Stillbirth due to SARS-CoV-2 placentitis without evidence of intrauterine transmission to fetus: association with maternal risk factors.

OBJECTIVES: To describe the placental pathology, fetal autopsy findings and clinical characteristics of pregnancies that resulted in stillbirth owing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, and to identify potential risk factors. METHODS: This was a prospective multicenter study of non-vaccinated pregnant women affected by coronavirus disease 2019 (COVID-19) in Greece from April 2020 to August 2021. A total of 165 placentas were examined histologically and six cases of stillbirth associated with SARS-CoV-2 placentitis were retrieved. Complete fetal autopsy was performed in three of these cases. Gross, histopathological, immunohistochemical, molecular and electron microscopy examinations were carried out in the stillbirth placentas and fetal organs. The histological findings of cases with SARS-CoV-2 placentitis were compared with those in 159 cases with maternal COVID-19 which resulted in a live birth. Regression analysis was used to identify predisposing risk factors for SARS-CoV-2 placentitis. RESULTS: The placentas of all six stillborn cases showed severe and extensive histological changes typical of SARS-CoV-2 placentitis, characterized by a combination of marked intervillositis with a mixed inflammatory infiltrate and massive perivillous fibrinoid deposition with trophoblast damage, associated with intensely positive immunostaining for SARS-CoV-2 spike protein, the presence of virions on electron microscopy and positive reverse-transcription polymerase chain reaction test of placental tissues. The histological lesions obliterated over 75% of the maternal intervillous space, accounting for intrauterine fetal death. Similar histological lesions affecting less than 25% of the placenta were observed in seven liveborn neonates, while the remaining 152 placentas of COVID-19-affected pregnancies with a live birth did not show these findings. Complete fetal autopsy showed evidence of an asphyctic mode of death without evidence of viral transmission to the fetus. The mothers had mild clinical symptoms or were asymptomatic, and the interval between maternal COVID-19 diagnosis and fetal death ranged from 3 to 15 days. Statistically significant predisposing factors for SARS-CoV-2 placentitis included thrombophilia and prenatally diagnosed fetal growth restriction (FGR). Multiple sclerosis was seen in one case. CONCLUSIONS: SARS-CoV-2 placentitis occurred uncommonly in COVID-19-affected pregnancies of non-vaccinated mothers and, when extensive, caused fetal demise, with no evidence of transplacental fetal infection. Thrombophilia and prenatally detected FGR emerged as independent predisposing factors for the potentially lethal SARS-CoV-2 placentitis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Evidence for respiratory viruses interactions in asymptomatic preschool-aged children.

AIM: To prospectively evaluate interferences between viruses of the upper respiratory tract in asymptomatic preschool children. METHODS: Nasal-pharyngeal swabs from 233 preschool aged children were prospectively collected over four consecutive time periods, during one school year. The samples were tested using a RT-PCR DNA/RNA microarray system for nine respiratory viruses. RESULTS: Respiratory syncytial virus (RSV) was a predictor of the presence of influenza virus (INFL) (OR: 9.12, CI: 1.52-54.75, p=0.016), and similarly, INFL predicted the presence of RSV (OR: 4.01, CI: 1.14-14.16, p=0.030). Also, rhinovirus (RV) was a predictor of adenovirus (ADV) presence (OR: 3.66, CI: 1.10-12.14, p=0.034), and similarly, ADV predicted the presence of RV (OR: 4.05, CI: 1.02-16.05, p=0.046). No other significant associations between viruses were observed. CONCLUSION: Our results indicate that respiratory viruses found in carrier stage in asymptomatic children may interact with other viruses and even facilitate their settling in the upper respiratory tract. The pathophysiological role of these interactions is not yet clear.

Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference.

