Cryptococcal Meningitis In HIV-negative Patients Research Articles

Analysis of the relationship between drug susceptibility of Cryptococcus neoformans isolates and mortality in HIV-negative cryptococcal meningitis

ObjectivesThe relationship between antifungal susceptibility and mortality of cryptococcal meningitis (CM) in HIV-negative patients is poorly understood. MethodsWe conducted a retrospective analysis of 1-year follow-up of 200 HIV-negative CM patients with an initial cerebrospinal fluid (CSF) culture for Cryptococcus neoformans. According to the cut-off values of minimum inhibitory concentration (MIC), two groups of five antifungal agents were classified: amphotericin B (AmB), ≤0.5 µg/mL, >0.5 µg/mL; 5-flucytosine (5-FC), ≤4 µg/mL, >4 µg/mL; fluconazole (FLU), ≤4 µg/mL, >4 µg/mL; itraconazole (ITR), ≤0.125 µg/mL, >0.125 µg/mL; and voriconazole (VOR), <0.25 µg/mL, ≥0.25 µg/mL. Comparisons were performed to analyse clinical features, laboratory, modified Rankin Scale (mRS) scores, and CSF findings under different prognosis outcomes in 1-year. ResultsAll of Cryptococcus neoformans isolates were sensitive to AmB and VOR, most of them were sensitive to 5-FC and FLU (95.5% and 90.5%, respectively) while only 55.0% of them were susceptible to ITR. Minimum inhibitory concentrations of ITR and VOR were significantly related to baseline mRS scores. All-cause mortality was not significantly related to MICs in Cryptococcus neoformans strains. The combination of actual antifungal agents and two groups of the MICs values for antifungal agents had no significant effects on all-cause mortality. ConclusionMost Cryptococcus neoformans isolates were sensitive to AmB, VOR, 5-FC, and FLU. Because of the small number of deaths, we are not able to comment on whether MIC is associated with mortality of CM in HIV-negative patients.

Performance of Metagenomic Next-Generation Sequencing for the Diagnosis of Cryptococcal Meningitis in HIV-Negative Patients.

ObjectivesMetagenomic next-generation sequencing (mNGS) has been applied more and more widely for the diagnosis of infectious diseases, but its performance in the diagnosis of cryptococcal meningitis (CM) remains unclear.MethodsCerebrospinal fluid (CSF) samples from 197 HIV-negative patients with suspected central nervous system infections were tested simultaneously by mNGS and routine methods [India ink staining, fungal culture, or cryptococcal antigen (CrAg) tests]. The performance of mNGS was evaluated.ResultsOf the 197 enrolled cases, 46 (23.4%) cases were finally diagnosed with CM, including 43 (93.5%) Cryptococcus neoformans infections and 3 (6.5%) Cryptococcus gattii infections. The sensitivity, specificity, positive predictive value, negative predictive value, and concordance rate of mNGS were 93.5% [95% confidence interval (CI) at 86.4%~100.0%], 96.0% (95% CI at 92.9%~99.1%), 87.8%, 98.0%, and 95.4%, respectively. Comparing to the conventional diagnostic methods, the sensitivity and concordance rate of mNGS were slightly lower than those of CrAg tests (97.4%) but higher than those of India ink (63.0%) and culture (76.7%). Besides, mNGS had a sensitivity of 100.0% against culture. It should be noted that mNGS could identify Cryptococcus at species level; C. gattii of the 3 cases was only distinguished by mNGS.ConclusionsCSF mNGS can be considered as a supplementary test to diagnose CM and directly distinguish C. gattii from C. neoformans in clinical specimens.

