Cryptococcus Neoformans Meningitis Research Articles

Cerebellar Hypermetabolism in a Hodgkin Lymphoma Leads to Diagnosis of Paucisymptomatic Cryptococcus neoformans Meningitis.

Malignancy-associated cerebellar hypermetabolism on [ 18 F]FDG PET/CT has 2 major causes: paraneoplastic autoimmune encephalitis and neoplasias (leptomeningeal/cerebellar metastases and primary cerebellar tumors). We present the case of a 33-year-old man with a newly diagnosed Hodgkin lymphoma and mere episodical headache, unexpectedly displaying intense cerebellar hypermetabolism on his staging [ 18 F]FDG PET/CT. Both neurolymphomatosis and paraneoplastic subacute cerebellar degeneration were ruled out by clinical presentation, MR, and repeated lumbar punctures. Instead, cerebrospinal fluid analysis unveiled a Cryptococcus neoformans meningitis, highlighting the possibility of paucisymptomatic central nervous system infections as differential diagnosis in malignancy-related cerebellar hypermetabolism in addition to (para)neoplastic causes.

Comparison of features and outcomes between HIV-negative patients with Cryptococcus gattii meningitis and Cryptococcus neoformans meningitis in South China.

The objective of this study is to compare the epidemiologic, clinical, laboratory, and imaging features, and outcomes in patients with Cryptococcus gattii meningitis (CGM) and Cryptococcus neoformans meningitis (CNM). We performed a retrospective study of HIV-negative patients with CGM and CNM (2015-2021) distinguished by metagenomic next-generation sequencing in cerebrospinal fluid in South China. A total of 81 patients (17 CGM, 64 CNM) were enrolled (72.8% male, median age 49 years, range 21-77 years), and CGM patients were younger (median, 43 vs 53 years, p=.005). Of 17 CGM, VGI and VGII accounted for 70.6% and 29.4%, respectively. CGM patients had less underlying diseases (7/17 [41.2%] vs 48/64 [75%], p=.018) and focal neurologic deficit (3/17 [17.6%] vs 35/64 [54.7%], p=.022), had higher intracranial pressure (15/17 [88.2%] vs 25/64 [39.1%], p=.002), more meningeal enhancement (14/17 [82.4%] vs 32/64 [50%], p=.034), less parenchymal involvement (median, 1 vs 3, p=.018), more lung cryptococcomas (6/12 [50%] vs 6/47 [12.8%], p=.014), faster CSF fungal clearance (p=.004), less complications (median, 1 vs 3, p < .001), and more favourable outcomes (16/17 [94.1%] vs 41/64 [64.1%], p=.035). This study demonstrated that species identification helps to guide therapy and predict outcomes.

Cryptococcus neoformans meningitis in kidney transplant recipients: A diagnostic and therapeutic challenge

Cryptococcosis is the third most common invasive fungal infection in solid organ transplant recipients. We describe three cases of neuro-meningeal cryptococcosis occurring among kidney transplant (KT) patients, and discuss the diagnostic and therapeutic challenges in this context.Median time from KT to infection was 6 months [range: 3–9]. The most common clinical manifestations at diagnosis were fever (2/3), headache (2/3), and confusion (2/3); none had extra-neurological involvement. CrAg was positive in all cases at diagnosis both in serum and cerebrospinal fluid (CSF). For two patients, analysis of previous samples showed that CrAg was detected in plasma up to 4 weeks before diagnosis. All patients received induction treatment with liposomal amphotericin-B (L-AmB) and flucytosine for a median duration of 10 days [range: 7–14], followed by fluconazole maintenance therapy. Acute kidney injury secondary to L-AmB therapy was observed in only one case, but all patients had a tacrolimus overdose following initiation of maintenance therapy due to drug-drug interactions between fluconazole and tacrolimus.Among KTR, early detection of Cryptococcus meningitis using serum CrAg is possible. Close monitoring of renal function during treatment is essential due to the nephrotoxicity of L-AmB, but also drug-drug interactions between fluconazole and calcineurin inhibitors.

