Clinical Characteristics and Risk Factors for Cryptococcal Meningitis in Diverse Patient Populations in New York City.

Background: Cryptococcal meningitis (CM) is responsible for 15%-20% of human immunodeficiency virus (HIV)-associated mortalities. CM prevalence has also increased in other immunocompromised populations of transplant recipients, patients with cancer, and individuals on immunomodulatory medication. Methods: This retrospective review included 51 definitive patients with CM hospitalized at a tertiary academic medical center in New York City between 2010 and 2023. We assessed clinical features and outcomes of CM, with additional analysis of factors related to antiretroviral therapy (ART) adherence in HIV-infected cases and immunomodulatory medication history of HIV-negative cases. Results: The cohort had a mean (standard deviation) age of 47.1 ± 15.1 years, and was predominantly male (37, 72.5%). Of 32 patients with HIV, 3 (9.4%) were newly diagnosed with HIV at the time of CM hospitalization, 5 (15.6%) had recurrent CM, and 2 (6.3%) had a CM relapse. The majority (30, 93.8%) of patients with HIV were ART nonadherent. Of 19 HIV-negative patients, 8 (42.1%) were solid-organ transplant recipients, 5 (26.3%) had autoimmune conditions of sarcoidosis or systemic lupus erythematosus, and 3 (15.8%) had chronic lymphocytic leukemia. Six (11.8%) patients died during hospitalization, 4 of whom had HIV. Conclusions: The burden of CM in people with HIV and immunocompromised patients continues even in settings with accessible standard antifungal treatment though interventions of increased ART adherence for those with HIV and antifungal prophylaxis may improve morbidity and mortality.

Using single-dose liposomal amphotericin B for cryptococcal meningitis induction therapy: nurse pearls and practical perspectives.

Background: In Uganda where the burden of HIV-associated cryptococcal meningitis is high, conventional amphotericin B deoxycholate has been standard to manage patients with cryptococcal meningitis in research settings. However, liposomal amphotericin B (AmBisome) is now available via the efforts of UNITAID. We sought to describe our nursing experience using AmBisome within a clinical trial for cryptococcal meningitis. Methods: We describe the experience of using single-dose 10mg/kg liposomal amphotericin B from the perspective of a research nurse in Uganda. Second, we described the process of preparing and administering amphotericin. Third, we assessed the nursing time required for the administration of daily amphotericin B versus single-dose liposomal amphotericin. Fourth, we discuss the major challenges faced while using liposomal amphotericin B. Results: We provide estimates for the nursing time required for reconstituting, filtering, diluting and administering liposomal amphotericin B and a visual aid for nursing tasks. Based on five trained nurses, the process of reconstitution and filtration lasts an average of 52 minutes (Range: 40 to 60 minutes), to reconstitute a mean of 11 (range: 8 to 15) 50mg vials (median weight 55kg). Overall, less nursing time was required for single-dose administration than for daily amphotericin B dosing. From a nursing perspective, liposomal amphotericin B was preferable to amphotericin B deoxycholate due to its reduced infusion reactions and other toxicities. Conclusions: Single-dose liposomal amphotericin B is a better alternative to daily amphotericin B. In addition to less toxicity, nosocomial infections, reduced hospital stay, and the potential for lower hospitalisation costs, the nursing implications should not be discounted. Quality nursing care is a finite resource in low- and middle-income countries, and single-dose amphotericin B reduced the nursing time required for the care of patients with cryptococcal meningitis.

In Uganda where the burden of HIV-associated cryptococcal meningitis is high, conventional amphotericin B deoxycholate has been standard to manage patients with cryptococcal meningitis in research settings. However, liposomal amphotericin B is now available via the efforts of UNITAID. Liposomal amphotericin B is known to be less nephrotoxic than amphotericin B deoxycholate. We demonstrated that liposomal amphotericin B is a better alternative to amphotericin B deoxycholate with less toxicity, nosocomial infections, reduced hospital stay, and the potential for lower costs of hospitalisation for both the patient and the healthcare system given the single, 10 mg/kg regimen. Despite the perceived high cost of liposomal amphotericin B and the tedious reconstitution process requiring training and adequate manpower, we believe that single-dose liposomal amphotericin B has enough advantages over the deoxycholate formulation to compel Ministries of Health to consider procuring liposomal amphotericin B as the drug of choice for the management of HIV-associated cryptococcal meningitis. The rollout will require training to facilitate widespread implementation, and we hope that this paper will serve to facilitate this training for nurses who will be using liposomal amphotericin B.

