Presumably hospital-transmitted Clostridium difficile infections based on epidemiological linkage.

OBJECTIVES: Given the traditionally low CDAD (Clostridium difficile associated diarrhoea) prevalence in Switzerland, CDAD patients are not routinely contact-isolated in our institution. In light of the globally changing C. difficile epidemiology, we sought to determine our institutional CDAD rate and to detect possible hospital transmission by means of epidemiological linkage. METHODS: We included every CDAD patient hospitalised in our institution, a tertiary-care hospital in eastern Switzerland, in 2009/2010. Patients with healthcare facility associated (HCFA) CDAD were grouped into cases with and without exposure to an infectious CDAD patient. Exposure was defined as sharing the room/ward with an infectious patient before symptom onset, either at the same time or within 30 days after discharge of the infectious patient. Molecular strain typing was not performed. RESULTS: We registered 141 CDAD episodes. Among them 108 were HCFA (associated with our institution), corresponding to an incidence of 2.3/10,000 patient days. Fifty-six percent (60/108) were exposed to an infectious CDAD patient, suggesting hospital transmission. The number of patients without exposure remained relatively stable, whereas presumably transmitted cases - often occurring within spatiotemporal clusters - showed high variability over time. Presumably transmitted cases were significantly older (p = 0.032) and more likely to have a Charlson score >1 (p = 0.001). CONCLUSION: In our setting, 56% of healthcare associated CDAD cases have been exposed to an infectious CDAD patient. In view of the clustering of these presumed hospital transmissions, we consider an intensification of our current infection control measures, mainly on wards with elderly and comorbid patients which are particularly prone to C. difficile transmission.

Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo.

The antiviral potency of the cytokine IFN-α has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-α-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-α treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated IFN-α/ribavirin (IFN-α/riba) combination therapy. IFN-α/riba therapy decreased HIV-1 viral load by -0.921 (±0.858) log(10) copies/mL in HIV/HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-α/riba treatment in patient-derived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's ρ), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-α/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-α in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.

MRSA admission screening in a low prevalence setting - much ado about nothing?

OBJECTIVE: To prospectively evaluate new guidelines for MRSA admission screening and pre-emptive isolation implemented in response to a doubling of newly diagnosed MRSA patients in 2007. DESIGN: One-year surveillance (04/2008-03/2009). SETTING: Patients admitted to the tertiary-care hospital in St. Gallen (700 beds) and 10 affiliated public hospitals (890 beds) in Eastern Switzerland (MRSA rate 2.5% in isolates). PATIENTS: Except for known MRSA carriers, all patients who underwent admission screening in accordance with the guidelines and all MRSA patients newly detected by a clinical sample were included. METHODS: Depending on epidemiological factors (stay in a foreign hospital, a Swiss hospital with known high MRSA prevalence, or a chronic care facility) and personal risk factors (wound, tracheostoma, urinary catheter, IVDU), patients were risk stratified into screening and isolation, only screening or no screening at all. MRSA admission screening included nasal, throat and axillary/inguinal swabs, supplemented by wound swabs, urine and respiratory secretion whenever appropriate (conventional culture). RESULTS: A total of 6/161 (3.7%) MRSA admission screenings yielded positive results (number needed to screen: 27). 2/32 (6.3%) pre-emptively isolated patients were positive (number needed to isolate: 16). Only 6/27 (22.2%) newly diagnosed MRSA patients were detected by admission screening, and the remaining patients were detected by clinical sample during hospitalisation. A total of 80% of the MRSA positive patients had wounds. Swabs of axilla/inguina did not increase the sensitivity of the admission screening. CONCLUSIONS: In the setting of low MRSA prevalence, admission screening of patients at high risk for MRSA carriage detected only one out of five newly diagnosed MRSA patients, emphasising the importance of standard precautions for the prevention of MRSA transmission.

Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland.

We screened 735 HIV-infected patients in Switzerland with unexplained alanine aminotransferase elevation for hepatitis E virus (HEV) immunoglobulin G. Although HEV seroprevalence in this population is low (2.6%), HEV RNA can persist in patients with low CD4 cell counts. Findings suggest chronic HEV infection should be considered as a cause of persistent alanine aminotransferase elevation.

Management of hepatitis C virus (HCV) infection in drug substitution programs.

