Randomized, double-blind comparative trial of subunit and virosomal influenza vaccines for immunocompromised patients

BACKGROUND: To our knowledge, no study to date has compared the effects of a subunit influenza vaccine with those of a virosomal influenza vaccine on immunocompromised patients. METHODS: A prospective, double-blind, randomized study was conducted to compare the immunogenicity and reactogenicity of subunit and virosomal influenza vaccines for adult patients who had an immunosuppressive disease or who were immunocompromised as a result of treatment. RESULTS: There were 304 patients enrolled in our study: 131 with human immunodeficiency virus (HIV) infection, 47 with a chronic rheumatologic disease, 74 who underwent a renal transplant, 47 who received long-term hemodialysis, and 5 who had some other nephrologic disease. There were 151 patients who received the subunit vaccine and 153 patients who received the virosomal vaccine. A slightly higher percentage of patients from the subunit vaccine group were protected against all 3 influenza vaccine strains after being vaccinated, compared with patients from the virosomal vaccine group (41% vs. 30% of patients; P = .03). Among HIV-infected patients, the level of HIV RNA, but not the CD4 cell count, was an independent predictor of vaccine response. Among renal transplant patients, treatment with mycophenolate significantly reduced the immune response to vaccination. The 2 vaccines were comparable with regard to the frequency and severity of local and systemic reactions within 7 days after vaccination. Disease-specific scores for the activity of rheumatologic diseases did not indicate flare-ups 4-6 weeks after vaccination. CONCLUSIONS: For immunosuppressed patients, the subunit vaccine was slightly more immunogenic than the virosomal vaccine. The 2 vaccines were comparable with regard to reactogenicity. Vaccine response decreased with increasing degree of immune suppression. Among HIV-infected patients, the viral load, rather than the CD4 cell count, predicted the protective immune response to the vaccine. CLINICAL TRIALS REGISTRATION: NCT00783380 .

Effectiveness and cost-effectiveness of traditional and new partner notification technologies for curable sexually transmitted infections: observational study, systematic reviews and mathematical modelling

BACKGROUND Partner notification is essential to the comprehensive case management of sexually transmitted infections. Systematic reviews and mathematical modelling can be used to synthesise information about the effects of new interventions to enhance the outcomes of partner notification. OBJECTIVE To study the effectiveness and cost-effectiveness of traditional and new partner notification technologies for curable sexually transmitted infections (STIs). DESIGN Secondary data analysis of clinical audit data; systematic reviews of randomised controlled trials (MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials) published from 1 January 1966 to 31 August 2012 and of studies of health-related quality of life (HRQL) [MEDLINE, EMBASE, ISI Web of Knowledge, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] published from 1 January 1980 to 31 December 2011; static models of clinical effectiveness and cost-effectiveness; and dynamic modelling studies to improve parameter estimation and examine effectiveness. SETTING General population and genitourinary medicine clinic attenders. PARTICIPANTS Heterosexual women and men. INTERVENTIONS Traditional partner notification by patient or provider referral, and new partner notification by expedited partner therapy (EPT) or its UK equivalent, accelerated partner therapy (APT). MAIN OUTCOME MEASURES Population prevalence; index case reinfection; and partners treated per index case. RESULTS Enhanced partner therapy reduced reinfection in index cases with curable STIs more than simple patient referral [risk ratio (RR) 0.71; 95% confidence interval (CI) 0.56 to 0.89]. There are no randomised trials of APT. The median number of partners treated for chlamydia per index case in UK clinics was 0.60. The number of partners needed to treat to interrupt transmission of chlamydia was lower for casual than for regular partners. In dynamic model simulations, > 10% of partners are chlamydia positive with look-back periods of up to 18 months. In the presence of a chlamydia screening programme that reduces population prevalence, treatment of current partners achieves most of the additional reduction in prevalence attributable to partner notification. Dynamic model simulations show that cotesting and treatment for chlamydia and gonorrhoea reduce the prevalence of both STIs. APT has a limited additional effect on prevalence but reduces the rate of index case reinfection. Published quality-adjusted life-year (QALY) weights were of insufficient quality to be used in a cost-effectiveness study of partner notification in this project. Using an intermediate outcome of cost per infection diagnosed, doubling the efficacy of partner notification from 0.4 to 0.8 partners treated per index case was more cost-effective than increasing chlamydia screening coverage. CONCLUSIONS There is evidence to support the improved clinical effectiveness of EPT in reducing index case reinfection. In a general heterosexual population, partner notification identifies new infected cases but the impact on chlamydia prevalence is limited. Partner notification to notify casual partners might have a greater impact than for regular partners in genitourinary clinic populations. Recommendations for future research are (1) to conduct randomised controlled trials using biological outcomes of the effectiveness of APT and of methods to increase testing for human immunodeficiency virus (HIV) and STIs after APT; (2) collection of HRQL data should be a priority to determine QALYs associated with the sequelae of curable STIs; and (3) standardised parameter sets for curable STIs should be developed for mathematical models of STI transmission that are used for policy-making. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Treatment-naive individuals are the major source of transmitted HIV-1 drug resistance in men who have sex with men in the Swiss HIV Cohort Study

