non-HIV Cryptococcal Meningitis Research Articles

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.

Nomogram to Predict the Outcome of Ventriculoperitoneal Shunt Among Patients with Non-HIV Cryptococcal Meningitis

BackgroundThe ventriculoperitoneal (VP) shunt is widely acknowledged as a treatment option for managing intracranial hypertension resulting from non-HIV cryptococcal meningitis (CM). Nonetheless, there is currently no consensus on the appropriate surgical indications for this procedure. Therefore, it is crucial to conduct a preoperative evaluation of patient characteristics and predict the outcome of the VP shunt to guide clinical treatment effectively. MethodsA retrospective analysis was conducted on data from 85 non-HIV CM patients who underwent VP shunt surgery at our hospital. The analysis involved studying demographic data, preoperative clinical manifestations, cerebrospinal fluid (CSF) characteristics, and surgical outcomes and comparisons between before and after surgery. A nomogram was developed and evaluated. ResultsThe therapy outcomes of 71 patients improved, whereas 14 cases had worse outcomes. Age, preoperative cryptococcus count, and preoperative CSF protein levels were found to influence the surgical outcome. The nomogram exhibited exceptional predictive performance (AUC = 0.896, 95% CI: 0.8292–0.9635). Internal validation confirmed the nomogram's excellent predictive capabilities. Moreover, decision curve analysis demonstrated the nomogram's practical clinical utility. ConclusionThe surgical outcome of VP shunt procedures in non-HIV CM patients was associated with age, preoperative cryptococcal count, and preoperative CSF protein levels. We developed a nomogram that can be used to predict surgical outcomes in non-HIV CM patients.

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

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

Clinical characteristics, treatment, and outcome of low-risk non-HIV-associated cryptococcal meningitis: A retrospective cohort study.

Although non-human immunodeficiency virus (HIV)-associated cryptococcal meningitis (CM) is a severe disease, there are still some non-HIV CM patients with a low risk of therapeutic failure. Recognizing clinical characteristics of low-risk non-HIV-associated CM may enable clinicians to treat non-HIV-associated CM more reasonably. According to the definition of low-risk non-HIV-associated CM in the 2010 Infectious Diseases Society of America guideline, a total of 220 non-HIV CM patients were divided into two groups (Group 1: 35 low-risk patients and Group 2: 185 non-low-risk patients). Clinical characteristics, treatment, and outcome were compared between the two groups. Compared with non-low-risk patients, low-risk patients had a lower rate of headache (82.9% vs. 95.7%, P=.012), cerebrospinal fluid (CSF) opening pressure (OP) at baseline (CSF OP<250-mm H2O, 60.0% vs. 32.4%, P=.001), and baseline CSF cryptococcal count (median, 0 vs. 2376, P<.001), higher baseline CSF white blood cell (median, 130 vs. 90, P=.029) and CSF protein (median, 0.87 vs. 0.73, P=.011). Multivariate analysis showed that baseline CSF OP<250-mm H2O (OR: 2.545, 95% CI 1.168, 5.545, P=.019) was independently associated with low-risk for non-HIV-associated CM. The lengths of AMB-d-based induction therapy of low-risk patients (median, 20 days) were shorter (P<.001) than that of non-low-risk patients (median, 38 days). The successful outcome rate of low-risk patients was higher than non-low-risk patients (97.1% vs. 54.6%, P<.001). We demonstrated that non-HIV-associated CM patients with baseline CSF OP< 250-mm H2O were prone to the low-risk status.

Neuroimaging of Cryptococcal Meningitis in Patients without Human Immunodeficiency Virus: Data from a Multi-Center Cohort Study

A clearer understanding is needed about the use of brain MRI in non-HIV patients with cryptococcal meningitis. Cerebral CT and MRI were studied in 62 patients in a multicenter study of cryptococcal meningitis in non-HIV patients. CT was performed in 51 and MRI in 44. MRI results are reported for the images read at NIH for 29 of the 44 patients. CT reports obtained from the original REDCap database were added to calculate the incidence of normal findings. CTs were read as normal in 24 of 51 (47%), MRIs were normal in 10% (three of 29). The most characteristic lesions of cryptococcal meningitis on MRI were small basal ganglia lesions representing dilated perivascular spaces in 24% and basal ganglia lesions with restricted diffusion (infarcts) in 38%. In the 18 patients who received contrast, contrast-enhancing lesions, likely representing masses of cryptococci and inflammatory cells, were found in the basal ganglia in 22% and elsewhere in the brain in 22%. Meningeal enhancement was seen in 56%, ependymal enhancement in 24%, and choroid plexus enhancement in 11%. Hydrocephalus was found in five (18%), though increased intacranial pressure was not detected. Suboptimal imaging (n = 6), lack of contrast administration (n = 11) and lack of follow-up, however, markedly limited the accurate assessment of abnormalities in multiple cases. MRI characteristics of non-HIV cryptococcal meningitis include hydrocephalus, meningeal and ependymal enhancement and basal ganglia lesions. Optimal imaging is, however, necessary to maximize the diagnostic and prognostic usefulness of MRI.

