HIV-negative Cryptococcal Meningitis Patients Research Articles

Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis.

Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P=0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P=0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.

Analysis of the relationship between drug susceptibility of Cryptococcus neoformans isolates and mortality in HIV-negative cryptococcal meningitis

ObjectivesThe relationship between antifungal susceptibility and mortality of cryptococcal meningitis (CM) in HIV-negative patients is poorly understood. MethodsWe conducted a retrospective analysis of 1-year follow-up of 200 HIV-negative CM patients with an initial cerebrospinal fluid (CSF) culture for Cryptococcus neoformans. According to the cut-off values of minimum inhibitory concentration (MIC), two groups of five antifungal agents were classified: amphotericin B (AmB), ≤0.5 µg/mL, >0.5 µg/mL; 5-flucytosine (5-FC), ≤4 µg/mL, >4 µg/mL; fluconazole (FLU), ≤4 µg/mL, >4 µg/mL; itraconazole (ITR), ≤0.125 µg/mL, >0.125 µg/mL; and voriconazole (VOR), <0.25 µg/mL, ≥0.25 µg/mL. Comparisons were performed to analyse clinical features, laboratory, modified Rankin Scale (mRS) scores, and CSF findings under different prognosis outcomes in 1-year. ResultsAll of Cryptococcus neoformans isolates were sensitive to AmB and VOR, most of them were sensitive to 5-FC and FLU (95.5% and 90.5%, respectively) while only 55.0% of them were susceptible to ITR. Minimum inhibitory concentrations of ITR and VOR were significantly related to baseline mRS scores. All-cause mortality was not significantly related to MICs in Cryptococcus neoformans strains. The combination of actual antifungal agents and two groups of the MICs values for antifungal agents had no significant effects on all-cause mortality. ConclusionMost Cryptococcus neoformans isolates were sensitive to AmB, VOR, 5-FC, and FLU. Because of the small number of deaths, we are not able to comment on whether MIC is associated with mortality of CM in HIV-negative patients.

Development and validation of a machine learning model to predict prognosis in HIV-negative cryptococcal meningitis patients: a multicenter study.

To predict prognosis in HIV-negative cryptococcal meningitis (CM)patients by developing and validating a machine learning (ML)model. This study involved 523 HIV-negative CM patients diagnosed between January 1, 1998, and August 31, 2022, by neurologists from 3 tertiary Chinese centers. Prognosis was evaluated at 10weeks after the initiation of antifungal therapy. The final prediction model for HIV-negative CM patients comprised 8 variables: Cerebrospinal fluid(CSF) cryptococcal count, CSF white blood cell (WBC), altered mental status, hearing impairment, CSF chloride levels, CSF opening pressure (OP), aspartate aminotransferase levels at admission, and decreased rate of CSF cryptococcal count within 2weeks after admission. The areas under the curve (AUCs) in the internal, temporal, and external validation sets were 0.87 (95% CI 0.794-0.944), 0.92 (95% CI 0.795-1.000), and 0.86 (95% CI 0.744-0.975), respectively. An artificial intelligence(AI) model was trained to detect and count cryptococci, and the mean average precision (mAP) was 0.993. A ML model for predicting prognosis in HIV-negative CM patients was built and validated, and the model might provide a reference for personalized treatment of HIV-negative CM patients. The change in the CSF cryptococcal count in the early phase of HIV-negative CM treatment can reflect the prognosis of the disease. In addition, utilizing AI to detect and count CSF cryptococci in HIV-negative CM patients can eliminate the interference of human factors in detecting cryptococci in CSF samples and reduce the workload of the examiner.

Seasonality and meteorological factors of HIV-negative cryptococcal meningitis in Guangdong Province, China.

Information about the seasonal characteristics of human immunodeficiency virus (HIV)-negative cryptococcal meningitis (CM) is quite limited. The aim of this study was to explore the seasonality and meteorological factors of HIV-negative patients with CM. We performed a retrospective study of 469 HIV-negative CM patients admitted to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. Their initial onset symptoms of CM occurred from January 2011 to December 2020. The temperature, precipitation, sunlight, humidity and wind speed for the corresponding period and the associated topographic, ecological type and soil type parameters data were collected. The Poisson regression model was used to determine the meteorological factors associated with CM onset. The geographical detector method was used to detect other environmental factors associated with CM onset. CM onset did not showed a seasonal fluctuation, but was strongly associated with mean temperature (β = .010, p = .028) and mean relative humidity (β = -.011, p = .006). In the rainy season, only mean wind speed remained significantly associated with CM onset (β = -.108, p = .041). In the dry season, mean temperature (β = .014, p = .016), mean relative humidity (β = -.016, p = .006) and hours of sunlight (β = -.002, p = .016) were significantly associated with CM onset. Topographic, ecological type and soil type factors did not add explanatory power. Our findings add the knowledge about the environmental factors of HIV-negative CM. Meteorological factors, especially temperature and humidity, may be the main environmental factors affecting the onset of HIV-negative CM.

