The clinic-based predictive modeling for prognosis of patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) is the most common fungal infection of the central nervous system that can cause significant morbidity and mortality. Although several prognostic factors have been identified, their clinical efficacy and use in combination to predict outcomes in immunocompetent patients with CM are not clear. Therefore, we aimed to determine the utility of those prognostic factors alone or in combination in predicting outcomes of immunocompetent patients with CM. METHODS: The demographic and clinical data of patients with CM were collected and analyzed. The clinical outcome was graded by the Glasgow outcome scale (GOS) at discharge, and patients were divided into good (score of 5) and unfavorable (score of 1-4) outcome groups. Prognostic model was created and receiver-operating characteristic curve analyses were conducted. RESULTS: A total of 156 patients were included in our study. Patients with higher age at onset (p = 0.021), ventriculoperitoneal shunt placement (p = 0.010), Glasgow Coma Scale (GCS) score of less than 15(p< 0.001), lower CSF glucose concentration (p = 0.037) and immunocompromised condition (p = 0.002) tended to have worse outcomes. Logistic regression analysis was used to create a combined score which had a higher AUC (0.815) than those factors used alone for predicting outcome. CONCLUSIONS: Our study shows that a prediction model based on clinical characteristics had satisfactory accuracy in prognostic prediction. Early recognition of CM patients at risk of poor prognosis using this model would be helpful in providing timely management and therapy to improve outcomes and to identify individuals who warrant early follow-up and intervention.

Therapeutic lumbar puncture and lumbar drainage: which is more effective for the management of intracranial hypertension in HIV patients with cryptococcal meningitis? Results of a prospective non-randomized interventional study in China.

OBJECTIVE: This study aimed to evaluate the effectiveness of therapeutic lumbar drainage (LD) compared to therapeutic lumbar puncture (LP) for the management of intracranial hypertension (ICH) among HIV-positive patients with cryptococcal meningitis (CM). METHODS: The study was a multicenter prospective non-randomized interventional clinical trial. One hundred and sixteen HIV-associated CM patients were identified who presented with ICH (≥250 mmH2O). The LP group comprised 76 cases, while the LD group consisted of 40 cases. We compared mortality, intracranial pressure (ICP) normalization rate, and clinical symptom remission at 10 weeks, between the two groups. RESULTS: The cumulative mortality at week 10 was 22.4% in the LP group and 20% in the LD group (p = .927), without any significant difference in mortality between the two groups. Improvement after treatment at 2-weeks, ICP normalization, and headache reversal event occurrence in the two groups showed no significant difference (p > .05). The incidence of CSF Cryptococcus clearance at two weeks in the LD group was significantly higher than in the LP group (p < .05). The frequency of invasive lumbar therapeutic procedures in the LP group during the first week was higher than that of the LD group (p < .05). Localized infection at the puncture site occurred more frequently in the LD group than in the LP group (p < .05). CONCLUSION: For HIV-positive CM patients with an elevated ICP, LD and LP are comparably effective and safe options to normalize ICP. LP increases the frequency of invasive lumbar therapeutic procedures but does not incur more risk of infection events at the puncture site, while LD may accelerate CSF Cryptococcus clearance but may induce more frequent localized infection. TRIAL REGISTRATION: This study was registered as one of 12 trials under a general project at the Chinese Clinical Trial Registry (ChiCTR1900021195).

Immune Reconstitution Inflammatory Syndrome Complicating Cryptococcal Meningitis in a Pediatric Heart Transplant Patient.

Immune reconstitution inflammatory syndrome can be a complication of cryptococcal meningitis after immune reconstitution from antiretroviral therapy in HIV or reduced immune suppression in transplant recipients. In this case report, the authors discuss the diagnosis and management of cryptococcal-associated immune reconstitution inflammatory syndrome in a 10-year-old pediatric heart transplant recipient.

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

BACKGROUND: The 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. METHODS: A 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. RESULTS: In 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. CONCLUSION: This 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.

Cryptococcal meningitis: a review for emergency clinicians.

INTRODUCTION: Cryptococcal Meningitis (CM) remains a high-risk clinical condition, and many patients require emergency department (ED) management for complications and stabilization. OBJECTIVE: This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of CM. DISCUSSION: This review evaluates the diagnosis, management, and empiric treatment of suspected CM in the ED. CM can easily evade diagnosis with a subacute presentation, and should be considered in any patient with a headache, neurological deficit, or who is immunocompromised. As a definitive diagnosis of CM will not be made in the ED, management of a patient with suspected CM includes prompt diagnostic testing and initiation of empiric treatment. Multiple types of newer Cryptococcal antigen tests provide high sensitivity and specificity both in serum and cerebrospinal fluid (CSF). Patients should be treated empirically for bacterial, fungal, and viral meningitis, specifically with amphotericin B and flucytosine for presumed CM. Additionally, appropriate resuscitation and supportive care, including advanced airway management, management of increased intracranial pressure (ICP), antipyretics, intravenous fluids, and isolation, should be initiated. Antiretroviral therapy (ART) should not be initiated in the ED for those found or known to be HIV-positive for risk of immune reconstitution inflammatory syndrome (IRIS). CONCLUSIONS: CM remains a rare clinical presentation, but carries significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with an infectious disease specialist is imperative, as is initiating symptomatic care.

