Efficacy and Safety of Amenamevir, a Helicase-Primase Inhibitor for the Treatment of Acyclovir-Resistant Herpes Simplex Virus 1 Keratitis.

PURPOSE: The purpose of this study was to describe the efficacy and tolerance of amenamevir (AMNV), an inhibitor of the viral helicase-primase, for the treatment of recalcitrant herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACVR) herpes simplex virus 1 strains. METHODS: In this retrospective case series, 6 consecutive patients with HSK caused by an ACVR herpes simplex virus 1 strain with a failure of conventional antiviral therapy were included after having been treated with AMNV (there was no control group of comparable patients for whom previous treatment would have been continued despite its inefficacy). Medical files were assessed for clinical data including reason(s) for AMNV introduction (frequent recurrences despite appropriate preventive antiviral treatment and/or clinical resistance to suppressive antiviral treatment of an ongoing clinical relapse), genotypical resistance to herpes simplex virus 1 documentation, immune status, clinical types and number of HSK episodes before and during AMNV treatment, adverse effects observed during AMNV treatment, and best corrected visual acuity. RESULTS: Of 6 patients, 4 (66%) did not experience a single recurrence during AMNV therapy while 2 others had recurrences (1 over 24 months of treatment and 2 over 23 months, ie two-fold less frequently than with conventional preventive treatment). On the overall history of these 6 patients, AMNV appeared to be associated with a reduction in HSK recurrences, with a mean of only 0.02 ± 0.04 episodes/month during follow-up under AMNV as compared to 0.14 ± 0.04 episodes/month in the year preceding AMNV introduction (P = 0.03). Improvement in vision acuity was also observed (mean best corrected visual acuity 0.17 ± 0.12 logarithm of the minimum angle of resolution at the end of follow-up vs. 0.30 ± 0.35 before AMNV onset), albeit nonsignificant probably due to the limited number of patients (P = 0.38). Neither clinical nor biological adverse effects were observed while under AMNV during the follow-up (16.5 ± 5.8 months). CONCLUSIONS: Although there was no control group, AMNV may be a valuable option to reduce ACVR HSK recurrences.

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.

Maternal and neonatal outcomes of French prospective multicenter cohort study COVIPREG during the first two COVID-19 waves.

BACKGROUND: SARS-CoV-2 infection on pregnant women was the subject of many questions since the COVID-19 pandemic. METHODS: We aim to assess maternal and neonatal outcomes of SARS-CoV-2 infection contracted during 2nd and 3rd trimesters of pregnancy during the first two COVID-19 waves across a prospective French multicenter cohort study. Patients were included between April 2020 and January 2021 in 10 maternity hospitals in Paris area with two groups (i) pregnant women with a positive SARS-CoV-2 nasopharyngeal RT-PCR between [14WG; 37WG[(symptomatic infection), (ii) pregnant women with a negative serology (or equivocal) at delivery and without a positive SARS-CoV-2 nasopharyngeal RT-PCR at any time during pregnancy (G2 group) MAIN FINDINGS: 2410 pregnant women were included, of whom 310 had a positive SARS-CoV-2 nasopharyngeal RT-PCR and 217 between [14WG; 37WG[. Most infections occurred between 28 and 37 weeks of gestation (56 %). Most patients could be managed as outpatients, while 23 % had to be hospitalized. Among women with a positive RT-PCR, multiparous women were over-represented (OR = 2.45[1.52;3.87]); were more likely to deliver before 37 weeks of gestation (OR = 2.19[1.44;3.24]) and overall cesarean deliveries were significantly increased (OR = 1.53[1.09;2.13]). CONCLUSIONS: This study highlights the maternal, obstetrical, and neonatal burden associated with SARS-CoV-2 infections during the first two pandemic waves before availability of vaccines. TRIAL REGISTRATION: NCT04355234 (registration date: 21/04/2020).

Diagnostic performance of real-time quantitative PCR in tear samples in various subtypes of herpes simplex keratitis.