The effect of serum uric acid, bilirubin and albumin levels on antioxidant status in HIV-negative immunocompetent cryptococcal meningitis patients with post-infectious inflammatory response syndrome.

Oxidative imbalances have been observed in various neurological diseases. Despite the microbiological control in cryptococcal meningitis (CM), a proportion of previously healthy patients experience a clinical deterioration known as post-infectious inflammatory response syndrome (PIIRS). However, the antioxidant status in PIIRS remains unclear. In this study, we found that the serum antioxidant status of HIV-negative immunocompetent CM patients during PIIRS episodes was lower than that of healthy controls. There was a relationship between baseline serum indirect bilirubin levels and the development of PIIRS, and serum uric acid levels may indicate the severity of the disease during PIIRS episodes. Oxidative stress may play a role in the development of PIIRS.

Cryptococcal Meningitis in HIV-Negative Patients: A 12-Year Single-Center Experience in China

Cryptococcal meningitis (CM) is a not rare condition in HIV-negative patients. Here, we describe the clinical characteristics, possible risk factors, and outcomes of HIV-negative patients with CM. Medical records from 99 HIV-negative patients with CM admitted to our hospital from 2010 to 2021 were reviewed systematically. We compared the clinical features and outcomes between patients with underlying diseases and otherwise healthy hosts. The 99 HIV-negative CM patients had a mean age at presentation of 56.2 ± 16.2 years, and the female-to-male ratio was 77:22. A total of 52 (52.5%) CM patients had underlying conditions, and 47 patients (47.5%) had no underlying conditions. Kidney transplant represented the most frequent underlying condition (11.1%), followed by rheumatic disease (10.1%) and hematological diseases (9.1%). Compared to patients without underlying conditions, those with underlying conditions had significantly more fever, more steroid therapy, higher serum creatinine, and lower albumin, IgG, hemoglobin, and platelets (p < 0.05 for each). CM patients without underlying conditions had significantly more alcohol abuse than those with underlying conditions (31.9% vs. 9.6%, p = 0.011). By logistic regression analysis, male gender (OR = 3.16, p = 0.001), higher CSF WBC (OR = 2.88, p = 0.005), and protein (OR = 2.82, p = 0.002) were significantly associated with mortality. Patients with underlying conditions had a similar mortality to patients without underlying conditions. Alcohol abuse was a probable risk factor for CM for previously healthy patients. Male gender, higher CSF WBC, and protein were significantly associated with mortality.

The effect on brain volume in HIV-negative and non-transplant cryptococcal meningitis

To explore the brain volume (BV) changes of HIV-negative and non-transplant cryptococcal meningitis (CM) in 1 year after initial therapy. Case data were collected from 78 CM patients who underwent magnetic resonance imaging (MRI) scanning at least 3 times in 1-year interval after initial therapy. The assessment of BV was measured by a non-commercial software, uAI Research Portal. Linear mixed model was used to investigate the association between clinical characteristics and the changes in BV. Longitudinal study showed a decrease in total brain volume (-4.65 cm3, P=.005), regional brain volume including white matter (-2.86 cm3, P=.031) and basal ganglia (-0.25 cm3, P=.007), and increase in cerebrospinal fluid (CSF) volume (3.58 cm3, P=.013) in CM patients in 1 year after initial therapy. Ventricular volume in patients with ventriculoperitoneal shunts (VPS) was lower than that in patients without VPS (-7.5 cm3, P<.05). Ventricular volume in patients with post-infectious inflammatory response syndrome (PIIRS) was larger than that in patients without PIIRS (7.1 cm3, P<.01). In addition, temporal lobe atrophy was associated with corticosteroid therapy (-6.8 cm3, P<.01). The present study suggested that brain atrophy, especially regional BV decrease, could happen in HIV-negative and non-transplant CM patients over a 1-year interval.

Analysis of the association of HLA subtypes with cryptococcal meningitis in HIV-negative immunocompetent patients.

Objective: We aimed to study the possible relationship between cryptococcal meningitis (CM) and HLA genotypes in HIV-negative immunocompetent patients. Methods: HLA loci of 53 HIV-negative immunocompetent Han Chinese CM patients were compared with those in 481 healthy individuals. Results: We found a significant association between DQB1*05:02 and CM patients compared with controls. There were no significant differences in the frequencies of HLA alleles between CM with and without postinfectious inflammatory response syndrome and controls. Correlation analysis showed DQB1*05:02 was correlated with susceptibility to CM. CM patients carrying the DQB1*05:02 allele had more severe focal neurological deficit, higher initial modified Rankin Scale and British Medical Research Council staging scores. Conclusion: This study provides the first evidence for the interaction between specific HLA class II alleles and HIV-negative immunocompetent CM patients.

