[Pemphigus and herpes: Multicentre survey and literature review]. / Pemphigus et herpès : enquête multicentrique et revue de la littérature.

BACKGROUND: Although herpes superinfection is a well-known complication of pemphigus, it has not been widely investigated. AIM: To investigate the frequency and features of herpes infection in patients with ongoing pemphigus. PATIENTS AND METHODS: We carried out a multicenter retrospective study between 2008 and 2016 in patients with newly diagnosed pemphigus presenting active herpes infection. Clinical, virological, immunological and therapeutic data were collated. We performed a literature review for pemphigus and herpes. RESULTS: Among the 191 pemphigus patients, screening for herpes (PCR or culture) was carried out in 11 to 71 % of subjects, depending on the center in question. Twenty-four patients (12 women, mean age 58 years) presented at least one episode of herpes infection. The frequency of positivity ranged from 0 to 42 % by center. Twenty-one cases consisted of pemphigus vulgaris and infection occurred at a mucosal site in 19 patients. Herpes infection was identified at the time of diagnosis in 15 patients and 17 patients received no specific treatment for their pemphigus. The virus was identified using PCR in 23 cases. Ten patients subsequently received prophylactic treatment for herpes. The mean duration of follow-up was 36 months (0-89 months). Thirteen of the 24 patients had 23 relapses of pemphigus; PCR testing for herpes was performed 19 times and was positive in 6 cases (31.5 %). CONCLUSION: Our study showed wide variation in the incidence of herpes superinfection in patients with pemphigus, reflecting the different screening approach at each center (being performed either routinely or only in the event of strong suspicion). The prognostic value of routine screening for herpes in patients with active pemphigus lesions remains to be demonstrated by further prospective investigations.

[Dermatoses and herpes superinfection: A retrospective study of 34 cases]. / Dermatoses et surinfection herpétique : étude rétrospective de 34 cas.

BACKGROUND: Although varicelliform Kaposi eruption is a well-known complication of dermatoses, it has not been widely investigated. AIM: To investigate features of dermatoses and herpes superinfection in patients hospitalized in a dermatology department. PATIENTS AND METHODS: We performed a single-centre, retrospective study between 2008 and 2014 that included cases of Kaposi varicelliform eruptions defined by positive PCR of an unconventional site of herpetic recurrence in a setting of active dermatitis. A record was compiled of each case giving details of the history, clinical and laboratory findings, therapeutic data and outcome. RESULTS: Thirty-four cases of Kaposi varicelliform eruptions in 30 subjects were studied. Mean age at diagnosis was 63.3±24.2 years. The underlying dermatoses were as follows: 7 pemphigus, 6 bullous pemphigoid, 3 cicatricial pemphigoid, 3 atopic dermatitis, 1 Darier disease, and 14 other dermatoses. Patients presented with skin (94.1 %) or mucous membrane lesions (62 %), mostly erosive (79 %), vesicular (27 %) or bullous (41 %), often painful (56 %) or pruritic (29 %). At diagnosis, 41.2 % were undergoing systemic immunotherapy and 24 % were on topical corticosteroids. PCR was positive for HSV1 in 20 cases and for HSV2 in 4 cases, and indeterminate in 10 cases. Lymphocytopenia was seen in 59 % of cases. The majority of patients received treatment. Nine patients experienced at least one relapse. CONCLUSION: Our study confirms the over-representation not only of the expected dermatoses (pemphigus and atopic dermatitis), but also of others such as pemphigoid and acute dermatoses; these results should be investigated in a more systematic prospective study.

Diagnostic accuracy of des-gamma-carboxy prothrombin for hepatocellular carcinoma in a French cohort using the Lumipulse® G600 analyzer.

