Cost-effectiveness of vaccination against cytomegalovirus (CMV) in adolescent girls to prevent infections in pregnant women living in France.

BACKGROUND: CMV infections are the most frequent congenital infections worldwide. AIM: Assess the cost-effectiveness of vaccination strategies of adolescent girls vs. current practice (hygiene counseling) to prevent CMV seroconversions during pregnancy in France. METHOD: A Markov decision-tree model simulated overtime the trajectory of a single fictive cohort of 390,000 adolescent women aged 14 years old, living in France. Impact of vaccination was explored until the end of their reproductive live 40 years later. STRATEGIES COMPARED: "S1: No vaccination" (current practice); "S2: Routine vaccination"; "S3: Screening and vaccination of the seronegative". MODEL PARAMETERS: Seroconversion rate without vaccination (0.035%/pregnant woman-week); fetal transmission risk (41%). Vaccine vs. no vaccination: a 50% decrease in maternal seroconversions. OUTCOMES: Quality-Adjusted Life-Years (QALYs) of the cohort-born babies; discounted costs; Incremental Cost-Effectiveness Ratio (ICER). RESULTS: S2 was the most effective strategy (with 35,000 QALYs gained) and the most expensive (€211,533,000); S1 was the least effective and least costly (€75,423,000). ICERs of strategy S3 vs. S1, and S2 vs. S3 were 6,000€/QALY gained (95% uncertainty range [2700-13,300]) and 16,000€/QALY [negative ICER (S3 dominated by S2) - 94,000] gained, respectively; highly cost-effective because ICER < 1∗France's GPD/capita = €30,000. SENSITIVITY ANALYSIS: If the seroprevalence was >62% (vs. 20% in the base case), S3 would become the most efficient strategy. CONCLUSION: In France, systematic vaccination of adolescent girls was the most efficient strategy to prevent maternal seroconversions. If the population was less than 62% immune, systematic screening and vaccination of susceptibles would become the most cost-effective approach.

Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell polyomavirus (MCPyV) is the main aetiological agent of Merkel cell carcinoma (MCC). Serum antibodies against the major MCPyV capsid protein (VP1) are detected in the general population, whereas antibodies against MCPyV oncoproteins (T antigens) have been reported specifically in patients with MCC. OBJECTIVES: The primary aim was to assess whether detection of serum antibodies against MCPyV proteins at baseline was associated with disease outcome in patients with MCC. The secondary aim was to establish whether evolution of these antibodies during follow-up was associated with the course of the disease. METHODS: Serum T-antigen and VP1 antibodies were assessed by enzyme-linked immunosorbent assay using recombinant proteins in a cohort of 143 patients with MCC, including 84 patients with serum samples available at baseline. RESULTS: Low titres of VP1 antibodies at baseline (< 10 000) were significantly and independently associated with increased risk of recurrence [hazard ratio (HR) 2·71, 95% confidence interval (CI) 1·13-6·53, P = 0·026] and death (HR 3·74, 95% CI 1·53-9·18, P = 0·004), whereas T-antigen antibodies were not found to be associated with outcome. VP1 antibodies did not differ between patients in remission and those with recurrence or progression during follow-up. However, T-antigen antibodies were more frequently detected in patients with recurrence or progression at 12 months (P = 0·020) and 24 months (P = 0·016) after diagnosis. CONCLUSIONS: VP1 antibodies constitute a prognostic marker at baseline, whereas T-antigen antibodies constitute a marker of disease recurrence or progression if detected > 12 months after diagnosis.

HSV-2 meningoencephalitis in an immunocompetent young man: what is the pathogenesis and what is the treatment?

Herpes simplex encephalitis is rarely caused by herpes simplex virus type 2 (HSV-2) after the neonatal period. The pathogenesis of HSV-2 encephalitis is not known and its treatment has not been discussed. We report a case of mild meningoencephalitis secondary to HSV-2 primary infection after sexual risk behaviour in a healthy young man. The diagnosis was established upon clinical, biological and electroencephalographic criteria. Aciclovir treatment led to rapid clinical improvement. This case highlights HSV-2 as a rare cause of meningoencephalitis, and questions the management of this rare manifestation of HSV-2 infection.

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.

Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients.

BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC.

