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.

Epidemiology and risk factors for non-Candida albicans candidemia in non-neutropenic patients at a Chinese teaching hospital.

The purpose of this study was to describe the epidemiology of nosocomial candidemia and identify risk factors involved in infections caused by non-C. albicans Candida species in a Chinese tertiary care center over a 10-year period. A total of 102 cases of nosocomial candidemia in non-neutropenic patients admitted from 1998 through 2007 were included in the study. Candida albicans remained the most common causative agent, accounting for 57.8% of all cases, followed by C. tropicalis (12.8%), C. parapsilosis (10.8%) and C. glabrata (10.8%). Comparison of C. albicans and non-C. albicans candidemia by multivariate logistic regression showed that factors independently associated with non-C. albicans candidemia included head trauma (OR, 5.34; 95% CI, 1.18-24.17; P = 0.029) and bacterial sepsis (OR, 3.58; 95% CI, 1.17-10.98; P = 0.026). Factors independently associated with C. albicans candidemia included tracheal intubation (OR, 0.26; 95% CI, 0.08-0.92; P = 0.037), and increased peripheral WBC count (OR, 0.84; 95% CI, 0.74-0.95; P = 0.006).

Cryptococcal meningitis in non-HIV-infected patients in a Chinese tertiary care hospital, 1997-2007.

Information remains sparse about non-HIV patients with cryptococcal meningitis in the era of triazole therapy. Particularly of interest are the clinical manifestations and prognosis of the infection in these previously healthy patients. We retrospectively reviewed 154 non-HIV-infected patients with cryptococcal meningitis who presented in our hospital from 1997 to 2007. We compared the clinical features and outcomes between predisposed and otherwise healthy hosts. The number of cases per year showed a steady increase over time. The majority of patients were otherwise apparently healthy (103 patients, 66.9%) and predisposing factors were identified in only 51 (33.1%) patients. Corticosteroid medication accounted for the most common underlying factor in these cases (n = 21). Morbidity was appallingly high, with seizures in 28.6%, cranial nerves palsies in 51.5% and cerebral herniation in 19.5%. Despite these complications, overall mortality during 1 year was 28.7% (41/143), close to that reported from other centers with non-HIV patients. Death attributed to cryptococcosis occurred in 19.6% (28/143) patients with most receiving amphotericin B as a component of their initial therapy. Among surviving patients who had lumbar punctures at weeks 2 and 10, those given amphotericin B for initial therapy achieved higher rates of overall response than those receiving initial fluconazole therapy at either week 2 (84.4% of 96 patients vs. 33.3% of 24 patients, P <0.001) or week 10 (85.0% of 93 patients vs. 66.7% of 24 patients, P = 0.041). In multivariate analysis, coma, cerebral herniation, and initial antifungal therapy without amphotericin B were independently correlated with both increased overall and attributable mortality, while advanced age (>/= 60 years) was correlated with increased overall mortality only. Patients with apparently normal immune status were overall younger than those who were immunocompromised. In addition, previously healthy patients for whom diagnosis was delayed had more severe disease, experiencing more brain herniation, coma, seizures, hydrocephalus and more surgical shunt procedures. On the other hand, immunocompromised patients were more commonly found to have high fever and brain parenchymal involvement. However, both groups had a similar treatment response and 1-year survival.

[The polymorphism of cytochrome P(450) 2C19 gene in patients with invasive fungal infections.].

OBJECTIVE: To investigate the polymorphism profile of cytochrome P(450) 2C19 (CYP2C19) in Chinese patients with invasive fungal infections. METHODS: Two major single nucleotide polymorphism loci of the CYP2C19 gene (CYP2C19*2 and CYP2C19*3) were genotyped with PCR and restriction fragment length polymorphism (PCR-RFLP) in 134 patients with invasive fungal infections and 134 healthy volunteers. Allele frequencies and the proportions of metabolizer phenotypes were compared. RESULTS: In patients with invasive fungal infections, CYP2C19*1, CYP2C19*2 and CYP2C19*3 alleles showed frequencies of 58.2%, 36.6% and 5.2%. In healthy volunteers, the frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 63.4%, 34.3% and 2.2%. There was no significant difference in allele frequencies between the two groups. Of the patients with invasive fungal infections, 33.6% were homozygous extensive metabolizers, 50.0% heterozygous extensive metabolizers and 16.4% poor metabolizers. Of the healthy volunteers, 40.3% were homozygous extensive metabolizers, 48.5% heterozygous extensive metabolizers and 11.2% poor metabolizers. The proportions of metabolizer phenotypes were similar between the two groups. CONCLUSIONS: Significant CYP2C19 polymorphism was detected in both groups. Approximately two thirds of the Chinese patients were either heterozygous extensive metabolizers or poor metabolizers. The genetic polymorphism may have important effect on drug metabolism in these patients.

