Episode Of Cryptococcal Meningitis Research Articles

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47-142; WBC: 45 cells/μL; IQR: 8-128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. NCT01802385.

Triple therapy versus amphotericin B plus flucytosine for the treatment of non-HIV- and non-transplant-associated cryptococcal meningitis: retrospective cohort study

ObjectivesAmphotericin B plus flucytosine is the most widely used induction therapy regimen for non-HIV-infected and non-transplant patients; however, the therapeutic outcomes are unsatisfactory, especially when two antifungal drugs are at sub-therapeutic doses.MethodsIn this study of induction therapy, all non-HIV-infected, non-transplant patients with a first episode of cryptococcal meningitis were divided into two groups. In group I, the patients received amphotericin B plus 5-flucytosine. In group II, in addition to amphotericin B and 5-flucytosine, the patients also received fluconazole.ResultsIn this study, 32 patients were included in group I, and the other 30 were in group II. Although patients from group II had higher fungal burdens with approximately 2100 Cryptococci/ml CSF before treatment, they had a significantly higher frequency of satisfactory outcomes (80% vs. 50%, respectively, P = 0.014). Less time for more patients in group II to have CSF sterilization (P = 0.021; P = 0.046). And more patients in group II had improved neurological function circumstances evaluated by comparing the BMRC staging between patients at discharge and follow-up 10 weeks (P = 0.032). No significant difference was observed in the incidence of adverse events between the two groups.ConclusionTriple therapy a superior alternative induction regimen for patients with non-HIV- and non-transplant-associated cryptococcal meningitis.

Diagnostic dilemma in managing relapsing episodes of Cryptococcal meningitis in HIV infected patient; a case report

HIV associated morbidity and mortality has dramatically been reduced over the past decade with introduction of antiretroviral therapy (ART). However, significant number of undiagnosed patients still present with advanced HIV disease. Cryptococcal meningitis, commonly caused by the fungus Cryptococcus neoformans , is one of the commonest central nervous system opportunistic infection among those who diagnosed during advanced stage of disease. Relapsing episodes of Cryptococcal meningitis is not uncommon following successful treatment. Relapses may occur due to treatment failure or development of paradoxical cryptococcal immune reconstitution inflammatory response (IRIS) following immunological recovery with ART. However, the exact cause of relapse occurring after commencement of ART is indistinguishable from treatment failures and IRIS. Here, we present a case of a patient with HIV who had been treated for Cryptococcal meningitis that subsequently developed two recurrent episodes of Cryptococcal meningitis after initial Cryptococcal treatment, within consecutive two months while on ART.

A Glucuronoxylomannan-Associated Immune Signature, Characterized by Monocyte Deactivation and an Increased Interleukin 10 Level, Is a Predictor of Death in Cryptococcal Meningitis.

Background. Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)–infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation.Methods. A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis.Results. Sixty participants were enrolled (median CD4+ T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan.Conclusions. Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.

Diagnostic performance of a multiplex PCR assay for meningitis in an HIV-infected population in Uganda

Meningitis remains a worldwide problem, and rapid diagnosis is essential to optimize survival. We evaluated the utility of a multiplex PCR test in differentiating possible etiologies of meningitis. Cerebrospinal fluid (CSF) from 69 HIV-infected Ugandan adults with meningitis was collected at diagnosis (n=51) and among persons with cryptococcal meningitis during therapeutic lumbar punctures (n=68). Cryopreserved CSF specimens were analyzed with BioFire FilmArray® Meningitis/Encephalitis panel, which targets 17 pathogens. The panel detected Cryptococcus in the CSF of patients diagnosed with a first episode of cryptococcal meningitis by fungal culture with 100% sensitivity and specificity and differentiated between fungal relapse and paradoxical immune reconstitution inflammatory syndrome in recurrent episodes. A negative FilmArray result was predictive of CSF sterility on follow-up lumbar punctures for cryptococcal meningitis. EBV was frequently detected in this immunosuppressed population (n=45). Other pathogens detected included: cytomegalovirus (n=2), varicella zoster virus (n=2), human herpes virus 6 (n=1), and Streptococcus pneumoniae (n=1). The FilmArray Meningitis/Encephalitis panel offers a promising platform for rapid meningitis diagnosis.

A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

IntroductionCryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data.MethodsFrom July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation.ResultsSixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score <14 of 15), moderate/severe neurological disability (modified Rankin Score >3 of 5) and confusion (Abbreviated Mental Test Score <8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes.ConclusionsMortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.

