Positive predictive value of seroconversion or positive rubella IgM in diagnosis of maternal rubella infection: Seven-years review of French National Reference Laboratory for Rubella.

BACKGROUND: In France, as in most developed countries, childbearing age women are routinely screened for rubella antibodies to identify and vaccinate susceptible women. Immunity to rubella is usually determined by measuring the rubella virus-specific immunoglobulin G (RV-IgG). In case of seroconversion for RV-IgG and/or positive RVIgM during pregnancy, laboratories usually send serum samples to the French National Reference Laboratory (FNRL) for Rubella in order to perform complementary investigations and confirm or exclude rubella infection during pregnancy. OBJECTIVE: Our aim is to report results of these investigations during a seven-year period (2013-2019) and evaluate the positive predictive value (PPV) of RV-IgG seroconversion or positive RV-IgM to diagnose maternal rubella infection in France. STUDY DESIGN: Between 2013 and 2019, 5398 serum samples collected from 4104 pregnant women, were addressed to FNRL because of RV-IgG seroconversion (N=899) or positive RV-IgM (N=3205). Additional serological tests were performed, mainly immunoblot (to look for the presence of anti-E1 protective antibody) and RV-IgG avidity (to exclude or confirm primary infection). RESULTS: Overall, for 3724/4104 (90.8 %) women, rubella primary-infection during pregnancy was formally excluded and maternal rubella primary-infection was only confirmed in 46/4104 (1.1 %) cases. CONCLUSION: Clinicians and biologists should be particularly aware that RV-IgG seroconversion or positive RV-IgM, in the current context of low RV circulation in France are most often not rubella primary infections. PPV of seroconversion to assess maternal rubella primary infection is as low as 0.2 % (95 % CI: 0 %; 0.5 %) and PPV of positive RV-IgM is only of 1.4 % (95 % CI: 0.99 %; 1.81 %).

Evolution of awareness and knowledge of congenital cytomegalovirus infection among health care providers in France between 2011 and 2018.

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital viral infection. Approximately 1 % of newborns are congenitally infected and in up to 10 % of them the consequences are severe. Antenatal and postnatal treatments, although promising, are still under evaluation. Hygiene counseling to prevent CMV infection is important and should be systematic. OBJECTIVE: To evaluate health care providers' awareness of CMV maternal and congenital infection in France. STUDY DESIGN: A questionnaire on CMV infection was sent in 2018 by e-mail to obstetricians, pediatricians, midwives and laboratory physicians, and members of medical or midwifery associations. We evaluated their knowledge concerning CMV epidemiology, transmission, symptoms in adults, newborns and long-term effects (scores from 0 to 30) and compared the results with those of our 2012 published study. RESULTS: Of the 597 respondents who completed the questionnaire, 91 % were unaware of the precise transmission route of CMV, 33 % wrongly thought thatin utero therapy for congenital CMV infection was a current standard of care in France, and less than half were familiar with the HAS (Haute Autorité de Santé) and CNGOF (Collège National des Gynécologues et Obstétriciens Français) recommendations. When respondents' knowledge of CMV was greater, patients were given more hygiene counseling. Between 2011 and 2018, knowledge improved among doctors and midwives concerning the route of transmission, the symptoms in adults, and the long-term effects of CMV infection. CONCLUSIONS: Knowledge is improving among healthcare providers, but gaps remain. To bridge these gaps, health care providers should improve their knowledge about congenital CMV by various means: medical reviews, continuing medical education, meetings, conferences, the Internet. Moreover, greater knowledge will allow for more effective counseling of pregnant women, as recommended by HCSP and CNGOF in France.

Aluminum and vaccines: Current state of knowledge.