BACKGROUND: In Switzerland, intravenous drug use (IDU) accounts for 80% of newly acquired hepatitis C virus (HCV) infections. Early HCV treatment has the potential to interrupt the transmission chain and reduce morbidity/mortality due to decompensated liver cirrhosis and hepatocellular carcinoma. Nevertheless, patients in drug substitution programs are often insufficiently screened and treated. OBJECTIVE/METHODS: With the aim to improve HCV management in IDUs, we conducted a cross sectional chart review in three opioid substitution programs in St. Gallen (125 methadone and 71 heroin recipients). Results were compared with another heroin substitution program in Bern (202 patients) and SCCS/SHCS data. RESULTS: Among the methadone/heroin recipients in St. Gallen, diagnostic workup of HCV was better than expected: HCV/HIV-status was unknown in only 1% (2/196), HCV RNA was not performed in 9% (13/146) of anti-HCV-positives and the genotype missing in 15% (12/78) of HCV RNA-positives. In those without spontaneous clearance (two thirds), HCV treatment uptake was 23% (21/91) (HIV-: 29% (20/68), HIV+: 4% (1/23)), which was lower than in methadone/heroin recipients and particularly non-IDUs within the SCCS/SHCS, but higher than in the, mainly psychiatrically focussed, heroin substitution program in Bern (8%). Sustained virological response (SVR) rates were comparable in all settings (overall: 50%, genotype 1: 35-40%, genotype 3: two thirds). In St. Gallen, the median delay from the estimated date of infection (IDU start) to first diagnosis was 10 years and to treatment was another 7.5 years. CONCLUSIONS: Future efforts need to focus on earlier HCV diagnosis and improvement of treatment uptake among patients in drug substitution programs, particularly if patients are HIV-co-infected. New potent drugs might facilitate the decision to initiate treatment.

Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.

BACKGROUND & AIMS: Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS: The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.

Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study.

BACKGROUND: HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single-nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies have reliably associated common SNPs to dyslipidemia in the general population. METHODS AND RESULTS: We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity, and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34 565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with genome-wide association study estimates. SNPs explained up to 7.6% (non-high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an approximately 3- to 5-fold increased risk of sustained dyslipidemia compared with an individual with the least dyslipidemic therapy and genetic background. CONCLUSIONS: In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.

Unusually high HIV infectiousness in an HIV-, HCV- and HSV-2-coinfected heterosexual man.

We report an HIV-HCV-HSV-2-coinfected man, who infected all of five sequential female sexual partners within seven years. HIV-RNA in semen was unusually high and exceeded that in plasma by one log10. Screening for sexually transmitted diseases remained negative with the exception of HSV-2-seropositivity. Recurrent asymptomatic genital herpes might explain the patient's increased HIV-RNA shedding in semen.

Delayed diagnosis of atypical mycobacterial skin and soft tissue infections in non-immunocompromized hosts.

Relapsing or persisting skin and soft tissue infections after injury with biological materials should prompt consideration of atypical mycobacteria, even in non-immunocompromized hosts. We report 3 cases where diagnosis was delayed for 3-10 months. Insidiously, Mycobacterium marinum infection can occur without any contact to fish tank or swimming pool.

Rho protein-mediated changes in the structure of the actin cytoskeleton regulate human inducible NO synthase gene expression.

Rho proteins (Rho, Rac, Cdc 42) are known to control the organization of the actin cytoskeleton as well as gene expression. Inhibition of Rho proteins by Clostridium difficile toxin B disrupted the F-actin cytoskeleton and enhanced cytokine-induced inducible nitric oxide synthase (iNOS) expression in human epithelial cells. Also specific inhibition by Y-27632 of p160ROCK, which mediates Rho effects on actin fibers, caused a disruption of the actin cytoskeleton and a superinduction of cytokine-induced iNOS expression. Accordingly, direct disruption of the actin cytoskeleton by cytochalasin D, latrunculin B, or jasplakinolide enhanced cytokine-induced iNOS expression. The transcription factor serum response factor (SRF) has been described as mediating actin cytoskeleton-dependent regulation of gene expression. Direct targets of SRF are activating protein 1 (AP1)-dependent genes. All compounds used inhibited SRF- and AP1-dependent reporter gene expression in DLD-1 cells. However, the enhancing effect of the actin cytoskeleton-disrupting compounds on human iNOS promoter activity was much less pronounced than the effect on iNOS mRNA expression. Therefore, besides transcriptional mechanisms, posttranscriptional effects seem to be involved in the regulation of iNOS expression by the above compounds. In conclusion, our data suggest that Rho protein-mediated changes of the actin cytoskeleton negatively modulate the expression of human iNOS.