Tackling cryptococcal meningitis in Nigeria, one-step at a time; the impact of training.

BACKGROUND: Nigeria is estimated to have 25,000 cases of cryptococcal antigenemia (CrAg) annually. CrAg screening with pre-emptive fluconazole treatment is recommended but not yet implemented in Nigeria. Trainings were conducted to improve health-care provider (HCP) awareness and clinical skills in the management and prevention of cryptococcal meningitis (CM). METHODS: HCPs providing care for people living with HIV were targeted for training at 13 sites from April to November 2018 Course content was adapted from CDC Cryptococcal Screening Program Training Manual and LIFE-website. "Hands-on" training on CrAg testing and lumbar puncture was included. A 14-point pre and post-test assessment instrument was designed to capture the impact of the training and focus group discussions (FGDs) were conducted. RESULTS: A total of 761 HCPs were trained. 519 HCPs completed the pre-test evaluation while 470 (90.6%) took part in the post-test evaluation. Post-training, HCPs were significantly more likely to respond correctly to all 14 assessment items, with the mean percentage score rising to 91.0% from a pre-training value of 60.0%. FGDs revealed that many of the HCPs were not aware of the CrAg screening and pre-emptive treatment recommendations in Nigerian guidelines, and reported not having seen or managed a case of CM. Also, they highlighted challenges with routine CrAg screening due to a lack of access to CD4 testing, CrAg test kits, antifungal drugs, as well as the need for similar trainings across all tiers of care in Nigeria. CONCLUSION: Training significantly improved HCPs' understanding of Nigerian policy on CrAg screening, CM diagnosis and best management practices. This training could be included in routine capacity building efforts for HCPs involved in HIV care in Nigeria.

Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co-infection.

Cryptococcal meningitis remains one of the leading causes of death among HIV-infected adults in the fourth decade of HIV era in sub-Saharan Africa, contributing to 10%-20% of global HIV-related deaths. Despite widespread use and early induction of ART among HIV-infected adults, incidence of cryptococcosis remains significant in those with advanced HIV disease. Cryptococcus species that causes fatal infection follows systemic spread from initial environmental acquired infection in lungs to antigenaemia and fungaemia in circulation prior to establishment of often fatal disease, cryptococcal meningitis in the CNS. Cryptococcus person-to-person transmission is uncommon, and deaths related to blood infection without CNS involvement are rare. Keen to the persistent high mortality associated with HIV-cryptococcal meningitis, seizures are common among a third of the patients, altered mental status is frequent, anaemia is prevalent with ensuing brain hypoxia and at autopsy, brain fibrosis and infarction are evident. In addition, fungal burden is 3-to-4-fold higher in those with seizures. And high immune activation together with exacerbated inflammation and elevated PD-1/PD-L immune checkpoint expression is immunomodulated phenotypes elevated in CSF relative to blood. Lastly, though multiple Cryptococcus species cause disease in this setting, observations are mostly generalised to cryptococcal infection/meningitis or regional dominant species (C neoformans or gattii complex) that may limit our understanding of interspecies differences in infection, progression, treatment or recovery outcome. Together, these factors and underlying mechanisms are hypotheses generating for research to find targets to prevent infection or adequate therapy to prevent persistent high mortality with current optimal therapy.

A correlation analysis between clinical manifestations, therapeutic strategies, and the prognosis of children with cryptococcal meningitis in China.

OBJECTIVE: This aim of this study was to analyze the correlations between clinical manifestations, treatment strategies, and the prognosis in cryptococcal meningitis (CM) in China. METHODS: This was a retrospective analysis of the clinical data of CM patients treated during the years 2002-2019. The clinical features and supplementary examinations, treatment strategies, and prognosis were summarized and then a correlation analysis was performed. RESULTS: Fifty patients were enrolled. The most common symptoms were fever, headache, and vomiting. Five of these patients died and five had visual impairment sequelae; nine of these patients were treated before 2010. Correlation analysis suggested that cerebral hernia, consciousness disorder, visual impairment, hydrocephalus, and an intracranial pressure >300mmH2O in cerebrospinal fluid (CSF) were associated with a poor prognosis. Whether or not the application of intrathecal administration had little effect on prognosis. Early surgical intervention with internal drainage helped to reduce the mortality and incidence of visual impairment sequelae, whether or not Cryptococcus was present in the CSF before surgery. CONCLUSIONS: Clinically, the presence of a cerebral hernia, consciousness disorder, hydrocephalus, visual impairment, or intracranial pressure >300mmH2O often indicates a poor prognosis in patients with CM. The prognosis improved significantly after 2010, following an adjustment of the treatment strategy. Early internal drainage is the key factor, and CSF positive for Cryptococcus before surgery is not a contraindication.