Immunological Predictors of Post Infectious Inflammatory Response Syndrome in HIV-Negative Immunocompetent Cryptococcal Meningitis.

ObjectiveThis research aims to study the correlation between serum immune factors and post-infectious inflammatory response syndrome (PIIRS) in immunocompetent cryptococcal meningitis (CM), and explore whether serum immune factors could be used to predict the development of PIIRS.MethodsA cohort of 30 patients with PIIRS and 87 patients without PIIRS was selected from 347 CM patients. We analyzed the general clinical information and immunological indexes (cytokines, complement, immunoglobulin, inflammation, related cytological and biochemical indexes). Spearman correlation analysis and principal component analysis were used to explore the effects of the variables on PIIRS. Additionally, the variables were identified by a random forest-based classifier for predicting the development of PIIRS. The clinical value of predictors was verified by survival analysis.ResultsCompared with patients without PIIRS, patients with PIIRS had lower baseline serum interleukin-6 (IL-6, P = 0.006), immunoglobulin M (IgM, P = 0.004), and a higher baseline neutrophil ratio (P <0.001). The baseline neutrophil ratio (r = 0.359, P = 0.001), IgM (r = −0.272, P = 0.025), and IL-6 (r = −0.259, P = 0.027) were significantly correlated with PIIRS. Combining principal component analysis and random forest results, neutrophil ratio, neutrophil count, IgM, IL-6, and D-dimer were useful predictors. The accuracy of random forest prediction was 75.00%, AUC, and sensitivity were 0.76 and 70%, respectively. Further survival analysis of the time from treatment to PIIRS revealed that the development of PIIRS was associated with IgM (more than 98 days of treatment) and neutrophil ratio/count.ConclusionBaseline neutrophils ratio, neutrophil count, IgM, IL-6, and D-dimer may be clinically useful predictors of PIIRS in HIV-negative immunocompetent CM patients.

Development and Validation of a Machine Learning Model to Predict Prognosis in HIV-Negative Cryptococcal Meningitis Patients: A Multicentre Retrospective Study

Development and Validation of a Machine Learning Model to Predict Prognosis in HIV-Negative Cryptococcal Meningitis Patients: A Multicentre Retrospective Study

The clinical profiles and outcomes of HIV-negative cryptococcal meningitis patients in type II diabetes mellitus

BackgroundThe clinical profiles and outcomes of cryptococcal meningitis have been shown to vary depending on the underlying condition. The aim of this study was to investigate clinical characteristics and outcomes in patients with and without type II diabetes mellitus.MethodsA retrospective study was performed. Clinical data of HIV-negative cryptococcal meningitis patients with type II diabetes mellitus (n = 26) and without type II diabetes mellitus (n = 52) referring to the Jiangxi Chest Hospital between January 2012 to December 2018 were analyzed. The data were analyzed using chi square, none-parametric tests, and logistic regression. P-values < 0.05 were considered significant.ResultsIn this study, cryptococcal meningitis patients suffering from type II diabetes mellitus had a higher mortality (23.08% vs. 7.69%; P = 0.055), and required longer hospitalization (59.58 vs. 42.88 days; P = 0.132). Moreover, cerebrospinal fluid examinations revealed that cryptococcal meningitis patients with type II diabetes mellitus had higher opening pressure (271.54 vs. 234.23 mmH2O; P = 0.125).The results of multivariate regression analysis revealed that cryptococcal meningitis patients with type II diabetes were more often presented with visual disorders (28.54% vs. 11.54%; [95% CI 0.056–0.705]; p = 0.012), and had higher cerebrospinal fluid protein levels (1027.62 ± 594.16 vs. 705.72 ± 373.88 mg/l; [95% CI 1.000–1.002]; p = 0.016). Among patients with type II diabetes mellitus, nausea and vomiting was more frequent at the initial visit in those died (100% vs. 50%; p = 0.027), and 66% of died type II diabetes mellitus patients were poorly controlled blood glucose level, compared with 30% in survival type II diabetes mellitus patients.ConclusionThis study suggests that cryptococcal meningitis patients with type II diabetes mellitus differ significantly from cryptococcal meningitis patients without type II diabetes mellitus with respect to clinical symptoms such as visual disorders and cerebrospinal fluid examination. The presence of nausea and vomiting among type II diabetes mellitus patients could have implication in mortality.

