[Meningeal cryptococcosis in patients living with HIV. Experience in intensive care]. / Criptococosis meníngea en pacientes viviendo con HIV. Experiencia en cuidados intensivos.

INTRODUCTION: Meningeal cryptococcosis (MC) is a frequent cause of meningoencephalitis in people living with HIV (PLHIV), leading to substantial morbidity (20-55%). Clinical characteristics, lethality and adverse prognostic factors in PLHIV with MC admitted to intensive care units (ICUs) are described. METHODS: A retrospective observational study. Period from 11/21/2006 to 05/24/2023. It involved 154 adult PLHIV diagnosed with MC and admitted to ICUs. Percentages and absolute values were compared by Chi-Square or Fisher's test and medians by Mann-Whitney test. The association with mortality was assessed by logistic regression. SPSS 23.0 software was used. A p-value <0.05 was considered significant. RESULTS: Patients who died and those who survived were comparable in age and sex (p>0.05). Univariate analysis showed that impaired functional and nutritional status, lack of previous highly active antiretroviral therapy, CD4 <100 cells, APACHE II ≥ 13 and a PLHIV prognostic score ≥ 8 points, requiring mechanical ventilation (MV), respiratory failure, renal failure, neurological dysfunction or sepsis could be associated (p<0.05) with mortality. Logistic regression established that impaired functional and nutritional status, a PLHIV prognostic score ≥ 8, need for MV and presence of sepsis would be independent variables associated with mortality. CONCLUSION: The results indicate that altered functional and nutritional status, a PLHIV prognostic score ≥ 8 points, requiring MV and suffering sepsis on admission to the ICU are more frequent in deceased patients, and they could therefore serve as independent variables to predict a higher risk of mortality.

Introducción: La criptococosis meníngea (CM) es una causa frecuente de meningoencefalitis en personas que viven con HIV (PVHIV) y produce una importante morbimortalidad (20-55%). Se describen las características clínicas, la letalidad y las variables de mal pronóstico en PVHIV con CM, en unidades de cuidados intensivos (UCI). Métodos: Estudio observacional y retrospectivo. Período 21/11/2006 a 24/05/2023. Población evaluada: 154 PVHIV adultos, admitidos en UCI con diagnóstico de CM. Los porcentajes y valores absolutos, fueron comparados mediante Chi-Cuadrado o test de Fisher y las medianas mediante test de Mann-Whitney. La asociación con mortalidad se evaluó por regresión logística. Se utilizó el programa SPSS 23.0. Un valor p<0.05 fue considerado significativo. Resultados: Los pacientes que fallecieron y los que sobrevivieron fueron comparables en edad y sexo (p>0.05). El análisis univariado, observó que un estado funcional y nutricional alterado, falta de tratamiento antirretroviral previo (TARV), CD4 <100 células/µl, APACHE II ≥ 13 y un score pronóstico de PVHIV ≥ 8 puntos, requerir ventilación mecánica (VM), sufrir insuficiencia respiratoria, renal, disfunción neurológica o sepsis, podrían estar asociados (p<0.05) con mortalidad. La regresión logística estableció que un estado funcional y nutricional alterado, un score pronóstico PVHIV ≥ 8, necesitar VM y sufrir sepsis serían variables independientes asociadas a mortalidad. Conclusión: Los resultados indican que el estado funcional y nutricional alterado, un score pronóstico PVHIV ≥ 8 puntos, requerir VM y sufrir sepsis al ingreso a UCI podrían servir como variables independientes para predecir un mayor riesgo de mortalidad.

Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study.

OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

The prevalence and mortality of cryptococcal meningitis in patients with autoimmune diseases: a systematic review and meta-analysis.