Clinical importance of cerebrospinal fluid protein levels in HIV-associated cryptococcal meningitis: Insights from a prospective cohort study in Uganda.

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.

Our study found that baseline cerebrospinal fluid (CSF) protein ≥ 100 mg/dl can be used as a prognostic tool for assessing disease severity in HIV-associated cryptococcal meningitis. A more pronounced CSF immune response and lower fungal burden were more frequently found in those with a CSF protein ≥ 100 mg/dl.

Fulminant Meningitis: A Rare Case of HSV-2 and Cryptococcal Co-Infection in a Patient With AIDS.

Cryptococcal meningitis (CM) is a severe and often fatal infection of the central nervous system that is caused by Cryptococcus spp. Cryptococcal meningitis mainly affects immunocompromised individuals such as those with AIDS, organ transplantation recipients, and those with conditions requiring prolonged immunosuppressive therapy. Infection typically begins with the inhalation of cryptococcal spores, often from bird droppings, which can remain dormant in the lungs and lymph nodes before disseminating to the central nervous system. Signs and symptoms include headache, nausea, and cognitive impairment, which can progress to severe neurological complications if not promptly treated. Even in the era of antifungal and antiretroviral therapies, CM remains a public health challenge with substantial morbidity and mortality. Although rare, sporadic cases of cryptococcal neoformans/gattii coinfection with Mycobacterium tuberculosis, Streptococcus pneumoniae, and Treponema pallidum have been reported in the literature. Herein, we describe an extremely rare case of fulminant meningitis due to herpes simplex virus (HSV)-2 and Cryptococcal neoformans coinfection. Our patient also had cryptococcemia, which is known to increase acute mortality rates in patients with CM.

State of the Field: Cytotoxic Immune Cell Responses in C. neoformans and C. deneoformans Infection.

Cryptococcus neoformans is an environmental pathogen that causes life-threatening disease in immunocompromised persons. The majority of immunological studies have centered on CD4+ T-cell dysfunction and associated cytokine signaling pathways, optimization of phagocytic cell function against fungal cells, and identification of robust antigens for vaccine development. However, a growing body of literature exists regarding cytotoxic cells, specifically CD8+ T-cells, Natural Killer cells, gamma/delta T-cells, NK T-cells, and Cytotoxic CD4+ T-cells, and their role in the innate and adaptive immune response during C. neoformans and C. deneoformans infection. In this review, we (1) provide a comprehensive report of data gathered from mouse and human studies on cytotoxic cell function and phenotype, (2) discuss harmonious and conflicting results on cellular responses in mice models and human infection, (3) identify gaps of knowledge in the field ripe for exploration, and (4) highlight how innovative immunological tools could enhance the study of cytotoxic cells and their potential immunomodulation during cryptococcosis.

Cryptococcal Meningitis in an HCV-Positive and IVDU- and HIV-Negative Patient: A Case Report and Literature Review.

Background: Cryptococcal meningitis (CM) is a central nervous system (CNS) infection that occurs mainly in immunocompromised individuals such as those with human immunodeficiency virus (HIV) infection. However, the prevalence of CM in immunocompetent patients has increased. Although CM has been reported in patients with hepatitis C virus (HCV) infection, it has not yet been fully established whether there is an association between both conditions. CM has also been reported in patients with intravenous drug use (IVDU), which is related to the immunosuppression caused by these drugs. Case Presentation: We report the case of a 24-year-old man who presented with meningitis secondary to Cryptococcus gattii infection. He had a history of IVDU and HCV infection, was HIV-negative and without antiviral treatment. The patient received adequate antifungal treatment during induction, consolidation, and maintenance phases. His condition relapsed, requiring dose adjustment, with an excellent response during clinical follow-up for both meningitis and HCV infection. A brain biopsy was requested during relapse to rule out other co-infection. Conclusion: The case of an individual diagnosed with cryptococcal meningitis, who had a history of IVDU and HCV infection, is presented. The coexistence of such events could shadow the prognosis of this group of subjects, related to immunosuppression that can be caused through different pathways. Having HCV and being a IVDU simultaneously could increase the risk of Cryptococcus infection.