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

ObjectiveTo investigate the clinical features and outcomes of cryptococcal meningitis (CM) in HIV-negative patients with and without lung infections.MethodsWe retrospectively reviewed the medical records of HIV-negative patients with CM admitted to two university hospitals in Southwest China over the past 5 years.ResultsSeventy-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).ConclusionHIV-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.

Lumbar drainage for the treatment of refractory intracranial hypertension in HIV-negative cryptococcal meningitis.

Aim: This study aims to evaluate lumbar drainage (LD) for controlling refractory intracranial hypertension among non-HIV cryptococcal meningitis patients. Patients & methods: A case-control study was designed to compare LD (case) with repeated lumbar puncture (control). Results: Both LD and repeated lumbar puncture can efficiently control refractory intracranial hypertension. LD group showed better clinical symptomremission, such as lower rate of headache, vision disorders, signs of meningeal irritation and conscious disturbance, than control group. LD group was reported with higher intracranial pressure reduction (173.75±17.72 mmH2O) than those among control group (113.50±14.94 mmH2O; p <0.05). Conclusion: LD is an effective and safe alternative to control refractory intracranial hypertension in HIV-negative cryptococcal meningitis patients.

Risk factors associated with acute/subacute cerebral infarction in HIV-negative patients with cryptococcal meningitis

ObjectiveTo explore the risk factors associated with acute/subacute cerebral infarction (ASCI) in HIV-negative patients with cryptococcal meningitis (CM). MethodsThis case-control study included 10 HIV-negative CM patients with ASCI and 30 age- and sex-matched HIV-negative control (1:3) CM patients without ASCI. The clinical manifestations and neuroimaging findings were collected. Risk factors for ASCI in the HIV-negative CM patients were confirmed by conditional logistic regression analysis. ResultsAmong the 10 HIV-negative CM patients with ASCI, all cases had lacunar infarctions. Single infarctions were found in 6 patients, and multiple infarctions in 4. Hydrocephalus (p=0.020, OR=23.77, 95% CI, 1.67–339.33) and smoking (p=0.039, OR=11.63, 95% CI, 1.14–118.96) were found to be independently associated with the occurrence of ASCI. ConclusionsHydrocephalus and smoking may increase the risk of ASCI in HIV-negative CM patients. In the clinical course, cerebral infarction should be strongly suspected in CM patients with hydrocephalus or smoking histories.

Diffusion tensor imaging study of white matter damage in chronic meningitis.

Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.

Cerebrospinal fluid 14‐3‐3‐γ protein level in eight HIV‐negative cryptococcal meningitis adults

The clinical data and cerebrospinal fluid (CSF) 14-3-3-gamma protein detection of eight adult HIV-negative cryptococcal meningitis (CM) cases were examined. The eight cases included six males and two females aged 35-70 years (mean = 49.8 years). The duration between the onset of CM symptoms and the first CSF study ranged from 1 to 60 days. Initial neuroimaging study was abnormal in 87.5% (7/8) of the cases. All the eight had positive initial and subsequent follow-up CSF 14-3-3-gamma protein detection. The densitometric values of CSF 14-3-3-gamma protein were not correlated with either the CSF white blood cell counts or the therapeutic results. The therapeutic results showed that three cases died and five survived. Significant neurologic deficits were shown in 60% (3/5) of the survivors. This study revealed that HIV-negative CM patients have elevated CSF 14-3-3-gamma protein levels, and that this level is not changed with a short-term treatment.

Time course of cerebral hemodynamics in cryptococcal meningitis in HIV-negative adults

To evaluate the cerebral hemodynamics in cryptococcal meningitis (CM) patients using non-invasive studies. Serial trans-cranial color-coded sonography (TCCS) and magnetic resonance angiography (MRA) studies were performed to measure the cerebral vasculopathy of 12 HIV-negative CM patients. With TCCS, 8 of the 22 middle cerebral arteries (MCAs) showed stenotic velocities, whereas the time-mean velocity (V(mean)) of the 20 anterior cerebral arteries (ACAs), 22 posterior cerebral arteries (PCAs), and 12 basilar arteries (BAs) did not. In total, five patients had stenotic velocities, three of whom had bilateral M1 stenosis (<50%), whilst two had unilateral M1 stenosis (<50%). The V(mean) of MCA increased from day 1 to day 35 and substantially decreased thereafter. The mean Pulsatility Index (PI) in the studied vessels was higher during the study period. A mismatch of the findings between TCCS and MRA studies were also demonstrated. There was a high incidence and a longer time-period of disturbed cerebral hemodynamics during the clinical course of CM. However, because of the limited case numbers for this study, further large-scale studies are needed to delineate the clinical characteristics and therapeutic influence of cerebrovascular insults in HIV-negative CM patients.