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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.

International audience; ObjectivesWe aimed to investigate the first Omicron cases detected in France in order to assess case characteristics and provide supporting information on the possible impact of this variant on the healthcare system.MethodsA standardized questionnaire was used to collect information from confirmed and probable Omicron cases.ResultsMedian age of 468 investigated cases was 35 years, 376 were symptomatic (89%); 64% were vaccinated with two doses and 7% had received three doses. Loss of smell and taste were reported by 8.3% and 9% of cases, respectively. Seven cases were hospitalized, three of those were unvaccinated (including two with reported precondition). No admissions to intensive care and no deaths were reported.ConclusionsOur results confirm a mild clinical presentation among the first Omicron cases detected in France and highlight the importance for the national COVID-19 surveillance system to quickly detect and adapt to the emergence of a new variant.

BackgroundRituximab (RTX) is associated with reduced humoral response to SARS-CoV-2 mRNA-based vaccine (1, 2). A recent study has shown that, despite their immunosuppression burden, kidney transplant recipients with previous exposure to SARS-CoV-2 showed a marked increase in antibody titer, even after a single dose of vaccine (3).ObjectivesTo describe the results of immunization after 1 to 3 doses of mRNA SARS-CoV-2 vaccine in RTX-treated patients with previous symptomatic COVID-19 infection.MethodsObservational prospective usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a 1 to 3-dose regimen of mRNA-based COVID-19 vaccination (BNT162b2 Pfizer/BioNTech or mRNA-1273, Moderna). Serum IgG antibody levels against SARS-CoV-2 spike proteins were measured at the time of the new RTX infusion. The SARS-CoV-2 S1/S2 IgG immunoassay (DiaSorin) was used for the quantitative determination of antibodies to the receptor-binding domain of the viral spike (S) protein. Seropositivity was defined by anti-S antibodies >15 UA/mL.ResultsWe included 69 patients (60 females, mean age 60±13 years) on maintenance therapy with RTX including 13 with previous symptomatic COVID-19, all proven by RT-PCR (10 females, mean age 58±12 years) (Table 1). SymptomaticCOVID-19 occurred between March 2020 and May 2021. The mean interval between the infection and vaccination was 8±3 months and the serological response was assessed after a mean of 74±58 days from the last dose of vaccination (3rd dose for 3 patients, 2nd dose for 6 patients and 1st dose for 4 patients). The 56 patients with no history of symptomatic COVID-19 infection all received 3 doses of vaccine and the serological response was assessed after a mean of 63±27 days from the 3rd dose of vaccination. The seropositivity rate was significantly higher in RTX-treated patients with previous symptomatic COVID-19 infection (11/13, 85% vs.15/56, 27%, pTable 1.Study populationPatients with previous symptomatic COVID-19 (n=13)Patients without symptomatic COVID-19 (n=56)Age (years), mean ± SD58±1260±11Females, n (%)10 (77)50 (89)Underlying disease: Rheumatoid arthritis10 (77)45 (80) Systemic sclerosis2 (15)5 (9) Systemic lupus erythematosus1 (8)1 (2) Sjögren syndrome0 (0)3 (5) Mixed connective tissue disease0 (0)2 (4)Disease duration (years), mean ± SD17±920±10Associated Methotrexate, n (%)9 (69)36 (64)Current treatment with corticosteroids, n (%)5 (38)21 (38)Corticosteroid dose >10 mg/day, n (%)0 (0)0 (0)CD19+ (/µL) (100-600), mean ± SD65±10645±51CD19 7 (54)33 (58)Figure 1.Distribution of SARS-CoV-2 spike antibody levels according to the history of proven symptomatic COVID-19. **** pConclusionRTX-treated patients with previous proven COVID-19 showed increased seropositivity and antibody titers after SARS-CoV-2 vaccination, even after a single-dose of vaccine. This response is strikingly different from that observed for SARS-CoV-2-naïve RTX treated patients who received 3 doses of SARS-CoV-2 mRNA-based vaccination. An “antigen dose phenomenon” may account for these discrepancies. A potential clinical implication might be to increase antibody response with an additional dose of vaccine following an exposure to SARS-CoV-2 in RTX-treated patients with absent or insufficient postvaccination antibody response.References[1]Avouac et al, Rheumatology 2021[2]Jyssum et al, Lancet Rheumatol 2021[3]Benotmane et al, Am J Transplant 2021Disclosure of InterestsNone declared

Introduction La prévalence des formes asymptomatiques d’infection COVID-19 en population générale est mal connue à ce jour (