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) can compromise antiretroviral therapy (ART) and thus represents an important public health concern. Typically, sources of TDR remain unknown, but they can be characterized with molecular epidemiologic approaches. We used the highly representative Swiss HIV Cohort Study (SHCS) and linked drug resistance database (SHCS-DRDB) to analyze sources of TDR. METHODS ART-naive men who have sex with men with infection date estimates between 1996 and 2009 were chosen for surveillance of TDR in HIV-1 subtype B (N = 1674), as the SHCS-DRDB contains pre-ART genotypic resistance tests for >69% of this surveillance population. A phylogeny was inferred using pol sequences from surveillance patients and all subtype B sequences from the SHCS-DRDB (6934 additional patients). Potential sources of TDR were identified based on phylogenetic clustering, shared resistance mutations, genetic distance, and estimated infection dates. RESULTS One hundred forty of 1674 (8.4%) surveillance patients carried virus with TDR; 86 of 140 (61.4%) were assigned to clusters. Potential sources of TDR were found for 50 of 86 (58.1%) of these patients. ART-naive patients constitute 56 of 66 (84.8%) potential sources and were significantly overrepresented among sources (odds ratio, 6.43 [95% confidence interval, 3.22-12.82]; P < .001). Particularly large transmission clusters were observed for the L90M mutation, and the spread of L90M continued even after the near cessation of antiretroviral use selecting for that mutation. Three clusters showed evidence of reversion of K103N or T215Y/F. CONCLUSIONS Many individuals harboring viral TDR belonged to transmission clusters with other Swiss patients, indicating substantial domestic transmission of TDR in Switzerland. Most TDR in clusters could be linked to sources, indicating good surveillance of TDR in the SHCS-DRDB. Most TDR sources were ART naive. This, and the presence of long TDR transmission chains, suggests that resistance mutations are frequently transmitted among untreated individuals, highlighting the importance of early diagnosis and treatment.

Strategies for partner notification for sexually transmitted infections, including HIV