1032. Janus Kinase Inhibition for Refractory Post-infectious Inflammatory Response in Previously Healthy Patients with Cryptococcal Meningoencephalitis

Abstract Background Post-infectious inflammatory response syndrome(PIIRS) is a previously reported complication of non-HIV cryptococcal meningitis (CM) involving a pathological T cell-mediated neuroinflammatory response once the fungus has been cleared. Although corticosteroids have been successfully used as therapy, side effects preclude prolonged use. Additionally, alternative targeted agents may be required as adjunctive therapy in steroid-refractory PIIRS. We report the clinical course in 3 patients in whom Janus kinase (JAK) inhibitor use led to favorable outcomes when used along with corticosteroids. Methods Medical records of three previously healthy CM-PIIRS patients admitted to the NIH between January 2021 to December 2021 were used to prepare this report. All were transferred from another facility due to worsening neurological status. Neurological exam and radiological findings were compared at baseline and one month after ruxolitinib initiation. CSF parameters including cellular markers of T-cell inflammation (HLA-DR+ CD4+ and HLA-DR+ CD8 cells and monocytes) and soluble CSF cytokines, including IL-6 and sCD25, were also included in the comparison. Results One patient was on 1mg/kg oral prednisone for 8 months with no improvement in symptoms despite VP shunt placement. The other two had also been on moderate-dose oral steroids for approximately 6 weeks for a recent diagnosis of PIIRS. All three were started on ruxolitinib (5-10 mg PO BID) as an adjunct to prednisone with a significant improvement in their neurological status, CSF inflammatory markers, and radiological findings. CSF fungal cultures remained negative with no occurrence of adverse events 3 months after ruxolitinib initiation. Therapy with ruxolitinib allowed continued corticosteroid taper without clinical flairs of disease in each patient. Conclusion The selective JAK1/2 inhibitor, ruxolitinib, was safe in a small group of HIV-negative patients with CM. This agent may offer promise in conjunction with corticosteroids in the treatment of non-HIV CM patients with refractory PIIRS who are at risk for adverse side effects related to prolonged steroid use. Further study will be required to determine efficacy, tolerability and ability to reduce corticosteroid use. Disclosures All Authors: No reported disclosures.

Ocular Findings of Cryptococcal Meningitis in Previously Healthy Adults.

Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce. A retrospective chart review was performed for previously healthy patients with CM who underwent a complete ophthalmological examination within a 5-year period at the National Institutes of Health. Demographics, CSF parameters, findings on initial ophthalmological examination, and MRI abnormalities were analyzed. Forty-four patients within a median of 12 weeks after CM diagnosis were included in our study; 27 patients (61%) reported abnormal vision on presentation. Seventy-one percent of patients were not shunted at the time of their initial eye examination. The most common ocular abnormalities were visual field defects in 21 (66%), decreased visual acuity in 14 (38%), and papilledema in 8 (26%) patients. Intraocular pressure was within normal range in all patients. Cranial nerve defects were identified in 5 patients and optic neuropathy in 2 patients. Patients who had hydrocephalus or did not receive a ventriculoperitoneal shunt were not noted to have worse ocular abnormalities. The most common ocular findings in our cohort of nontransplant, non-HIV cryptococcal meningitis patients were visual field defects, decreased visual acuity, and papilledema. Our results emphasize the need for a comprehensive eye examination in patients with CM who may not always report a change in vision on presentation.

Tocilizumab as steroid-sparing agent for post-infectious inflammatory response syndrome in two non-HIV cryptococcal meningitis patients

Non-HIV Cryptococcal Meningitis (CM) is often complicated by a post-infectious inflammatory response syndrome (PIIRS), characterized by neurologic deterioration in previously-healthy patients with CM after appropriate antifungal therapy and conversion of CSF fungal cultures to negative. PIIRS is due to an appropriate inflammatory response to fungal antigen released during therapy, mediated by IFN-gamma and IL-6 stimulating T-helper cells, leading to immune-mediated host damage. At the National Institutes of Health (NIH), patients with non-HIV CM-related PIIRS have been successfully treated with methylprednisolone burst and slow prednisone taper.

