Pierre-Yves Bochud

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.

Bacteremia due to viridans streptococci in neutropenic patients: A review

Viridans streptococci have long been considered, with the exception of the ability to cause endocarditis, as minor pathogenic agents. More recently, however, these bacteria have become a major concern in neutropenic patients undergoing a chemotherapeutic treatment. In this high-risk population, they can be responsible for up to 39% of bacteremia cases and are the most frequent cause of this type of infection. The most frequently isolated species in blood cultures are Streptococcus mitis and Streptococcus sanguis II. Viridans streptococcus bacteremia can be accompanied by serious complications, like adult respiratory distress syndrome (ARDS) (3% to 33%), shock (7% to 18%) or endocarditis (7% to 8%). Mortality rates range from 6% to 30%. Case-control studies have identified the following risk factors: severe neutropenia (< 100 neutrophils/mm3), prophylactic antibiotic treatments with quinolone or co-trimoxazole, absence of intravenous antibiotics at the time of bacteremia, high doses of cytosine arabinoside, oropharyngeal mucositis, and heavy colonization by viridans streptococci. The introduction of penicillin in prophylactic antibiotic treatments has reduced the incidence of these infections, but the long-term use of penicillin could be compromised by the emergence of resistant strains.

Cutting Edge: A Toll-Like Receptor 2 Polymorphism That Is Associated with Lepromatous Leprosy Is Unable to Mediate Mycobacterial Signaling

Toll-like receptors (TLRs) are key mediators of the innate immune response to microbial pathogens. We investigated the role of TLRs in the recognition of Mycobacterium leprae and the significance of TLR2Arg677Trp, a recently discovered human polymorphism that is associated with lepromatous leprosy. In mice, TNF-α production in response to M. leprae was essentially absent in TLR2-deficient macrophages. Similarly, human TLR2 mediated M. leprae-dependent activation of NF-κB in transfected Chinese hamster ovary and human embryonic kidney 293 cells, with enhancement of this signaling in the presence of CD14. In contrast, activation of NF-κB by human TLR2Arg677Trp was abolished in response to M. leprae and Mycobacterium tuberculosis. The impaired function of this TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy and may have important implications for understanding the pathogenesis of other mycobacterial infections.

Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C.

BACKGROUND & AIMS The host immune response during the chronic phase of hepatitis C virus infection varies among individuals; some patients have a no interferon (IFN) response in the liver, whereas others have full activation of IFN-stimulated genes (ISGs). Preactivation of this endogenous IFN system is associated with nonresponse to pegylated IFN-α (pegIFN-α) and ribavirin. Genome-wide association studies have associated allelic variants near the IL28B (IFNλ3) gene with treatment response. We investigated whether IL28B genotype determines the constitutive expression of ISGs in the liver and compared the abilities of ISG levels and IL28B genotype to predict treatment outcome. METHODS We genotyped 109 patients with chronic hepatitis C for IL28B allelic variants and quantified the hepatic expression of ISGs and of IL28B. Decision tree ensembles, in the form of a random forest classifier, were used to calculate the relative predictive power of these different variables in a multivariate analysis. RESULTS The minor IL28B allele was significantly associated with increased expression of ISG. However, stratification of the patients according to treatment response revealed increased ISG expression in nonresponders, irrespective of IL28B genotype. Multivariate analysis of ISG expression, IL28B genotype, and several other factors associated with response to therapy identified ISG expression as the best predictor of treatment response. CONCLUSIONS IL28B genotype and hepatic expression of ISGs are independent predictors of response to treatment with pegIFN-α and ribavirin in patients with chronic hepatitis C. The most accurate prediction of response was obtained with a 4-gene classifier comprising IFI27, ISG15, RSAD2, and HTATIP2.