Determinants of measles seroprevalence among pregnant women in Paris, France.

Non-immune pregnant women are at risk of severe measles. As the measles vaccination is contraindicated during pregnancy, women should be vaccinated before conception or during the postpartum period. Nevertheless, measles serology is not recommended during pregnancy in France, and there are no data available concerning measles susceptibility and its associated risk factors among pregnant women. The socio-demographic determinants of measles seronegativity have been identified in a prospective cohort of 826 pregnant women in Paris, France. Measles seronegativity was 10.41% (95% CI 8.32-12.50). Women from higher socio-economic groups, born in France after 1980, were more frequently seronegative.

Acute viral encephalitis.

Acute viral encephalitis is a rare but devastating complication of common virus infections. Primary viral encephalitis is due to brain invasion by the virus and subsequent replication in the central nervous system, whereas postinfectious encephalitis is thought to be immune-mediated. The most frequent causes of primary encephalitis worldwide are rabies and the arboviruses, which comprise different families of viruses distributed according to geography and seasonality. Herpes simplex virus (HSV) is the commonest cause of encephalitis in Western countries. Herpes simplex encephalitis (HSE) occurs at all ages during infancy and childhood with a peak incidence during the first year of life. Its pathogenesis remains unsolved, although defects in the innate immune response have been observed in a few cases. Direct and sensitive virological diagnosis is available, but may be difficult at early stages of the disease. Specific antiviral therapy has proven to improve the prognosis of HSE dramatically, if administered early. Despite use of antiviral drugs, sequelae remain high and relapses may occur, presumably secondary to HSV latency in the brain. In addition, deleterious host inflammatory responses might account for failure of therapy. Immunomodulatory treatments have been proposed but require a better understanding of the respective roles of the multiple pathways of the immune response.

Measles immunity and measles vaccine acceptance among healthcare workers in Paris, France.

BACKGROUND: In Europe, including France, a measles outbreak has been ongoing since 2008. Unprotected healthcare workers (HCWs) may contract and spread the infection to patients. AIM: The objective of this study was to evaluate HCWs' measles immunity and vaccine acceptance in our setting. METHODS: In a survey-based study conducted in three university hospitals in Paris, 351 HCWs were included between April and June 2011. The following data were collected at enrolment: age, hospital unit, occupation, history of measles infection and vaccination, previous measles serology and acceptance of a measles vaccination in case of seronegativity. Sera were tested for the presence of specific anti-measles IgG antibodies using the CAPTIA(®) measles enzyme-linked immunosorbent assay. FINDINGS: The mean age of the participating HCWs was 36 years (range: 18-67) and 278 (79.2%) were female. In all, 104 four persons (29.6%) declared a history of measles, and 90 (25.6%) declared never having received a measles vaccination. Among the 351 HCWs included in the study, 322 (91.7%) were immunized against measles (IgG >90 mIU/mL). The risk factors for not being protected were age [18-29 years, adjusted odds ratio: 2.7 (95% confidence interval: 1.1-6.9) compared with ≥30 years], no history of measles infection or vaccination. The global acceptance rate for a measles vaccination, before knowing their results, was 78.6%. CONCLUSION: In this cohort of HCWs, 8.3% were susceptible to measles; the group most represented were aged <30 years. Acceptance of the measles vaccine was high. A vaccination campaign in healthcare settings should target specifically healthcare students and junior HCWs.

[Genetic susceptibility to herpes simplex encephalitis]. / Sensibilité génétique à l'encéphalite herpétique.

Herpes simplex encephalitis (HSE) is a rare but severe complication of frequent and mostly benign infection with herpes simplex virus (HSV). Although rapid and sensitive diagnosis tools and active antiviral drugs are available, HSE morbidity/mortality levels remain unsatisfactory. Molecular and cellular determinants of HSE are incompletely understood. The rarity and severity of the disease have suggested an increased susceptibility of some subjects to HSV infection. Numerous experimental studies have investigated the respective role of host and viral factors in HSE. The results of these studies have illustrated the major role of the innate immune response, in particular interferons (IFNs), in limiting access of the virus into and/or virus replication in the central nervous system (CNS). In a few children with HSE, specific defects of the immune innate response have been identified, which impair the IFN-α/ß and IFN-λ production of fibroblasts and/or neurons infected with HSV and render these cells more permissive to infection. The mutations affect proteins involved in the IFN pathway induced by stimulation of the TLR3 receptor. The patients' susceptibility to infection is restricted to HSV CNS invasion, underlining the major role of TLR3 in CNS protection against viral infection. The incomplete clinical penetrance of these molecular defects suggests that other factors (age, infectious dose) are involved in HSE. Whether pathogenesis of adult HSE is similar has not been investigated.