French people have never been so wary about vaccines. The use of aluminum salts in vaccine adjuvants to enhance effectiveness is one of the major reasons for this lack of confidence. The direct toxicity of aluminum is often put forward. Direct toxicity of aluminum has long been known-especially with occupational exposure-to be associated with characteristic clinical manifestations and increased blood aluminum level. Intoxication related to the excessive amount of an element in the body, whether be it lead poisoning following exposure to lead or mercury poisoning for instance, is always associated with metal increase in biological media. To date no link has been established between the direct toxicity of aluminum and vaccines. Aluminum levels in biological media of vaccinated subjects are not different from those of unvaccinated subjects. This is consistent with the very small amount of aluminum contained in one dose of vaccine. Indirect toxicity of aluminum was suggested to explain macrophagic myofasciitis in humans in 2011, a disease that could be mediated by an autoimmune/autoinflammatory mechanism. This hypothesis has recently been refuted in a large pharmaco-epidemiological study proving that aluminum-containing adjuvants of vaccines are not responsible for this autoimmune/autoinflammatory syndrome.

Determination of rubella virus-specific humoral and cell-mediated immunity in pregnant women with negative or equivocal rubella-specific IgG in routine screening.

BACKGROUND: Immunity to rubella-virus (RV) is commonly determined by measuring specific IgG (RV-IgG). However, RV-IgG results may be different and even discordant, depending on the assay used. Cell-mediated immunity is not routinely investigated for diagnostic purposes. OBJECTIVES: Our aim was to investigate humoral and cellular immunity of women with negative or equivocal RV-IgG before, and after post-partum vaccination. STUDY DESIGN: A total of 186 pregnant women were included in the study. During pregnancy, humoral immunity was investigated with two RV-IgG immunoassays, an immunoblot and a T-cell mediated immunity test. In the post-partum vaccination period, measuring RV-IgM and RV-IgG avidity allowed us to determine whether women raised a primary or a secondary immune response. RESULTS: Before vaccination, 52.2% women, supposed to be susceptible, had positive anti-E1 RV-IgG indicating strong evidence of previous exposure to RV. All (100%) pregant women who had a positive immunoblot before immunization raised a secondary immune response to vaccination, and 96.8% who had a negative immunoblot before immunization, raised a primary immune response to vaccination. All women who raised a primary immune response after vaccination had negative anti-E1 RV-IgG and negative cell-mediated immunity. DISCUSSION: These results indicate that individuals can have evidence of protective immunity against rubella despite negative RV-IgG.

Cytomegalovirus non-primary infection during pregnancy. Can serology help with diagnosis?

Diagnosis of cytomegalovirus (CMV) primary infection is reliable, but diagnosis of CMV non-primary infection (NPI) is questionable. Our aim is to highlight the difficulties met in diagnosis of CMV NPI. We illustrate that in proven cases of CMV NPI, very different serologic and molecular patterns may be observed and that routine serologic testing may fail to help with diagnosis. These results point out that many data available in literature concerning the prevalence of NPI, materno-fetal transmission rates and consequences of NPI may be wrong. We need to know how frequently they occur, are transmitted and cause fetal damages. Diagnosis of NPI must be improved, along with our understanding of the mechanisms leading to intrauterine CMV transmission and congenital infection in babies born to women with preexisting immunity.

Analytical issues possibly affecting the performance of commercial human cytomegalovirus IgG avidity assays.

In the majority of cytomegalovirus (CMV) immunoglobulin G (IgG) avidity assays, avidity determination can be performed on the entire CMV IgG measurable positive concentration range. However, in some exceptional samples with very low IgG levels, inappropriately low avidity indexes have been described. In this study, we addressed some possible causes and the clinical importance of these inappropriately low avidity indexes. We compared VIDAS (bioMérieux), Liaison (DiaSorin), and Architect (Abbott) CMV IgG avidity assays on 129 samples from patients with past CMV infections, focusing on samples with low IgG levels. Inappropriately low avidity samples were further evaluated using seven different urea-based IgG avidity assays. We confirmed that inappropriately low avidity indexes in samples with very low IgG levels occur, but are rare. We could show that this phenomenon is not confined to a single assay and that assays employing chaotropic agents are affected more frequently and profoundly. In situations where the CMV IgG avidity is performed on CMV immunoglobulin M (IgM)-negative samples, the avidity index should be interpreted cautiously in cases of very low CMV IgG levels, whatever the technique used.