The increasing incidence of hepatocellular carcinoma (HCC) in Western countries requests reliable tumour markers for preclinical diagnosis. We evaluated the diagnostic accuracy of des-gamma-carboxy prothrombin (DCP), in comparison with alpha-fetoprotein (AFP) in a French cohort using a new analyser. One hundred and sixty-two patients with virus-related cirrhosis (46 HCC patients and 116 controls) were recruited in this retrospective proof-of-concept study. DCP was measured on new Lumipulse® G600 analyzer and AFP on usual Cobas e602 analyzer in serum samples that were collected at the time of HCC diagnosis for HCC patients or during follow-up for controls. DCP and AFP levels were higher in HCC patients. The area under receiver operating characteristic curve was larger for DCP than for AFP (0.89 vs 0.77, P=.03). At the cut-off value of 128 mAU/mL, sensitivity and specificity for DCP were 74% and 92%. At the cut-off value of 20 µg/L, sensitivity and specificity for AFP were 63% and 82%. NRI>0 for the association of "AFP+DCP" were 101%, P<.0001, and 23%, P=.03, compared to "AFP" or "DCP" alone, respectively. We conclude that DCP outperformed AFP for the detection of HCC.

The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.

BACKGROUND: There is a relationship between liver stiffness measurement (LSM) and outcome of HCV patients. AIM: To evaluate the performance of LSM to predict outcome of HCV patients at risk of liver-related complication. METHODS: We established a retrospective longitudinal cohort of 341 HCV patients with unequivocal cirrhosis. All underwent LSM and were followed from September 2006 to July 2015. Outcome measure was a composite end-point of end-stage liver disease (ESLD) and/or hepatocellular carcinoma (HCC). Cox models and areas under receiver operating characteristic (AUROC) curves were used to evaluate independent risk factors of outcome. RESULTS: Overall, LSM was below the 12.5 kPa threshold in 129 (37.8%) patients, including three-fourth and one-third of patients with or without a sustained virological response respectively. Liver disease progressed in 136 (39.9%) patients after a median observational period of 23.5 months. Older age, male gender, alcohol use disorders, metabolic syndrome and LSM were independent risk factors of liver disease progression. Age, alcohol use disorders and LSM were independently associated with ESLD. Age, gender and metabolic syndrome, but not LSM, were associated with HCC. The AUROC curves for disease progression, ESLD and HCC were 0.67, 0.70 and 0.58 respectively. Patients with a liver stiffness >12.5 kPa were at the highest risk of liver disease progression; below 12.5 kPa, liver stiffness was not discriminant. CONCLUSION: Liver stiffness measurement is not a surrogate of disease progression of HCV patients with cirrhosis. HCV patients with cirrhosis should undergo the recommended follow-up, regardless of liver stiffness measurement.

Clinical severity and molecular characteristics of circulating and emerging rotaviruses in young children attending hospital emergency departments in France.

Group A rotavirus (RVA) is the leading cause of acute gastroenteritis in young children worldwide. A prospective surveillance network has been set up to investigate the virological and clinical features of RVA infections and to detect the emergence of potentially epidemic strains in France. From 2009 to 2014, RVA-positive stool samples were collected from 4800 children <5 years old attending the paediatric emergency units of 16 large hospitals. Rotaviruses were then genotyped by RT-PCR with regard to their outer capsid proteins VP4 and VP7. Genotyping of 4708 RVA showed that G1P[8] strains (62.2%) were predominant. The incidence of G9P[8] (11.5%), G3P[8] (10.4%) and G2P[4] (6.6%) strains varied considerably, whereas G4P[8] (2.7%) strains were circulating mostly locally. Of note, G12P[8] (1.6%) strains emerged during the seasons 2011-12 and 2012-13 with 4.1% and 3.0% prevalence, respectively. Overall, 40 possible zoonotic reassortants, such as G6 (33.3%) and G8 (15.4%) strains, were detected, and were mostly associated with P[6] (67.5%). Analysis of clinical records of 624 hospitalized children and severity scores from 282 of them showed no difference in clinical manifestations or severity in relation to the genotype. The relative stability of RVA genotypes currently co-circulating and the large predominance of P[8] type strains may ensure vaccine effectiveness in France. The surveillance will continue to monitor the emergence of new reassortants that might not respond to current vaccines, all the more so as all genotypes can cause severe infections in infants.