Cerebrospinal Fluid Lactate Levels as a Prognostic Indicator in Patients With Cryptococcal Meningitis Who Are HIV Negative: A Retrospective Cohort Study.

Background: Cryptococcal meningitis (CM) is a severe central nervous system infection. In patients with HIV infections and coexisting CM, elevated baseline cerebrospinal fluid (CSF) lactate levels can predict increased mortality. However, the CSF lactate level's significance in patients with CM who are HIV negative remains unclear, necessitating further investigation to elucidate the potential distinctions and enhance patient management. This study investigated the significance of CSF lactate levels in patients with CM who were HIV negative. Methods: This retrospective study utilized data from the clinical databases of patients who underwent lumbar punctures at a medical center in Kaohsiung City, southern Taiwan. Demographic data, CSF lactate levels, routine CSF analyses, and hematologic and neurologic findings were evaluated. The optimal CSF lactate threshold value was determined by the Youden index. Results: This retrospective study included 70 patients with CM, among whom 44 (63%) and 26 (37%) tested negative and positive for HIV, respectively. The group without HIV exhibited higher CSF lactate levels, with an optimal CSF lactate cutoff point of 7.935 mmol/L for predicting 90-day mortality, resulting in significant predictive accuracies (area under the curve, 0.755; sensitivity, 57.1%; specificity, 100%); this value was an independent mortality predictor in patients who were HIV negative. In patients with CM who were HIV negative, CSF lactate levels ≥7.935 mmol/L correlated with higher mortality rates but without statistical significance. All patients with CM who were HIV negative and had CSF lactate levels ≥7.935 mmol/L died within 3 months of admission. Conclusions: Patients with CM who were HIV negative had elevated CSF lactate levels that correlated with adverse outcomes, enabling early identification of high-risk individuals.

A Rare Modality of Concurrent Cryptococcal and Tubercular Meningitis in a Patient Living With HIV.

Patients with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) and a low CD4 count have decreased humoral and cellular immunity, predisposing them to opportunistic infections. Opportunistic infections are one of the main causes of morbidity and mortality in immunocompromised individuals due to impaired immune systems, particularly in persons living with HIV/AIDS. Common opportunistic infections in patients living with HIV include bacterial infections such as Mycobacterium tuberculosis and Mycobacterium avium complex (MAC); viral infections such as cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1); fungal infections such as Pneumocystis carinii pneumonia (PCP) and cryptococcal meningitis; and parasitic infections such as cryptosporidiosis and toxoplasmosis. Concurrent infection with cryptococcal and tubercular meningitis in patients with HIV is very rare. Here, we present the case of a 48-year-old male living with HIV who presented with complaints of breathlessness, fever, and weight loss and was evaluated and put on antitubercular medications for pulmonary tuberculosis. However, the presence of a continuous headache led us to investigate further. Upon brain imaging and cerebrospinal fluid evaluation, it was determined to be meningitis due to co-infection with Mycobacterium tuberculosis and Cryptococcus neoformans. The patient was treated with antitubercular therapy along with antifungal therapy. He is under regular follow-up without any further events.

The emerging links between immunosenescence in innate immune system and neurocryptococcosis.

Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.

Evolution of Laboratory Diagnostics for Cryptococcosis and Missing Links to Optimize Diagnosis and Outcomes in Resource-Constrained Settings.

Cryptococcal meningitis is one of the leading causes of death in sub-Saharan Africa among patients with advanced HIV disease. Early diagnosis is crucial in improving treatment outcomes. Despite advances and the availability of modern and point-of-care diagnostics for cryptococcosis, gaps still exist in resource-constrained settings, leading to unfavorable treatment outcomes. Here, we review the current outstanding issues or missing links that need to be filled to optimize the diagnosis of cryptococcosis in resource-constrained settings to improve treatment outcomes. We highlight the evolution of cryptococcosis diagnostics; the roles of early fungicidal activity, cryptococcal antigen titers, antifungal susceptibility testing, and therapeutic drug monitoring; and the missing links to optimize diagnosis and outcomes, including practical recommendations.