BACKGROUND Partner notification (PN) is the process whereby sexual partners of an index patient are informed of their exposure to a sexually transmitted infection (STI) and the need to obtain treatment. For the person (index patient) with a curable STI, PN aims to eradicate infection and prevent re-infection. For sexual partners, PN aims to identify and treat undiagnosed STIs. At the level of sexual networks and populations, the aim of PN is to interrupt chains of STI transmission. For people with viral STI, PN aims to identify undiagnosed infections, which can facilitate access for their sexual partners to treatment and help prevent transmission. OBJECTIVES To assess the effects of different PN strategies in people with STI, including human immunodeficiency virus (HIV) infection. SEARCH METHODS We searched electronic databases (the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE) without language restrictions. We scanned reference lists of potential studies and previous reviews and contacted experts in the field. We searched three trial registries. We conducted the most recent search on 31 August 2012. SELECTION CRITERIA Published or unpublished randomised controlled trials (RCTs) or quasi-RCTs comparing two or more PN strategies. Four main PN strategies were included: patient referral, expedited partner therapy, provider referral and contract referral. Patient referral means that the patient notifies their sexual partners, either with (enhanced patient referral) or without (simple patient referral) additional verbal or written support. In expedited partner therapy, the patient delivers medication or a prescription for medication to their partner(s) without the need for a medical examination of the partner. In provider referral, health service personnel notify the partners. In contract referral, the index patient is encouraged to notify partner, with the understanding that the partners will be contacted if they do not visit the health service by a certain date. DATA COLLECTION AND ANALYSIS We analysed data according to paired partner referral strategies. We organised the comparisons first according to four main PN strategies (1. enhanced patient referral, 2. expedited partner therapy, 3. contract referral, 4. provider referral). We compared each main strategy with simple patient referral and then with each other, if trials were available. For continuous outcome measures, we calculated the mean difference (MD) with 95% confidence intervals (CI). For dichotomous variables, we calculated the risk ratio (RR) with 95% CI. We performed meta-analyses where appropriate. We performed a sensitivity analysis for the primary outcome re-infection rate of the index patient by excluding studies with attrition of greater than 20%. Two review authors independently assessed the risk of bias and extracted data. We contacted study authors for additional information. MAIN RESULTS We included 26 trials (17,578 participants, 9015 women and 8563 men). Five trials were conducted in developing countries. Only two trials were conducted among HIV-positive patients. There was potential for selection bias, owing to the methods of allocation used and of performance bias, owing to the lack of blinding in most included studies. Seven trials had attrition of greater than 20%, increasing the risk of bias.The review found moderate-quality evidence that expedited partner therapy is better than simple patient referral for preventing re-infection of index patients when combining trials of STIs that caused urethritis or cervicitis (6 trials; RR 0.71, 95% CI 0.56 to 0.89, I(2) = 39%). When studies with attrition greater than 20% were excluded, the effect of expedited partner therapy was attenuated (2 trials; RR 0.8, 95% CI 0.62 to 1.04, I(2) = 0%). In trials restricted to index patients with chlamydia, the effect was attenuated (2 trials; RR 0.90, 95% CI 0.60 to 1.35, I(2) = 22%). Expedited partner therapy also increased the number of partners treated per index patient (three trials) when compared with simple patient referral in people with chlamydia or gonorrhoea (MD 0.43, 95% CI 0.28 to 0.58) or trichomonas (MD 0.51, 95% CI 0.35 to 0.67), and people with any STI syndrome (MD 0.5, 95% CI 0.34 to 0.67). Expedited partner therapy was not superior to enhanced patient referral in preventing re-infection (3 trials; RR 0.96, 95% CI 0.60 to 1.53, I(2) = 33%, low-quality evidence). Home sampling kits for partners (four trials) did not result in lower rates of re-infection in the index case (measured in one trial), or higher numbers of partners elicited (three trials), notified (two trials) or treated (one trial) when compared with simple patient referral. There was no consistent evidence for the relative effects of provider, contract or other patient referral methods. In one trial among men with non-gonococcal urethritis, more partners were treated with provider referral than with simple patient referral (MD 0.5, 95% CI 0.37 to 0.63). In one study among people with syphilis, contract referral elicited treatment of more partners than provider referral (MD 2.2, 95% CI 1.95 to 2.45), but the number of partners receiving treatment was the same in both groups. Where measured, there was no statistical evidence of differences in the incidence of adverse effects between PN strategies. AUTHORS' CONCLUSIONS The evidence assessed in this review does not identify a single optimal strategy for PN for any particular STI. When combining trials of STI causing urethritis or cervicitis, expedited partner therapy was more successful than simple patient referral for preventing re-infection of the index patient but was not superior to enhanced patient referral. Expedited partner therapy interventions should include all components that were part of the trial intervention package. There was insufficient evidence to determine the most effective components of an enhanced patient referral strategy. There are too few trials to allow consistent conclusions about the relative effects of provider, contract or other patient referral methods for different STIs. More high-quality RCTs of PN strategies for HIV and syphilis, using biological outcomes, are needed.

Clinical signs of deformed wing virus infection are predictive markers for honey bee colony losses.