Hepatitis B Infection in HIV-1-Infected Patients Receiving Highly Active Antiretroviral Therapy in Lome; Togo: Prevalence and Molecular Consequences

BACKGROUND:No data are available on HIV/hepatitis B virus (HBV) or hepatitis C virus coinfection in Togo; and patients are not routinely tested for HBV infection.OBJECTIVE:To determine the prevalence of HBV and the risk of HBV drug resistance during antiretroviral treatment in HIV-coinfected patients in Togo.METHOD:This cross-sectional study was carried out in Lome; Togo; from January 2010 to December 2011 among HIV-infected patients who had been on antiretroviral therapy (ART) for at least 6 months.RESULTS:In total; 1 212 patients (74.9% female) living with HIV/AIDS and treated with ART were included in the study. The seroprevalence of hepatitis B surface antigen (HBsAg) was 9.7% (117/1 212; 95% confidence interval (CI) 8.04 - 11.45). Of these 117 HBsAg-positive patients; 16 (13.7%) were hepatitis B e-antigen (HBeAg)-positive; and 115 (98.3%) were on lamivudine. The HBV DNA load was etgt;10 IU/mL in 33/117 patients overall (38%); and in 87.5% of 16 HBeAg-positive patients (petlt;0.0001). In multivariate analysis; factors associated with HBV DNA load etgt;10 IU/mLwere HBeAg positivity (adjusted odds ratio (aOR) 6.4; p=0.001) and a higher level of education (aOR 6.5; p=0.026). The prevalence of HBV resistance to lamivudine was 13.0% (15/115; 95% CI 7.0 - 19.0). The detected resistance mutations were rtL180M (14/15 patients) and rtM204V/I (15/15).CONCLUSION:The seroprevalence of HBV among ART-treated HIV-infected patients in Togo was 9.7%. The prevalence of HBV lamivudine resistance mutations after 2 years of ART was 13.0%. These results suggest that HBV screening before ART initiation can be based on HBsAg testing

Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN.

OBJECTIVE: The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine. DESIGN: 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA <12 IU/mL for at least 12 months) were randomised into two groups: one received five intramuscular injections of vaccine (weeks 0, 8, 16, 40 and 44) and one did not receive the vaccine. Analogues were stopped after an additional 48 weeks of treatment in patients who maintained HBV DNA <12 IU/mL with no clinical progression and monthly HBV DNA for 6 months. The primary endpoint was defined as viral reactivation at week 72 (HBV DNA >120 IU/mL) or impossibility of stopping treatment at week 48. RESULTS: Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA <2000 IU/mL in 33%; 99% of adverse reactions were mild to moderate. Immune responses were evaluated by enzyme-linked immunosorbent spot and proliferation assays: there was no difference in the percentage of patients with interferon-γ secreting cells and a specific T-cell proliferation to HBcAg but not to HBsAg after reactivation in each group. CONCLUSIONS: Although it is fairly well tolerated, the HBV DNA vaccine does not decrease the risk of relapse in HBV-treated patients or the rate of virological breakthrough, and does not restore the anti-HBV immune response despite effective viral suppression by analogues. TRIAL REGISTRATION NUMBER: NCT00536627.

Markers of a recent bocavirus infection in children with Kawasaki disease: "a year prospective study".