A Novel Cryptococcal Meningitis Therapy: The Combination of Amphotericin B and Posaconazole Promotes the Distribution of Amphotericin B in the Brain Tissue.

The deficient brain tissue distribution of amphotericin B (AMPB) seriously restricts its treatment for the clinical efficacy of cryptococcus neoformans meningitis (CNM). We strive to develop a tactic to increase its concentration in brain tissue. We aimed to investigate whether the combination of AMPB and posaconazole (POS) could be more effective in the treatment of CNM and to elucidate its potential mechanisms. HPLC analysis was used to analyze the concentration of AMPB in mouse serum, brain tissue, and BCECs cells. Schrodinger molecular docking, in vitro plasma balance dialysis, and ultrafiltration analysis were performed to evaluate the combinative effect of AMPB and POS with serum albumin and POS on AMPB plasma protein binding. H&E staining and colonization culture experiment of CN were employed to assess the effect of POS on the efficacy of AMPB. POS + AMPB significantly reduced the concentration of plasma total AMPB and increased its concentration in the brain tissue. However, the P-gp inhibitor zosuquidar, BCRP inhibitor Ko143, and a common inhibitor of both, elacridar, had no significant effect on its concentration. Molecular docking, balance dialysis, and ultrafiltration analysis showed that AMPB and POS had potential binding properties to serum albumin. Meanwhile, 4 and 8 μg/mL POS could significantly increase the concentration of free AMPB in plasma. POS and three inhibitors all had no significant effect on the uptake of AMPB by BCECs, but serum albumin had. The therapeutic effect of CNM in mice was confirmed that AMPB and AMPB+POS could restrain the infiltration of neutrophils and lymphocytes in cortical neurons and improve the bleeding and markedly inhibit the proliferation of CN. Collectively, we propose that POS competitively binds to the plasma protein sites of AMPB, thereby increasing its level in the brain tissue. Meanwhile, POS could enhance the efficacy of AMPB in the treatment of CNM, which may be independent of P-gp and BCRP proteins.

Cryptococcus Neoformans Meningitis Cases Among China's HIV-Infected Population may have been Severely Under-Reported.

Cryptococcal meningitis (CM) is the leading fungal infection of the central nervous system. Globally, most CM cases have been reported from patients with compromised immunities, especially those infected with HIV. However, reports from China have shown that most CM infections were from HIV-negative, immunocompetent hosts. Here, we reviewed the published reports and found those studies were almost exclusively based on patients from hospitals associated with Chinese universities but not from specialized infectious diseases hospitals where most Chinese HIV-infected patients have been treated. Thus, we believe CM cases among China’s HIV-infected population may have been severely under-reported. Analyses of CM cases in specialized infectious diseases hospitals are needed to identify the true epidemiological pattern of CM in China.

Synergistic and antagonistic drug interactions in the treatment of systemic fungal infections

Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap2 method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with Cryptococcus neoformans meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.

An HIV-infected patient with acute retinal necrosis as immune reconstitution inflammatory syndrome due to varicella-zoster virus.

An HIV-infected patient with acute retinal necrosis as immune reconstitution inflammatory syndrome due to varicella-zoster virus.

Isolates of Cryptococcus Neoformans from Non-HIV and Non-Transplant Hospitalized Patients

A retrospective cross-sectional study for patients with confirmed Cryptococcus neoformans meningitis (CM) in non-HIV-infected and non-transplant hosts in two class-A tertiary hospitals in Guangzhou, China is reported. 181 CM patients were enrolled during the study period, 48% (87/181) of which died. Underlying diseases were risk factor associated with higher mortality, among which diabetes mellitus ranked first for the incidence of CM. The mortality was not related to antifungal drug susceptibility. All strains were considered susceptible to amphotericin B, although interpretative breakpoints for amphotericin B have not yet been established. According to the CLSI guidelines, most of the strains in our study were susceptible to voriconazole, fluconazole, fluorocytosine and dose-dependently susceptible to itraconazle.

Cryptococcal Meningitis in a HIV-Negative Patient.

