Neonatal herpes: case series in two obstetric centres over a 10-year period (2013-2023), France.

Neonatal herpes simplex virus (HSV) infection (HSV infection in infants less than 6 weeks of age) is rare but mortality and morbidity rates are high after disseminated disease and encephalitis. In France, the epidemiology is poorly described, and two decades ago, incidence was estimated to be 3 per 100,000 live births a year. We describe determinants, epidemiologic and clinical characteristics of neonatal HSV infection in a managed-care population attending in two major obstetric and paediatric centres, Paris, France, over a 10-year period. This retrospective case series study was conducted from 2013 to 2023, in infants less than 42 days of age who had virologically confirmed HSV infection. We report an overall rate of neonatal herpes of 5.5 per 100,000 live births a year and an incidence of symptomatic cases of 1.2 per 100,000 live births a year. HSV-1 was the major serotype involved (84.2%) and post-natal acquisition through the orolabial route reached 63.2%. All neonates who had neonatal HSV PCR screening (owing to clinical signs in parents) and who received prompt acyclovir treatment remained asymptomatic. Symptomatic forms accounted for 21.1% cases of the total and mortality was high (62.5% of symptomatic forms).   Conclusion: This case series confirms that neonates at risk for HSV disease and poor outcome are those born to HSV-seronegative mothers, preterm infants, and those who received acyclovir after onset of symptoms (mainly because mothers did not present evidence of acute HSV infection). Our study confirms the major role of HSV-1 and the frequency of its early post-natal acquisition. What is known: • Neonatal herpes simplex virus infection is rare but motality and morbidity rates are high after disseminted disease and encephalitis. National recommendations exist worldwide but mangement of this disease is not always easy. What is new: • As in France epidemiology of neonatal herpes is poorly described, our report is potentially an important addition to the existing literature. Moreover, we describe local practice that may be useful to physicians.

Congenital Rubella Syndrome Following Rubella Vaccination During Pregnancy.

Rubella vaccine is usually given in combination with measles and mumps vaccines as a measles-mumps-rubella vaccination. Because it contains live attenuated virus, its use is contraindicated during pregnancy. However, since the introduction of rubella vaccine, no cases of congenital rubella syndrome have been reported following vaccination during pregnancy. We report a case of a female infant, born to a woman inadvertently vaccinated with measles-mumps-rubella vaccination early in pregnancy, who manifested a phenotype of cardiac and neurologic defects, neurodevelopmental delay, and lymphocytopenia consistent with congenital rubella syndrome.

Cytomegalovirus Specific Serological and Molecular Markers in a Series of Pregnant Women With Cytomegalovirus Non Primary Infection.

(1) Background: In a period where systematic screening of CMV during pregnancy is still debated, diagnosis of non primary infection (NPI) remains challenging and an obstacle to systematic screening. Our aim is to report kinetics of serological and molecular CMV markers of NPI. (2) Methods: We identified immunocompetent pregnant women with CMV NPI as women known to be seropositive for CMV before pregnancy who gave birth to cCMV infected infants. We performed CMV-IgG, CMV-IgM, CMV-IgG avidity and CMV PCR retrospectively on sequential serum samples collected during pregnancy. (3) Results: We collected 195 serum samples from 53 pregnant women with NPI during pregnancy. For 29/53 (55%) patients, no markers of active infection were observed (stable IgG titers, negative IgM and negative PCR). CMV PCR was positive in at least one serum for 18/53 (34%) patients and median viral load was 46 copies/mL, IQR (21-65). (4) Conclusions: For more than half of patients with confirmed CMV NPI during pregnancy, available diagnostic tools are liable to fail in detecting an active infection. These should therefore not be used and universal neonatal screening for CMV remains the only way to detect all cCMV infections.

Contribution of Serum Cytomegalovirus PCR to Diagnosis of Early CMV Primary Infection in Pregnant Women.