In the WHO-EURO region, around 28 million people are currently living with chronic viral hepatitis, and 120,000 people die every year because of it. Lack of awareness and understanding combined with the social stigma and discrimination exacerbate barriers related to access to prevention, diagnosis and treatment services for those most in need. In addition, the persisting economic crisis has impacted on public health spending, thus posing challenges on the sustainable investment in promotion, primary and secondary prevention, diagnosis and treatment of viral hepatitis across European countries. The Hepatitis B and C Public Policy Association in cooperation with the Hellenic Center for Disease Prevention and Control together with 10 partner organizations discussed at the Athens High Level Meeting held in June 2014 recent policy developments, persisting and emerging challenges related to the prevention and management of viral hepatitis and the need for a de minimis framework of urgent priorities for action, reflected in a Call to Action (Appendix S1). The discussion confirmed that persisting barriers do not allow the full realisation of the public health potential of diagnosing and preventing hepatitis B and C, treating hepatitis B and curing hepatitis C. Such barriers are related to (a) lack of evidence-based knowledge of hepatitis B and C, (b) limited access to prevention, diagnosis and treatment services with poor patient pathways, (c) declining resources and (d) the presence of social stigma and discrimination. The discussion also confirmed the emerging importance of fiscal constraints on the ability of policymakers to adequately address viral hepatitis challenges, particularly through increasing coverage of newer therapies. In Europe, it is critical that public policy bodies urgently agree on a conceptual framework for addressing the existing and emerging barriers to managing viral hepatitis. Such a framework would ensure all health systems share a common understanding of definitions and indicators and look to integrate their responses to manage policy spillovers in the most cost-effective manner, while forging wide partnerships to sustainably and successfully address viral hepatitis.

Anastrozole plus leuprorelin in early maturing girls with compromised growth: the "GAIL" study.

PURPOSE: Aromatase inhibitors have been used to increase predicted adult height (PAH) in boys but in girls only in McCune-Albright syndrome. We investigated whether anastrozole combined with leuprorelin for up to 2 years is safe and effective in improving PAH in girls with early puberty and compromised growth, compared to leuprorelin alone. METHODS: The "GAIL" study: girls treated with an aromatase inhibitor and an LHRH analogue, ISRCTN11469487, was a 7-year prospective phase IIa study with parallel design, performed at Athens Medical Center (C-A), and Attikon University Hospital, Athens, Greece (C-B). Forty girls, consecutively referred for early puberty (onset 7.5-9 years) with a PAH <-2 or >1.5 SD lower than their target height (TH), were included. Twenty started on leuprorelin sc/im 0.3 mg/kg/month plus anastrozole 1 mg/d p.o. (group-A, C-A) and 20 on leuprorelin (group-B, C-B) for 2 years or until the age of 10 years. Groups did not differ in age, height, BMI, bone age advancement (BAA), and distance of PAH from TH. Follow-up was at 6, 12, 18, and 24 m. RESULTS: Reduction in BAA was significantly higher in group-A compared to group-B already by 6 m. Despite the transiently significant decrease in height velocity in group-A, gain in PAH SD was almost double by 12 and 18 m vs group-B and reached the maximum of +1.21 ± 0.45 (7.51 cm) vs +0.31 ± 0.37 (1.92 cm, p = 0.001) in group-B at 24 m. Group-A had no clinical or biochemical hyperandrogenism, unchanged normal bone density, and lumbar spine X-rays. CONCLUSION: The co-administration of anastrozole with leuprorelin safely improves PAH in girls with compromised growth.

Fetal brain imaging provides valuable information in cCMV infected infants.

BACKGROUND: Congenital CMV infection (cCMV) is the most common congenital infection with 10-15% of cases developing symptomatic disease. Early antiviral treatment is of essence when symptomatic disease is suspected. Recently, the use of neonatal imaging has been implicated as a prognostic tool for long term sequalae among asymptomatic newborns at high risk. Even though neonatal MRI is commonly used in neonatal symptomatic cCMV disease, it is less often used in asymptomatic newborns, mainly due to cost, access and difficulty to perform. We have therefore developed an interest in assessing the use of fetal imaging as an alternative. Our primary aim was to compare the fetal and neonatal MRIs in a small cohort 10 asymptomatic neonates with congenital CMV infection. METHODS: We performed a single-center retrospective cohort study (case-series) on a convenience sample of children born from January 2014 to March 2021 with confirmed congenital CMV infection who had undergone both fetal and neonatal MRIs. We created a checklist of relevant cerebral abnormalities and asked 4 blinded radiologists to assess the MRIs (2 for each, namely fetal and neonatal) and then compared the findings between the fetal and neonatal imaging as well as the concordance in reporting of abnormalities within each category. FINDINGS: Overall concordance between prenatal and postnatal scans was high (70%). When comparing the two blinded reports for each MRI, we found high levels of concordance: 90% concordance for fetal MRIs and 100% for neonatal MRIs. The most common abnormalities identified in both fetal and neonatal scans were "abnormal white matter hyperintensity" and "subependymal cysts." INTERPRETATION: Even though this is a small descriptive study, it indicates that fetal MRI could potentially provide us with similar information as neonatal imaging. This study could form the basis for subsequent larger future studies.