Sarcoidosis is a risk factor for the development of cryptococcal infection due to dysfunction at T-cell level. Its rarity may, however, delay diagnosis and treatment. We describe the case of a 60-year-old man, diagnosed with sarcoidosis since 1999. He had never received systemic immunomodulatory therapy, such as corticosteroid therapy. In 2012, he was diagnosed with pulmonary cryptococcosis and treated with fluconazole. In April 2013, he presented with symptoms compatible with central nervous system (CNS) infection, namely, Cryptococcus neoformans meningitis. He was treated with amphotericin B, followed by fluconazole. The clinical outcome was favourable.LEARNING POINTSAlthough rare, in patients with sarcoidosis and central nervous system (CNS) symptomatology, it is important to verify the existence of cryptococcal meningitis.Antifungal treatment should be started as early as possible.Before the diagnosis of pulmonary cryptococcosis, dissemination to the CNS should be outruled due to the need for more aggressive treatment.

MLST-Based Population Genetic Analysis in a Global Context Reveals Clonality amongst Cryptococcus neoformans var. grubii VNI Isolates from HIV Patients in Southeastern Brazil.

Cryptococcosis is an important fungal infection in immunocompromised individuals, especially those infected with HIV. In Brazil, despite the free availability of antiretroviral therapy (ART) in the public health system, the mortality rate due to Cryptococcus neoformans meningitis is still high. To obtain a more detailed picture of the population genetic structure of this species in southeast Brazil, we studied 108 clinical isolates from 101 patients and 35 environmental isolates. Among the patients, 59% had a fatal outcome mainly in HIV-positive male patients. All the isolates were found to be C. neoformans var. grubii major molecular type VNI and mating type locus alpha. Twelve were identified as diploid by flow cytometry, being homozygous (AαAα) for the mating type and by PCR screening of the STE20, GPA1, and PAK1 genes. Using the ISHAM consensus multilocus sequence typing (MLST) scheme, 13 sequence types (ST) were identified, with one being newly described. ST93 was identified from 81 (75%) of the clinical isolates, while ST77 and ST93 were identified from 19 (54%) and 10 (29%) environmental isolates, respectively. The southeastern Brazilian isolates had an overwhelming clonal population structure. When compared with populations from different continents based on data extracted from the ISHAM-MLST database (mlst.mycologylab.org) they showed less genetic variability. Two main clusters within C. neoformans var. grubii VNI were identified that diverged from VNB around 0.58 to 4.8 million years ago.

Clinical analysis of invasive fungal infection in children of nephrology department

Objective To explore the clinical features of invasive fungal infection in 27 children treated at nephrology department between 1999 and 2014. Methods Twenty-seven cases of invasive fungal infection at nephro-logy department were analyzed retrospectively. Results Candida urinary infection was found in 9 cases, pneumocystis carinii pneumonia were found in 8 cases, invasive pulmonary aspergillosis and urinary aspergillosis found in 4 cases and 1 case respectively, cryptococcus neoformans meningitis and pulmonary candidiasis found respectively in 2 cases, and pulmonary filamentous fungal disease was found in 1 case.These 27 cases showed different features of illness: 10 primary nephrotic syndrome, 7 secondary nephrotic syndrome, 6 malformation of urinary development and 4 preterm birth <32 weeks gestational age with low birth weight.All of the cases had the history of taking antibiotics.Seventeen cases of them had used corticosteroid and cytotoxic drugs in a long-term.Sixteen cases had experienced invasive procedures.All children had fever in varying degrees, 14 cases showed gasp, 7 cases had progressive hypoxia and respiratory failure, and 5 cases developed into multiple organs failure.Chest computed tomographic(CT) imaging data showed diffuse ground-glass opacity with mosaic sign of pneumocystis carinii pneumonia(8 cases). The features of pulmonary aspergillosis included multiple nodules and cavity in bilateral lungs(4 cases). The radiologic findings showed patching lesions with indistinct edge and uncertained density of bilateral middle-lower lung fields with pulmonary candidiasis(2 cases). Full dose of antifungal drug was given to 23 cases of them, 16 cases recovered completely, 3 got better, 4 cases died.Four cases gave up full dose antifungal therapy. Conclusions Long-term use of corticosteroid and cytotoxic drugs, use of broad-spectrum antibiotics, invasive therapies, such as indwelling centralvenous catheters, endotracheal intubation with mechanical ventilation, and preterm birth with low birth weight were risk factors in predicting invasive fungal infection.Chest CT findings were different among these cases.Even though not specific, the relatively differences were helpful to the differential diagnosis of these diseases. Key words: Nephrology department; Invasive fungal infection; Clinical analysis; Child