(1) Background: What is the role of serum CMV PCR in the diagnosis of recent primary infection (PI) in pregnant women when IgG avidity is uninformative? (2) Methods: Retrospective cohort study to compare serum versus whole blood CMV PCR. (a) Qualitative assessment: CMV PCR was performed on 123 serum samples and 74 whole blood samples collected from 132 pregnant women with recent CMV PI. PCR positivity rate was used to calculate sensitivity in serum and whole blood. (b) Quantitative assessment: CMV PCR was performed on 72 paired samples of serum and whole blood collected on the same day from 57 patients. (3) Results: In pregnant women, PCR positivity rate was 89% for serum samples versus 100% in whole blood in the case of very recent PI (<15 days), but only 27% in serum versus 68% in whole blood for PI occurring from 6 weeks to 3 months before. Comparing CMV viral loads between serum and whole blood, we determined the limit of CMV DNA detection in serum as 3 log copies/mL (whole blood equivalent). (4) Conclusions: Serum CMV PCR is reliable in confirming PI in cases when only IgM is detected. It is therefore a valuable tool in introducing valaciclovir treatment as early as possible to prevent mother-to-child CMV transmission.

When EBV serology needs a blot to conclude: a case report / Quand un immunoblot EBV est nécessaire pour conclure une sérologie anti-EBV : cas clinique

A 14-year-old patient underwent liver transplant. Three months after transplantation, EBV associated lymphoma was suspected. EBV serologies before and after transplantation were particularly discrepant. Eighteen months before transplantation, the serological profile suggested a recent EBV primary-infection, four months before transplantation, we had isolated anti-EBNA IgG and five days after transplantation, the serological profile suggested a past infection. All EBV PCR performed on whole blood were negative. Retrospectively, immunoblots anti-EBV IgG were performed. Blots showed no anti-EBV IgG before and until the day of liver transplantation. Five days after transplantation, slight bands of both IgG anti-p18 (VCA) and anti-EBNA-1 were found, without any other serological marker. These were probably due to passive transfers of IgG during surgery. There was therefore no argument for an immunization against EBV before or after liver transplant for this patient.

Un patient de 14 ans a subi une transplantation hépatique. Trois mois après la transplantation, un lymphome associé à l'EBV a été suspecté. Les sérologies anti-EBV (IgG anti-VCA et anti-EBNA, IgM anti-VCA) montraient des résultats particulièrement discordants et ininterprétables : profil de primo-infection EBV récente 18 mois avant la greffe, IgG anti-EBNA isolées 4 mois avant la greffe et profil d'infection ancienne 5 jours après la greffe. Les PCR EBV réalisées sur sang total étaient toujours indétectables. Rétrospectivement, des immunoblots IgG anti-EBV ont été réalisés. Les blots ne montraient pas d'IgG anti-EBV en pré-greffe jusqu'au jour de la transplantation. Cinq jours après la greffe, le blot montrait la présence d'anti-p18 (VCA) et anti-EBNA-1 présents sous forme de traces, sans autre marqueur sérologique d'infection EBV, très probablement dues à des transferts passifs d'anticorps pendant la transplantation. Aucun argument sérologique ni moléculaire n'a été retenu pour une immunisation anti-EBV avant ou après la transplantation hépatique pour ce patient.

Rubella virus-associated uveitis: The essentiality of aqueous humor virological analysis.

AIMS / BACKGROUND: Rubella virus-associated uveitis (RVAU) classically presents with the clinical features of Fuchs uveitis syndrome (FUS). We report a series RVAU, and discuss the relevance of available diagnostic strategies, and how vaccination could potentially prevent disease. METHODS: We retrospectively included patients with RV-positive aqueous humor (AH) with RT-PCR and/or intraocular RV-IgG production, between January 2014 and December 2019. RV-IgG titers from AH and serum were compared with other virus-specific IgG titers (VZV and/or CMV and/or HSV-1), to determine the derived Goldmann-Witmer coefficient (GWC'). Clinical findings at presentation and during follow-up are reported, as well as the anti-RV vaccination status. RESULTS: All 13 included patients demonstrated intraocular synthesis of RV-IgG (median GWC': 9.5; 3.2-100). RV-RNA was detected in one patient while PCR results were negative for other HSV1, VZV and CMV. The mean delay in diagnosis was 13 ± 12.6 years, with an initial presentation of FUS in only 3 patients (23%). Only four patients had been vaccinated, but all after the recommended age. CONCLUSION: As RVAU is a pleiomorphic entity, virological analysis (RV RT-PCR and GWC') of aqueous humor is essential to improve the diagnosis and management of this entity. Improper vaccination against RV appears to be implicated in RVAU.