Clinical evaluation of the Roche Elecsys CMV IgG Avidity assay.

Congenital cytomegalovirus (CMV) infection has potentially severe consequences in newborns. The testing of pregnant women for CMV-specific antibodies may be useful for the identification of women at risk of transmitting the infection to the fetus. The determination of CMV IgG avidity helps to establish the timing of infection as IgG avidity matures during the course of infection. This study examines the performance of the Elecsys CMV IgG Avidity assay using preselected samples from patients at different phases of CMV infection. The Elecsys CMV IgG Avidity assay was tested at three sites using sequential samples from patients with recent primary CMV infection, as well as single samples from patients with recent primary or past CMV infection. The Elecsys assay discriminated well between early (low avidity) and late (high avidity) phases of infection in sequential serum samples. Overall, 98.8% of low-avidity samples corresponded to infection onset <180 days before sampling and 77.8% of all high-avidity results corresponded to infection onset >90 days before sampling. The assay's sensitivity was 90-97%, with specificity ranging from 89 to 100%, depending on the consideration of gray-zone avidity values. Single samples from recent primary or past infection showed similar distributions of avidity results. The Elecsys CMV IgG Avidity assay results are in agreement with preselected samples from patients with primary or past CMV infection, showing that the test is an adequate predictor of the phase of infection.

A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome.

OBJECTIVE: To analyze the outcome of maternal primary cytomegalovirus (CMV) infection. METHODS: Retrospective analysis of a cohort of 238 patients with maternal primary CMV infection detected at routine screening. The cases were managed with serial ultrasound (US) scans, and amniocentesis was performed in 36.1% of cases. All prenatal results were confirmed at birth. RESULTS: The average age was 31.9 (18-44) years. Patients were symptomatic in 21% of cases. The rate of intrauterine transmission was 24.9%, and it was 8.8%, 19%, 30.6%, 34.1% and 40% in the preconceptional period, the periconceptional period, and the first, second and third trimesters of pregnancy, respectively (p = 0.025). There was a significantly higher risk of US abnormalities when maternal infection occurred during the preconceptional or periconceptional period and the first trimester compared with later (p < 0.001). Because of US abnormalities, pregnancy was terminated in 18 cases at the parents' request. Three infected newborns were symptomatic; all three cases were suspected at US before birth. We did not observe any symptomatic fetal infection when maternal infection occurred after 14 weeks of gestation. A number of clinically asymptomatic cases (5.5%) developed hearing loss. CONCLUSION: The rate of materno fetal transmission is linearly correlated to the gestational age at infection. No severe case of congenital infection was observed if maternal infection occurred after 14 weeks of gestation.

Clinical evaluation of new automated cytomegalovirus IgM and IgG assays for the Elecsys(®) analyser platform.

Cytomegalovirus (CMV) is a leading cause of physical and neurological abnormalities in newborns. Hence, the diagnosis of CMV infection in pregnant women is necessary in order to allow appropriate management of their pregnancy. New assays have been developed for the Roche Elecsys® immunoassay platform that detect CMV-specific immunoglobulin (Ig)M and IgG, with the IgM assay designed to target IgM produced at the start of infection rather than IgM persisting later in infection. This study aimed to evaluate the performance of the new assays compared with other commercial kits widely distributed in laboratories. The performance of the Elecsys and comparator CMV IgM and IgG assays was assessed using 967 preselected patient samples characterised by CMV infection status, as well as being compared using 1,668 unselected clinical samples. The Elecsys CMV IgM and IgG assays performed consistently with comparator assays using the preselected samples. The Elecsys CMV IgM assay showed improved sensitivity compared with the Enzygnost® assay in primary infection (91.2 % vs. 79.4 %) and improved specificity over the Architect® assay in potentially cross-reacting samples (94.1 % vs. 82.4 %). The Elecsys IgM assay reported fewer positive results in the later stages of CMV infection compared with ETI-CYTOK-M ELISA, while the Elecsys IgG assay reported slightly fewer negative results in the early stages of infection compared with ETI-CYTOK-G ELISA. There was good agreement between Elecsys and comparator assays using unselected clinical samples (range 90.4-99.4 %). The Elecsys CMV IgM and IgG assays compare well with routinely used assays and are suitable for clinical use.