Introduction L’efficacité vaccinale anti-SARS-CoV-2 est réduite chez les patients traités par rituximab (RTX) [1]. L’objectif de ce travail a été d’identifier quels facteurs influencent la réponse humorale aux vaccins contre la COVID-19 chez les patients traités par RTX. Patients et méthodes Étude observationnelle prospective de soin courant incluant consécutivement des patients atteints de rhumatismes inflammatoires chroniques et de maladies systémiques hospitalisés pour réalisation d’une nouvelle perfusion de RTX entre avril 2021 et juin 2021. L’ensemble des patients avaient reçu deux doses de vaccins anti-COVID-19. Une sérologie COVID-19 était systématiquement réalisée le jour de l’hospitalisation, permettant la détection et la quantification des anticorps dirigés contre les protéines virales Spike (anti-S, seuil > 15 UA/mL, LIAISON® SARS-CoV-2 S1/S2 IgG immunoassay, DiaSorin). Un dosage systématique des CD19 était également effectué le jour de la perfusion (Aquios, Beckman Coulter). Résultats Quarante-cinq patients (39 femmes) ont été inclus, avec un âge moyen de 63 ± 11 ans et une durée moyenne d’évolution de la maladie de 19 ± 9 ans. La majorité des patients avaient une polyarthrite rhumatoïde (PR, 34 patients, 76 %) ; 5 avaient une sclérodermie systémique, 2 un lupus systémique, 2 une connectivite mixte et 2 un syndrome de Sjögren. La dose cumulée moyenne reçue de RTX était de 7 ± 5,5 g et 25/45 patients (56 %) avaient des CD19 indétectables ( 30, la maladie de fond, la dose cumulée de RTX, les CD19 > 18/mL, une durée entre la dernière perfusion de RTX et la vaccination > 6 mois, le taux de gammaglobulines, un traitement associé par méthotrexate et corticoïdes a identifié les CD19 > 18/mL comme l’unique variable associée à une sérologie positive (odds ratio : 35,2, IC95 % : 3,59–344,20). Conclusion La déplétion lymphocytaire B est le principal facteur de réponse humorale à la vaccination anti-SARS-CoV-2 chez les patients traités par RTX. La surveillance des CD19 pourrait être intéressante afin d’identifier la meilleure période pour effectuer la vaccination.

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/β 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.

Resume Introduction L’hepatite est une complication rare et potentiellement mortelle de l’infection herpetique. Elle touche avec predilection l’adulte immunodeprime. Les signes cutaneo-muqueux ne sont pas systematiquement presents ou bien peuvent etre trompeurs. Nous rapportons un nouveau cas lors d’une primo-infection a Herpes simplex virus de type 2 (HSV-2) chez un malade ayant un lupus systemique. Observation Un homme de 57 ans, atteint d’un lupus dissemine, developpait, au decours de bolus de corticoides et sous corticotherapie generale, une infection a HSV-2 cutanee disseminee varicelliforme compliquee d’une hepatite aigue severe. L’amplification genomique par PCR sur le serum et sur une lesion de la muqueuse buccale confirmait le diagnostic. L’evolution etait favorable apres traitement par acyclovir parenteral. Discussion L’hepatite herpetique est une complication grave, parfois mortelle, touchant principalement l’adulte immunodeprime lors d’une primo-infection ou d’une recurrence. Si elle est traitee precocement par antiviraux, l’hepatite est curable ce qui impose d’evoquer son diagnostic systematiquement devant toute fievre associee a une leucopenie et a une cytolyse hepatique massive. Les manifestations cutanees ou muqueuses sont presentes dans 57 a 70 p. 100 des cas. Un examen soigneux cutane et muqueux doit etre systematique devant toute hepatite aigue pour orienter les prelevements viraux. La viremie herpetique dans le contexte peut suffire a faire le diagnostic. Les malades atteints d’un lupus systemique sont sensibles aux infections communes et opportunistes a la fois par les traitements immunosuppresseurs, mais aussi par l’existence de nombreuses anomalies intrinseques de l’immunite.

Objectif Etude de la strategie diagnostique virologique et de la prise en charge therapeutique des retinites necrosantes herpetiques. Patients et methodes Analyse retrospective portant sur 36 cas (46 yeux) de retinite necrosante herpetique de type ARN (Acute Retinal Necrosis) ou PORN (Progressive Outer Retinal Necrosis), diagnostiquee entre mars 1997 et juin 2001. Trente-trois patients ont beneficie d’un prelevement intraoculaire a la recherche des virus du groupe herpes, par amplification genique (PCR) et/ou evaluation du coefficient de charge immunitaire (CCI). Resultats L’âge moyen etait de 43,4 ans. Les investigations ont mis en evidence l’implication d’un agent pathogene viral dans 28/36 cas (80,5 %). Dans le groupe ARN (32 cas, 38 yeux), le virus de l’herpes simplex (HSV) etait implique dans 11 cas (34,4 %), le virus de la varicelle et du zona (VZV) dans 9 cas (28,1 %) le cytomegalovirus (CMV) dans 4 cas (12,5 %) et le virus d’Epstein Barr (EBV) dans 1 cas (3,1 %). La bilateralisation etait d’emblee presente dans 6 cas et secondaire dans 4 cas. Dans le groupe PORN (4 patients, 8 yeux), l’atteinte etait d’emblee bilaterale et le VZV etait implique dans tous les cas. Deux patients ont ete traites par aciclovir en monotherapie, 6 par foscarnet en monotherapie, 10 par foscarnet associe a l’aciclovir, et 18 par foscarnet associe aux injections intravitreennes de ganciclovir. Les principales complications sont la cataracte (26 %), l’atrophie optique (23,9 %) et le decollement de retine (17,4 %). L’acuite visuelle finale est superieure ou egale a 1/10 e pour 24 yeux (52,2 %). Conclusions La severite du tableau clinique et l’evolution peuvent etre differentes selon le virus implique, d’ou l’importance d’une confirmation etiologique. Le pronostic visuel final, ameliore par un traitement antiviral intensif, demeure reserve en cas de complications, malgre un controle antiviral optimal.