Deciphering prognostic indicators in non-HIV cryptococcal meningitis: Constructing and validating a predictive Nomogram model.

Cryptococcal meningitis (CM) is a well-recognized fungal infection, with substantial mortality in individuals infected with the human immunodeficiency virus (HIV). However, the incidence, risk factors, and outcomes in non-HIV adults remain poorly understood. This study aims to investigate the characteristics and prognostic indicators of CM in non-HIV adult patients, integrating a novel predictive model to guide clinical decision-making. A retrospective cohort of 64 non-HIV adult CM patients, including 51 patients from previous studies and 13 from the First Hospital of Shanxi Medical University, was analyzed. We assessed demographic features, underlying diseases, intracranial pressure, cerebrospinal fluid characteristics, and brain imaging. Using the least absolute shrinkage and selection operator (LASSO) method, and multivariate logistic regression, we identified significant variables and constructed a Nomogram prediction model. The model's calibration, discrimination, and clinical value were evaluated using the Bootstrap method, calibration curve, C index, goodness-of-fit test, receiver operating characteristic (ROC) analysis, and decision curve analysis. Age, brain imaging showing parenchymal involvement, meningeal and ventricular involvement, and previous use of immunosuppressive agents were identified as significant variables. The Nomogram prediction model displayed satisfactory performance with an akaike information criterion (AIC) value of 72.326, C index of 0.723 (0.592-0.854), and area under the curve (AUC) of 0.723, goodness-of-fit test P = 0.995. This study summarizes the clinical and imaging features of adult non-HIV CM and introduces a tailored Nomogram prediction model to aid in patient management. The identification of predictive factors and the development of the nomogram enhance our understanding and capacity to treat this patient population. The insights derived have potential clinical implications, contributing to personalized care and improved patient outcomes.

Cryptococcal meningitis (CM) is a serious fungal infection that can affect the brain and spinal cord. It is well known to occur in people with HIV, but it can also affect those without HIV, although this is less common. This study focuses on understanding how CM affects non-HIV patients, which is not as well understood as its effects on HIV patients. We analyzed data from 64 non-HIV patients with CM to identify factors that might influence their recovery or lead to poor outcomes, such as severe disability or death. Using advanced statistical methods, we developed a predictive tool called a nomogram. This tool helps doctors estimate the likelihood of a poor outcome in non-HIV Cryptococcal meningitis (CM) patients based on specific factors like age, brain imaging results, and the use of certain medications. Our findings suggest that older patients and those with specific brain imaging abnormalities may be at higher risk. On the other hand, patients who have previously used immunosuppressive drugs might have a better prognosis, which is a surprising and new insight. This research is important because it provides new knowledge that could help doctors better manage CM in non-HIV patients, leading to more personalized and effective treatments. The predictive tool we developed could be used in hospitals to improve decision-making and patient care, ultimately improving outcomes for those suffering from this serious condition.

MRI changes in cryptococcal meningoencephalitis exacerbated by antifungal treatment due to post-infectious inflammatory syndrome: A case report.

Cryptococcal meningitis is one of the most common fungal meningitis in adults and causes disabling morbidity and mortality worldwide. The occurrence of postinfectious inflammatory response syndrome during cryptococcal meningitis treatment presents a diagnostic challenge. This time course seems paradoxical because patients show worsening symptoms and imaging findings. However, laboratory data improve with antifungal treatments. Herein, we present a case of an older woman diagnosed with cryptococcal meningitis who later developed postinfectious inflammatory response syndrome. Despite the initial antifungal treatment and improvements in cerebrospinal fluid analysis results, the patient's neurological condition deteriorated; imaging findings worsened. Magnetic resonance imaging at the time of postinfectious inflammatory response syndrome showed more prominent meningeal enhancement and brain edema, consistent with postinfectious inflammatory response syndrome, combined with negative repeat cerebrospinal fluid cultures for cryptococcal species. This case highlights the importance of considering postinfectious inflammatory response syndrome when patients with cryptococcal meningitis show clinical worsening during treatment. Prompt corticosteroid therapy significantly improves patient outcomes. Radiologists and clinicians should be aware of postinfectious inflammatory response syndrome to provide appropriate therapeutic options and improve prognosis in patients with cryptococcal meningitis.