Successful treatment of Cryptococcus neoformans immune reconstitution inflammatory syndrome in an immunocompetent host using thalidomide

Immune reconstitution inflammatory syndrome (IRIS) can complicate antifungal treatment of cryptococcosis. There are limited data on managing cryptococcal-associated IRIS. We describe an immunocompetent patient who developed IRIS complicating Cryptococcus neoformans meningitis, successfully treated with thalidomide following failure of corticosteroid therapy. Data on thalidomide use in cryptococcal IRIS are awaited.

Cryptococcus neoformans meningitis with negative cryptococcal antigen: Evaluation of a new immunochromatographic detection assay.

Detection of cryptococcal antigen in serum or cerebrospinal fluid allows cryptococcal meningitis diagnosis within few hours with >90% sensitivity. In an HIV-positive patient with Cryptococcus neoformans meningitis, initial antigen detection by immunoagglutination was negative. We thus evaluated a new immunochromatographic detection assay that exhibited a higher sensitivity.

Increased permeability of blood–brain barrier is mediated by serine protease during Cryptococcus meningitis

To determine the role of serine protease in the disruption of the blood-brain barrier (BBB) during Cryptococcus neoformans meningitis. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to determine the production of serine protease by different strains of C. neoformans. BBB permeability in immunosuppressed rats inoculated with C. neoformans or C. neoformans plus aprotinin was examined via Evans blue staining. Invitro BBB permeability (transwell passage of horseradish peroxidase) was determined in human brain microvascular endothelial cells (BMECs) cultured with serine protease or serine protease plus aprotinin. Electron microscopy of rat brain tissue was used to visualise C. neoformans infection. Serine protease mRNA and protein were detected in all C. neoformans serotypes. C. neoformans infection increased BBB permeability invivo, but this effect was ameliorated by aprotinin. Treatment of BMECs with serine protease increased permeability invitro. This effect was reversed by aprotinin. Serine protease secreted by C. neoformans leads to BBB disruption during Cryptococcus meningitis. Serine protease may be a novel treatment target for Cryptococcus meningitis.

Cryptococcal Meningitis Presenting with Alerted Mental Status in a Patient with Cirrhosis: Diagnostic Dilemmas

Purpose: Altered mental status is a frequent reason for admission for patients with cirrhosis, and is usually caused by hepatic encephalopathy. In this abstract, we report a patient with cirrhosis who was admitted with altered mental status and eventually found to have cryptococcal meningitis. Case Report: A 48-year-old AA female with cirrhosis caused by NASH was admitted with suspected hepatic encephalopathy. Vital signs showed a temperature of 38.4°C, heart rate of 82 /min, blood pressure of 110/70 mmHg, and respiratory rate of 19 /min. On neurological exam, she was not oriented to time, place, and person, and had no signs of meningism. She did not have any focal neurological signs. Labs: AST/ALT: 46/118, Alk Phos: 251, INR: 1.5; ammonia level was elevated at 52 umol/L. Her electrolytes and renal functions were within normal range. Her MELD was 13. and she had Child Pugh class B. Blood cultures remained negative for any microbial growth. Her HIV test was negative. She was promptly started on lactulose, and started having adequate bowel movements. However, her mental status deteriorated over the next 72 hours, and a lumbar puncture (LP) was performed. CSF studies showed a WBC count of 1875 cells/mm3 (69% neutrophils, 30% lymphocytes), glucose of 30 mg/dl, protein 50 mg/dl and cryptococcal antigen titer of 1:8. CSF cultures grew Cryptococcus neoformans, and she was started on liposomal amphoterecin B. She responded well to treatment, with remarkable improvement in mental status. Discussion:Cryptococcus neoformans meningitis is very uncommon in patients with cirrhosis. Unless the clinician keeps a high index of suspicion, it can be easily missed; especially since every patient with altered mental status is labeled as hepatic encephalopathy. Moreover, LP is difficult in cirrhotic patients, due to coagulopathy and thrombocytopenia, potentially delaying or preventing the diagnostic studies such as CSF culture or crytococcal antigen. While serum crytococcal antigen test is not very sensitive, and false positive tests can occur (in infections with Trichosporon asahii fungus or Stomatococcus and Capnocytophaga bacteriae), one might have to rely solely on serum antigen for a diagnosis in many patients with severe coagulopathy. This diagnostic dilemma is further accentuated by potential toxicities of fungicidal drugs, (amphotericin B and/or flucytosine) in patients with compromised hepatic function and reduced renal function secondary to hepatorenal syndrome. Conclusion: Cryptococcal meningitis can masquerade as hepatic encephalopathy in patients with cirrhosis. A high clinical suspicion, along with early initiation of diagnostic studies and therapies, are needed for effective treatment.