Growing evidence suggests that autoimmune diseases (AIDs) are risk factors for cryptococcal meningitis (CM). Therefore, understanding the epidemiological and clinical profile of CM in patients with AIDs is important. This meta-analysis assessed the prevalence, clinical profiles, and clinical outcomes of CM in AIDs. Studies on CM in patients with AIDs were searched for in PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure, and meta-analyses were performed using the statistical program of R. Nineteen studies with 36,631 patients with AIDs were analyzed. The overall pooled CM prevalence was 0.4% (95% confidence interval [CI], 0.3-0.6%), 90.7% of which occurred in female patients. Thirteen studies with 77 patients with AIDs diagnosed with CM were analyzed, and the mortality rate was 26.7% (95% CI, 9.5-47.2%). Of patients with systemic lupus erythematosus, 30.1% of CM cases were initially misdiagnosed (95% CI, 0-65.6%). The primary symptom of CM with AIDs was headache (99.4%; 95% CI, 92.1-100%), followed by fever (93.7%; 95% CI, 82.8-100%) and vomiting (37.2%; 95% CI, 13.2-61.2%). The prevalence of CM infections among patients with AIDs should not be underestimated despite non-specific clinical presentations as there were fatal outcomes. Our results suggest that more research is needed to understand the relationship between AIDs and CM, and clinical trials are necessary to improve treatment strategies.

Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome.

Existing evidence revealed grave prognosis for cryptococcal meningitis (CM), particularly its short-term mortality. However, its long-term survival and prognostic factors remained unknown. This study investigated 3-year mortality and analyzed its predictive factors in patients with CM. This retrospective cohort study with 83 cerebrospinal fluid culture-confirmed CM patients was conducted at China Medical University Hospital from 2003 to 2016. The 3-year mortality rate in patients with CM was 54% (45 deaths among 83 patients). Advanced age, human immunodeficiency virus (HIV) seronegative state, low Glasgow Coma Scale score on admission, decreased hemoglobin and hyperglycemia on diagnosis were associated with 3-year mortality. After multivariate adjustment in the Cox proportional hazard model, only severe hyperglycemia (serum glucose ≥200 mg/dL) on diagnosis could predict 3-year mortality.

Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa.

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00-1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07-1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94-1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. LAY SUMMARY: We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

Treatment and mortality outcomes in patients with other extrapulmonary cryptococcal disease compared with central nervous system disease.

BACKGROUND: Determining the extent of cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localised pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. METHODS: This is a retrospective, single-centre study of all hospitalised patients with nonpulmonary cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox regression analysis. RESULTS: Of 193 patients analysed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, p = .9). In the comorbidity-adjusted multivariable Cox regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, p < .001). CONCLUSION: Patients with OE CD had similar 90-day mortality compared to those with CNS disease. Despite current guideline recommendations, patients with OE disease were less likely to receive appropriate induction therapy with AmB and flucytosine compared to patients with CNS disease.

Prevalence of Asymptomatic Cryptococcal Antigenemia and Association with Follow-up Risk of Cryptococcal Meningitis and Mortality among HIV Infected Patients in North West India: A Prospective Cohort Study.

OBJECTIVE: Cryptococcal meningitis is an important cause of morbidity and mortality in HIV infected individuals. In the era of universal antiretroviral therapy, the incidence of immune reconstitution inflammatory syndrome (IRIS) related cryptococcal meningitis has increased. Detection of serum cryptococcal antigen in asymptomatic PLHIV (People Living With HIV) and preemptive treatment with fluconazole can decrease the burden of cryptococcal disease. We conducted this study to find the prevalence of asymptomatic cryptococcal antigenemia in India and its correlation with mortality in PLHIV. METHOD AND MATERIALS: This was a prospective observational study. HIV infected ART naïve patients with age of ≥ 18 years who had CD4 counts ≤ 100 /µL were included and serum cryptococcal antigen test was done. These patients were followed for six months to look for the development of Cryptococcal meningitis and mortality. RESULTS: A total of 116 patients were analyzed. Asymptomatic cryptococcal antigenemia was detected in 5.17% of patients and is correlated with increased risk of cryptococcal meningitis and mortality on follow-up in PLHIV. CONCLUSION: Serum cryptococcal antigen positivity is correlated with an increased risk of Cryptococcal meningitis and mortality in PLHIV. We recommend the screening of asymptomatic PLHIV with CD4 ≤ 100/µL for serum cryptococcal antigen, so that pre-emptive treatment can be initiated to reduce morbidity and mortality.