BACKGROUND: Retrospective studies and case-reports have suggested the possible role of various viruses in the pathogenesis of the Kawasaki disease. OBJECTIVES: To determine prospectively the incidence of Kawasaki diseases associated with a recent bocavirus infection in the course of a year. STUDY DESIGN: Thirty-two children with Kawasaki disease were enrolled in a 13 months prospective study to assess the frequency of human bocavirus type 1 infections. Seasonal shedding of virus, markers of recent infection such as viraemia, viral load, and serum interferon alpha were analyzed. RESULTS: Three of 32 (9%) children had HBoV-DNA in the serum suggesting a recent infection. HBoV-DNA was detected in naso-pharyngeal aspiration of 7/32 (21.8%) children with Kawasaki Disease and six of them (18%) had an increased viral load. No common respiratory viruses were isolated from the 32 patients with the exception of one adenovirus. The seven bocaviruses were identified during the winter-spring season. In addition, 4 of 7 of Kawasaki disease patients shedding bocavirus had detectable interferon alpha in the blood, indicating a possible active or recent viral infection. CONCLUSIONS: This study shows that a recent bocavirus infection is concomitant with the onset of some cases of Kawasaki disease. Bocavirus may be a cofactor in the pathogenesis of this disease as previously reported for other infectious agents.

Immunological and antiviral responses after therapeutic DNA immunization in chronic hepatitis B patients efficiently treated by analogues.

A substudy of a phase I/II, prospective, multicenter clinical trial was carried out to investigate the potential benefit of therapeutic vaccination on hepatitis B e antigen-negative patients with chronic hepatitis B (CHB), treated efficiently with analogues. Patients were randomized in 2 arms, one receiving a hepatitis B virus (HBV) envelope DNA vaccine, and one without vaccination. At baseline, HBV-specific interferon (IFN)-γ-producing T cells were detected in both groups after in vitro expansion of peripheral blood mononuclear cells. Vaccine-specific responses remained stable in the vaccine group, whereas in the control group the percentage of patients with HBV-specific IFN-γ-producing T cells decreased over time. The vaccine-specific cytokine-producing T cells were mostly polyfunctional CD4(+) T cells, and the proportion of triple cytokine-producer T cells was boosted after DNA injections. However, these T-cell responses did not impact on HBV reactivation after stopping analogue treatment. Importantly, before cessation of treatment serum hepatitis B surface antigen (HBsAg) titers were significantly associated with DNA or HBsAg clearance. Therapeutic vaccination in CHB patients with persistent suppression of HBV replication led to the persistence of T-cell responses, but further improvements should be searched for to control infection after treatment discontinuation.

Impact of travel on the seroprevalence of hepatitis A in children.

BACKGROUND: Recent data about hepatitis A virus (HAV) seroprevalence in industrialized countries and the impact of travels to endemic areas are sparse or absent, particularly for children. OBJECTIVE: To determine the impact of travel to endemic areas on HAV seroprevalence and estimate the overall HAV seroprevalence in children in France. To identify risk factors for positive HAV serologic results. STUDY DESIGN: This prospective multicentre cross-sectional seroprevalence study took place in eight paediatric emergency units throughout France. Children 1-16 years of age following all inclusion and exclusion criteria were included. Demographic, socioeconomic, and travel data were prospectively collected with a standardized questionnaire before measurement of specific HAV antibodies. HAV seroprevalence was determined and its association with diverse variables assessed by univariate and multivariate analyses. RESULTS: 430 children were included, of whom 116 had travelled to endemic areas. The HAV seroprevalence in the overall population was 5% (95%CI, 3-7) and was higher among the travellers (12% [95%CI, 6-18]) than among the others (2% [95%CI, 0-3]), OR=7.0 [95%CI, 2.6-18.8]. Risk factors identified for positive serologic results for HAV were travel to an endemic area >7 days (adjusted OR [aOR]=4.3 [95%CI, 1.5-12]), age of 14-16 years (aOR=7.7 [95%CI, 1.6-38.3]) and mother's birth in an endemic area (aOR=5.2 [95%CI, 1.8-14.8]). CONCLUSION: Statistical evidence showed that travel to endemic areas and parents' place of birth both play a role in HAV serologic results in children with a significant difference of HAV seroprevalence between traveller and non-traveller children in France.