The clinical, virological and immunocytochemical features of three children who recovered from acute herpes simplex encephalitis (HSE) before the age of 2 years, and who developed secondary severe focal epilepsy after a symptom-free period, leading to neurosurgery 3-10 years later are described. In one child, relapse of HSE occurred immediately after surgery. In all three patients, brain sample biopsies showed abundant CD3-positive T lymphocytes with a majority of CD8 cells, and abundant activated macrophage-microglial cells, a pattern similar to that found in acute HSE. Herpes simplex virus DNA was retrieved from the tissue biopsy in one case. The long-term persistent cerebral inflammatory process observed after HSE differed from that observed in another chronic viral disease, subacute sclerosing panencephalitis. This inflammatory reaction may be a result either of low-grade viral expression or self-induced immune activation. The role of inflammation in triggering epilepsy remains hypothetical. Solving these issues should have major therapeutic implications, Herpes simplex virus DNA latency in brain may be the source of replicative HSE relapse.

L'infection maternelle en cours de grossesse expose le fœtus au risque d'infection congenitale. Cette infection survient dans 40 a 50 % des cas s'il s'agit d'une primo-infection maternelle et dans 0,5 a 3 % des cas s'il s'agit d'une reactivation. L'infection a cytomegalovirus (CMV) est donc la plus frequente des infections maternofœtales. Selon les etudes, elle atteint 0,5 % a 2 % des nouveau-nes[21]. A cote de la classique, mais rare (1 pour 10 000 naissances), « maladie des inclusions cytomegaliquesou forme multiviscerale avec atteinte neurologique de tres severe pronostic, il existe des formes paucisymptomatiques ou asymptomatiques qui restent meconnues en l'absence de depistage systematique. Plusieurs etudes [10–16] soulignent le fait que les nouveau-nes ayant une infection congenitale asymptomatique ont un risque de 5 a 15 % de developper ulterieurement des sequelles neurosensorielles comme une surdite ou un retard psychomoteur. Pendant la grossesse, le diagnostic d'infection a CMV chez le fœtus est discute dans deux circonstances: la mise en evidence d'une primo-infection maternelle et la decouverte d'anomalies morphologiques fœtales. La question du bien-fonde d'un depistage maternel de la primo-infection en cours de grossesse est actuellement a l'etude.

Purpose Since 2004, different studies have reported on the pathophysiology of Fuchs cyclitis, which may be due to rubella virus infection. The purpose of this study is to investigate clinical profile and prognosis of rubella virus associated uveitis. Retrospective, observational, bicentric study. Methods All patients managed between January 2009 & march 2013 for an atypical form of Fuchs cyclitis were included. Clinical features for these patients were assessed. An extensive work-up of anterior or intermediate uveitis was performed in all cases. An anterior chamber tap was done for molecular detection of herpesviruses and intraocular anti-rubella virus antibody synthesis. Treatment was adapted to the results of ocular fluids analysis. Results The series included 17 patients (M/F : 11/6) with a proven diagnosis of rubella virus-associated uveitis. The mean age was 43.3years (27-70)). All patients had a positive outcome for intraocular antibody production against rubella virus with a Goldmann-Witmer coefficient > 3. Only 3 patients (15%) fulfilled the classical Fuchs cyclitis criteria with stellar keratic precipitates + heterochromia/iris atrophy + cataract + vitritis. Uveitis was bilateral in 3 patients (20%) and 7 patients (35%) had an uncontrolled IOP requiring glaucoma surgery. Conclusion For most of these patients, intraocular rubella virus serology allowed the final diagnosis of Fuchs cyclitis despite incomplete clinical criteria. Intraocular rubella virus detection can help for the diagnosis of atypical forms of Fuchs cyclitis. This avoids unnecessary additional tests and prescription of local or systemic corticosteroids. Secondary glaucoma remains a major complication and needs a close monitoring.

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/β 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.

Resume L'infection congenitale a cytomegalovirus est une infection frequente. La forme symptomatique a la naissance, de tres severe pronostic est rare. Elle est le plus souvent totalement asymptomatique, mais peut se compliquer ulterieurement, dans 10 a 15 % des cas, de sequelles neuro-sensorielles et en particulier de surdite. Les formes symptomatiques ne peuven etre reconnues que par un depistage systematique. L'opportunite de ce depistage et ses modalites (pre ou post natal) sont discutees ici.

Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

Purpose To analyze the etiological distribution of long-lasting and severe anterior uveitis based on the analysis of the aqueous humor. Methods Retrospective study of patients presenting with atypical and severe anterior uveitis and managed in a tertiary referral centre, between January 2008 and December 2009. Patients with panuveitis, intermediate and posterior uveitis and typical B27-associated uveitis or herpes zoster ophthalmicus were excluded. Patients were divided into three groups : atypical viral uveitis (group 1), typical herpetic uveitis (group 2), Fuchs uveitis (group 3). An anterior chamber paracentesis was performed in all cases. Results The medical files of 153 patients were analysed. The mean age was 49 years (range 8-83 Years), the M/F sex ratio was 84/69. Uveitis was unilateral in 86.5% of cases. Group 1 included 42 patients with sarcoidosis (13 cases), tuberculosis (7 cases), endophthalmitis (6 cases), spondylarthropathy (10 cases), syphilis (2 cases), neoplasia (2 cases) and multiple sclerosis (2 cases). Group 2 included 83 cases. A viral agent was definitely identified in 33 cases (39.8%). The distribution of herpes viruses was the following : CMV (19 cases), HSV-1 (8 cases) and VZV (6 cases). The yield of anterior chamber paracentesis is increased by repetition of the procedure (up to 77.4% for CMV). The PCR-negative patients in Group 2 responded well to a specific antiviral treatment. None of the patients with Fuchs uveitis (Group 3) had a positive PCR for CMV. Conclusion Most cases of atypical anterior uveitis, especially when unilateral, are viral-induced. Molecular tools applied to ocular fluids may confirm a viral infection in atypical cases of anterior uveitis, leading to a specific antiviral therapy.

Purpose To assess the etiologic distribution of necrotizing retinopathies based on an extensive work-up including molecular tools applied to ocular fluids Methods All patients referred for the diagnostic and therapeutic management of an atypical posterior or panuveitis underwent an extensive work-up to exclude an infectious condition. All patients underwent anterior chamber paracentesis or vitrectomy for diagnostic purposes. PCR and cytology were performed in order to confirm an infectious entity or a masquerade syndrome Results The clinical findings of 218 patients were analyzed in this retrospective study. The sex-ratio (M/F) was 1.44 including 129 men and 89 women. The mean age was 46.6 years (range from 7 To 90 yo). A viral infection was confirmed in 146 cases (67,5%). Viral distribution determined 55 CMV retinitis, 48 VZV retinitis, 34 HSV 1 or 2 retinitis and 9 EBV panuveitis. Nonviral causes of infectious or inflammatory retinopathies were determined in 66 cases, masquerading as a viral retinopathy. Most of the cases were due to a parasitic infection (59%) followed by a primary intraocular lymphoma (12,1%), a bacterial uveitis (7,5%), Behcet’s disease (7,5%), endogenous endophthalmitis (3%), sarcoidosis (1,5%) and others (9,4%). Six cases remained idiopathic Conclusion All patients with an atypical retinopathy and a suspicion of infectious etiology deserve an extensive work-up, including ocular fluid analysis. The yield of PCR technology remains excellent for viral retinopathies. Even though most of the cases are viral-induced, other entities may present with similar clinical findings. Therefore, prompt diagnosis remains the best strategy to avoid further sight and rarely life-threatening complications

The risk for fragility fracture represents a problem of enormous magnitude. It is estimated that only a small fraction of women with this risk take the benefit of preventive measures. The relationship between estrogen and bone mass is well known as they are the other factors related to the risk for fracture. There are precise diagnostic methods, including a tool to diagnose the risk for fracture. Yet there continues to be an under-diagnosis, with the unrecoverable delay in instituting preventive measures. Women under the age of 70 years, being much more numerous than those older, and having risk factors, are a group in which it is essential to avoid that first fragility fracture. Today it is usual not to differentiate between the treatment and the prevention of osteoporosis since the common aim is to prevent fragility fractures. Included in this are women with osteoporosis or with low bone mass and increased risk for fracture, for whom risk factors play a primary role. There is clearly controversy over the type of treatment and its duration, especially given the possible adverse effects of long-term use. This justifies the concept of sequential treatment, even more so in women under the age of 70, since they presumably will need treatment for many years. Bone metabolism is age-dependent. In postmenopausal women under 70 years of age, the increase in bone resorption is clearly predominant, related to a sharp drop in estrogens. Thus a logical treatment is the prevention of fragility fractures by hormone replacement therapy (HRT) and, in asymptomatic women, selective estradiol receptor modulators (SERMs). Afterwards, there is a period of greater resorption, albeit less intense but continuous, when one could utilise anti-resorptive treatments such as bisphosphonates or denosumab or a dual agent like strontium ranelate. Bone formation treatment, such as parathyroid hormone (PTH), in women under 70 years will be uncommon. That is because it should be used in cases where the formation is greatly diminished and there is a high risk for fracture, something found in much older women. © 2012 Informa UK, Ltd.

Four patients with acquired immunodeficiency syndrome, a 27-year-old female intravenous drug abuser and three males (two drug addicts aged 27 and 33 years and a 40-year-old homosexual) presented with a rapidly progressive encephalopathy. Two had generalized varicella-zoster virus skin infection, one had had a regressive thoracic zoster rash 7 months previously and one had no history of cutaneous eruption. Neuropathological examination revealed, in each case, multifocal necrotic changes with numerous, intranuclear Cowdry type A inclusion bodies in glial cells, endothelial cells, macrophages and neurons, within and around the lesions. These inclusion bodies were stained positively for varicella-zoster virus by immunocytochemistry and contained herpes virus nucleocapsids by electron microscopy. Molecular biology using the polymerase-chain-reaction method demonstrated viral genome. In one case, zoster-induced non-inflammatory vasculopathy involved medium sized leptomeningeal vessels and was associated with circumscribed areas of cortico-subcortical infarction. In another case, varicella-zoster virus encephalitis was associated with human immunodeficiency virus encephalitis and a secondary cerebral lymphoma. Multinucleated giant cells expressing human immunodeficiency virus proteins in their cytoplasm, were found in the lymphomatous deposits and in the varicella-zoster virus necrotic lesions. In these latter lesions, Cowdry type A inclusion bodies could be seen in the nuclei of some multinucleated giant cells confirming previous observations of MGCs co-infected by HIV and CMV, and supporting the hypothesis that DNA viruses interact with HIV, thus increasing its effect.