The ectoparasitic mite Varroa destructor acting as a virus vector constitutes a central mechanism for losses of managed honey bee, Apis mellifera, colonies. This creates demand for an easy, accurate and cheap diagnostic tool to estimate the impact of viruliferous mites in the field. Here we evaluated whether the clinical signs of the ubiquitous and mite-transmitted deformed wing virus (DWV) can be predictive markers of winter losses. In fall and winter 2007/2008, A.m. carnica workers with apparent wing deformities were counted daily in traps installed on 29 queenright colonies. The data show that colonies which later died had a significantly higher proportion of workers with wing deformities than did those which survived. There was a significant positive correlation between V. destructor infestation levels and the number of workers displaying DWV clinical signs, further supporting the mite's impact on virus infections at the colony level. A logistic regression model suggests that colony size, the number of workers with wing deformities and V. destructor infestation levels constitute predictive markers for winter colony losses in this order of importance and ease of evaluation.

Survey of bluetongue virus infection in free-ranging wild ruminants in Switzerland.

BACKGROUND In 2006, bluetongue virus serotype 8 (BTV-8) was detected for the first time in central Europe. Measures to control the infection in livestock were implemented in Switzerland but the question was raised whether free-ranging wildlife could be a maintenance host for BTV-8. Furthermore Toggenburg orbivirus (TOV), considered as a potential 25th BTV serotype, was detected in 2007 in domestic goats in Switzerland and wild ruminants were considered a potential source of infection. To assess prevalences of BTV-8 and TOV infections in wildlife, we conducted a serological and virological survey in red deer, roe deer, Alpine chamois and Alpine ibex between 2009 and 2011. Because samples originating from wildlife carcasses are often of poor quality, we also documented the influence of hemolysis on test results, and evaluated the usefulness of confirmatory tests. RESULTS Ten out of 1,898 animals (0.5%, 95% confidence interval 0.3-1.0%) had detectable antibodies against BTV-8 and BTV-8 RNA was found in two chamois and one roe deer (0.3%, 0.1-0.8%). Seroprevalence was highest among red deer, and the majority of positive wild animals were sampled close to areas where outbreaks had been reported in livestock. Most samples were hemolytic and the range of the optical density percentage values obtained in the screening test increased with increasing hemolysis. Confirmatory tests significantly increased specificity of the testing procedure and proved to be applicable even on poor quality samples. Nearly all samples confirmed as positive had an optical density percentage value greater than 50% in the ELISA screening. CONCLUSIONS Prevalence of BTV-8 infection was low, and none of the tested animals were positive for TOV. Currently, wild ruminants are apparently not a reservoir for these viruses in Switzerland. However, we report for the first time BTV-8 RNA in Alpine chamois. This animal was found at high altitude and far from a domestic outbreak, which suggests that the virus could spread into/through the Alps. Regarding testing procedures, hemolysis did not significantly affect test results but confirmatory tests proved to be necessary to obtain reliable prevalence estimates. The cut-off value recommended by the manufacturer for the screening test was applicable for wildlife samples.

Risk factors for anal cancer in persons infected with HIV: a nested case-control study in the Swiss HIV Cohort Study

Although persons infected with human immunodeficiency virus (HIV), particularly men who have sex with men, are at excess risk for anal cancer, it has been difficult to disentangle the influences of anal exposure to human papillomavirus (HPV) infection, immunodeficiency, and combined antiretroviral therapy. A case-control study that included 59 anal cancer cases and 295 individually matched controls was nested in the Swiss HIV Cohort Study (1988-2011). In a subset of 41 cases and 114 controls, HPV antibodies were tested. A majority of anal cancer cases (73%) were men who have sex with men. Current smoking was significantly associated with anal cancer (odds ratio (OR) = 2.59, 95% confidence interval (CI): 1.25, 5.34), as were antibodies against L1 (OR = 4.52, 95% CI: 2.00, 10.20) and E6 (OR = ∞, 95% CI: 4.64, ∞) of HPV16, as well as low CD4+ cell counts, whether measured at nadir (OR per 100-cell/μL decrease = 1.53, 95% CI: 1.18, 2.00) or at cancer diagnosis (OR per 100-cell/μL decrease = 1.24, 95% CI: 1.08, 1.42). However, the influence of CD4+ cell counts appeared to be strongest 6-7 years prior to anal cancer diagnosis (OR for <200 vs. ≥500 cells/μL = 14.0, 95% CI: 3.85, 50.9). Smoking cessation and avoidance of even moderate levels of immunosuppression appear to be important in reducing long-term anal cancer risks.