Cryptococcal meningitis in non-HIV patients in the State of Amazonas, Northern Brazil.

Cryptococcosis is a life-threatening fungal infection caused by the Cryptococcus neoformans/Cryptococcus gattii species complex. Most cases are recorded in patients suffering from HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome). However, this infection also occurs in non-HIV patients with a proportion of 10-30% of all cases. The study aimed at the clinical and molecular characterization of non-HIV patients diagnosed with cryptococcosis at the Tropical Medicine Foundation (FMT-HVD) from July 2016 to June 2019. Medical records of respective patients were analyzed to describe the course of cryptococcosis in non-HIV patients. In addition, multi-locus sequence typing (MLST) was applied to identify the sequence types of the isolated Cryptococcus strains, to perform phylogenetic analysis, and to evaluate the isolates' genetic relationship to global reference strains. Antifungal susceptibility profiles to amphotericin B, fluconazole, and itraconazole were assessed by broth microdilution. From a total of 7 patients, 4 were female, the age range varied between 10 and 53 years (median of 36.3 years). Cryptococcal meningitis was the common clinical manifestation (100%). The period between onset of symptoms and confirmed diagnosis ranged from 15 to 730 days (mean value of 172.9 days), and the observed mortality was 57.1%. Of note, comorbidities of the assessed cryptococcosis patients comprised hypertension, diabetes mellitus, and intestinal tuberculosis. Genotyping applying PCR-RFLP of the URA5 gene identified all clinical isolates as C. gattii genotype VGII. Using MLST, it was possible to discriminate the sequence types ST20 (n = 4), ST5 (n = 3), and the newly identified sequence type ST560 (n = 1). The antifungals amphotericin B, fluconazole, and itraconazole showed satisfactory inhibitory activity (microdilution test) against all C. gattii VGII strains.

Cerebrospinal fluid microscopy as an index for predicting the prognosis of cryptococcal meningitis patients with and without HIV.

Aim: To evaluate the clinical data and quantitative cerebrospinal fluid for associations with the outcome of cryptococcal meningitis (CM) patients in the hospital. Patients & methods: We retrospectively analyzed a total of 139 CM patients comprising 108 without HIV and 31 with HIV admitted in a Jiang Xi hospital. Resµlts: We found that CM patients with the high fungal burden (≥10 yeasts/µl) (26.3%) had a worse prognosis than those with the low fungal burden (<10 yeasts/µl). (4.9%) (p = 0.0007 <0.05). Conclusion: In CM patients, a fungal burden of 10 yeasts/µl in the first cerebrospinal fluid test may be used as an indicator of patient prognosis, and we can personalize patients' treatment based on the fungal burden to improve prognosis.

Determinants of two-year mortality among HIV positive patients with Cryptococcal meningitis initiating standard antifungal treatment with or without adjunctive dexamethasone in Uganda.

Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of mortality among HIV infected patients especially in sub-Saharan Africa where 75% of the deaths occur. Most of the studies evaluating mortality have reported short-term mortality (at or before 10 weeks of therapy). We determined mortality and associated factors among patients treated for CCM in the CryptoDex trial (ISRCTN59144167) in Uganda, and the effect of dexamethasone adjunctive therapy on mortality at two years. We conducted a retrospective cohort study between May 2017 and July 2017 to determine the long term survival (up to 2 years post-randomization) of all patients who had been enrolled into the CryptoDex trial in Uganda. The CryptoDex trial recruited between April 2013 and February 2015. We estimated mortality rates and determined factors affecting mortality at two years using Cox regression. The study followed up 211 participants, 127 (60.2%) of whom were male. Sixteen participants (7.58%) were diagnosed with HIV at the same admission when CCM was diagnosed. By two years following randomization 127 (60%) participants had died, a mortality rate of 67 deaths per 100 person-years. Mortality was associated with Glasgow coma score (GCS) below 15 (adjusted Hazard ratio (aHR) 1.77, 95% CI: 1.02-2.44), p = 0.040; weight (aHR 0.97, per 1 Kg increase; 95% CI: 0.94-0.99), p = 0.003; and presence of convulsions (aHR 2.31, 95% CI: 1.32-4.04), p = 0.004, while dexamethasone use and fungal burden had no effect. Long-term mortality in CCM patients remains high even among patients receiving recommended therapy. Strategies to improve long-term survival in CCM patients are urgently needed, especially targeting those with reduced GCS, low weight, and convulsions.

Surgical treatment and operation time in human immunodeficiency virus-negative cryptococcal meningitis.

There are still no unified guidelines of surgical treatment and timing for human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM).The clinical data and follow-up data were collected from HIV-negative CM patients in Xiangya Hospital of Central South University from January 2009 to November 2018, and 42 patients who were treated with surgical intervention were enrolled in the present study. These 42 patients were divided into ventriculoatrial (VA) group, ventriculoperitoneal group, external ventricle drainage (EVD) group, hydrocephalus (HYC) group, non-HYC group, EVD group, and non-EVD group (VA/ ventriculoperitoneal) according to different surgical procedures. Statistical analyses were conducted using SPSS (version 19.0, Chicago, IL).Signs of headache, fever, and loss of consciousness in the VA group were significantly improved compared with the EVD group at 1 week after operation (P < .05). The mortality rate of the VA group was significantly lower than that of the EVD group (P < .05). Moreover, male patients were more prone to have HYC (P < .05). Younger patients tended to develop HYC (P < .05). Cerebrospinal fluid sugar in the non-HYC group was significantly lower compared with the HYC group (P < .05). Time of CM-to-operation in the non-HYC group was markedly shorter compared with the HYC group (P < .01).VA procedure could be one of the first choices for the treatment of uncontrollable intracranial hypertension caused by CM. Severe uncontrollable headache, loss of consciousness, and cerebral hernia were indications of emergency surgery. Repeated headache, hearing impairment, and especially progressive loss of vision were indications of early surgery to avoid permanent damage to nerve functions of HIV-negative CM patients.

Comparison of cryptococcal meningitis in HIV-negative patients with and without lung infections.

OBJECTIVE: To investigate the clinical features and outcomes of cryptococcal meningitis (CM) in HIV-negative patients with and without lung infections. METHODS: We retrospectively reviewed the medical records of HIV-negative patients with CM admitted to two university hospitals in Southwest China over the past 5 years. RESULTS: Seventy-one patients were included, of whom 35 (49.3%) had lung disease. Compared with patients without lung infection, CM patients with lung infection tended to be male and younger (≤30 years), experienced more fever, less vomiting and fewer central nervous system symptoms; more often had low white blood cell (WBC) counts (<20 × 106/L), and fewer often had ethmoid sinusitis, maxillary sinusitis, paranasal sinusitis, and otitis media. Cryptococcus neoformans isolates from these patients were sensitive to itraconazole, voriconazole, fluconazole, and amphotericin B but resistant to flucytosine. CM patients with lung infection had higher mortality at discharge compared with patients without lung infection (8.6% vs. 0%). Multivariable analyses showed that a WBC count <20 × 106/L was significantly associated with poor treatment outcome (odds ratio 0.01, 95% confidence interval 0-0.83). CONCLUSION: HIV-negative CM patients with lung infections tended to be male and younger. Fever, fewer central nervous system symptoms, and WBC counts <20 × 106/L were characteristic of this patient group.

Ventriculoperitoneal shunt insertion in human immunodeficiency virus infected adults: a systematic review and meta-analysis.