Purpose To determine the long-term ocular complications and visual outcome in patients with necrotising herpetic retinitis (NHR). Methods 26 patients (33 eyes) with NRH diagnosed between June 1987 and January 2002 at Pitie-Salpetriere Hospital, in Paris, France, were retrospectively reviewed. Demographic data, clinical presentation, viral identification (when possible), initial therapeutic management, long-term antiviral therapy, complications and final visual acuity were analyzed. Results 16 patients (61.5%) were male, 10 (38.5%) were female. Age ranged from 11 to 67 years (mean 40.6 years). All patients were treated with intensive intravenous antiviral therapy, 9 (34.6%) with additional intravitreous ganciclovir injections. At last examination, 20 patients (76.9%) were still under prophylactic antiviral treatment. Complications were cataract (63.6%), retinal detachment (48.5%), recurrence (33.3%), macular edema (36.4%), optic atrophy (30.3%) and epimacular membrane (27.3%). Final visual acuity was below 20/200 in 15 eyes (45.5%). The minimal follow-up was 3 years. Conclusion Despite aggressive antiviral therapy, visual prognosis remains guarded in patients with NHR. Retinal vasculopathy and optic disc alterations are major factors to consider in order to improve the visual outcome.

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.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.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.

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.

We aimed to study prevalence and features of Campylobacter jejuni and cytomegalovirus (CMV)-associated Guillain-Barré syndromes (GBS) in a French care unit.We studied 264 patients with GBS admitted at Raymond Poincaré hospital (Garches) between 1996 and 2001. Clinical data were obtained prospectively. Sera were collected at patients entry and tested retrospectively for anti-C. jejuni, anti-CMV and antigangliosides GM1 et GM2 antibodies.GBS associated with a serological evidence for a recent C. jejuni infection were the more frequent (58/264, 22%); they affected predominantly men of mature years (mean age: 51.3 years; sex-ratio M/F: 1.76), mostly after a gastrointestinal illness (52%); they were often pure motor forms (57%), were severe (mechanical ventilation: 40%) and associated to an anti-GM1 IgG and/or IgM response (44%). GBS cases involving a primary CMV infection were less frequent (40/264, 15%), but were severe too (mechanical ventilation: 37.5%); they occurred preferentially in young women (mean age: 35.9 years; sex-ratio MF: 0.82), often after respiratory tract symptoms (28%) or an influenza-like syndrome (15%) and were frequently associated with sensory loss (73%) and with an anti-GM2 IgM response (47%).C. jejuni and CMV proved to be major triggering agents of GBS in France. They are associated with distinct presentations, which are both severe.

IFN-alpha detection is useful in some clinical circumstances, but its use has never been validated in young infants with viral infections.The authors wanted to determine it there was any difference in the assessment of IFN-alpha production between infants under or over six months of age.A series of 233 children with identified common viral infections who had been assessed for IFN-alpha production was retrospectively analyzed. The viral infections were enteroviral meningitis (n =103), respiratory syncytial virus infections (n =60), and rotavirus gastroenteritis (n =70). Data collected from the group of infants under six months of age (n =105) was compared to that of the older children (n =128). Qualitative and quantitative values of interferon-alpha were determined for each group.Interferon-alpha was detected in very young infants (81.9% of cases) as often as in the older age group (80.3% of cases), for any of the three viral infections (P =0.3-0.63). The mean level of interferon-alpha production detected was not lower in the youngest group, and even higher in the group under six months of age with enteroviral meningitis.Interferon-alpha detection in very young infants is efficient and may be useful to differentiate between viral and bacterial infection particularly when the etiological diagnosis appears uncertain.

To study the viral cause and present the management of necrotizing herpetic retinopathies.Charts of patients presenting with acute retinal necrosis (ARN) or progressive outer retinal necrosis (PORN) diagnosed between March 1997 and June 2001 were retrospectively reviewed. Intraocular specimens were obtained in 33 cases to determine the viral cause using polymerase chain reaction-based assays and/or detection of intraocular antibody production.The mean age was 43.4 Years. Herpesvirus genome was identified in 29 patients (80.5%). In the ARN group (32 patients, 38 eyes), herpes simplex virus (HSV) DNA was found in 11 patients (34.4%), varicella-zoster virus (VZV) in nine patients (28.1%), and cytomegalovirus (CMV) in four patients (12.5%). One patient (3.1%) presented an Epstein-Barr virus (EBV) infection. ARN was bilateral at initial examination in six patients and secondary bilateralization was observed in four patients. In the PORN group (four patients, eight eyes), the retinitis was bilateral and VZV DNA was detected in all cases. Two patients were treated with intravenous acyclovir, six with foscarnet alone, ten with intravenous foscarnet + acyclovir, 18 with intravenous foscarnet and intravitreous ganciclovir injections. Complications of necrotizing herpetic retinitis were cataract (26%), optic nerve atrophy (23.9%), and retinal detachment (17.4%). Final visual acuity was less or equal to 20/200 in 47.8% of cases.It is important to determine the specific viral etiology since progression and prognosis may be different in herpetic necrotizing retinitis caused by HSV, VZV, or CMV. Visual prognosis is improved by intensive antiviral therapy, but remains poor if complications occur.

Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

The availability of methods of detection of DNA by PCR amplification has deeply modified the knowledge on herpes simplex virus infections. These methods have allowed a better understanding of the physiopathogeny of the disease. In particular, PCR has revealed the importance of asymptomatic viral shedding in infected patients. PCR helps diagnosis in many situations where viral isolation by culture proves difficult or impossible, i.e. in treated or atypical lesions, or in newborn central nervous system infections. In addition, PCR has underlined the existence of prolonged viremia in infected newborns. PCR helps sequencing of the viral genome for further epidemiological studies or analysis of resistance to antiviral drugs. Recent PCR-derived techniques have been developed to quantify viral load in real time, and allow to obtain a diagnosis in a few hours. Despite these major advances, the use of PCR in several clinical situations still needs to be further validated.

A real-time PCR assay was developed to quantify human cytomegalovirus (HCMV) DNA in amniotic fluid (AF) samples collected from 30 pregnant women with primary HCMV infection as detected either from HCMV-immunoglobulin G (IgG) seroconversion or by the presence of HCMV-specific IgG and IgM associated with a low IgG avidity. Clinical information available for each case included ultrasonographic examination and fetal or newborn outcome. HCMV infection of fetuses or newborns was confirmed for the 30 studied cases. AF samples were subdivided into three groups. In group A ( n = 13), fetuses presented major ultrasound abnormalities, and pregnancy was terminated. In group B ( n = 13), fetuses had normal ultrasound findings, the pregnancy went to term, and the newborns were asymptomatic at birth. In group C ( n = 4), fetuses had no or minor ultrasonographic signs, and pregnancy was terminated. The HCMV DNA load values in AF samples were significantly higher in group A (median, 2.8 × 10 5 genome equivalents [GE]/ml) than in group B (median, 8 × 10 3 GE/ml) ( P = 0.014). Our findings suggest that HCMV load level in AF samples correlates with fetal clinical outcome but might also be dependent on other factors, such as the gestational age at the time of AF sampling and the time elapsed since maternal infection.

Le carcinome a cellules de Merkel est une tumeur neuroendocrine cutanee du sujet âge ou immunodeprime. Le genome du Polyomavirus de Merkel (MCPyV) est present dans la majorite des MCC etudies a ce jour. De plus, l’integration clonale du genome viral, la presence de mutations dans la sequence codant l’antigene LT, analogue de proteines oncogenes des Polyomavirus, et l’expression d’un Ag LT tronque suggerent l’implication du virus dans l’oncogenese. Cependant une minorite de MCC est depourvue de genome MCV. Ce phenomene pourrait s’expliquer par un mecanisme « hit and run », ou le virus via l’expression de la proteine LT induirait la tumorigenese, puis l’acquisition d’aberrations chromosomiques dans les cellules transformees permettrait a la fois de s’emanciper de l’expression de l’antigene LT et d’eliminer le genome viral. Trois lignees cellulaires ont ete etablies a partir de tissus MCC provenant de deux patients. L’integration du genome MCPyV a ete demontree dans les trois lignees en phase precoce de culture. Dans la lignee ganglionnaire metastatique du premier patient, l’integration et l’expression de la proteine LT ont persiste apres plusieurs mois en culture, les cellules injectees par voie sous cutanee a la souris scid-nod-gamma ont reproduit des tumeurs conservant ces memes caracteristiques au long cours. Malgre la perte en quelques semaines du genome viral de la lignee tumorale du second patient, la tumorigenese des cellules injectees a la souris etait conservee voire accrue par rapport au modele precedent. Deux modeles d’oncogenese ont donc ete etablis : le premier illustre l’oncogenese dependante de l’expression de l’Ag LT du MCPyV, tandis que le second semble illustrer l’oncogenese de type « hit and run » ou le genome viral initie la transformation cellulaire puis est elimine.

The clinical, virological and immunocytochemical features of three children who recovered from acute herpes simplex encephalitis (HSE) before the age of 2 years, and who developed secondary severe focal epilepsy after a symptom-free period, leading to neurosurgery 3-10 years later are described. In one child, relapse of HSE occurred immediately after surgery. In all three patients, brain sample biopsies showed abundant CD3-positive T lymphocytes with a majority of CD8 cells, and abundant activated macrophage-microglial cells, a pattern similar to that found in acute HSE. Herpes simplex virus DNA was retrieved from the tissue biopsy in one case. The long-term persistent cerebral inflammatory process observed after HSE differed from that observed in another chronic viral disease, subacute sclerosing panencephalitis. This inflammatory reaction may be a result either of low-grade viral expression or self-induced immune activation. The role of inflammation in triggering epilepsy remains hypothetical. Solving these issues should have major therapeutic implications. Herpes simplex virus DNA latency in brain may be the source of replicative HSE relapse.