Poor long-term outcomes for cryptococcal meningitis in rural South Africa

To explore linkage to and retention in HIV care after an episode of cryptococcal meningitis (CM) in rural South Africa. Design. A retrospective case series of adult individuals (> or = 16 years old) with laboratory-confirmed CM from January - December 2007 at Hlabisa Hospital--a district hospital in northern KwaZulu-Natal. Inpatient mortality and associated risk factors were analysed. The proportion alive and on antiretroviral therapy (ART) at 2 years was determined by linkage to the HIV treatment programme. One hundred and four individuals were identified with laboratory diagnosis of CM; 74/104 (71.2%) with complete records were included in the analysis. Inpatient mortality was high (40.5%) and was significantly associated with reduced conscious level (aHR 3.09, 95% CI 1.30 - 7.33) and absence of headache (aHR 0.33 for headache, 95% CI 0.13 - 0.87). Only 8 individuals (10.8% of all study subjects) were alive and receiving ART 2 years after the CM episode. Long-term outcomes of CM are poor in routine practice. Interventions to strengthen linkage to HIV treatment and care and continuation of secondary fluconazole prophylaxis are critical.

Combination Flucytosine and High‐Dose Fluconazole Compared with Fluconazole Monotherapy for the Treatment of Cryptococcal Meningitis: A Randomized Trial in Malawi

Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.

Utility of clinical assessment, imaging, and cryptococcal antigen titer to predict AIDS-related complicated forms of cryptococcal meningitis

BackgroundThis study aimed to evaluate the prevalence and predictors of AIDS-related complicated cryptococcal meningitis. The outcome was complicated cryptococcal meningitis: prolonged (≥ 14 days) altered mental status, persistent (≥ 14 days) focal neurologic findings, cerebrospinal fluid (CSF) shunt placement or death. Predictor variable operating characteristics were estimated using receiver operating characteristic curve (ROC) analysis. Multivariate analysis identified independent predictors of the outcome.ResultsFrom 1990-2009, 82 patients with first episode of cryptococcal meningitis were identified. Of these, 14 (17%) met criteria for complicated forms of cryptococcal meningitis (prolonged altered mental status 6, persistent focal neurologic findings 7, CSF surgical shunt placement 8, and death 5). Patients with complicated cryptococcal meningitis had higher frequency of baseline focal neurological findings, head computed tomography (CT) abnormalities, mean CSF opening pressure, and cryptococcal antigen (CRAG) titers in serum and CSF. ROC area of log2 serum and CSF CRAG titers to predict complicated forms of cryptococcal meningitis were comparable, 0.78 (95%CI: 0.66 to 0.90) vs. 0.78 (95% CI: 0.67 to 0.89), respectively (χ2, p = 0.95). The ROC areas to predict the outcomes were similar for CSF pressure and CSF CRAG titers. In a multiple logistic regression model, the following were significant predictors of the outcome: baseline focal neurologic findings, head CT abnormalities and log2 CSF CRAG titer.ConclusionsDuring initial clinical evaluation, a focal neurologic exam, abnormal head CT and large cryptococcal burden measured by CRAG titer are associated with the outcome of complicated cryptococcal meningitis following 2 weeks from antifungal therapy initiation.

High‐Dose Amphotericin B with Flucytosine for the Treatment of Cryptococcal Meningitis in HIV‐Infected Patients: A Randomized Trial

The standard therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis of amphotericin B (AmB; 0.7 mg/kg per day) plus flucytosine frequently takes >2 weeks to sterilize the cerebral spinal fluid, and acute mortality remains high. A dosage range for AmB of 0.7-1 mg/kg per day is noted in current guidelines, but there are no data comparing 0.7 mg/kg per day with 1 mg/kg per day. Sixty-four HIV-seropositive, antiretroviral therapy-naive patients in Cape Town, South Africa, who experienced their first episode of cryptococcal meningitis during the period May 2005-June 2006 were randomized to receive either (1) AmB, 0.7 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 1; 30 patients); or (2) AmB, 1 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 2; 34 patients). Regimens were given for 2 weeks, followed by treatment with oral fluconazole. The primary outcome measure was early fungicidal activity, as determined by results of serial, quantitative cerebral spinal fluid cryptococcal cultures. Secondary outcome measures were safety and mortality. The median duration of follow-up was 1 year. Early fungicidal activity was significantly greater for group 2 than for group 1 (mean +/- SD, -0.56 +/- 0.24 vs. -0.45 +/- 0.16 log cfu/mL of cerebral spinal fluid per day; P = .02). The incidence of renal impairment did not significantly differ between the 2 groups. Anemia was associated with female sex and, less strongly, with membership in group 2. Renal impairment and anemia reversed after the regimen was switched to fluconazole. Two- and 10-week mortality rates were 6% and 24%, respectively, with no difference between groups. AmB, 1 mg/kg per day, plus flucytosine is more rapidly fungicidal than is standard-dose AmB plus flucytosine. Because of its size, this study provides limited data on any difference in toxicity between the regimens, but toxicities were manageable and reversible. ISRCTN68133435 (http://www.controlled-trials.com).