BACKGROUND: Hydrocephalus is a common, life threatening complication of human immunodeficiency virus (HIV)-related central nervous system opportunistic infection which can be treated by insertion of a ventriculoperitoneal shunt (VPS). In HIV-infected patients there is concern that VPS might be associated with unacceptably high mortality. To identify prognostic indicators, we aimed to compare survival and clinical outcome following VPS placement between all studied causes of hydrocephalus in HIV infected patients. METHODS: The following electronic databases were searched: The Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), EMBASE, CINAHL Plus, LILACS, Research Registry, the metaRegister of Controlled Trials, ClinicalTrials.gov, African Journals Online, and the OpenGrey database. We included observational studies of HIV-infected patients treated with VPS which reported of survival or clinical outcome. Data was extracted using standardised proformas. Risk of bias was assessed using validated domain-based tools. RESULTS: Seven Hunderd twenty-three unique study records were screened. Nine observational studies were included. Three included a total of 75 patients with tuberculous meningitis (TBM) and six included a total of 49 patients with cryptococcal meningitis (CM). All of the CM and two of the TBM studies were of weak quality. One of the TBM studies was of moderate quality. One-month mortality ranged from 62.5-100% for CM and 33.3-61.9% for TBM. These pooled data were of low to very-low quality and was inadequate to support meta-analysis between aetiologies. Pooling of results from two studies with a total of 77 participants indicated that HIV-infected patients with TBM had higher risk of one-month mortality compared with HIV non-infected controls (odds ratio 3.03; 95% confidence-interval 1.13-8.12; p = 0.03). CONCLUSIONS: The evidence base is currently inadequate to inform prognostication in VPS insertion in HIV-infected patients. A population-based prospective cohort study is required to address this, in the first instance.

Cryptococcal antigenemia is associated with meningitis or death in HIV-infected adults with CD4 100-200 cells/mm3.

BACKGROUND: Cryptococcal antigen (CrAg) screening with fluconazole prophylaxis has been shown to prevent cryptococcal meningitis and mortality for people living with HIV (PLWH) with CD4 < 100 cells/mm3. While cryptococcal meningitis occurs in individuals with CD4 100-200 cells/mm3, there is limited evidence that CrAg screening predicts cryptococcal meningitis or mortality among this group with moderate immunosuppression. Current IDSA and WHO clinical guidelines recommend restricting CrAg screening to PLWH with CD4 < 100 cells/mm3. METHODS: We conducted a prospective cohort study of PLWH 18+ years who had not initiated ART in South Africa. We followed participants for 14 months to determine onset of cryptococcal meningitis or all-cause mortality. At study completion, we retrospectively tested stored serum samples for CrAg using an enzyme immunoassay (EIA). We calculated CD4-stratified incidence rates of outcomes and used Cox proportional hazards to measure associations between CrAg positivity and outcomes. RESULTS: We enrolled 2383 PLWH, and 1309 participants had serum samples tested by CrAg EIA. The median CD4 was 317 cells/mm3 (interquartile range: 173-491 cells/mm3). By CD4 count at baseline, there were 209 individuals with a CD4 count of 100-200 cells/mm3 and available CrAg test results. Of these, four (1.9%) tested positive. Two of four (IR: 58.8 per 100 person-years) CrAg+ participants and 11 of 205 (IR: 5.6 per 100 person-years) CrAg- participants developed cryptococcal meningitis or died for an overall rate of death or cryptococcal meningitis that was 10.0-times higher for those who were CrAg+ (95% confidence interval: 2.2-45.3). Among those with CD4 < 100 cell/mm3 and CrAg EIA test results (N = 179), ten (5.6%) participants tested CrAg+. Among this group, seven of ten (IR: 137.6 per 100 person-years) CrAg+ participants and 26 of 169 (IR: 17.8 per 100 person-years) CrAg- participants developed cryptococcal meningitis or died, for a rate of death or cryptococcal meningitis that was 6.3-times higher for those who were CrAg+ (95% confidence interval: 2.7-14.6). CONCLUSIONS: Although few PLWH with moderate immunosuppression screened CrAg positive, a positive CrAg test was predictive of increased risk of cryptococcal meningitis or death. Similar to those with a CD4 < 100 cell/mm3, systematic CrAg screening may reduce morbidity and mortality in PLWH with CD4 100-200 cells/mm3.