Integration of genomic and pharmacokinetic data to predict clinical outcomes in HIV-associated cryptococcal meningitis.

Cryptococcal meningitis causes an estimated 112,000 global deaths per annum. Genomic and phenotypic features of the infecting strain of Cryptococcus spp. have been associated with outcomes from cryptococcal meningitis. Additionally, population-level pharmacokinetic variability is well documented in these patient cohorts. The relative contribution of these factors to clinical outcomes is unknown. Based in Malawi, we conducted a sub-study of the phase 3 Ambition-CM trial (ISRCTN72509687), collecting plasma and cerebrospinal fluid at serial time points during the first 14 days of antifungal therapy. We explored the relative contribution of pathogen genotype, drug resistance phenotype, and pharmacokinetics on clinical outcomes including lumbar opening pressure, pharmacodynamic effect, and mortality. We report remarkable genomic homogeneity among infecting strains of Cryptococcus spp., within and between patients. There was no evidence of acquisition of antifungal resistance in our isolates. Genotypic features of the infecting strain were not consistently associated with adverse or favorable clinical outcomes. However, baseline fungal burden and early fungicidal activity (EFA) were associated with mortality. The strongest predictor of EFA was the level of exposure to amphotericin B. Our analysis suggests the most effective means of improving clinical outcomes from HIV-associated cryptococcal meningitis is to optimize exposure to potent antifungal therapy. IMPORTANCE: HIV-associated cryptococcal meningitis is associated with a high burden of mortality. Research into the different strain types causing this disease has yielded inconsistent findings in terms of which strains are associated with worse clinical outcomes. Our study suggests that the exposure of patients to potent anti-cryptococcal drugs has a more significant impact on clinical outcomes than the strain type of the infecting organism. Future research should focus on optimizing drug exposure, particularly in the context of novel anticryptococcal drugs coming into clinical use.

Lactate dehydrogenase-1 may play a key role in the brain energy disturbance caused by cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) may affect the conversion of lactate to pyruvate in the brain, resulting in abnormal levels of adenosine triphosphate (ATP) throughout the brain. Lactate conversion to pyruvate is mainly caused by lactic dehydrogenase 1 (LDH1), which is composed of four LDHB subunits. However, the underlying mechanism of LDH1 in CM remains unclear. METHODS: Cerebrospinal fluid (CSF) from 17 patients was collected, including eight patients with non-infectious diseases of the central nervous system and nine patients with CM. Based on clinical data and laboratory reports, data regarding intracranial pressure, CSF white cell counts, lactate dehydrogenase (LDH), adenosine deaminase, glucose, protein, and chloridion were collected. Meanwhile, LDH1, LDH5, lactate, pyruvate, and ATP levels were detected in CSF. Whereafter, the levels of lactate, pyruvate, ATP, and the amplitude and frequency of action potentials in the neurons with low expression of LDHB were explored. RESULTS: Intracranial pressure and white cell count in CSF were significantly increased in patients with CM. In patients with CM, the LDH1, pyruvate, and ATP levels in the CSF were significantly decreased, and the levels of lactate were found to be increased. Furthermore, pyruvate and ATP levels were decreased, while lactate was increased in the neurons with low expression of LDHB. The amplitude and frequency of APs in the neurons with low expression of LDHB were significantly decreased. CONCLUSION: Reduced levels of LDH1 in the brain of patients with CM may lead to increased lactate levels, decreased pyruvate and ATP levels, and negatively affect neuronal activity.

Efficacy of Liposomal Nystatin in a Rabbit Model of Cryptococcal Meningitis.