Comparison of cryptococcal meningitis in HIV-negative patients with and without lung infections

ObjectiveTo investigate the clinical features and outcomes of cryptococcal meningitis (CM) in HIV-negative patients with and without lung infections.MethodsWe retrospectively reviewed the medical records of HIV-negative patients with CM admitted to two university hospitals in Southwest China over the past 5 years.ResultsSeventy-one patients were included, of whom 35 (49.3%) had lung disease. Compared with patients without lung infection, CM patients with lung infection tended to be male and younger (≤30 years), experienced more fever, less vomiting and fewer central nervous system symptoms; more often had low white blood cell (WBC) counts (<20 × 106/L), and fewer often had ethmoid sinusitis, maxillary sinusitis, paranasal sinusitis, and otitis media. Cryptococcus neoformans isolates from these patients were sensitive to itraconazole, voriconazole, fluconazole, and amphotericin B but resistant to flucytosine. CM patients with lung infection had higher mortality at discharge compared with patients without lung infection (8.6% vs. 0%). Multivariable analyses showed that a WBC count <20 × 106/L was significantly associated with poor treatment outcome (odds ratio 0.01, 95% confidence interval 0–0.83).ConclusionHIV-negative CM patients with lung infections tended to be male and younger. Fever, fewer central nervous system symptoms, and WBC counts <20 × 106/L were characteristic of this patient group.

Cryptococcal meningitis in HIV-negative patients with systemic connective tissue diseases

Background:Cryptococcal meningitis (CM) is a rare condition in non-HIV patients. The clinical manifestations in patients with systemic lupus erythematosus (SLE) are often confused with immunological activity, resulting in delayed diagnosis.Aims:We describe the natural history and outcome of eight HIV-negative patients with SLE and confirmed CM.Results:Mean age at the time of infection was 30·2 years (20–42). Mean dose of prednisone was 38·3 ± 13 mg/day and of azathioprine was 95 ± 37 mg/day. The most common clinical manifestation was headache with nausea or vomit (75%), followed by altered sensorium (50%), fever (50%), cranial nerve deficits (37%), or seizures (25%). Mean time between symptoms onset and diagnosis was 19 days (6–56). All patients had low lymphocyte cell counts (504 ± 229 cells/μl) and low CD4+ cell counts (113·2 ± 59·2 cells/μl). Active SLE assessed by a systemic lupus erythematosus disease activity index (SLEDAI) score ≧4 was found in 83% patients at the time of the diagnosis and 87% had renal involvement. The positivity of cryptococcal antigen, India ink stain, and culture in the cerebrospinal fluid (CSF) was 90, 70, and 50%, respectively. Magnetic resonance was abnormal in 90% of the patients. Higher titers of cryptococcal antigen were suggestive of worse outcome and increased hospital stay. After a mean follow-up of 4·9 years, one patient had a relapse of the CM, associated with persistent low CD4+ cell counts.Conclusions:Cryptococcal meningitis in patients with SLE was associated with severe delay in diagnosis and profound lymphopenia. Follow-up should include CD4+ cell counts, and maintenance treatment with fluconazole should be continued until lymphopenia resolution.

Cryptococcal Meningitis in HIV-Negative Patients with Systemic Connective Tissue Diseases (P01.249)

Cryptococcal Meningitis in HIV-Negative Patients with Systemic Connective Tissue Diseases (P01.249)

Cryptococcal meningitis in HIV-negative patient with liver cirrhosis due to hepatitis C