This multicentre retrospective study describes the clinical features and prognostic significance of Varicella-zoster virus (VZV)-associated neurological complications. The study was performed in patients with human immunodeficiency virus (HIV) infection, hospitalized for VZV neurological complications, confirmed in every case by positive VZV polymerase chain reaction (PCR) in cerebrospinal fluid (CSF). Between 1990 and 1995, 34 HIV-infected patients were included in the study. At diagnosis, 59% had AIDS, with a median CD4 count of 11 x 10(9)/l. A past history of zoster was noted in 35% of cases. A concomitant herpes zoster rash and/or acute retinal necrosis were noted in 71% and 12% of patients, respectively. The predominant neurological manifestations were encephalitis (13), myelitis (8), radiculitis (7) and meningitis (6). The mean CSF white blood cell count was 126/mm3 and the mean CSF protein concentration was 2.3 g/l. Interferon-alpha level was increased in 36% of patients. VZV was isolated from CSF cultures in 2/6 cases. Magnetic resonance imaging was abnormal, demonstrating encephalitis lesions. After intravenous antiviral therapy, complete recovery was obtained in 18 cases (53%), serious sequelae were observed in 10 cases (29%) and 6 patients died (18%). Severe symptoms and a low CD4 cell count appeared to be associated with death or sequelae. In conclusion, VZV should be considered as a possible cause of encephalitis, myelitis, radiculitis or meningitis in HIV-infected patients, especially in patients with a history of or concomitant herpes zoster or acute retinal necrosis. VZV-PCR in the CSF may allow rapid diagnosis and early specific antiviral treatment.

The human herpesviruses share common structural and biological properties. After primary infection, they remain in a latent state during the life-time. Whereas infections are most often benign in immunocompetent individuals, severe infectious or tumoral complications may occur particularly in patients with cellular immunodeficiencies. Anti-viral drugs target viral replication, but have no effect on latency, which remains poorly understood.

Background: Herpesvirus infections of the central nervous system are often severe but are fortunately rare. The incidence of these infections has however, increased in recent years as a consequence of an increase in the number of immune-compromised individuals. New diagnostic procedures have improved our ability to diagnose these infections and herpesviruses may yet be implicated as the cause of further neurological diseases with no known aetiology. Methodological standards for selection and evaluation of patient materials are essential to the provision of reliable diagnosis, yet few studies have addressed this important issue. Objectives: To describe and define methodological standards and reference methodology for diagnosis of herpesvirus infections of the CNS. Study design: Information gathered by literature review. Results: Only for herpes simplex encephalitis is there sufficient data to allow the definition of reference methodology. Good methodological standards exist but few studies have adhered to these standards. As methods for the detection of specific intrathecal antibody synthesis are well established yet under-used in diagnostic virology, the principle of these measurements is reviewed in some detail. Conclusions: Herpesvirus infections of the CNS are of increasing importance. High quality, multi-centre studies are needed to establish the value of the new diagnostic test procedures if further improvement in the diagnostic sensitivity and specificity of these procedures is to be achieved.

Congenital cytomegalovirus infection is frequent. Symptomatic disease at birth is infrequent but very severe. In most cases the infection is totally asymptomatic but neurosensorial damage can occur in 10 % to 15 % of children, hearing loss being the most frequent. Maternal or neonatal screening is the only way to recognise asymptomatic disease. Wether the screening has to be done, and if so when, will be discussed here.

A case of bilateral progressive outer retinal necrosis occurred after herpes zoster ophthalmicus in a patient with acquired immunodeficiency syndrome. This case does not correspond to the classical picture of progressive outer retinal necrosis. The disease led to blindness despite intravenous therapy with acyclovir and foscarnet. PCR could not identify any virus in the aqueous humour, but VZV is evidenced in cerebrospinal fluid. Acute retinal necrosis is now clearly defined by the American Uveitis Society, which should allow to determine its incidence and risk factors. Herpes zoster usually precedes the acute outer retinal necrosis. The infectious theory (VZV, HSV, CMV) widely prevails over the immune theory. We prefer the virus genome identification in the aqueous humor or in the vitreous by PCR to confirm diagnosis rather than the specific antibody titration. Therapy consists in acyclovir, foscarnet and ganciclovir. But whatever the treatment, the visual prognosis is poor.

The first case of prenatal diagnosis of congenital varicella by amniotic fluid viral culture and PCR is reported. Chickenpox is a benign disease in children, but it can lead to severe complications in the adult, especially in the pregnant woman. Five percent of women in childbearing age are not immunised, and the incidence of gestational chickenpox is between 1 and 7 per 10,000. The consequences of this primary infection during pregnancy can be severe for the mother, because of the risk of serious varicella pneumonia, and for the fetus. The fetal infection depends on the gestational age at which the maternal infection occurs. The 2% evaluated risk of fetopathy is maximal between the 7th and 20th week of amenorrhoea. The reported congenital abnormalities are essentially cutaneous, neurological, ophthalmological and musculo-squeletal lesions. A prenatal diagnosis can be suggested: the revelation of defects by ultrasound scan confirms the fetal affection, and can justify pregnancy termination; on the other hand, amniocentesis and cordocentesis are not totally safe, and cannot always assert the fetal contamination or its level of affection. From the therapeutical point of view, prevention with polyvalent gamma-globulin is prescribed to non-immunised pregnant women who have been in contact with the virus. On the opposite, in case of contracted chickenpox, the treatment of the mother with an association of polyvalent gamma-globulin and acyclovir is still controversial since, although probably effective, it may not be safe for the fetus. The solution may reside in the vaccination, soon available, of non-immunised women in childbearing age.