Cryptococcal meningitis (CM) causes significant global morbidity and mortality. Current therapeutic strategies rely on deoxycholated or liposomal forms of the polyene amphotericin B. Nystatin is also a polyene with broad-spectrum antimicrobial activity. Treatment with systemic nystatin has been limited by toxicity, which is a consistent challenge with polyene therapeutics. One mechanism to improve the toxicity is usage of a liposomal form of the active agent. Previous data from a murine candidemia model indicated that liposomal nystatin may be an effective antifungal drug formulation. Since the rabbit model of CM is a highly predictive preclinical system for evaluating antifungal therapeutics, we tested the effectiveness of two doses of daily liposomal nystatin, 3 and 8 mg/kg in the rabbit model of CM. Treatment with liposomal nystatin in this model did not reduce the fungal burden in the cerebrospinal fluid. A subsequent clinical trial also did not find activity in a human population. These data indicate that liposomal nystatin in the current form and at the tested dosages is not an effective therapy for CM. The data provide further evidence for the predictive power of the rabbit model of CM as a vital preclinical system for testing novel antifungal therapeutics for CM.

Trends in Clinico-Epidemiological Profile and Outcomes of Patients with HIV-Associated Cryptococcal Meningitis in Shanghai, China, 2013-2023.

The study aimed to analyze changes in the clinical and epidemiological aspects of HIV-associated cryptococcal meningitis (CM) patients and to identify factors influencing their prognosis. Clinical data of patients with HIV-associated CM treated in Shanghai, China between 2013 and 2023 were collected. This study included 279 cases, 2.89% of AIDS patients, showing a yearly decrease in CM prevalence among AIDS patients (p < 0.001). Overall mortality was 10.39% with rates declining from a 2013 peak of 15.38% to 0% in 2023 despite no significant temporal pattern (p = 0.265). Diagnosis took an average of 18 ± 1 days post-symptoms, and admission CD4 counts averaged 29.2 ± 2.5 cells/µL, hinting at a non-significant decline. Frequent symptoms included fever (62.4%), headache (61.6%), fatigue (44.1%), and appetite loss (39.8%), with younger patients more likely to initially show signs of meningeal irritation. Logistic regression analysis underscored the prognostic importance of cerebrospinal fluid (CSF) white blood cell (WBC) count and procalcitonin levels. Over the decade spanning from 2013 to 2023, the incidence and mortality rates of CM among AIDS patients exhibited a downward trend. The average duration from the onset of CM to confirmation of diagnosis remained prolonged. CSF WBC count and procalcitonin levels were associated with unfavorable outcomes.

Implementation of single high-dose liposomal amphotericin B based induction therapy for treatment of HIV-associated cryptococcal meningitis in Uganda: a comparative prospective cohort study.

BACKGROUND: In 2022, the World Health Organization (WHO) recommended a single 10mg/kg dose of liposomal amphotericin B in combination with 14 days of flucytosine and fluconazole (AMBITION-cm regimen) for induction therapy of HIV-associated cryptococcal meningitis, based on the results of the multisite AMBITION-cm trial. We evaluated outcomes after real-world implementation of this novel regimen in Uganda. METHODS: We enrolled Ugandan adults with cryptococcal meningitis into an observational cohort receiving the AMBITION-cm regimen with therapeutic lumbar punctures in routine care during 2022-2023. We compared 10-week survival and CSF early fungicidal activity with the outcomes observed in the AMBITION-cm clinical trial conducted at the same sites. RESULTS: During 2022-2023, 179 adults were treated with the AMBITION-cm regimen via routine care and compared to the 171 adults randomized to the AMBITION-cm trial interventional arm in Uganda from 2018-2021. No significant difference in 10-week survival occurred between the observational cohort (68.6%; 95%CI 61.6%-76.3%) and AMBITION-cm trial participants in the intervention arm (71.7%; 95%CI 65.2%-78.8%; absolute risk difference = -3.1%; 95%CI -13.1% to 6.9%; p=.61). Early fungicidal activity did not differ (0.42 vs 0.39 log10CFU/mL/day; p=.80) between groups. Among observational cohort participants discharged alive initially and for whom follow up data were available, the incidence of re-hospitalizations due to persistently elevated intracranial pressure was 2.8% (4/144). CONCLUSION: The AMBITION-cm regimen for cryptococcal meningitis resulted in similar outcomes as observed in the AMBITION-cm clinical trial when implemented in routine care. Intracranial pressure management during hospitalization and awareness after discharge are key components of optimizing outcomes.