Impaired consciousness and decreased glucose concentration of CSF as prognostic factors in immunocompetent patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) is the most common fungal infection of the central nervous system and has high morbidity and mortality. Almost studies about prognostic factors have largely focused on the immunocompromised population rather than immunocompetent patients. So that we sought to conduct a retrospective study to determine prognostic factors which predict the outcomes in immunocompetent patients with CM. METHODS: We retrospectively collected and analyzed the demographic and clinical data of 76 apparently immunocompetent patients with cryptococcal meningitis from January 2003 to June 2019 in China. The clinical outcome was graded by the Glasgow outcome scale (GOS) at discharge, and patients were divided into good (score of 5) and unfavorable (score of 1-4) outcome groups, potential prognostic factors were analyzed. RESULTS: Non-parametric test confirmed that unfavorable outcome was associated with lower glucose level of CSF(P = 0.001), and Pearson's χ2 analysis confirmed that unfavorable outcome was associated with opening pressure of CSF(>300mmH20, P = 0.038), impaired consciousness (P = 0.001), hydrocephalus(P = 0.045), and Shunt surgery (P = 0.045), and then multiple logistic regression analysis confirmed that impaired consciousness(P = 0.015) and lower glucose concentration of CSF(P = 0.012) increased the likelihood of unfavorable outcome in CM patients. CONCLUSION: Impaired consciousness and decreased glucose concentration of CSF were independently prognostic factors which predict the unsatisfactory outcome in immunocompetent patients with CM.

Clinical characteristic of 15 cases of cryptococcal meningitis treated with Ommaya reservoir.

Cryptococcal meningitis is a severe subacute fungal meningoencephalitis. Intracerebroventricular (ICV) injection of antifungal medication and aspiration of cerebrospinal fluid (CSF) through Ommaya reservoir were reported to be useful cryptococcal meningitis treatment method. We want to evaluate the role of Ommaya reservoir in the treatment of refractory cryptococcal meningitis. We retrospectively analyzed clinical records and data of 15 refractory cryptococcal meningitis patients who were treated with Ommaya reservoir in Sir Run Run Shaw hospital from June 2013 to June 2017. Fifteen patients who underwent Ommaya reservoir implanted surgery include eight women and seven men. Headache and fever were the common clinical symptoms. Underlying diseases mainly include diabetes mellitus and hypertension. Three patients occurred renal dysfunction and four patients experienced liver damage. Thirteen patients recovered completely, whereas two patients died. Implant Ommaya reservoir which can serial extract CSF and ICV injection of Amphotericin B is a valuable approach in the treatment of Cryptococcal meningitis, especially for patients with refractory intracranial hypertension.

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 symptom remission, 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.

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain.

Cryptococcus neoformans, the encapsulated yeast acquired through inhalation, remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long-term usage of drugs leads to organ damage. As T11-target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C neoformans infection was prepared by intraperitoneal injection and the brains of rats examined 7 days post-infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on Cryptococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C neoformans infected rats, upregulates toll-like receptors 2, -4 and -9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T-lymphocytes along with increased MHC I and MHC II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease.

A Comparison of the Clinical Characteristics and Outcomes of Cryptococcal Meningitis in HIV-negative Individuals With and Without Immunosuppression.

Cryptococcal meningitis (CM) is found to occur in immunosuppressed patients and those who are immunocompetent. This study aimed to compare the presentation and outcome of CM in patients who are human immunodeficiency virus (HIV) negative with and without immunosuppression. We reviewed 255 clinical records from patients with CM who are HIV negative. The demographic and clinical characteristics, cerebrospinal fluid profiles, brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. Among the 255 patients with CM, 91 (35.7%) appeared immunocompetent. CM was present in a younger population in the immunocompetent group (above 50 y, 19.8% vs. 32.3%, P=0.026), with higher initial complaints of visual and auditory symptoms (45.1% vs. 27.4%, P=0.004; 19.8% vs. 9.1%, P=0.016; respectively) and higher cerebrospinal fluid white blood cell counts (30.8% vs. 45.1%, P=0.009) compared with the immunocompromised patients. In addition, the immunocompetent patients had a higher proportion of normal brain images than did the immunocompromised patients (10% vs. 2%, P=0.028). There were no differences in hospital mortality and satisfactory outcomes between the groups (mortality: 10.9% vs. 7.0%, P=0.416; satisfactory outcomes: 76.4% vs. 80.2%, P=0.585). We found significant differences between the immunocompetent and HIV-negative immunocompromised patients; however, there were fewer differences between the groups than expected. Further studies assessing the immune responses in both groups should be performed.