Diagnosis of herpes simplex keratitis (HSK) is mostly based on clinical findings, yet biological confirmation supports management of challenging cases. This study evaluated the place of real-time quantitative PCR (RT-qPCR) on tear samplings in the management of HSK. Clinical records of patients who underwent tear sampling tested by RT-qPCR for herpes simplex virus type 1 for an acute episode of corneal inflammation or defect between January 2013 and December 2021 were retrospectively reviewed, and results were compared to clinical diagnosis (i.e., HSK or not) based on biomicroscopic findings and medical history. Of 465 tested tear samples from 364 patients, a clinical diagnosis of active (ongoing) HSK was recorded in 240 cases, among which 76 were RT-qPCR positive (global sensitivity of 31.6%, specificity of 99.5%). Sensitivity of RT-qPCR was higher in epithelial (97.4%) and stromal keratitis with ulceration (48.7%), compared to other types of HSK (23.5% in keratouveitis, 13.6% in endotheliitis, 11.1% in postherpetic neurotrophic keratopathy, and 8.1% in stromal keratitis without ulceration). The highest viral loads were detected from epithelial and stromal keratitis with ulceration, while in HSK with no epithelial involvement, the viral load detected was 196-fold lower, on average. The proportion of clinically characterized HSK patients with negative tear samples was higher in patients receiving antiviral treatment (P < 0.0001). RT-qPCR, performed on tear samples, can help in confirming diagnosis in case of presumed HSK, including clinical forms with no obvious epithelial involvement. The sensitivity of tear sampling is much higher whenever epithelial keratitis is present.

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.

Transplacental transfer of anti-SARS-CoV-2 neutralizing antibodies in comparison to other pathogens total antibodies.

BACKGROUNDS: Due to immaturity of their immune system, passive maternal immunization is essential for newborns during their first months of life. Therefore, in the current context of intense circulation of SARS-CoV-2, identifying factors influencing the transfer ratio (TR) of neutralizing antibodies against SARS-CoV-2 (NAb) appears important. METHODS: Our study nested in the COVIPREG cohort (NCT04355234), included mothers who had a SARS-CoV-2 PCR positive during their pregnancy and their newborns. Maternal and neonatal NAb levels were measured with the automated iFlash system. RESULTS: For the 173 mother-infant pairs included in our study, the median gestational age (GA) at delivery was 39.4 weeks of gestation (WG), and 29.7 WG at maternal SARS-CoV-2 infection. Using a multivariate logistic model, having a NAb TR above 1 was positively associated with a longer delay from maternal positive SARS-CoV-2 PCR to delivery (aOR 1.09, 95% CI: 1.03 - 1.17) and with a later GA at delivery (aOR = 1.58, 95% CI: 1.09 - 2.52). It was negatively associated with being a male newborn (aOR 0.21, 95% CI: 0.07 - 0.59). In 3rd trimester SARS-CoV-2 infected mothers, NAb TR was inferior to VZV, toxoplasmosis, CMV, measle and rubella's TR. However, in 1st or 2nd trimester infected mothers, only measle TR was different from NAb TR. CONCLUSION: Male newborn of mothers infected by SARS-CoV-2 during their pregnancy appear to have less protection against SARS-CoV-2 in their first months of life than female newborns. Measle TR was superior to NAb TR even in case of 1st or 2nd trimester maternal SARS-CoV-2 infection. Future studies are needed to investigate possible differences in transmission of NAb following infection vs vaccination and its impact on TR.

Primary, Secondary, and Tertiary Prevention of Congenital Cytomegalovirus Infection.

Cytomegalovirus infection is the most common congenital infection, affecting about 1% of births worldwide. Several primary, secondary, and tertiary prevention strategies are already available during the prenatal period to help mitigate the immediate and long-term consequences of this infection. In this review, we aim to present and assess the efficacy of these strategies, including educating pregnant women and women of childbearing age on their knowledge of hygiene measures, development of vaccines, screening for cytomegalovirus infection during pregnancy (systematic versus targeted), prenatal diagnosis and prognostic assessments, and preventive and curative treatments in utero.

Nasopharyngeal SARS-CoV-2 load and perinatal outcomes after maternal infection diagnosed close to delivery.