Factors influencing the efficacy of two injections of a pandemic 2009 influenza A (H1N1) nonadjuvanted vaccine in systemic lupus erythematosus.

OBJECTIVE: To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). RESULTS: The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5-87.5%], seroconversion rate 71.8% [95% CI 63.4-80.2%], and GMR 10.3 [95% CI 2.9-14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9-75.4%], seroconversion rate 60.4% [95% CI 51.3-69.5%], and GMR 8.5 [95% CI 3.2-12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of ≤ 1.0 × 109/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. CONCLUSION: Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE.

Factors associated with delay to acyclovir administration in 184 patients with herpes simplex virus encephalitis.

The main predictor of outcomes in herpes simplex virus (HSV) encephalitis (HSE) is the delay between hospital admission and initiation of acyclovir. In this study, factors associated with late initiation of acyclovir were identified. The study included adults from northern France whose cerebrospinal fluid (CSF) was positive for HSV by PCR. Late initiation of acyclovir was defined as a delay of >1 day from hospital admission. In total, 184 patients were retrospectively enrolled from January 1991 to December 2002. The median age was 60 years (range: 17-91), and 102 (55.4%) were male. Acyclovir was initiated >1 day after hospital admission in 68 patients (37.0%). According to multivariate analysis, independent risk factors for late initiation of acyclovir were severe underlying disease (Knaus score >or=C) (OR 4.1; 95% CI 1.5-11.7); alcohol abuse (OR 3.4; 95% CI 1.3-8.9); and a delay of >1 day from admission to first brain imaging (OR 8.4; 95% CI 3.9-18.0). In addition, univariate analysis suggested an association between a finding of <10 leukocytes/mm(3) in CSF at admission (OR 2.5; 95% CI 0.7-5.8). These characteristics were found in 26 (14.1%), 23 (12.5%), 66 (35.9%) and 27 (14.7%) patients, respectively. One risk factor was identified in 109 (59.2%) patients, two in 29 (15.8%), and three in six (3.3%). Patients with HSE often present with severe underlying disease, chronic alcohol abuse, or atypical CSF findings, and such factors should not be allowed to delay diagnosis and administration of acyclovir.

[Cytomegalovirus and pregnancy]. / Cytomégalovirus et grossesse.

Cytomegalovirus infection is the most common viral infection transmitted from the mother to the fetus. Congenital CMV infection occurs in approximately 1% of all newborns. The most serious fetal damages mainly occur (10%) after primary infection during pregnancy. Clinically apparent infections are characterized by involvement of multiple organs particularly the central nervous system with severe sequelae such as mental retardation, deafness and ocular defects. Diagnosis of CMV maternal/fetal infection could be justified by its frequency and its potential severity but the absence of reliable prognostic markers of congenital CMV disease makes difficult its management during pregnancy. A better knowledge of the physiopathology of CMV placental infection, correct counselling, identification of prognostic markers of fetal CMV infection may avoid the occurrence of the most severe fetal infections before development of safe and efficient vaccines and treatments.

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.

[Acute hepatitis during primary herpes simplex type 2 infection in a patient with systemic lupus erythematosus]. / Hépatite aiguë lors d'une primo-infection à Herpès simplex virus 2 chez un malade atteint d'un lupus érythémateux disséminé