©2011 Elsevier Editora Ltda. All rights reserved. Dear Editor, Before AIDS, cryptococcal meningitis, a disease caused by the basidiomycete fungus Cryptococcus neoformans, occurred at an incidence rate of one case per one million person-years.1 After AIDS, transplants and the use of immunosuppressive therapies, the incidence rate increased tenfold.1,2 We report a case of a 46-year-old male with a history of headache, confusion, nausea and vomiting for one month. The patient also had type 2 diabetes mellitus, in use of metformin, with good control, and liver cirrhosis due to hepatitis C. Treatment with pegylated interferon and ribavirin had begun two months before clinical presentation. After the second dose of interferon, pancytopenia was observed (hemoglobin: 10.9 g/dL, leukocytes: 3,660 cells/μL, platelets: 36,000/μL), decompensated cirrhosis and diabetes mellitus, characterized by moderate ascites and grade 3 hepatic encephalopathy, which overlapped the clinical symptoms described above, despite treatment with therapeutic doses of furosemide, spironolactone, lactulose, NPH and regular human insulin. Patient was listed for liver transplantation. Model of End-Stage Liver Disease (MELD) score equals 14 points. At presentation, cerebrospinal fluid (CSF) showed 21 cells/mL, total protein = 96 mg/dL, glucose = 34 mg/dL (serum glucose: 290 mg/dL), positive India ink staining and cryptococcal antingen titer greater than 1/1,024. Culture for C. neoformans was positive in the CSF, but negative in blood, bone marrow and ascites. Central nervous system computed tomography and magnetic resonance imaging has showed only mild supratentorial hydrocephalous. Patient evolved with intracranial hypertension (the first opening pressure: 36 cmH2O), without improvement by lumbar puncture. Ventriculoperitoneal shunt was performed after two units of apheresis platelets transfusion. The patient was treated with amphotericin B lipid complex 5 mg/kg/day for 30 days and 5-fluorocytosine 100 mg/kg/day for 14 days until three negative cultures for C. neoformans were obtained. During treatment, he presented elevated creatinine (2.0 mg/dL), but without requiring dialysis. There was no worsening of pancytopenia during treatment. Strict monitoring of renal and liver function and bone marrow was performed. Before starting fluconazole 800 mg/day, the patient has presented bloodstream infection associated with central venous catheter by Enterococcus faecalis, and despite appropriate treatment with vancomycin for 10 days, the patient progressed with septic shock syndrome and multiple organ dysfunction syndrome (MODS) and died 40 days after admission. Cryptococcosis affects the central nervous system in 51.3% of HIV-negative patients, after the introduction of azole agents in the market, and in 39% of patients with cirrhosis, as suggested by the two largest studies in the literature.3,4 The peritoneum is the site most associated with cryptococcal infection in cirrhotic patients (45%).4 In 306 HIV-negative patients, the underlying causes were steroids (28%), organ transplant (18%), chronic shortage of organs (liver, respiratory and renal) (18%), neoplasm (18%), rheumatic diseases (13%), and unknown risk factor (22%).3 Malnutrition, in addition to compromised phagocytosis, immunoglobulins and cellular immunity result in increased risk of cryptococcosis in cirrhotic patients.4 The case fatality rate associated with cryptococcosis in cirrhotic patients is 83%, 92% of which attributed to cryptococcosis. In 53% of cases, death occurs in the second week of diagnosis. Culture positivity is 67% and India ink in around 50% in cirrhotic patients and HIV-negative, respectively.1,2

Cryptococcal meningitis presenting with recurrent syncope in a patient with chronic lymphoid leukemia: a case report

The clinical presentations of cryptococcal meningitis in HIV-negative patients may be different from that infected with HIV. We report a case of 75-year old male with chronic lymphoid leukemia presenting with recurrent syncope, bi-frontal headache and diplopia. This case discusses the atypical presentations of cryptococcal meningitis in HIV-negative patients and its importance of early diagnosis.

The prognostic factors of cryptococcal meningitis in HIV-negative patients

Seventy-one patients with cryptococcal meningitis, 46 males and 25 females, aged 15–83 years, were included in this study. Their initial clinical manifestations, cerebrospinal fluid (CSF) features, and therapeutic results were analysed. Patients were treated with three different regimens: amphotericin B, fluconazole, and combination therapy. Based on the therapeutic results, the 71 patients were also divided into cured, improved, and failed groups. For statistical comparison, the clinical manifestations and CSF features, were compared according to therapeutic outcome. There was no statistical difference in outcome among the three different antifungal regimens. However, patients treated with fluconazole required 36% fewer days of hospitalization compared with those receiving amphotericin B. Significant prognostic factors, included low CSF glucose, high CSF lactate, high CSF cryptococcal antigen titre (≥1: 1024), initial level of consciousness, the presence of seizure, hydrocephalus, and central nervous system vasculitis. Multiple logistic regression analysis showed that only initial level of consciousness, and CSF antigen titre were strongly associated with therapeutic failure after other potentially confounding factors were adjusted for. Because some of the prognostic factors in cryptococcal meningitis can be corrected, early diagnosis, early use of appropriate antifungal treatment, and the correction of the underlying metabolic derangements are important in management.