BACKGROUND: The occurrence of COVID-19 during the pregnancy can cause several negative maternal and neonatal outcomes. Nasopharyngeal viral load is associated with inflammatory markers and might influence the disease severity in non-pregnant patients, but there are no data about the relationship between viral load and perinatal outcomes in pregnant patients. OBJECTIVE: To investigate the hypothesis that nasopharyngeal SARS-CoV-2 load (estimated with real-time polymerase chain reaction delta cycle (ΔCt), measured in hospital clinical laboratories) is associated with perinatal outcomes, when COVID-19 is diagnosed in the third trimester of pregnancy. STUDY DESIGN: International, retrospective, observational, multi-center, cohort study enrolling 390 women (393 neonates, three pairs of twins), analyzed with multivariate generalized linear models with skewed distributions (gamma) and identity link. The analyses were conducted for the whole population and then followed by a subgroup analysis according to the clinical severity of maternal COVID-19. RESULTS: The estimated viral load in maternal nasopharynx is not significantly associated with gestational age at birth (adjusted B: -0.008 (95%CI: -0.04; 0.02); p = 0.889), birth weight (adjusted B: 4.29 (95%CI: -25; 35); p = 0.889), weight Z-score (adjusted B: -0.01 (95%CI: -0.03; 1); p = 0.336), 5' Apgar scores (adjusted B: -0. -9.8e-4 (95%CI: -0.01; 0.01); p = 0.889), prematurity (adjusted OR: -0.97 (95%CI: 0.93; 1.03); p = 0.766) and the small for gestational age status (adjusted OR: 1.03 (95%CI: 0.99; 1.07); p = 0.351). Similar results were obtained in subgroup analyses according to COVID-19 clinical severity. CONCLUSIONS: The estimated maternal nasopharyngeal viral load in pregnant women affected by COVID-19 during the third trimester is not associated with main perinatal outcomes.

Transmission of SARS-CoV-2 from mother to fetus or neonate: What to know and what to do?

SARS-CoV-2 can be vertically transmitted from the mother to the fetus and the neonate. This transmission route is rare compared to the environmental or horizontal spread and therefore, the risk can be deemed inconsequential by some medical providers. However, severe, although just as rare, feto-neonatal consequences are possible: fetal demise, severe/critical neonatal COVID-19 and multi-inflammatory syndrome (MIS-N) have been described. Therefore, it is important for the clinicians to know the mechanism of vertical transmission, how to recognize this, and how to deal with neonatal COVID-19 and MIS-N. Our knowledge about this field has significantly increased in the last three years. This is a summary of the pathophysiology, diagnostics, and therapeutics of vertical SARS-CoV-2 transmission that clinicians apply in their clinical practice.

[Monkeypox: Proposals for care in pregnancy]. / Variole du singe : propositions de conduite à tenir chez les femmes enceintes.

Although the 2022 Monkeypox virus epidemic mostly affects males, particularly men having sex with men, transmission to women may also occur. In case of MPXV infection in pregnancy, transmission to the fetus can result in very severe disease. Thus, caregivers should be aware of the measures to be taken according to the available evidence, in case of exposure or in case of symptoms particularly skin rash compatible with this diagnosis in a pregnant woman. Pregnant women should have access to vaccination, vaccinia immunoglobulin or antiviral medications as required.

Maternal and congenital toxoplasmosis in Mayotte: Prevalence, incidence and management.

BACKGROUND: Toxoplasmosis is an infection caused by an intracellular protozoan, Toxoplasma gondii. It is usually asymptomatic, but toxoplasmosis acquired during pregnancy can cause congenital toxoplasmosis, potentially resulting in fetal damage. Epidemiological information is lacking for toxoplasmosis in Mayotte (a French overseas territory). We evaluated (1) the prevalence of maternal toxoplasmosis, (2) the incidence of maternal and congenital toxoplasmosis, and (3) the management of congenital toxoplasmosis in Mayotte. METHODOLOGY / PRINCIPAL FINDINGS: We collected all the available data for toxoplasmosis serological screening during pregnancy and maternal and congenital cases of toxoplasmosis obtained between January 2017 and August 2019 at the central public laboratory of Mayotte (Mamoudzou). Using toxoplasmosis serological data from samples collected from 16,952 pregnant women we estimated the prevalence of toxoplasmosis in Mayotte at 67.19%. Minimum maternal toxoplasmosis incidence was estimated at 0.29% (49/16,952, 95% CI (0.0022-0.0038)), based on confirmed cases of maternal primary infection only. The estimated incidence of congenital toxoplasmosis was 0.09% (16/16,952, 95% CI (0.0005-0.0015). Missing data made it difficult to evaluate management, but follow-up was better for mothers with confirmed primary infection and their infants. CONCLUSIONS / SIGNIFICANCE: The seroprevalence of toxoplasmosis among pregnant women and the incidence of toxoplasmosis are higher in Mayotte than in mainland France. There is a need to improve the antenatal toxoplasmosis screening and prevention programme, providing better information to physicians and the population, to improve management and epidemiological monitoring.

