%; 25 of 112) or low CSF lactate (9%; 9 of 97; P  =<.0001). After multivariate adjustment, CSF lactate >5 mmol/L remained independently associated with excess mortality (adjusted hazard ratio = 3.41; 95% confidence interval, 1.55–7.51; P  = .002). We found no correlation between baseline CSF lactate levels and blood capillary lactate levels. Conclusions Baseline point-of-care CSF lactate levels are a prognostic marker of disease severity and mortality in cryptococcal meningitis. Individuals with an elevated baseline CSF lactate level are more likely to present with altered mental status, seizures, and elevated CSF opening pressure and are at a greater risk of death. Future studies are needed to determine targeted therapeutic management strategies in persons with high CSF lactate. [ABSTRACT FROM AUTHOR]

Background The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay's PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. Methods We prospectively enrolled 102 human immunodeficiency virus (HIV)–positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. Results Subjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality—worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra–negative (30%) probable TBM cases (P  = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P  = .48). Ct tertile was significantly associated with baseline CSF lactate (P  = .03). Conclusions High CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care. [ABSTRACT FROM AUTHOR]

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure. Methods We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19–compatible illness. We measured hydroxychloroquine whole-blood concentrations. Results We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was.72 (95% CI,.44–1.16; P =.18) and for twice-weekly was.74 (95% CI,.46–1.19; P =.22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82–120) with once-weekly and 200 ng/mL (IQR, 159–258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19–compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P =.08). Conclusions Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19–compatible illness among healthcare workers. Clinical Trials Registration Clinicaltrials.gov NCT04328467. [ABSTRACT FROM AUTHOR]

Background Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections. Methods We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010–2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia. Results Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259–2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9–70) and did not differ by the presence of CMV viremia (P =.47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07–4.49; P =.03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49–7.10; P =.003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups. Conclusions Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect). Clinical Trials Registration NCT01075152. [ABSTRACT FROM AUTHOR]

Background Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. Methods We evaluated 1201 human immunodeficiency virus–seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic–symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. Results We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P =.91). Conclusions Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus -negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. Clinical Trials Registration NCT01802385. [ABSTRACT FROM AUTHOR]