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

Influence of Geographical Origin and Ethnicity on Mortality in Patients on Antiretroviral Therapy in Canada, Europe, and the United States

Our objective was to assess differences in all-cause mortality, as well as AIDS and non-AIDS death rates, among patients started on antiretroviral therapy (ART) according to their geographical origin and ethnicity/race in Europe, Canada, and the United States. METHODS: This was a collaboration of 19 cohort studies of human immunodeficiency virus-positive subjects who have initiated ART (ART Cohort Collaboration) between 1998 and 2009. Adjusted mortality hazard ratios (AHRs) were estimated using Cox regression. A competing risk framework was used to estimate adjusted subdistribution hazard ratios for AIDS and non-AIDS mortality. RESULTS: Of 46 648 European patients, 16.3% were from sub-Saharan Africa (SSA), 5.1% Caribbean and Latin America, 1.6% North Africa and Middle East, and 1.7% Asia/West; of 1371 patients from Canada, 14.9% were First Nations and 22.4% migrants, and of 7742 patients from North America, 55.5% were African American and 6.6% Hispanic. Migrants from SSA (AHR, 0.79; 95% confidence interval [CI], .68-.92) and Asia/West (AHR, 0.62; 95% CI, .41-.92) had lower mortality than Europeans; these differences appeared mainly attributable to lower non-AIDS mortality. Compared with white Canadians, mortality in Canadian First Nations people (AHR, 1.48; 95% CI, .96-2.29) was higher, both for AIDS and non-AIDS mortality rates. Among US patients, when compared with whites, African Americans had higher AIDS and non-AIDS mortality, and hazard ratios for all-cause mortality increased with time on ART. CONCLUSIONS: The lower mortality observed in migrants suggests "healthy migrant" effects, whereas the higher mortality in First Nations people and African Americans in North America suggests social inequality gaps. KEYWORDS: HIV infection, antiretroviral therapy, ethnic minorities, migrants Comment in Addressing disparities in HIV mortality: antiretroviral therapy is necessary but not sufficient. [Clin Infect Dis. 2013]

Prevalence and risk factors of late presentation for HIV diagnosis and care in a tertiary referral centre in Switzerland.

QUESTIONS UNDER STUDY We sought to identify reasons for late human immunodeficiency virus (HIV) testing or late presentation for care. METHODS A structured chart review was performed to obtain data on test- and health-seeking behaviour of patients presenting late with CD4 cell counts below 350 cells/µl or with acquired immunodeficiency syndrome (AIDS), at the Zurich centre of the Swiss HIV Cohort Study between January 2009 and December 2011. Logistic regression analyses were used to compare demographic characteristics of persons presenting late with not late presenters. RESULTS Of 281 patients, 45% presented late, 48% were chronically HIV-infected non-late presenters, and an additional 7% fulfilled the <350 CD4 cells/µl criterion for late presentation but a chart review revealed that lymphopenia was caused by acute HIV infection. Among the late presenters, 60% were first tested HIV positive in a private practice. More than half of the tests (60%) were suggested by a physician, only 7% following a specific risk situation. The majority (88%) of patients entered medical care within 1 month of testing HIV positive. Risk factors for late presentation were older age (odds ratio [OR] for ≥50 vs <30 years: 3.16, p = 0.017), Asian versus Caucasian ethnicity (OR 3.5, p = 0.021). Compared with men who have sex with men (MSM) without stable partnership, MSM in a stable partnership appeared less likely to present late (OR 0.50, p = 0.034), whereas heterosexual men in a stable partnership had a 2.72-fold increased odds to present late (p = 0.049). CONCLUSIONS The frequency of late testing could be reduced by promoting awareness, particularly among older individuals and heterosexual men in stable partnerships.

Recommendations for the Management of Hepatitis C Virus Infection Among People Who Inject Drugs

In the developed world, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). The burden of HCV-related liver disease in this group is increasing, but treatment uptake among PWID remains low. Among PWID, there are a number of barriers to care that should be considered and systematically addressed, but these barriers should not exclude PWID from HCV treatment. Furthermore, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provides a framework for HCV assessment, management, and treatment. Further research is needed to evaluate strategies to enhance assessment, adherence, and SVR among PWID, particularly as new treatments for HCV infection become available.