Outcome of HIV-1-associated cryptococcal meningitis, Denmark 1988–2008

The risk of HIV-1-associated Cryptococcus neoformans meningitis (CM) has decreased and the outcome has improved with the use of combination antiretroviral therapy (cART). Outcome has not been reported in Denmark in the cART era. A review of all cases of HIV-1-associated CM treated at 2 hospitals in Denmark was carried out. Survival was compared by time-updated Cox proportional hazards analysis. A total of 45 cases were evaluated. Six individuals (13.3%) died within 30 days of being diagnosed with CM. cART was initiated a median of 15 days (range 3-53) after a diagnosis of CM for 12 individuals and did not affect 30-day outcome. Older age, however, was associated with an increased risk of death at 30 days (mortality rate ratio (MMR) 1.16 (95% confidence interval (95% CI) 1.05-1.30) per y increment). Twenty-four (55.8%) of 43 individuals (2 had emigrated) died within the 1(st) y. Initiation of cART significantly improved 1-y outcome (MMR 0.22, 95% CI 0.06-0.77). Mental status, CD4 T cell count, and antifungal did not affect short- or long-term outcome. We found that long-term survival after HIV-1-associated CM has improved significantly with the use of cART. Short-term mortality was not affected by initiation of cART and remained high.

The effect of the expression of virulence-associated DEAD-box RNA helicase mRNA on the imbalance of Th1-Th2 cytokines in the CSF of patients with Cryptococcus neoformans meningitis

Virulence-associated DEAD-box RNA helicase (VAD1) is an important factor regulating the virulence of Cryptococcus neoformans. We established a real-time quantitative polymerase chain reaction (PCR) assay to measure the expression of VAD1 mRNA in the cerebrospinal fluid (CSF) of C. neoformans meningitis (CNM) patients, and we also detected the levels of IFN-γ, IL-12 and IL-10 proteins in these CSF samples and controls. Patients with head injuries were selected as controls. We found that the expression of VAD1 mRNA was significantly higher in the acute phase than in the stable phase of CNM. The level of CSF IFN-γ and IL-10 in the acute phase (9.45pg/ml ± 2.06 and 36.28pg/ml ± 10.86, respectively) were different to that in the controls (11.89pg/ml ± 1.75 and 7.33pg/ml ± 1.68, respectively). The IFN-γ/IL-10 and IL-12/IL-10 ratios were significantly higher in controls than in the acute phase, but lower than in the stable phase. The expression of VAD1 mRNA is inversely related to IFN-γ and is correlated with IL-10 but not to IL-12. The Th2 response is dominant in the acute phase, whereas the immune response switches to a Th1 response in the stable phase. The expression of VAD1 mRNA is related to the imbalance of Th1-Th2 responses, which could be one of the mechanisms by which C. neoformans escapes the immune system.