Recurrent pulmonary cryptococcosis in a patient with idiopathic CD4 lymphocytopenia

A case of recurrent cryptococcosis with idiopathic CD4 lymphocytopenia is reported in this article. After an initial cryptococcal infection in the lung, the patient experienced one episode of cryptococcal meningitis and two more episodes of cryptococcal pneumonia within a period of 12 years. Genetic studies revealed that all isolated microbes were identical, indicating that all subsequent episodes were recurrence instead of re-infection.

Antegrade and Retrograde Endoscopic Approach in the Establishment of a Neo-Esophagus

Background Although total obstruction or secondary atresia of the esophagus is extremely rare, high-grade strictures are not uncommon. The retrograde approach was previously described to achieve dilation when the conventional antegrade method fails. Setting Gastroenterology laboratory in a tertiary referral center. Patient A 30-year-old man with congenital T-cell immunodeficiency had complete esophageal obstruction after a severe episode of cryptococcal meningitis that required prolonged nasogastric intubation. For the next 3 years, he had daily episodes of regurgitations and several hospitalizations for aspiration pneumonia. A barium study revealed a dilated megaesophagus, with no contrast reaching to the stomach. Intervention Initially, a new track was created by using access from above and below the obstruction. This was followed by placement of a self-expandable silicone stent after allowing sufficient time for the new track to mature. Main Outcome Measurements Restoration of esophageal continuity, which allowed resolution of the patient's aspiration pneumonia and resumption of oral feeding. Conclusions Complete esophageal obstruction after prolonged nasogastric intubation is a rare but serious complication. A novel endoscopic approach can be used to restore esophageal continuity, minimize complications, and avoid major reconstructive surgeries.

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy.

Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients

To evaluate whether oral fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients, we conducted a case-control study of patients cared for in a university teaching hospital and two urban HIV-outpatient clinics. Cases consisted of HIV-infected patients with CD4 cell counts less than 250/μL who developed a first episode of cryptococcal meningitis between July 1, 1990, and June 30, 1993. For each case (n=18), 4 control subjects were chosen from HIV-infected patients (CD4 count < 250/μL) whose cerebrospinal fluid was negative for cryptococcal antigen and culture, and who were matched by age, sex, and time of lumbar puncture. There were no significant differences between cases and controls in age, sex, insurance status, mean CD4 count, history of oral candidosis, presence of a previous AIDS-defining illness, the number of visits to the HIV-outpatient clinic, or use of antiretroviral therapy. In the 6 months before lumbar puncture, 2 of 18 cases (11%) and 26 of 72 controls (36%) were exposed to fluconazole, a finding that gives a matched odds ratio (adjusted for race, route of HIV infection, and CD4 count) of 0·08 (95% Cl 0·01-0·84; p=0·035) and indicates a 92% protective efficacy. We conclude that fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients with a CD4 count less than 250/uL. Although the optimum dose and duration of fluconazole could not be determined, our results suggest that less than daily use was effective in the prevention of cryptococcal meningitis.

Fluconazole Compared with Amphotericin B plus Flucytosine for Cryptococcal Meningitis in AIDS

To compare the efficacy of fluconazole with amphotericin B plus flucytosine in the treatment of cryptococcal meningitis. Patients were randomly assigned to oral fluconazole, 400 mg/d, for 10 weeks or to amphotericin B, 0.7 mg/kg body weight daily for 1 week, then three times weekly for 9 weeks combined with flucytosine, 150 mg/kg d, in four divided doses. Los Angeles County-University of Southern California Medical Center. Between 15 February and 7 December 1988, 42 patients had evidence of their first episode of cryptococcal meningitis, of whom 21 participated in the trial. All patients enrolled were men with the acquired immunodeficiency syndrome (AIDS) except one woman who was receiving prednisone therapy and was excluded from the final analysis. Of 14 patients with AIDS assigned to fluconazole, 8 (57%; 95% CI, 29% to 82%) failed; none of the 6 patients with AIDS failed who were assigned to amphotericin B plus flucytosine therapy (0%; CI, 0% to 46%) (Fisher exact test, P = 0.04). The mean duration of positive cerebrospinal fluid cultures was 40.6 +/- 5.4 days in patients receiving fluconazole and 15.6 +/- 6.6 days in patients receiving amphotericin B plus flucytosine (Mann-Whitney test, P = 0.02). Overall, 4 patients assigned to fluconazole therapy died whereas no patient assigned to amphotericin B plus flucytosine therapy died (Fisher exact test, P = 0.27). Amphotericin B used in combination with flucytosine has superior mycologic and clinical efficacy compared with fluconazole for the treatment of cryptococcal meningitis in patients with AIDS.