Chronic hepatitis B virus coinfection is associated with renal impairment among Zambian HIV-infected adults.

Among 6789 HIV-infected Zambian adults screened for hepatitis B virus (HBV) coinfection, estimated glomerular filtration rate (eGFR) was 50-90 mL/minute/1.73 m(2) in 17.6% and <50 mL/minute/1.73 m(2) in 2.5%. Human immunodeficiency virus/HBV coinfection was associated with eGFR <50 mL/minute/1.73 m(2) (adjusted odds ratio, 1.96 [95% confidence interval, 1.34-2.86]), adjusted for age, sex, CD4(+) count, and World Health Organization disease stage.

Persistent and compartmentalised disruption of dendritic cell subpopulations in the lung following influenza A virus infection.

Immunological homeostasis in the respiratory tract is thought to require balanced interactions between networks of dendritic cell (DC) subsets in lung microenvironments in order to regulate tolerance or immunity to inhaled antigens and pathogens. Influenza A virus (IAV) poses a serious threat of long-term disruption to this balance through its potent pro-inflammatory activities. In this study, we have used a BALB/c mouse model of A/PR8/34 H1N1 Influenza Type A Virus infection to examine the effects of IAV on respiratory tissue DC subsets during the recovery phase following clearance of the virus. In adult mice, we found differences in the kinetics and activation states of DC residing in the airway mucosa (AMDC) compared to those in the parenchymal lung (PLDC) compartments. A significant depletion in the percentage of AMDC was observed at day 4 post-infection that was associated with a change in steady-state CD11b+ and CD11b- AMDC subset frequencies and significantly elevated CD40 and CD80 expression and that returned to baseline by day 14 post-infection. In contrast, percentages and total numbers of PLDC were significantly elevated at day 14 and remained so until day 21 post-infection. Accompanying this was a change in CD11b+and CD11b- PLDC subset frequencies and significant increase in CD40 and CD80 expression at these time points. Furthermore, mice infected with IAV at 4 weeks of age showed a significant increase in total numbers of PLDC, and increased CD40 expression on both AMDC and PLDC, when analysed as adults 35 days later. These data suggest that the rate of recovery of DC populations following IAV infection differs in the mucosal and parenchymal compartments of the lung and that DC populations can remain disrupted and activated for a prolonged period following viral clearance, into adulthood if infection occurred early in life.

Metabolomics reveals that aldose reductase activity due to AKR1B10 is upregulated in hepatitis C virus infection

To understand the changes in the metabolome of hepatitis C virus (HCV)-infected persons, we conducted a metabolomic investigation in both plasma and urine of 30 HCV-positive individuals using plasmas from 30 HCV-negative blood donors and urines from 30 healthy volunteers. Samples were analysed by gas chromatography-mass spectrometry and data subjected to multivariate analysis. The plasma metabolomic phenotype of HCV-positive persons was found to have elevated glucose, mannose and oleamide, together with depressed plasma lactate. The urinary metabolomic phenotype of HCV-positive persons comprised reduced excretion of fructose and galactose combined with elevated urinary excretion of 6-deoxygalactose (fucose) and the polyols sorbitol, galactitol and xylitol. HCV-infected persons had elevated galactitol/galactose and sorbitol/glucose urinary ratios, which were highly correlated. These observations pointed to enhanced aldose reductase activity, and this was confirmed by real-time quantitative polymerase chain reaction with AKR1B10 gene expression elevated sixfold in the liver. In contrast, AKR1B1 gene expression was reduced 40% in HCV-positive livers. Interestingly, persons who were formerly HCV infected retained the metabolomic phenotype of HCV infection without reverting to the HCV-negative metabolomic phenotype. This suggests that the effects of HCV on hepatic metabolism may be long lived. Hepatic AKR1B10 has been reported to be elevated in hepatocellular carcinoma and in several premalignant liver diseases. It would appear that HCV infection alone increases AKR1B10 expression, which manifests itself as enhanced urinary excretion of polyols with reduced urinary excretion of their corresponding hexoses. What role the polyols play in hepatic pathophysiology of HCV infection and its sequelae is currently unknown.