Child abuse experience, training, knowledge, and attitude of healthcare professionals in sixty hospitals in Greece.

OBJECTIVE: This study aims to record the overall perception of healthcare professionals on child abuse and identify potential affecting factors in a nationwide scale in Greece as well as to provide information that might be useful for future educational actions. MATERIALS AND METHODS: A total of 1,185 healthcare professionals in 60 hospitals with pediatric departments across Greece participated in this cross-sectional study. Participants included pediatricians, pediatric surgeons, residents, nurses, psychiatrists, psychologists, and social workers. Sections under investigation involved experience and training in child abuse, knowledge of formal and judicial issues, clinical knowledge, and self-assessment. RESULTS: Although more than half of the participants had confronted child abuse (n=712, 60.08%), only 273 (38.34% of them) submitted reports. One third of participants reported that they had received some training (n=440, 37.13%), mainly of postgraduate nature and based on personal initiative. Of those who reported child abuse, 175 (64.10%) had been trained. Each professional category was aware of topics regarding its own interest, without adequate knowledge of other disciplines. One third of psychiatrists, psychologists, and social workers felt confident in discussing with children and parents. Relevant scores were lower in the other categories. The lower scores were recorded among nurses and residents. The training deficit and reluctance to engage with judicial issues were the main causes of avoidance to deal with child abuse. CONCLUSIONS: Focused and organized training in child abuse is crucial to create reliable professionals in the field. The internet is a considerably helpful tool. Professionalism must characterize knowledge and practice in child abuse at the same level as in other medical topics. Motivation to engage should be early inspired and developed during the graduate years.

Decrease of antibiotic consumption in children with upper respiratory tract infections after implementation of an intervention program in Cyprus.

To assess the impact of intervention on antibiotic misuse in children, parents' and pediatricians' knowledge, attitudes, and practices (KAP) concerning antibiotic use were evaluated pre- and postintervention in Larnaca (Cyprus) and Limassol (Cyprus). Concurrently, pediatricians documented upper respiratory tract infection (URTI) visits and pharmacists provided antibiotic consumption data. Intervention was implemented for parents and pediatricians residing in Larnaca. The consumption/URTI incidence index was significantly reduced in Larnaca but not in Limassol. Parental responses to a KAP questionnaire remained unchanged; therefore, antibiotic consumption reduction is attributable to pediatricians' education.

Seroepidemiology of hepatitis A among Greek children indicates that the virus is still prevalent: Implications for universal vaccination.

A national cross-sectional seroprevalence survey was conducted in order to evaluate the current seroepidemiology of hepatitis A among 1,383 children, aged 0-14 years, residing in Greece. Stratification of the study population was conducted according to age and area of residence. Sera from study participants were tested for the presence of anti-HAV IgG antibodies. Immigrant children, as well as children residing in rural areas, had lower immunization rates. Among unvaccinated children, the seroprevalence rate of anti-HAV was 17.1%. Nationality was shown to have a marginally significant effect since non-immunized immigrant children had a higher seroprevalence rate (22.4% vs. 15.9%, OR = 1.52, P = 0.064). Significant differences between geographic areas for both vaccination coverage and natural immunity were observed. The study findings indicate that hepatitis A is prevalent in Greece and therefore universal infant hepatitis A immunization should be implemented.

Time trends in pediatric hospitalizations for hepatitis A in Greece (1999-2013): Assessment of the impact of universal infant immunization in 2008.

Hepatitis A vaccine was introduced in the Greek National Immunization Program in 2008. To estimate possible impact of the universal vaccination implementation, time trends of hospitalizations for hepatitis A at the Infectious Diseases Unit of a Tertiary Pediatric Hospital in Athens during 1999-2013 were analyzed. Hepatitis A hospitalizations were recorded from the discharge database and were expressed as frequencies and rate of annual departmental hospitalizations. Time series analysis (ARIMA) was used to explore trends and the impact of the vaccination. Moreover, changes in patient age, population group distribution and the duration of hospitalization were also examined. Hepatitis A hospitalizations rate significantly decreased between pre-vaccination (1999-2008) and post-vaccination (2009-2013) era from 50.5 to 20.8/1000 hospitalizations (p = 0.005). A 3-year periodicity and a trend of reduction on hepatitis A hospitalizations rates across years were noted. Roma children had significant higher rates of hepatitis A hospitalization, followed by immigrant children. Importantly, possibly due to preceding vaccine availability with considerable uptake in private market and unvaccinated group/pockets of children (Roma), overall vaccination effect was less apparent when compared to data from other countries that implemented universal vaccination. No significant change in patient age, population group distribution, or duration of hospitalization was observed. High risk groups such as Roma children should be targeted for vaccination to reduce future outbreaks.