Drug development for cryptococcosis treatment: what can patents tell us?

BACKGROUND Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance. OBJECTIVES The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field. METHODS We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence. FINDINGS Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts. CONCLUSION The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.

[Cryptococcal Meningitis in a Patient with Breast Cancer Receiving Everolimus: A Case of Successful Treatment with Continuous Cerebrospinal Fluid Drainage].

Cryptococcosis is a fungal infection that mainly occurs in immunocompromised patients. We present the first case of cryptococcal meningitis in a patient who was being administered everolimus for breast cancer. Everolimus, a selective inhibitor of mammalian target of rapamycin, is a molecular targeting agent that is administered not only as an immunosuppressive agent, but also as an anticancer therapeutic. A 72-year-old woman with recurrent breast cancer had been receiving everolimus. She was admitted to our hospital with headache and vomiting. Lumbar puncture revealed high opening pressure, and cerebrospinal fluid (CSF) evaluation diagnosed cryptococcal meningitis. She was administered liposomal amphotericin-B, followed by fosfluconazole. Daily lumbar puncture was insufficient to reduce the high intracranial pressure; thus, continuous lumbar drainage was needed to improve her symptoms. The indwelling catheter was replaced regularly to prevent bacterial infection. She was treated successfully with extracorporeal CSF drainage for 86 days and fosfluconazole administration over 17 weeks. The patient recovered fully and was discharged on day 153 of hospitalization. As patients who receive everolimus are potentially immunocompromised hosts, we recommend that the medicine be administered with caution considering opportunistic infections when used in patients with cancer. (Received April 19, 2018; Accepted August 9, 2018; Published November 1, 2018).

Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis.

BACKGROUND: Persistent and uncontrollable intracranial hypertension (ICH) and difficulty in reducing Cryptococcus count are severe problems in cryptococcal meningitis (CM) patients. The therapeutic effects of ventriculoperitoneal shunts (VPS) in non-HIV CM patients are not fully known, and the procedure is somewhat unusual. Here, our study offers a review to investigate the role of VPS in non-HIV CM. METHODS: We retrospectively collected data on 23 non-HIV CM patients with and without ventriculomegaly from 2010 to 2016. Their demographic data, clinical manifestations, cerebrospinal fluid (CSF) features and outcomes were analysed. RESULTS: We found that non-HIV CM patients without ventriculomegaly were older, had earlier treatment times and had shorter symptom durations than CM patients with ventriculomegaly. In both groups, headache, vomiting, fever and loss of vision were the most common clinical features. CSF pressure and Cryptococcus count were significantly decreased after operation. VPS could provide sustained relief from ICH symptoms such as headache. 13% of patients had poor outcomes because of serious underlying disease, while 87% of patients had good outcomes. CONCLUSIONS: The use of a VPS is helpful in decreasing ICH and fungal overload in non-HIV CM patients, and VPS should be performed before CM patients present with symptoms of severe neurological deficit.

Treatment of cryptococcosis in non-HIV immunocompromised patients.

PURPOSE OF REVIEW: Cryptococcosis has become a common opportunistic infection among non-HIV immunocompromised hosts. Recent reports have shown the incidence of Cryptococcosis among HIV-negative immunocompromised patients reaches close to half of the overall cases reported in the USA. Management of this infection in this population carries unique challenges. We aim to review relevant and recent research findings to develop treatment recommendations for this type of population. RECENT FINDINGS: Most of the recommendations for the management of non-HIV immunocompromised host are extrapolated from HIV studies. Cryptococcosis among non-HIV patients is common but often overlooked. Some clinical factors, when present, may increase the risk of Cryptococcosis among HIV-negative patients and appropriate screening and assessment for the disease is necessary. Treating clinicians should consider a longer duration of induction with Amphotericin B depending on the type of host, immunocompromised state, antifungal response and presence of neurological complications. Baseline fluconazole resistance can reach up to 12%, which is an important consideration for cryptococcal meningitis relapses or suboptimal responses to therapy. SUMMARY: Cryptococcus spp. conveys a high disease burden among immunocompromised hosts. Clinicians must consider numerous variables and factors in a dynamic way to offer the best possible treatment and to monitor their response to therapy. Due to the high cost and associated toxicities, we still need new affordable therapies and studies among non-HIV immunocompromised patients.

Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy.

Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.