The Change in the Neutrophil/Lymphocyte Ratio Predicts the Prognosis of Patients with Cryptococcal Meningitis.

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied in many diseases. However, their roles in cryptococcal meningitis (CM) are unclear. The purpose of this article was to analyse the roles of the PLR and NLR in CM patients during treatment. 139 newly diagnosed CM patients were enrolled. We divided patients into two groups: the successful group (n = 121) and the failure group (n = 18) based on the prognosis of patients. Then, we analyzed changes in clinical data of two groups, which were measured at the time of admission, after 2weeks and 4weeks in the hospital. Then the patients were divided into HIV group (n = 26) and non-HIV group (n = 113) to determine whether HIV status had an impact on the prognosis and clinical data of patients. Most patients were male living in rural areas; headache was the most common symptom before admission. In the subgroup analysis based on HIV status, there were significantly fewer patients with HIV (26 individuals) than without HIV (113 individuals), and 40.7% non-HIV CM patients had no underlying diseases. There was no significant difference in prognosis (p = 0.746), lymphocytes (p = 0.109) or neutrophils (p = 0.269) between patients with and without HIV. A mixed-effect model indicated that there was no difference (p = 0.171) in PLR between successful group and failure group. However, the change of NLR was statistically significant (p = 0.004 < 0.05) between successful group and failure group. An increase in the NLR during treatment may be used as an indicator of treatment failure.

Immune reconstitution inflammatory syndrome in non-HIV cryptococcal meningitis: Cross-talk between pathogen and host.

BackgroundCryptococcal meningitis (CM)‐associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non‐HIV populations.ObjectivesWe aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non‐HIV CM IRIS populations.MethodsIn this observational cohort study, 101 previously untreated non‐HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared.ResultsImmune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non‐HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non‐HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP‐1) became the only cytokine correlated with both IRIS and LTA4H SNPs.ConclusionsOur study suggested that non‐HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP‐1.

Triple therapy combined with ventriculoperitoneal shunts can improve neurological function and shorten hospitalization time in non-HIV cryptococcal meningitis patients with increased intracranial pressure

BackgroundRaised intracranial pressure (ICP) and insufficient antifungal regimens are the two main factors result to unsatisfactory outcomes in non-HIV cryptococcal meningitis (CM) patients. In this study, we try to discuss that whether triple therapy of amphotericin B (AmB), fluconazole, 5-flucytosine (5-FC) plus ventriculoperitoneal shunts (VPS) is superior to AmB, 5-FC, fluconazole plus intermittent lumbar puncture in induction therapy in non-HIV CM patients with increased ICP.MethodsWe reviewed 66 clinical records from non-HIV CM patients with increased ICP. The demographic and clinical characteristics, BMRC staging, cerebrospinal fluid profiles (CSF), brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. All non-HIV CM patients with increased ICP (≥ 25 cmH2O) were divided into two groups, including 27 patients treated with triple antifungal agents and 39 patients treated with the same triple therapy plus VPS.ResultsTriple therapy plus VPS group had more satisfactory outcomes, more CSF sterilization at 10 weeks follow-up, lower CSF opening pressure, lower BMRC staging scores one week after VPS, less CSF C. neoformans counts and CSF culture positive. Besides, these patients had shorter hospital stay than triple therapy group.ConclusionsTriple antifungal agents combined with VPS could effectively reduce ICP, had faster rate of clearance of C. neoformans counts, more improved neurological function, shorten hospitalization time and better outcomes in non-HIV CM patients with increased ICP. Our study indicated that triple therapy plus early VPS may be an optimal treatment for non-HIV CM patients with increased ICP.