Awareness and knowledge of congenital cytomegalovirus infection among health care providers in France.

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital virus infection. CMV infects approximately 1% of newborns at birth with severe consequences among 10% of them and antenatal and postnatal treatments, although promising, are still under evaluation in randomised control trials. Efficacy of hygienic counselling to prevent CMV infection is nowadays established and should be spread. OBJECTIVE: To evaluate health care providers' awareness of CMV infection during pregnancy in France. STUDY DESIGN: A questionnaire on CMV infection was sent by e-mail to obstetricians, paediatricians, midwives and laboratory physicians, members of medical or midwives association. We evaluated their knowledge concerning CMV epidemiology, transmission, symptoms in adults, newborns and children. RESULTS: The questionnaire was completed by 800 respondents (half midwives and one third obstetricians). Most of them were unaware of the precise transmission route of CMV. Laboratory physicians had the highest score concerning maternal symptoms and post natal long term effects. 20% of respondents were wrongly convinced that in utero treatment options for congenital CMV infection were already available in France at the time of the study. The mean knowledge scores regarding transmission and neonatal symptoms increased with a more advanced career stage (i.e. older age) among obstetrician. CONCLUSIONS: This study tends to confirm that there is a large gap between knowledge of CMV during pregnancy and the burden of this disease. To bridge this gap, health care providers should improve their knowledge about congenital CMV by various means: medical reviews, continuing medical education, meetings, conferences, the Internet.

[Measles in pregnancy: a review]. / Rougeole chez la femme enceinte : mise au point.

Although measles is usually considered a benign viral disease of childhood, people may be affected whatever their age with severe pneumologic or neurologic consequences are more frequent before 5 years old and after 20 years old. The consequences of a congenital measles, defined as a newborn eruption within 10 days after birth, can be dramatic. The incidence of measles has significantly decreased since first vaccines were introduced in the late 1960s. In France, active immunization for measles is proposed since 1983. Since the beginning of 2008, France has been experiencing a measles outbreak with more than 17,000 notified cases. The current measles outbreak affects more particularly very young children and young adults and, among these, pregnant women. Measles during pregnancy may be severe mainly due to pneumonia. Measles is associated with a risk of miscarriage and prematurity, but congenital anomalies have not been described. If rash occurs near term, the consequences of congenital measles could be severe. Prevention of measles in pregnant women is based on improving immunization coverage, currently insufficient to eradicate virus circulation. The aim of this review is to state on the latest data concerning measles virus, give latest vaccine recommendations, and also to suggest management of measles contact or measles infection during pregnancy.

Awareness of cytomegalovirus infection among pregnant women in France.

BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital virus infection. Approximately 1% of newborns are infected by CMV at birth with severe consequences among 10% of them. Efficacy of hygienic counselling is nowadays established and should be spread. OBJECTIVE: To evaluate pregnant women's awareness of cytomegalovirus infection in France. STUDY DESIGN: Pregnant women receiving prenatal care, at any moment of their pregnancy, in two different obstetrics clinics with different information policies, were asked to complete a written questionnaire about CMV infection. RESULTS: More than half (217/362, 60%) of the pregnant women had heard of congenital CMV infection, and most of them (72%) knew the hygiene measures to use to prevent infection. Nevertheless, most could not correctly identify the symptoms associated with congenital CMV disease. Awareness was associated with hospital's policy concerning CMV infection information, the mother's educational level, parity, and employment in health care. Indeed, when information is supposed to be given (hospital A), 74% (vs 34%) know congenital CMV infection and among them the knowledge is more precise. CONCLUSIONS: This study tends to confirm that there is a large gap between knowledge of CMV and the burden of this disease. To bridge this gap, women should receive education about congenital CMV. Hospital-based prenatal education increases awareness and knowledge about CMV and CMV prevention.

[A suspected case of in utero transmission of influenza A (H1N1) 2009]. / Un possible cas de transmission in utero du virus de la grippe A (H1N1).