Background: Respiratory viruses, including influenza, bocavirus and respiratory syncytial are common agents of acute asthma exacerbation in children. Objective of the study: To compare the incidence of influenza and other respiratory viruses in ambulatory and hospitalized children with asthma exacerbation. Patients and Methods: From November 2005 to May 2009, viral immunofluorescence and bocavirus PCR were performed on nasopharyngeal aspirates in children (2-15y) examined in an hospital emergency room for acute asthma attack during the winter seasons and hospitalised or not. Results: Bocavirus was found in 11.6% of hospitalized and 13% of ambulatory patients with exacerbation of asthma, and respiratory syncytial virus in 13.5% and 17.7%, respectively. However, influenza A virus was detected in 2.6% of hospitalized and 14.1% (p

A single pair of oligonucleotide primers selected within a highly conserved region of the DNA polymerase gene of the herpesviruses was designed to amplify related viral genomes, i.e., herpes simplex virus type 1, herpes simplex virus type 2, Epstein-Barr virus, and cytomegalovirus, by the polymerase chain reaction. A simple restriction enzyme analysis of these amplified products allowed accurate characterization of the herpesvirus type. Ninety-nine cerebrospinal fluid samples from 36 patients (including newborns, children, and adults) with acute encephalitis were tested for the presence and identification of herpesvirus DNA by this approach. High levels of viral DNA, which were readily visualized by simple ethidium bromide staining, were found in all these patients from the first days of the disease and, in some cases, until the third week following the onset of acute encephalitis. The herpesvirus type was rapidly identified by enzymatic digestion in 33 patients' samples and by hybridization and direct sequencing in the last 3 patients' samples. Our results show that the polymerase chain reaction provides a highly sensitive and specific technique for the identification of herpesviruses DNA in cerebrospinal fluid that should be of value for early and rapid diagnosis, therapeutic decisions, prognostic evaluation, and epidemiological studies.

The ontogenesis of GABAergic neurons in the rat hippocampus was studied using an anti-GABA serum. GABA immunoreactivity appeared at the 18th day of gestation. At this stage, GABA-immunoreactive (GABA-IR) cells are grouped in two layers, one located deeply in the intermediate zone near the ventricular zone, and the other found superficially in the marginal zone near the hippocampal fissure. During the late embryonic and early postnatal life, GABA-IR neurons progressively disappeared from these two layers. The transient appearance of an abundant network of GABAergic neurons might be due to transient expression of GABA in some neurons or to cellular death. Later on, from the third postnatal day, the GABA-IR neurons appeared throughout the whole hippocampus according to a dorsoventral and lateromedial gradient. The setting of neuronal bodies preceded that of GABA-IR puncta (supposed to be mainly synaptic boutons) around the neuronal cell bodies and along the dendritic shafts. The puncta are only visible from the sixth day onwards and their number increased rapidly during the first 3 postnatal weeks. Our results indicate that GABA may have a role in neurotransmission in the hippocampus from a very early stage of development.

Pathological findings in four cases of hemimegalencephaly are presented. These cases demonstrated diffuse enlargement of the cortex with disappearance of horizontal layering of the neurons restricted to one hemisphere. In all cases there was marked enlargement of a high percentage of neurons. The nosological situation is discussed and is considered to be heterogeneous; cases 1-3 had cerebral lesions without lesions of the skin or viscera. In these three cases, significant glial abnormalities were found in only one. These cases and others quoted in the literature were considered to be a separate entity completely different from Bourneville's tuberous sclerosis. The aetiology of this developmental malformation remains unknown; genetic factors were not found. Case 4 was associated with a cardiac lesion and with a linear sebaceous naevus characteristic of Solomon's syndrome. Periventricular tumours resembling candlewax drippings were noted. This case, close to Bourneville's disease, could be incorporated into the framework of neuroectodermoses together with tuberous sclerosis.

The hippocampus taken from E18-E19 rat embryos was dissociated into a cell suspension and was either grafted into the hippocampus of adult rats or cultured. The growth of GABAergic neurons was examined using a GABA directed antiserum. The implanted tissue was capable of survival and growth without exhibiting a laminar organization. Most of the various morphological neuronal types could be observed, establishing different types of synapses; however, granule neurons were rarely encountered. A substantial proportion of GABA-positive neurons was detected within the graft with profuse labelling of the neuropil. In cultures issued from the same cell suspension, GABA-immunoreactive neurons were numerous and had different morphologies. Altogether these data suggest that GABA neurons express a high potential for growth and sprouting in vitro and in vivo.