Comparison of performance between three SARS-CoV-2 molecular assays (Aptima™, Laboratory Developed Test-Fusion, and R-GENE®) with special attention to turnaround time, a key point in laboratory management.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of rapid diagnostic testing to identify individuals with SARS-CoV-2 infections and to limit the spread of the virus. Many molecular assays have become commercially available to cope with this surging demand for timely diagnosis of COVID-19 cases, but identifying individuals requires accurate diagnostic tools. We compared the performance of three molecular SARS-CoV-2 assays: Aptima™ SARS-CoV-2 assay running on the Panther system (Hologic), an in-house assay (Laboratory Developed Test, LDT) running on the Fusion module of the Panther Fusion system (LDT-Fusion; Hologic), and the R-GENE® SARS-CoV-2 assay (bioMérieux). In addition, we also evaluated the turnaround time. This parameter is crucial to managing the SARS-CoV-2 diagnosis and represents a key point in the quality management at the laboratory. Aptima™ and LDT-Fusion assays exhibited an excellent positive percent agreement (PPA) (100.0%), while the R-GENE® assay showed a slightly decreased PPA (98.2%). The Hologic assays have a higher throughput with less hands-on time than the R-GENE® assays (24-25 vs. 71 min). Both Hologic assays are used on a fully automated random-access testing system with on-demand testing capabilities that avoid run series, unlike the R-GENE® assay. Automated random-access testing systems should be preferred during periods of high SARS-CoV-2 prevalence.

What is the true place of the SARS-CoV-2 rapid point-of-care antigen test in the hospital setting? Lessons learned from real life.

To assist in the clinical management of patients and to support infection control, we tested the use of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) point-of-care antigen test (AgPOC) for unplanned hospitalization, coupled with a nucleic acid amplification test (NAAT) using specimens collected at the same time upon arrival. The aim of this study was to assess the performance of the AgPOC in this specific use compared to NAAT for SARS-CoV-2 diagnosis, in the context of the low prevalence of infection. For 5 months (between two peaks in France of the SARS-CoV-2 pandemic), all patients admitted who undertook the AgPOC/NAAT paired tests were included in the study. AgPOC performances were determined considering the clinical status and the delay of symptoms onset. NAAT and AgPOC results were available for 4425 subjects. AgPOC results showed a homogeneous specificity (>97%) but a low sensitivity at 45.8%. Considering the national guidelines, sensitivity dropped to 32.5% in cases of symptomatic patients with symptoms older than 5 days or more. This study shows the poor performance of AgPOC for entry screening of patients in hospitals. AgPOC may represent a useful tool in the hospital setting only if the use is restricted to patients with consistent symptoms less than 4 days old.

Positive predictive values of CMV-IgM and importance of CMV-IgG avidity testing in detecting primary infection in three different clinical settings. A French retrospective cohort study.

BACKGROUND: Diagnosis of Cytomegalovirus (CMV) primary infection during pregnancy or in immunocompetent patients relies on serology with detection of specific CMV-IgG and IgM. In case of positive CMV-IgM in pregnant women, CMV-IgG avidity is now widely recommended, but in general population it is not currently performed. OBJECTIVE: In this study, we aimed to determine CMV-IgM positive predictive values (PPV) in different clinical settings. MATERIAL AND METHODS: We conducted a retrospective study on positive CMV-IgM in our virology laboratory from 2013 to 2019, in three clinical groups: screening in non-symptomatic pregnant women (group 1), pregnant women with ultrasound (US) abnormalities (group 2) and patients (general population) with clinical signs suggestive of CMV primary infection (group 3). CMV-IgG avidity had been performed in all cases allowing to evaluate PPV of positive CMV-IgM to diagnose CMV primary-infection in each group. RESULTS: Between 2013 and 2019, 6859 serum samples were found positive for CMV-IgM and had been tested for CMV-IgG avidity, with 6560 sera for group 1, 30 for group 2 and 269 for group 3. Overall, low avidity confirming primary infection was observed respectively in 16.4 % for group 1, 36.7 % for group 2, and 35.3 % for group 3. CMV-IgM PPV was significantly lower in group 1 compared to groups 2 (p = 0.01) and 3 (p < 0.001). DISCUSSION: Our observations highlight the major importance of including CMV-IgG avidity in the diagnostic algorithm, whatever the clinical situation (for immunocompetent patients), to confirm or exclude a recent CMV primary infection in case of positive CMV-IgM.