A 34-year-old woman consulted the day before a scheduled caesarean for dry cough. A positive rhinopharyngeal sample for PCR testing for influenza A H1N1 led to a curative oseltamivir (Tamiflu®) treatment. At delivery a direct contact between the newborn and mother lasted only few seconds. The first healthy baby boy developped dry cough with a rhinopharyngeal sample positive for A H1N1. The minimal contact between mother and child and the positive neonatal sample only four hours after birth allow to think that it is a rare case of prenatal transmission of influenza A H1N1 to the fetus.

A 2-year study on cytomegalovirus infection during pregnancy in a French hospital.

OBJECTIVES: To evaluate the proportion of pregnant women agreeing to cytomegalovirus (CMV) serologic screening. To collect data on CMV infection during pregnancy. DESIGN: Prospective study. SETTING: During two years, all pregnant women were informed on CMV infection. If the patient agreed, serological testing was performed around 12 weeks of gestation (WG) and, if negative, redone around 36 WG. POPULATION: Four thousand two hundred and eighty-seven pregnant women followed from 12 weeks to delivery. METHODS: If the first CMV serologic test was negative, detailed hygiene information was given to the parents. Diagnosis of primary infection was based on the detection of CMV-G, CMV-M and low CMV-G avidity index. When maternal infection was confirmed, diagnosis of CMV congenital infection was done in the newborns by urine culture within the three days following birth. Crude infection-rate data consisted of the number of CMV infection cases and person-time units for both exposed to hygiene CMV information (12 to 36 WG) and unexposed pregnant women (first 12 WG). MAIN OUTCOME MEASURES: Rate of CMV seropositive and seronegative women. Rate of women agreeing for screening. Rate of primary infection. Rate of seroconversion. Number of CMV-infected newborns. RESULTS: Among the 4287 women followed, 3792 were either seronegative or with an unknown immune status. 96.7% out of them agreed for screening. 53.2% were initially CMV-specific IgG negative. Primary infection was detected in nine women between 0 and 12 WG (0.46%) and seroconversion was diagnosed in five women between 12 and 36 WG (0.26%) (mid P = 0.02, 95% CI [1.07-13.6]). CONCLUSIONS: If clear information on CMV infection during pregnancy is given, patients frequently agree to screening. The rate of seroconversion after information, observed in this study, is low after counselling.

[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.

Humoral immune response after primary rubella virus infection and after vaccination.

We measured rubella virus immunoglobulin G (IgG) and IgM levels, as well as IgG avidity indexes, in serum samples taken before or after 6 months either after infection or after vaccination. The results obtained indicate that humoral immune responses are different after primary infection and after vaccination. This may have important consequences on the serological diagnosis of rubella virus infection.

Impact of highly active antiretroviral therapy on the maturation of anti-HIV-1 antibodies during primary HIV-1 infection.

OBJECTIVES: To study the impact of highly active antiretroviral therapy (HAART) on isotype switching and avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with primary HIV-1 infection (PHI). METHODS: We studied the emergence and the evolution of anti-HIV IgG antibodies by quantitative immunoblotting to analyse IgG subclasses and IgG avidity. Serum samples were obtained from 16 PHI patients from the French PRIMO Cohort Study at various points in the first year of infection: eight patients received no treatment (group I), and eight patients received efficient HAART (group II) during the study period. RESULTS: Early initiation of HAART in PHI patients partially prevented an increase in anti-HIV-1 IgG levels. Within IgG subclasses, the amount of anti-HIV-1 IgG1 gradually increased with time in both groups, although levels remained lower in treated patients. The anti-p24 IgG2 level was always lower in group II. We observed a decrease in anti-p24 IgG3 over time in both groups. Treatment did not affect the maturation of HIV-1 IgG avidity, which increased in both groups until month 3 and then remained high until the end of the 12-month follow-up period. CONCLUSIONS: HAART in PHI partially prevents the emergence of HIV-1 IgG antibodies, but does not affect the quality of these antibodies, as reflected in their isotype and avidity.