High levels of serum hepatitis B virus DNA in patients with 'anti-HBc alone': role of HBsAg mutants.

It remains unclear how the detection of hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) should be interpreted and whether all patients with this pattern need to be tested for hepatitis B virus (HBV)-DNA. This study aimed at reassessing the significance of 'anti-HBc alone' in unselected sera referred to the clinical laboratory and determining whether significant HBV viraemia can be found in this setting. Of the 6431 patients tested for HBsAg, total anti-HBc and anti-HBs in a Paris hospital over a 1-year period, 362 (5.6%) had 'anti-HBc alone' (24.8% of anti-HBc-positive patients). Only 11 of the 362 sera (3.0%) were found to be false positive. One patient was in the resolving phase of acute hepatitis B. HBV-DNA was detected in 10 of 362 (2.8%) patients, using a commercial standardized assay (threshold: 350 IU/mL). Viral loads exceeded 10(4) copies/mL in 6 of 10 patients. Mutations in the HBsAg immunodominant region were identified in seven of the viraemic patients. HBsAg was detected in only two cases when retested by one of the latest, multivalent assays. Neither human immunodeficiency virus nor hepatitis C virus serostatus distinguished between patients with and without HBV-DNA. In conclusion, 'anti-HBc alone' should be considered a risk marker for a so-called 'false occult' HBV infection with significant viraemia. Indeed, results in this hospital population indicate that a small proportion of patients with 'anti-HBc alone' have high viral loads, revealing the occurrence of infection with HBV mutants that escape detection even by multivalent HBsAg assays.

[Anti-hepatitis A virus seropositivity in children of immigrant parents living in France and vaccination recommendations]. / Séroprévalence de l'hépatite A chez les enfants issus de familles immigrées vivant en France et conséquences pour la vaccination.

The hepatitis A-seropositivity rate for children born in France is very low: 0 of 81 born to two French-born parents and 5 of 126 (4 %) infants for whom at least one parent was born in an endemic area. In contrast, the rate was high (28.8 %, 17/59) for children born in an endemic area. Hence, recommendations to vaccinate children who could be exposed during overseas trips to visit family or by visiting family members coming from endemic areas are fully justified.

[Comparison of two ELISA tests to study the seroprevalence of herpes simplex 1 et 2 infection in a maternity near Paris]. / Comparaison de deux techniques Elisa pour l'étude de la séroprévalence de l'infection à herpes simplex 1 et 2 dans une maternité de la région parisienne.

UNLABELLED: The diagnosis of herpes simplex virus (HSV) genital infection is primarily clinical. The primary indication for serodiagnosis is to detect seronegativity in pregnant women at risk of acquiring the HSV virus during the course of their pregnancy. In this study, two ELISA tests were compared for the detection of HSV infection among a population of 307 pregnant women followed at the maternity of a community-based hospital in France (Robert Ballanger hospital in the Seine-Saint-Denis department). The two tests compared were: Test Captia anti-HSV-1 and anti-HSV-2 specifics IgG of Trinity Biotech and the ELISA IgG HerpesSelect 1 and 2 of FOCUS Diagnostics distributed by Eurobio Courtaboeuf, France. RESULTS: Both tests results were similar in terms of population prevalence for HSV-1 and HSV-2 infections (respectively 86.64% and 85.99% for HSV-1; 17.59% and 15.31% for HSV-2). Whereas the prevalence of the HSV-1 virus was described in the literature as being superior to our current results, the prevalence of HSV-2 according to the results of both ELISA tests studied was similar to the one described in previous cohort studies.

Quantification of neutralizing antibodies to human type I interferons using division-arrested frozen cells carrying an interferon-regulated reporter-gene.