Evaluation and optimisation of commercial Zika IgG avidity assay.

BACKGROUND: ZIKV infection has potentially severe consequences particularly in fetuses/newborns born to mothers that were infected early in pregnancy. Diagnosis relies on the detection of ZIKV IgM that can also be detected due to cross reactivity or to nonspecific polyclonal activation of the immune system. Therefore, in case of ZIKV IgM detection, identification of a recent infection can be of major importance for the optimal management of pregnant women. OBJECTIVE: This study evaluates the performances of a commercially available assay to measure ZIKV-IgG avidity. STUDY DESIGN: A total of 110 serum or plasma samples collected from symptomatic or asymptomatic patients living or returning from a ZIKV endemic area were classified according to epidemiological and clinical information, and to serology and molecular assays' results. Samples were tested with the IgG ZIKV Avidity Test (DIA.PRO®) according to manufacturer's instruction and with a modified protocol. RESULTS: By using the manufacturer's Avidity Index cut-off, distinction between recent and past infection was unclear with similar AIs in the two situations (p = 0.8872). Sensitivity and specificity in identifying recent infection were poor, 67.3 % and 4.5 % respectively. By using a modified protocol, a better discrimination was observed with significant differences between mean AIs (p = 0.0318), and with higher sensitivity and specificity, respectively 87.8 % and 100 %. CONCLUSION: Our results highlight that IgG ZIKV Avidity Test DIA.PRO® assay is not reliable enough to be used in clinical practice without modifications.

Autochthonous Hepatitis E during Pregnancy, France.

Acute hepatitis E virus infections occurred during the third trimester in 2 pregnant women in France who sought treatment with nonspecific symptoms or asymptomatic elevation of liver enzymes. Infection cleared quickly in both women. We detected no hepatitis E RNA in 1 newborn's feces at 3 weeks of age.

Natural non-homologous recombination led to the emergence of a duplicated V3-NS5A region in HCV-1b strains associated with hepatocellular carcinoma.

BACKGROUND: The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies. METHODS: Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event. RESULTS: Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients. CONCLUSIONS: These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.

A cluster of three cases of trichinellosis linked to bear meat consumption in the Arctic.

We report here three cases of trichinellosis due to polar bear meat consumption in East Greenland. In the past 20 years, 31 cases of trichinellosis have been reported in French travellers to the Arctic (North Quebec, Nunavut and Greenland) who consumed undercooked meat from black, brown, or polar bears. If local communities are increasingly becoming aware of the risk of trichinellosis, travellers visiting regions where bear meat is consumed should be informed of the risk of eating raw or non-heat-processed meats.

Assessing Immunity to Rubella Virus: a Plea for Standardization of IgG (Immuno)assays.