Mortality from HIV-associated meningitis in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. METHODS: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months). RESULTS AND DISCUSSION: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes. CONCLUSIONS: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region.

Evaluation of the Biofire FilmArray meningitis/encephalitis assay for the detection of Cryptococcus neoformans/gattii.

OBJECTIVES: Cryptococcal meningitis (CM) remains an important cause of morbidity and mortality among immunocompromised patients. Laboratory diagnostics for CM includes antigen detection, staining and culture. Data on the performance of the Biofire® FilmArray® meningitis/encephalitis (ME) panel for detecting Cryptococcus neoformans/gattii is limited, with several reports describing false negativity for this target. METHODS: A retrospective analysis of 1384 physician-ordered ME panel tests ordered between January 2017 to October 2018 was performed. ME panel results were compared to cerebrospinal fluid (CSF) cryptococcal antigen (CrAg) and CSF culture testing and clinical significance of cryptococcal detection was determined. RESULTS: There were 34 patients positive for cryptococcal detection by either ME panel, CSF CrAg or CSF culture in 2.7% of CSF specimens tested (38/1384). Of the 34 patients positive for cryptococcal detection, 85.3% were human immunodeficiency virus positive (29/34). The ME panel detected 32/38 (84.2%) cryptococcal-positive specimens, culture detected 28/38 (73.7%) and CSF CrAg was positive in 37/38 specimens (97.4%). The ME panel had a sensitivity and specificity of 96.4% (95% CI 81.7-99.9%) and 99.6% (95% CI 99.2-99.9%) compared with culture, and 83.8% (95% CI 68.0-93.8%) and 99.9% (95% CI 99.6-100.0%) compared to CSF CrAg testing, respectively. CrAg titres were lower among ME panel-negative, culture-negative specimens compared with ME panel-positive, culture-negative specimens (reciprocal median end-point titres of 128 ± 60 vs. 1920 ± 1730, p 0.04). All five CrAg-positive, ME panel- and culture-negative specimens were obtained from previously treated CM patients. DISCUSSION: The ME panel had high correlation with CSF culture and a somewhat lower correlation with CSF CrAg testing. The potential utility of using negative ME panel test results to predict culture sterility among patients undergoing treatment for CM warrants further study.

Optimizing Laboratory Diagnostic Services for Infectious Meningitis in the Meningitis Belt of sub-Saharan Africa.

For longer than a century, the "meningitis belt" of sub-Saharan Africa has experienced the largest-ever global meningitis epidemic. Whereas HIV-associated immunosuppression drives higher susceptibility to environmental infectious organisms with tropism for the central nervous system (CNS), most diagnostic laboratories in the belt stick to N. meningitidis, H. influenzae, and S. pneumoniae. Cryptococcus neoformans has been the leading cause of death (incidence, 89%; death, 75%). To establish whether diagnostic services target geographically important pathogens, there is a need to know the current spectrum of etiology. Given Africa's agro-silvo-pastoralism, the One Health diagnostic approach is recommended. Considering  multipathogen detection capacity, needed speed for corticosteroid therapy decision, and susceptibility/resistance to antimicrobials with improved CNS penetration, proposed laboratory categorization will help neurologists to choose suitable services.

Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial.

BACKGROUND: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. METHODS: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7-14 days of intravenous amphotericin B (0·7-1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93-1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 -log10 CFU/mL per day [95% CI 0·37-0·50] in the sertraline group vs 0·47 -log10 CFU/mL per day [0·40-0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. INTERPRETATION: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. FUNDING: National Institutes of Health and Medical Research Council, Wellcome Trust.