Development of neutralizing antibodies (NAbs) to interferons (IFNs) can reduce the clinical response to IFN therapy. As current cell-based assays for quantifying NAbs have limitations, a highly sensitive and reproducible assay was developed, using division-arrested frozen human U937 cells transfected with the luciferase reportergene controlled by an IFN-responsive chimeric promoter, which allows IFN activity to be determined with precision within hours. Assay-ready PIL5 cells can be stored frozen for >3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting <1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from <1.0 to 100 IU/mL and able to measure different IFN subtypes and their pegylated variants. The use of this assay has shown that NAbs from patients treated with IFN-alpha2 exhibited markedly lower titers against 10 LU/mL of low specific activity IFNs, namely, IFN-alpha1, PEG-Intron(TM) (Schering-Plough, Levallois-Perret,France), or Pegasys(TM) (Hoffmann-La Roche, Neuilly-sur-Seine, France, than against 10 LU/mL IFN-alpha2. Similarly, NAbs from patients treated with IFN-beta1a exhibit lower titers against 10 LU/mL of low specific activity IFN-beta1b than against IFN-beta1a. The combination of the use of division-arrested, IFN-responsive human cells transfected with the luciferase reporter-gene makes the rapid PIL5 assay for NAbs highly advantageous.

[Different human cytomegalovirus glycoprotein B (gB) genotype distribution]. / Distribution de différents génotypes de la glycoprotéine B (gB) du cytomégalovirus humain.

The glycoprotein B (gB) is the major glycoprotein of the envelope of the human cytomegalovirus, it is encoded by UL55 open reading frame, implicated in host cell, entry cell to cell virus transmission and fusion of infected cells and a significant is an important target for immuno-reactions humoral and cellular. A prospective analysis of cytomegalovirus glycoprotein B genotype was conducted on 31 immunodepressed (transplant recipients and AIDS patients). The DNA was extracted directly from the bronchoalveolar liquid (BAL) of these patients. The gB genotypes of CMV was determined by using the polymerase chain reaction, followed by the digestion of two enzymes of restriction HinfI and RsaI. The distribution of the gB genotype of the CMV was: gB1 38,70%; gB2 25,80%; gB3 16,12% and gB4 19,35%. The analysis of the peptide sequence of this region (codons 437-520), indicate the variation was more frequent between codons 448-480.

Detection of human bocavirus in children with Kawasaki disease.

Human bocavirus (HboV) is an emerging virus that has been implicated as a cause of acute upper and lower respiratory tract infection in children. As no serological assay is available, PCR was used to screen nasopharyngeal, serum or stool samples from 16 patients with Kawasaki disease for HBoV nucleic acid. HBoV was identified by PCR in five (31.2%) patients, suggesting that this emerging virus may also play a pathogenic role in some cases of Kawasaki disease.

Oromucosal interferon therapy: relationship between antiviral activity and viral load.

Intraperitoneal (i.p.) administration of 20,000 IU recombinant murine IFN-alpha (rMuIFN-alpha) was highly effective in protecting mice challenged i.p. with doses of encephalomyocarditis virus (EMCV) ranging from 44 to 440 LD(50) (p<0.001). Oromucosal (o.m.) IFN therapy was also found to be effective in protecting mice challenged with a lethal dose of EMCV. Thus, 40% of animals infected with 44 LD(50) of EMCV and treated o.m. with 20,000 IU rMuIFN-alpha survived infection with a mean survival time of 12.0 +/- 2.46 days relative to a mean of 6.11 +/- 0.38 days in the control group (p<0.05). Oromucosal IFN therapy was found to be ineffective, however, in animals infected with higher doses of EMCV (88-440 LD(50)), even though intraperitoneal administration of the same dose of rMuIFN-alpha resulted in the survival of 90%, 50%, and 60% of animals infected with 88, 220, and 440 LD(50) of EMCV, respectively. These results suggest that oromucosal IFN therapy is effective at relatively low viral load only and that the mechanism of action of oromucosal IFN therapy may be different from that of parenterally administered IFN. Our results suggest that oromucosal IFN therapy may be most effective in chronic viral infections as an alternative to parenterally administered IFN, which is clinically effective but poorly tolerated.