Immunity to rubella virus (RV) is commonly determined by measuring specific immunoglobulin G (RV IgG). However, RV IgG results and their interpretation may vary, depending on the immunoassay, even though most commercial immunoassays (CIAs) have been calibrated against an international standard and results are reported in international units per milliliter. A panel of 322 sera collected from pregnant women that tested negative or equivocal for RV IgG in a prior test (routine screening) was selected. This panel was tested with two reference tests, immunoblotting (IB) and neutralization (Nt), and with 8 CIAs widely used in Europe. IB and Nt gave concordant results on 267/322 (82.9%) sera. Of these, 85 (26.4%) sera were negative and 182 (56.5%) sera were positive for both tests. All 85 IB/Nt-negative samples were classified as negative with all CIAs. Of the 182 IB/Nt-positive samples, 25.3 to 61.5% were classified as equivocal and 6 to 64.8% were classified as positive with the CIAs. Wide variations in titers in international units per milliliter were observed. In our series, more than half of the women considered susceptible to RV based on CIA results tested positive for RV antibodies by IB/Nt. Our data suggest that (i) sensitivity of CIAs could be increased by considering equivocal results as positive and (ii) the definition of immunity to RV as the 10-IU/ml usual cutoff as well as the use of quantitative results for clinical decisions may warrant reconsideration. A better standardization of CIAs for RV IgG determination is needed.

[Diagnosis of maternofetal infections]. / Prescription et interprétation des bilans sérologiques dans le cadre d'infections maternelles à risque de transmission fœtale.

Prevention is an essential aspect of management of infections that can be transmitted from mother to fetus during pregnancy: The prescription and interpretation of serologic markers differ according to clinical context: screening, counts, clinical signs, or ultrasound signs. Testing for rubella IgG antibodies is recommended at the beginning of pregnancy, in the absence of written results proving either immunity or previous vaccination with two doses. Monthly serologic monitoring (IgG and IgM) is recommended for woman lacking immunity to toxoplasmosis. Diagnosis of a primary infection requires the concomitant detection of IgG and IgM. Nonetheless, the presence of specific IgM is not necessarily a marker of recent infection. IgG avidity must be measured to confirm or rule out a recent primary infection when IgM is positive. The observation of stable antibody titers is often inaccurately considered to be reassuring. In fact, depending on the individuals tested and especially the technique used, antibodies may reach a plateau several days or several weeks after the onset of the infection. Clinical diagnosis of rubella is not reliable, and its rarity today means that physicians are unlikely to recognize it or consider it as a possible differential diagnosis. Nonetheless, residual circulation of the rubella virus continues in France. A chickenpox rash is diagnosed clinically. For atypical eruptions, the virus can be sought directly in the vesicular fluid. Serology is not helpful in this case.

Rubella and pregnancy: diagnosis, management and outcomes.

Rubella is a mild viral disease that typically occurs in childhood. Rubella infection during pregnancy causes congenital rubella syndrome, including the classic triad of cataracts, cardiac abnormalities and sensorineural deafness. Highly effective vaccines have been developed since 1969, and vaccination campaigns have been established in many countries. Although there has been progress, the prevention and diagnosis of rubella remain problematic. This article reviews the implications and management of rubella during pregnancy.

[Rubella: a current issue?]. / La rubéole : une question d'actualité ?

Sporadic cases of rubella infection are reported each year in France due to insufficient vaccination coverage. Rubella virus is a very unstable enveloped RNA virus. For this reason, transportation and storage of samples collected for its detection require particular conditions. The genetic stability of rubella virus has allowed the development of very effective vaccines. During the recent rubella outbreaks in Algeria and Tunisia, an unusual high rate of encephalitis was reported. The role of the laboratory is crucial in the management of rubella infection during pregnancy. Rubella serological results must be interpreted with caution. Congenital rubella is a severe disease that should already be eliminated thanks to a very effective vaccine that has been developed. All women of childbearing age should be vaccinated. Rubella vaccination of an unknowingly pregnant woman is not an indication for abortion.

[Infections transmitted from the mother to the fetus: diagnostic issues and management of pregnancy]. / Infections materno-fœtales: difficultés diagnostiques et prise en charge maternelle.

Some infections are considered as feared risks during pregnancy. These infections may lead to severe damage of the fetus or the newborn depending on the infectious agent and the term of pregnancy where the infection occurred. Antenatal screening (in France it concerns toxoplasmosis, rubella, syphilis and hepatitis B) play an important role in prevention and management of vertically transmissible infections. However, biological diagnosis is also essential when maternal/neo-natal clinical symptoms or abnormal ultrasound findings are observed. In this article we chose to focus on rubella, varicella, syphilis, toxoplasmosis, hepatitis B and cytomegalovirus and parvovirus infections.