Baseline C-reactive Protein as a Risk Factor for Cryptococcal Meningitis and Death in HIV-associated Cryptococcal Antigenemia With CrAg Titer as an Effect Modifier.

Background: Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concentrations are positively associated with increased mortality. We hypothesized that CRP might also be associated with meningitis or death in persons with cryptococcal antigenemia. Methods: We measured plasma CrAg titers and CRP concentrations on cryopreserved serum from prospectively enrolled persons with HIV and cryptococcal antigenemia. Using time-to-event analyses, we compared 24-week meningitis-free survival in persons with normal CRP (<8 mg/L) and elevated CRP (≥8 mg/L). Logistic regression was used to assess how CRP concentration and CrAg titer might interact as covariates. Results: Of the 94 persons with elevated CRP, 19 (20.2%) developed meningitis or death, whereas of the 88 persons with normal CRP, 8 (9.1%) developed meningitis or death (P = .035). Persons with CrAg titer <1:160 and normal CRP had an ∼5% (3/61) event rate, whereas those with CrAg titer <1:160 but elevated CRP had an ∼20% (12/59) event rate. Importantly, we identified a statistically significant interaction effect between CrAg titer and CRP groups, in which elevated CRP increased risk in the low CrAg titer group (odds ratio, 1.54; 95% confidence interval, 1.16-2.04), but this effect was not present in high CrAg titer group (odds ratio, 0.78; 95% confidence interval, .53-1.15). Conclusions: Our findings demonstrate that CrAg titer may modify the direction of effect of CRP with meningitis-free survival; future studies should account for this interaction.

Choroid Plexitis and Obstructive Hydrocephalus Secondary to Cryptococcal Meningoencephalitis in an Immunocompetent Individual With Remarkable Imaging Findings: A Case Report.

Cryptococcus is an invasive and opportunistic fungus usually associated with immunocompromised individuals. Invasion of the choroid plexus by Cryptococcus is rare. This report presents the radiologic findings of a previously healthy male with bilateral choroid plexus invasion complicated by obstructive hydrocephalus.

CSF Cytokines and Chemokines Involved in Cytotoxic Cell Function and Risk of Acute 14-Day Mortality in Persons with Advanced HIV and Cryptococcal Meningitis.

BACKGROUND: Despite availability of HIV treatment globally, cryptococcal meningitis continues to cause considerable morbidity and mortality. The role of the immune response in acute mortality remains unclear. METHODS: To investigate the immune environment in the central nervous system, cerebrospinal fluid (CSF) from 337 Ugandans with advanced HIV and first-episode cryptococcal meningitis was collected at time of hospitalization. Participants were treated with standard of care amphotericin-B and fluconazole. Cytokines and chemokines in the CSF were quantified and compared by 14-day survival, stratification by quartiles, and logistical regression to determine association with acute mortality. RESULTS: 84 (24.9%) of the participants died by day 14 of hospitalization. Persons who survived to day 14 had higher levels of proinflammatory macrophage inflammatory protein (MIP)-3ß and interferon (IFN)-ß and cytotoxicity-associated Granzyme-B and inflammatory protein (IP)-10 compared to those who died (P<.05 for each). Logistical regression analysis revealed that per two-fold increase in proinflammatory IL-6, IL-1α, MIP-1ß, MIP-3ß, and IFN-ß and cytotoxicity-associated IL-12, TNF-α, Granzyme-B, and IP-10 CSF concentrations, the risk of acute 14-day mortality decreased. Similar biomarkers were implicated when stratified by quartiles and further identified that lower concentrations of anti-inflammatory IL-10 and IL-13 as associated with 14-day mortality (P<.05 for each). CONCLUSION: Proinflammatory and cytotoxicity-associated cytokine and chemokine responses in the CSF decrease the risk of acute 14-day mortality. These data suggest that a cytotoxic immune environment in the CSF could potentially improve acute survival. Further research on cytotoxic cells is crucial to improve understanding of innate and adaptive immune responses in cryptococcal meningitis.