Validation of a SARS-CoV-2 Surrogate Virus Neutralization Test in Recovered and Vaccinated Healthcare Workers.

Vaccination against COVID-19 is the main public health approach to fight against the pandemic. The Spike (S) glycoprotein of SARS-CoV-2 is the principal target of the neutralizing humoral response. We evaluated the analytical and clinical performances of a surrogate virus neutralization test (sVNT) compared to conventional neutralization tests (cVNTs) and anti-S eCLIA assays in recovered and/or vaccinated healthcare workers. Our results indicate that sVNTs displayed high specificity and no cross-reactivity. Both eCLIA and sVNT immunoassays were good at identifying cVNT serum dilutions ≥1:16. The optimal thresholds when identifying cVNT titers ≥1:16, were 74.5 U/mL and 49.4 IU/mL for anti-S eCLIA and sVNT, respectively. Our data show that neutralizing antibody titers (Nab) differ from one individual to another and may diminish over time. Specific assays such as sVNTs could offer a reliable complementary tool to routine anti-S serological assays.

Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections.

OBJECTIVE: This study aimed to describe the characteristics of fetal demise after SARS-CoV-2 infections and clarify whether it is associated with clinical severity, placental lesions, or malformations or due to actual fetal infections. DATA SOURCES: PubMed and Web of Science databases were searched between December 1, 2019, and April 30, 2022. STUDY ELIGIBILITY CRITERIA: Cohort, cross-sectional, and case-control studies and case series or case reports describing stillbirths or late miscarriages (ie, pregnancy loss occurring between 14 and 22 weeks of gestation, before and after the onset of labor) from mothers with SARS-CoV-2 infection during pregnancy (demonstrated by at least 1 positive real-time reverse transcription-polymerase chain reaction from nasopharyngeal swabs and/or SARS-CoV-2 placental infection). No language restriction was applied; cases with other causes possibly explaining the fetal demise were excluded. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines were followed. The quality of the case series and case reports was evaluated using the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data and placental and fetal virology and histology findings were collected. Data were summarized with descriptive statistics using the World Health Organization criteria to classify disease severity and fetal-neonatal infections. RESULTS: Data from 184 mothers and 190 fetuses were analyzed. No clear link to maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demise cases occurred during the second and third trimesters of pregnancy, approximately 6 to 13 days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms. Most placentas (88%) were positive for SARS-CoV-2 or presented the histologic features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (85%-91%). Of note, 11 fetuses (5.8%) had a confirmed in utero transmitted SARS-CoV-2 infection, and 114 fetuses (60%) had a possible in utero transmitted SARS-CoV-2 infection. CONCLUSION: The synthesis of available data showed that fetal demise generally occurs a few days after the infection with histologic placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

Is CMV PCR of inner ear fluid during cochlear implantation a way to diagnose CMV-related hearing loss?