Pandemic influenza A vs seasonal influenza A in hospitalized children in Athens.

BACKGROUND: Data on pandemic H1N1 influenza (pH1N1) virus infection in hospitalised children are limited. AIMS AND OBJECTIVES: To examine the epidemiological and clinical characteristics of children hospitalised with pH1N1 at a large tertiary-care centre in Athens and compare them with those of children hospitalised with seasonal influenza A in previous years. METHODS: All children (n = 146) admitted with confirmed pH1N1 between October 2009 to February 2010 and January 2011 to May 2011 were included. Data on children ≧ 6 months of age (n = 109) were compared with those of 138 children admitted with seasonal influenza A who were examined during two previous influenza seasons (2002-2003 and 2004-2005). RESULTS: The age distribution was similar between seasonal and pandemic H1N1. Bronchial asthma was significantly more common in the seasonal influenza group but the clinical presentation was similar in the two groups, except that fever was more common in patients with pH1N1. Children admitted with seasonal influenza were more likely to develop acute otitis media. There were no significant differences between the two groups for severe outcomes (admission to the ICU, mechanical ventilation or death). Only one child with seasonal influenza (0.6%) and three with pH1N1 influenza (2%) required admission to the ICU. Mean length of hospitalisation was longer in the seasonal influenza group. CONCLUSION: Clinical manifestations were similar between pH1N1 and seasonal influenza, and the pandemic virus did not appear to cause more severe disease in hospitalised children.

Alteration in the proportion of CD4 T lymphocytes in a subgroup of human immunodeficiency virus-exposed-uninfected children.

OBJECTIVE: The age-related changes in the proportion of CD4 and CD8 lymphocytes in human immunodeficiency virus (HIV)-seronegative children born to HIV-infected mothers (seroreverters) were compared with the changes in these lymphocyte subsets in children born to seronegative women to assess a possible effect of exposure to HIV without infection. DESIGN: There were 146 seroreverter and 72 seronegative children. The median CD4 and CD8 percentages for each of these two groups of children were compared retrospectively at 3-month intervals from birth through 27 months and at a tenth interval for the time beyond 27 months. The weighted average of the within-subject rate of change of CD4 and CD8 percentages were also compared between the two groups. Finally, for each subject, the proportion of the subject's CD4 percentage assays which were <10th percentile of the entire study population (30%) was calculated, and the distributions of the subject-specific proportions were then compared between the seronegative and seroreverter groups using the Wilcoxon rank sum test. The proportion of CD8 assays <10th percentile (12%) or > 90th percentile (26%) were also computed for each subject, and the distributions of the proportions were compared similarly. . RESULTS: The median CD4 percentage of seroreverter children was lower than that for the seronegative children at every interval from birth through 27 months and for the last interval for values obtained at greater than 27 months, although the comparison was statistically significant only at the 4- to 6-month period. The weighted average of the within-subject rate of change of CD4 percentage was -0.09 and -3.0 per year (P = .04), and of CD8 percentage was 1.3 and 1.0 (P = .67), for the seroreverter and seronegative children, respectively. There were significantly more children in the seroreverter group than in the seronegative group who had repeated assays in which the CD4 percentage was < 10th percentile for age (P < .00005). In addition, there was a subset of 10 seroreverter children (6.8%) who had CD4 percentages < 30% on > 50% of their assays, as compared with only one (1.4%) seronegative child. The proportion of CD8 assays < 10th percentile or > 90th percentile were not significantly different between the two groups of children. CONCLUSIONS: The CD4 proportions were persistently lower in the seroreverter than in the seronegative population, although only reaching statistical significance in 1 of 10 3-month intervals. This finding may be due to a subgroup of seroreverter children who have persistently low CD4 lymphocyte percentages.

Lymphocyte proliferative responses to HIV-1 envelope and core antigens by infected and uninfected adults and children.