BACKGROUND: Herpes simplex virus hepatitis is a rare complication associated with a poor prognosis and a high mortality rate. It mainly affects adults with impaired cell-mediated immunity. Mucocutaneous involvement is seen in only 57% to 70% of patients and the clinical aspects of the lesions may sometimes be misleading. Here we report a new case that developed during primary HSV-2 infection in a patient with systemic lupus erythematosus. CASE REPORT: A 57 year-old man with systemic lupus erythematosus treated with oral prednisone presented a disseminated varicella-like eruption with acute liver failure related to primary genital HSV-2 infection. Type-specific HSV deoxyribonucleic acid amplification by polymerase chain reaction on serum and oral lesion samples revealed type 2 HSV. Dramatic improvement was observed with parenteral acyclovir. DISCUSSION: Hepatitis due to HSV is a rare but potentially fatal disorder chiefly affecting adults with impaired immune systems. In this case, HSV affects the liver during primary or recurrent infection. If initiated quickly, parenteral acyclovir can cure hepatitis, which means that this diagnosis must be considered in both immunocompromised and immunocompetent patients with high fever, leucopoenia and marked elevation of aminotransferase levels. Mucocutaneous signs are present in only 57 to 70% of cases. Careful physical examination to detect herpes lesions should be done in all cases of acute liver failure. HSV viremia testing may confirm the diagnosis by non-invasive means. Patients with systemic lupus erythematosus are at increased risk for infection due to immunosuppressive drugs, but also to numerous intrinsic immunologic abnormalities such as a recently reported deficit in NK cells and plasmacytoid dendritic cells.

[Human herpes virus type 6, etiology of an acute encephalitis in childhood: case report]. / L'HHV-6, une cause de leucoencéphalite aiguë disséminée du nourrisson: à propos de 1 observation.

Primary infection with human herpesvirus-6 (HHV-6) causes the classical roseola infantum. Otherwise the infection is clinically silent but it may sometimes be responsible for central nervous system involvement. In order to illustrate such a type of lesions, we report on a 16-month-old girl with acute leucoencephalitis. The disease started with pyrexia 40 degrees C, followed by an episode of seizure, erythematous rash on the trunk and then coma. Brain MRI showed wide lesions on white matter. HHV-6 DNA was detected by PCR in the CSF and serum at the acute stage, and tests for HHV-6 antibody showed a significant increase of IgG antibody titre between acute and convalescent sera. One month later complete clinical recovery was observed while the MRI showed a partial disappearance of the lesions. The sero-conversion associated with the detection of the viral DNA in the serum identified a primary HHV-6 infection and the detection of viral nucleic acid in CSF gives arguments for the responsibility of the virus in the pathogenesis. When facing an acute leuco-encephalitis in infants, it is important to perform exhaustive virology investigations to rule out the implication of HHV-6 as well as other commonly incriminated pathogens (EBV, CMV, mycoplasma, enterovirus) to avoid accusing wrongly the vaccines.

Case report: cytomegalovirus primoinfection may be associated with severe outcome in burns.

We report two cases of severe cytomegalovirus (CMV) primoinfection in seriously burned patients. The infection may have contributed to both patients' fatal outcome. This underlines the importance of research in viral aetiology, especially with regard to CMV, when immunodeficient patients - as burn patients are - develop unexplained fever. We propose a monitoring and a prevention strategy for CMV in the most severely burned patients. The prevention strategy involves the use of skin allografts and blood products in seronegative patients. CMV infection should not be underestimated in severely burned patients.

Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis.

AIM: To describe the diagnostic and therapeutic management of cytomegalovirus (CMV) anterior uveitis unassociated with retinal necrosis in immunocompetent patients. METHODS: Patients referred between 2001 and 2003 for management of unilateral, chronic, recurrent uveitis associated with secondary glaucoma underwent extensive investigation including laboratory tests for herpes virus infections. Specific antiviral treatment was initiated in all cases and the level of ocular inflammation was evaluated during the follow up. RESULTS: Five patients, three men and two women, were included. Median age was 50 years old (range 30-80 years). Anterior unilateral uveitis without iris atrophy was observed in all cases. Uveitis was chronic in three cases and recurrent in two cases. Glaucoma was observed in all patients with a median intraocular pressure of 30 mm Hg (range 22-43 mm Hg). Five patients responded initially to specific anti-CMV therapy. Even though glaucoma surgery was necessary in two cases, both ocular inflammation and glaucoma were controlled in all cases. Relapses occurred in three cases after cessation of therapy, requiring prolonged maintenance therapy with valganciclovir. CONCLUSIONS: CMV infection and specific antiviral therapy should be considered in all cases of relapsing or chronic iridocyclitis and secondary glaucoma. Maintenance regimens of valganciclovir may be necessary to prevent further relapses.