To evaluate the diagnostic performance of cytomegalovirus (CMV) polymerase chain reaction (PCR) on inner ear fluid collected during cochlear implantation and to assess its interest in current practice. This monocentric prospective study included consecutive children presenting with severe to profound sensorineural hearing loss (SNHL) who were candidates for unilateral and/or bilateral cochlear implantation. The etiology of the SNHL was determined before cochlear implantation when possible. During the surgery, drop-like samples of inner ear fluid and blood were collected. CMV PCR was then performed on both samples. Between January 2017 and September 2021, 113 children with severe to profound SNHL underwent cochlear implantation with inner ear fluid collection. Among these children, 77 of them presented with a known cause of SNHL (68%) and 36 of them had an unknown cause of SNHL at the time of surgery (32%). Sensitivity and specificity of the CMV PCR on inner ear fluid were 60% (95% CI: [49-71]) and 98% (95% CI: [96-100]), respectively. Positive and negative predictive values were 90% (95% CI: [83-97]) and 92% (95% CI: [86-98]), respectively. A sensitivity analysis according to age at cochlear implantation showed a decrease with age. CONCLUSION: Sampling of inner ear fluid during cochlear implant surgery is an interesting, simple and safe way to diagnose CMV-related hearing loss, especially when the diagnosis of congenital infection can no longer be confirmed. However, the sensitivity decreases with age. TRIAL REGISTRATION: NCT04724265 What is Known: • Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children. In the absence of systematic screening at birth, many cCMV infections go undetected and are often undiagnosed despite the development of sensorineural sequelae.  • Nearly 40% of indications for cochlear implantation are of unknown etiology. WHAT IS NEW: • Performing CMV PCR on inner ear fluid at the time of cochlear implantation is a safe way with high diagnostic performance (PPV = 90%, NPV = 92%) to detect a CMV-related hearing loss. • This sample may be interesting in cases of unknown cause of hearing loss in order to identify undiagnosed cCMV infections.

Persistence of Neutralizing Antibodies and Clinical Protection up to 12†Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection in the Elderly.

Background: Coronavirus disease 2019 (COVID-19) has severely affected the elderly, who are expected to display decreased immune responses due to immunosenescence. Methods: This study retrospectively assesses neutralizing antibody (NAb) production up to 12 months after infection in long-term care patients. We used Roche Diagnostics immunoassay to quantify anti-spike (S) antibodies and a competitive immunoassay from YHLO as a surrogate test for NAb. Results: We included 91 patients (mean age, 86 years). There was no significant variation in anti-S titers over time. There was a significant decrease of NAb titers between month 3 and month 6 but no further significant change up to month 12. Overall, 75 of 91 (82%) and 52 of 91 (57%) patients had, at least once, anti-S titers >75 U/mL and NAb titers >50 AU/mL, respectively, corresponding to a significant neutralizing activity in vitro. All 68 patients studied at M12 had detectable anti-S antibodies and 60 (88%) had detectable NAb; 60 of 68 (88%) and 29 of 68 (42.6%) still had anti-S titers >75 U/mL and NAb titers >50 AU/mL. Higher NAb titers were correlated with severe infection, higher levels of C-reactive protein, and lower lymphocyte counts. No patient developed reinfection. Conclusions: Elderly people can display robust and persistent humoral response after severe acute respiratory syndrome coronavirus 2 infection, with NAb lasting up to 12 months.

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.

The Essentials about Neonatal Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Coronavirus Disease: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can occur in neonates as the virus can be transmitted both horizontally (from the environment) and vertically (during the pregnancy or at the delivery). Compared to the adult outbreak, neonatal infections do not represent a public health problem. Nonetheless, severe and life-threatening cases may rarely occur and both obstetricians and neonatologists should have a good knowledge of perinatal SARS-CoV-2 infection and related consequences. A high suspicion index must be applied and ruling out neonatal SARS-CoV-2 infection must become a part of the routine clinical workout. Moreover, neonates may be affected by the multisystem inflammatory syndrome, due to a dysregulated host response in the absence of any SARS-CoV-2 infection. We performed a narrative review to summarize here the available literature describing the essentials that should be known by every neonatologist and obstetrician, starting from what has been discovered in 2020 and adding what has been learned in the following years. The paper describes the mechanisms of transmission, clinical features, diagnostic tools, and criteria, as well as possible treatment and prevention strategies. The goal is to provide the practical points to be remembered at the bedside while caring for a pregnant woman or a neonate with suspected or proven coronavirus disease 2019 or multisystem inflammatory syndrome. KEY POINTS: · SARS-CoV-2 neonatal infections occur both vertically (30%) and horizontally (70%).. · Approximately, half of patients do not have clinical manifestations; clinical and laboratory signs are similar to those of adults but usually milder.. · Remdesivir and steroids can be used as a treatment..