[Factors associated with mortality in cryptococcal meningitis].

OBJECTIVE: To investigate factors associated with mortality in non-AIDS patients with cryptococcal meningitis. METHODS: We retrospectively reviewed 154 cases of non-HIV cryptococcal meningitis in a tertiary care hospital in China, from 1997 through 2007. RESULTS: 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. CONCLUSION: 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.

[Evaluation of low-dose amphotericin B and flucytosine in the treatment of cryptococcal meningitis].

OBJECTIVE: To evaluate the efficacy and safety of low-dose amphotericin B (< 0.7 mg x kg(-1) x d(-1)) and flucytosine in patients with non-AIDS-associated cryptococcal meningitis. METHODS: In non-AIDS patients with cryptococcal meningitis admitted to Huashan Hospital, Fudan University in Shanghai from January 1998 to December 2007, 31 were initially treated with low-dose amphotericin B and flucytosine for more than 1 week. The clinical characteristics, clinical responses, drug-related adverse reactions and outcome of these patients were retrospectively evaluated. RESULTS: Among the 31 patients enrolled in this study, 8 patients had one or more predisposing factors. Headache, fever, meningeal irritation and vomiting were common clinical symptoms and signs when cryptococcal meningitis was diagnosed. The result of cranial CT scan and/or MRI showed abnormality in 22 cases (78.6%). When the therapy of low-dose amphotericin B and flucytosine ended, the complete response rate was 19.4% (6/31), partial response rate was 54.8% (17/31), and total effective rate was 74.2%. Except for 1 patient lost to follow-up, the 1-year attributable and all-cause mortality among the remaining 30 patients were 0 (0/30) and 10.0% (3/30) respectively. On the other hand, 26 (83.9%) patients had amphotericin B-related adverse reactions, including renal impairment, liver injury, arrhythmia, and anemia, etc. However, most of these reactions were tolerable. CONCLUSION: Low-dose amphotericin B and flucytosine can be used in non-AIDS-associated cryptococcal meningitis with both acceptable efficacy and safety.

Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients.

BACKGROUND: As important regulators of the immune system, the human Fcγ receptors (FcγRs) have been demonstrated to play important roles in the pathogenesis of various infectious diseases. The aim of the present study was to identify the association between FCGR polymorphisms and cryptococcal meningitis. METHODOLOGY/PRINCIPAL FINDINGS: In this case control genetic association study, we genotyped four functional polymorphisms in low-affinity FcγRs, including FCGR2A 131H/R, FCGR3A 158F/V, FCGR3B NA1/NA2, and FCGR2B 232I/T, in 117 patients with cryptococcal meningitis and 190 healthy controls by multiplex SNaPshot technology. Among the 117 patients with cryptococcal meningitis, 59 had predisposing factors. In patients with cryptococcal meningitis, the FCGR2B 232I/I genotype was over-presented (OR = 1.652, 95% CI [1.02-2.67]; P = 0.039) and the FCGR2B 232I/T genotype was under-presented (OR = 0.542, 95% CI [0.33-0.90]; P = 0.016) in comparison with control group. In cryptococcal meningitis patients without predisposing factors, FCGR2B 232I/I genotype was also more frequently detected (OR = 1.958, 95% CI [1.05-3.66]; P = 0.033), and the FCGR2B 232I/T genotype was also less frequently detected (OR = 0.467, 95% CI [0.24-0.91]; P = 0.023) than in controls. No significant difference was found among FCGR2A 131H/R, FCGR3A 158F/V, and FCGR3B NA1/NA2 genotype frequencies between patients and controls. CONCLUSION/SIGNIFICANCE: We found for the first time associations between cryptococcal meningitis and FCGR2B 232I/T genotypes, which suggested that FcγRIIB might play an important role in the central nervous system infection by Cryptococcus in HIV-uninfected individuals.