1717. Cryptococcal Meningitis: A Comparison of Clinical Features and Outcomes by HIV Status

BackgroundCryptococcal meningitis is an opportunistic fungal infection associated with HIV and other forms of immunosuppression. We lack a clear understanding of cryptococcal meningitis (CM) among HIV-negative patients in the United States. Our aim was to compare clinical features and outcomes across HIV status in patients with laboratory-confirmed cryptococcal meningitis.MethodsWe conducted a retrospective cohort study of patients with laboratory-confirmed (positive culture or antigen test) cryptococcal disease treated at a tertiary care center from January 2000 to September 2018. Patients were identified via local laboratory and TrinetX datasets. Data were gathered on demographics, HIV status, site of infection, clinical presentation, cerebrospinal fluid (CSF) profiles, hospital course, and mortality. Organ transplant recipients and/or non-meningeal infections were excluded.ResultsSeventy patients with cryptococcal disease were identified. Our final sample included 36 CM patients with a mean age of 48.8 ± 13.2 years; 66.7% (n = 24) had HIV. Median (IQR) absolute CD4 count for the HIV group was 35/μL (10–80/μL). Non-HIV patients were significantly older (P < 0.001) and had higher rates of altered mental status (AMS) on presentation (58.3% vs. 25%, P = 0.05). There was no significant variation in temperature, blood pressure, white blood cell count, serum sodium, or CSF opening pressure. Non-HIV patients had significantly higher CSF cell count (P = 0.02) and protein (P < 0.001), and lower glucose (P = 0.005) compared with HIV patients. There was no significant variation in length of stay or rates of intensive care unit admission. Overall, 90-day all-cause mortality was 19.4%: mortality rates were significantly higher in non-HIV patients at both 90 days (P = 0.017) and one year (P = 0.047).ConclusionCompared with individuals with HIV, non-HIV cryptococcal meningitis patients have a more inflammatory CSF profile at the time of diagnosis, higher rates of AMS on presentation, and higher rates of 90-day and 1-year all-cause mortality. We postulate that reversible immunosuppression among HIV patients may partially explain these findings. Further research is needed to identify hallmarks of cryptococcal meningitis in non-HIV patients to facilitate early intervention. Disclosures All authors: No reported disclosures.

Clinical Aspects of Immune Damage in Cryptococcosis.

To perform an extensive review of recent literature and provide an update on the current epidemiology, clinical features and management of cryptococcal disease with a focus on the differences between patients depending on their immune status. Emerging literature has highlighted the inflammatory pathophysiology and varied manifestations of cryptococcal infections in patients who are apparently healthy but paradoxically have a more critical clinical course compared to their immunosuppressed counterparts. Non-HIV cryptococcal meningitis has greater mortality compared to that seen in HIV patients. Basic science experiments closely analyzing the underlying pathophysiological response to this infection have demonstrated the predominant role of T cell-mediated inflammatory injury in causing worse clinical outcomes. Further studies are needed to define the need for immunosuppressive agents in the treatment of this illness.

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.

Genetic Influence of Toll-Like Receptors on Non-HIV Cryptococcal Meningitis: An Observational Cohort Study

Background Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to compare single nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) in non-HIV CM patients with those of healthy controls, and to assess the links among TLR SNPs, cytokine concentrations in cerebrospinal fluid (CSF), and clinical severity. Methods This observational cohort study was done in 2 stages: a discovery stage and a validation stage. We conducted a case-control genetic association study between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility were further validated in a second cohort of 583 subjects from a certain district. Cytokine concentrations in CSF were used to evaluate the in situ immune response of CNS after infection. Correlations among TLR SNPs, CSF cytokine concentrations, and clinical severity were validated in a third prospective cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity. Findings In the discovery stage, the genotype distributions of 8 TLR SNPs in non-HIV CM patients exhibited a significant difference in comparison with controls, of which 3 SNPs remained statistically significant in patients without predisposing factors. In the validation stage, 5 of the 8 nominated TLR SNPs were found to influence CSF cytokine expression. Eighteen cytokines were significantly up-regulated in severely ill patients, among which 12 were affected by TLR2 rs3804099. The rs3804099 was also found in relation to disease severity. High IL-10 levels in CSF (OR 2*97, 95% CI 1*49-5*90; p=0*002) was suggested as an independent predictor for severity after adjusted for possible confounders. Interpretation TLR participate in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. Our findings inform of an opportunity for early evaluation and treatment of non-HIV CM. TLR might also become a potential target on which to base host-directed immunotherapy. Funding: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program). Declaration of Interest: We declare no competing interests. Ethical Approval: Ethical approval was obtained from the medical ethics committee of Huashan Hospital, Mengchao Hepatobiliary Hospital, Fujian HIV/AIDS Diagnosis and Treatment Center, and No. 476 Hospital of Fuzhou General Hospital.

Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis

BackgroundPersistent 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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.