Quantification of cerebrospinal fluid lactic acid in the differential diagnosis between HIV chronic meningitis and opportunistic meningitis

Approximately 40% of HIV infected patients have chronic meningitis at various stages during the infection, 59% are asymptomatic. This is a diagnosis of exclusion and a confounding factor in cerebrospinal fluid (CSF) analysis, any other causes of chronic meningitis by opportunistic or co-infection must be ruled out. The aim of this study was to analyze CSF lactic acid (LA) as an adjuvant biomarker in chronic meningitis due to HIV. CSF LA was quantified in 223 CSF samples by the Dimension AR (Dade Behring, Deerfield, IL, USA), distributed into nine groups: 1) HIV positive with an increase in CSF WBCs (n=17); 2) HIV positive with normal CSF (n=20); 3) enterovirus meningitis (n=33); 4) Herpesviridae meningoencephalitis (n=30); 5) fungal meningitis (n=25); 6) tuberculosis (TB) meningitis (n=17); 7) toxoplasmosis (n=18); 8) neurosyphilis (n=6); 9) control group (n=57). CSF LA (median; IQR) was higher in samples with TB meningitis (5.5; 2.9-7.5 mmol/L) and Cryptococcus neoformans meningitis (3.9; 2.7-5.8 mmol/L) compated with samples with HIV chronic meningitis (1.7; 1.4-1.9 mmol/L) and other groups (p ≤ 0.0001). For the diagnosis of HIV chronic meningitis, using a cut-off of 3.5 mmol/L, CSF LA showed high sensitivity and negative predictive value, although low specificity. CSF LA helps to discriminate between C. neoformans or TB meningitis and HIV chronic meningitis: CSF LA can be included with the methods currently used to identify these specific pathogens, though it does not replace them. It is rapid, inexpensive and easy to perform, and can be used in developing countries.

Evaluation for the treatment efficacy for cryptococcus neoformans meningitis by VAD1 mRNA detection with real-time fluorescent quantitative polymerase chain reaction

Objective To establish a new approach for quantitative detection of VAD1 mRNA in cryptococcus neoformans by RT-FQ-PCR, and evaluate the treatment efficacy of CNM. MethodsThe primers and TaqMan probe were designed according to the published sequence of VAD1 mRNA (GenBank),and RT-FQ-PCR method to detect VAD1 mRNA was established. Cerebrospinal fluid from 25 CNM patients and 30 controls were detected and sensitivity and specificity of the method were evaluated. VAD1 mRNA concentration in cerebrospinal fluid from both acute phase and recovery phase of 25 CNM patients were also detected and significance of CNM treatment efficacy with VAD1 mRNA analysis was evaluated. Results Correlation coefficient of standard curve was - 0. 997 9 in detection of VAD1 mRNA by RT-FQ-PCR, and the detection limit was 101 copies/μl. The intra CV of plasmid standard for high, medium and low concentrations were 0. 65% ,0. 89% and 1.23% respectively, the sensitivity of cryptococcus neoformans detection by RT-FQPCR was 96% (24/25) ,while specificity was 100% (30/30). VAD1 mRNA concentration in acute phase were significant higher than that in recovery phase (3. 042 ±0. 906 vs 2. 187 ±0. 665 ,t =4. 583 ,P ＜0. 01).Conclusions The established RT-FQ-PCR method for the detection of VAD1 mRNA is provided with sound sensitivity, specificity and reproducibility, which might be fit for the detection of VAD1 mRNA. The expression level of VAD1 mRNA is relevant with the treatment efficacy of CNM. Key words: Meningitis,cryptococcal; Cryptococcus neoformans; DEAD-box RNA helicases:Polymerase chain reaction

Cryptococcus neoformansmeningitis in a diabetic patient - the perils of an overzealous immune response: a case report

Uncontrolled diabetics are prone to infections due to numerous factors as the glucose-rich blood serves as an excellent media for growth. Cryptococcus neoformans is an opportunistic fungus that is an important cause of CNS infections among immunocompromised patients, but it has only sporadically been reported in non-HIV-positive persons. The presence of elevated pro-inflammatory cytokines and abnormalities in numerous systemic indicators of inflammation in diabetics makes it conceivable that diabetics mount an exaggerated immune response to C. neoformans (paradoxical to their defective immune state) leading to grave outcomes. We present a fatal case of C. neoformans meningitis in a diabetic patient which emphasizes the perils of an overzealous immune response.