Pathogenesis of sepsis: new concepts and implications for future treatment

Severe sepsis and septic shock are important causes of death in intensive care units. Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated into clinical benefit. Several new treatment approaches have given encouraging results. Evidence suggests that the way forward is to develop pathogen specific regimens rather than assume that one treatment fits all. #### Summary points Bacterial cell walls, endotoxins, and exotoxins are powerful activators of innate and acquired immune responses Molecules expressed by pathogens interact with Toll-like receptors on immune cells, activating the immune response Cytokines are important in the pathogenesis of sepsis Susceptibility to sepsis may be due to inherited or acquired mutations of innate immune genes Severe sepsis and septic shock are clinical manifestations of a dysregulated immune response to invasive pathogens Adjunctive therapy with low dose steroids, activated protein C or early supportive care can reduce mortality from severe sepsis and septic shock Pathogen recognition receptors (such as Toll-like receptors) and mediators of sepsis (such as macrophage migration inhibitory factor) might be novel targets for treatment We selected articles for this review by searching Medline using the keywords sepsis, therapy, and Toll-like receptors. We concentrated on publications on the pathogenesis of sepsis and treatment of septic shock. As the number of references that could be cited was limited, we have often referenced review articles rather than original publications. Severe sepsis and septic shock are life threatening complications of infections and the most common cause of death in intensive care units. However, a lack of widely accepted definitions of these complications has made it difficult to obtain accurate estimates of their frequency. A study published by the Centers for Disease Control in the United States indicated that the incidence of septicaemia had increased from 73.6 per 100 000 patients in …

Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C

BACKGROUND/AIMS While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression. METHODS We identified 1189 patients from the Swiss Hepatitis C Cohort database with at least one biopsy prior to antiviral treatment and assessable date of infection. Stage-constant fibrosis progression rate was assessed using the ratio of fibrosis Metavir score to duration of infection. Stage-specific fibrosis progression rates were obtained using a Markov model. Risk factors were assessed by univariate and multivariate regression models. RESULTS Independent risk factors for accelerated stage-constant fibrosis progression (>0.083 fibrosis units/year) included male sex (OR=1.60, [95% CI 1.21-2.12], P<0.001), age at infection (OR=1.08, [1.06-1.09], P<0.001), histological activity (OR=2.03, [1.54-2.68], P<0.001) and genotype 3 (OR=1.89, [1.37-2.61], P<0.001). Slower progression rates were observed in patients infected by blood transfusion (P=0.02) and invasive procedures or needle stick (P=0.03), compared to those infected by intravenous drug use. Maximum likelihood estimates (95% CI) of stage-specific progression rates (fibrosis units/year) for genotype 3 versus the other genotypes were: F0-->F1: 0.126 (0.106-0.145) versus 0.091 (0.083-0.100), F1-->F2: 0.099 (0.080-0.117) versus 0.065 (0.058-0.073), F2-->F3: 0.077 (0.058-0.096) versus 0.068 (0.057-0.080) and F3-->F4: 0.171 (0.106-0.236) versus 0.112 (0.083-0.142, overall P<0.001). CONCLUSIONS This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates. This observation may have important consequences for the management of patients infected with this genotype.

IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study.

Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.

Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review.

Objective:In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for antimicrobial therapy for patients with severe sepsis and septic shock that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis. Design:The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. Methods:The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591. Conclusion:Since the prompt institution of therapy that is active against the causative pathogen is one of the most important predictors of outcome, clinicians must establish a system for rapid administration of a rationally chosen drug or combination of drugs when sepsis or septic shock is suspected. The expanding number of antibacterial, antifungal, and antiviral agents available provides opportunities for effective empiric and specific therapy. However, to minimize the promotion of antimicrobial resistance and cost and to maximize efficacy, detailed knowledge of the likely pathogens and the properties of the available drugs is necessary for the intensivist.

IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

A new polymorphism near the IL28B locus negatively affects induction of IL28B and exhibits strong predictive value for HCV treatment response and spontaneous resolution.

Response prediction in chronic hepatitis c by assessment of IP-10 and IL28B-related single nucleotide polymorphisms

Background High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. Methods and Findings In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. Conclusions Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.