Increased activity of the complement system in cerebrospinal fluid of the patients with Non-HIV Cryptococcal meningitis

BackgroundsCryptococcal meningitis (CM) has been known to lead to significant morbidity and mortality. The relative contribution of the complement system in protection and pathogenesis during CM remains largely unknown. The purpose of this study was to evaluate the baseline complement component profiles in human cerebrospinal fluid (CSF) and plasma from non-HIV patients with CM, and therefore to provide insights of possible roles of the complement system in CM.MethodsCSF and blood samples from forty two CM patients not infected with HIV and thirteen non-CM control patients (Ctrl) were retrospectively selected and evaluated from the patients admitted to the hospital with a suspected diagnosis of CM. CSF and blood samples were collected at the admission. Enzyme-linked immunosorbent assay (ELISA) for complement components, cytokine IL-12 and western blot for C3 activation were performed on CSF and plasma samples. The levels of complement C1q, factor B (FB), mannose binding lectin (MBL), C2, C3, C4, C5, C4 binding protein (C4BP), Factor I (FI), Factor H (FH), sC5b-9 in CSF and plasma samples were compared. Pearson’s correlation coefficients were calculated on variables between complement components and the levels of total protein in the CSF samples.ResultsOur data demonstrated that the CSF levels of complement components of C1q, FB, MBL as well as complement pathway factors sC5b-9 and complement regulator FH were all elevated in patients with CM as compared to the controls, CSF C3 breakdown products iC3b were found in both CSF and plasma samples of the CM patients. A positive correlation was found between the levels of CSF protein and MBL, C1q or FB.ConclusionsThe activity of the complement system in CSF was increased in non-HIV patients with CM. C1q, MBL and FB are the important participants in the complement activation in CM. The relative contribution of each of the specific complement pathways and complement cascades in protection and inflammation resolution against CM warrant further investigation.

Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis.

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.

Genotypes Coding for Mannose-Binding Lectin Deficiency Correlated With Cryptococcal Meningitis in HIV-Uninfected Chinese Patients

Background. There is increasing evidence that mannose-binding lectin (MBL) has a complex role in many diseases, particularly in infectious diseases. However, the relationship between MBL deficiency and cryptococcal meningitis has not been clarified. The purpose of this study was to investigate the correlation between MBL polymorphism and non-HIV cryptococcal meningitis. Methods. A case-controlled genetic association study was conducted. Patients with cryptococcal meningitis and control subjects were genotyped for 6 alleles of MBL2 gene (H/L, Y/X, P/Q, A/D, A/B, and A/C). The distributions in allele frequency, genotypes, haplotypes, and genotype groups were compared between patients and control subjects. Results. Study participants included 103 HIV-uninfected patients with cryptococcal meningitis and 208 healthy control subjects, all of Chinese Han ethnicity. The homozygous mutative genotypes (O/O) of the coding region were associated with cryptococcal meningitis (P = .023; odds ratio [OR], 4.29; 95% confidence interval [CI], 1.11–19.88), the correlation more overt in immunocompetent patients (P = .005; OR, 6.65; 95% CI, 1.49–33.05). MBL-deficient participant group was associated with cryptococcal meningitis (P = .039; OR, 2.09; 95% CI, .96–4.51), particularly in immunocompetent patients (P = .028; OR, 2.51; 95% CI, .96–6.22). Conclusions. This is the first to show genotypes coding for MBL deficiency are associated with cryptococcal meningitis in nonimmunocompromised hosts.

Factors associated with mortality in cryptococcal meningitis

To investigate factors associated with mortality in non-AIDS patients with cryptococcal meningitis. We retrospectively reviewed 154 cases of non-HIV cryptococcal meningitis in a tertiary care hospital in China, from 1997 through 2007. The 1-year attributable mortality was 19.6% (28/143), and overall mortality was 28.7% (41/143). Advanced age (> or = 60 years), delay in diagnosis (> 4 months), hematologic malignancy, solid malignancy, altered mental status (coma, seizure, herniation), and CSF drainage or shunting were factors associated with increased death; factors associated with increased survival were amphotericin B based initial therapy and flucytosine containing therapy. In multivariate analysis, age > or = 60 years, the time from symptom onset to diagnosis > 4 months, coma, cerebral herniation, and non-amphotericin B based initial therapy were independently associated with increased overall mortality; factors independently associated with cause-specific mortality were time from symptom onset to diagnosis > 4 months, cerebral herniation and non-amphotericin B based initial therapy. A variety of factors were associated with mortality in non-AIDS cryptococcal meningitis. Amphotericin B based initial treatment was independently correlated to improved 1-year survival.