Lymphocytes derived from children and adults infected with the human immunodeficiency virus (HIV-1), as well as from seronegative children and adults, were tested for their ability to proliferate in response to recombinant HIV envelope (env) and core (cor) peptides. Proliferative responses to env were seen in 9% of control children compared with 27% of infected children (p less than 0.02). There was no difference in the response rates of seropositive and seronegative adults (17% and 16%, respectively). Proliferative responses to cor were seen more frequently in children and adults (22% and 28%, respectively) than their seronegative cohorts (11% and 12%, respectively). Also, the proliferative response to env and cor was seen in 27% and 37%, respectively, of seronegative children who were born to seropositive mothers and then subsequently seroreverted. These results suggest that sensitization to HIV recombinant antigens has resulted in a cell-mediated immune response in some HIV-infected individuals. Furthermore, the significant cell-mediated immune response to these antigens in seroreverting children raises the possibility that they may have been sensitized to this antigen by previous HIV infection.

Lack of predictive value of maternal human immunodeficiency virus p24 antigen for transmission of infection to their children.

The association of maternal-to-infant transmission of human immunodeficiency virus type 1 (HIV-1) with maternal p24 antigenemia was assessed in 86 HIV-1-infected mothers. We retrospectively examined serum or plasma samples collected in the peripartum period (delivery +/- 11 days; sd 16.89 days; range, delivery +/- 2 months). Immune complexes of p24 antigen and anti-p24 antibody were dissociated using acid hydrolysis (Method A, glycine-HCl buffer; Method B, HCl) in an attempt to increase the sensitivity of the test. The detection of HIV-1 p24 antigenemia in serum was increased from 23 of 86 (26.7%) to 37 of 82 (45.1%) following acid hydrolysis with Method A (chi square = 5.4, P = 0.02) and to 36 of 78 (46.1%) with Method B (chi square = 5.874, P = 0.015). Mothers of HIV-1-infected children were no more likely to have p24 antigenemia than mothers of seroreverted infants when untreated samples were assayed (7 of 23 vs. 10 of 48; chi square = 0.348, P = 0.55). Although acid hydrolysis increased the ability to detect p24 antigen, it did not enhance any association between p24 antigenemia and maternal-to-infant transmission of HIV infection: Method A, 9 of 23 in mothers of infected children vs. 21 of 45 in mothers of seroreverted children (chi square = 0.112, P = 0.738); and Method B, 9 of 22 in mothers of infected children vs. 18 of 42 in mothers of seroreverted children (chi square = 0.014; P = 0.907), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral L-arginine supplementation and faecal calprotectin levels in very low birth weight neonates.

OBJECTIVE: The objective of this study is to determine the potential effect of oral L-arginine supplementation on intestinal inflammation in very low birth weight (VLBW) neonates, as estimated by faecal calprotectin levels. STUDY DESIGN: The study enrolled 83 VLBW neonates with birth weight ≤1500 g and gestational age ≤34 weeks. In this double-blind study, 40 neonates received daily oral L-arginine supplementation of 1.5 mmol kg(-1) per day between the 3rd and 28th day of life, and 43 neonates placebo. Stool samples were collected on days 3, 14 and 28, and calprotectin was measured by enzyme-linked immunosorbent assay. RESULT: Calprotectin values significantly decreased over time in both groups (P=0.032). No difference in faecal calprotectin values was recorded between neonates receiving arginine supplementation and neonates receiving placebo at days 3, 14 and 28. CONCLUSION: Faecal calprotectin values decrease with increasing postnatal age in VLBW infants, but this is not related to arginine supplementation.

Subclinical VZV reactivation in immunocompetent children hospitalized in the ICU associated with prolonged fever duration.

A prospective observational study was conducted to examine whether asymptomatic VZV reactivation occurs in immunocompetent children hospitalized in an ICU and its impact on clinical outcome. A secondary aim was to test the hypothesis that vaccinated children have a lower risk of reactivation than naturally infected children. Forty immunocompetent paediatric ICU patients and healthy controls were enrolled. Patients were prospectively followed for 28 days. Clinical data were collected and varicella exposure was recorded. Admission serum levels of TNF-a, cortisol and VZV-IgG were measured. Blood and saliva samples were collected for VZV-DNA detection via real-time PCR. As a comparison, the detection of HSV-DNA was also examined. Healthy children matched for age and varicella exposure type (infection or vaccination) were also included. VZV reactivation was observed in 17% (7/39) of children. Children with VZV reactivation had extended duration of fever (OR = 1.17; 95% CI, 1.02-1.34). None of the varicella-vaccinated children or healthy controls had detectable VZV-DNA in any blood or saliva samples examined. HSV-DNA was detected in saliva from 33% of ICU children and 2.6% of healthy controls. Among children with viral reactivation, typing revealed wild-type VZV and HSV-1. In conclusion, VZV reactivation occurs in immunocompetent children under severe stress and is associated with prolonged duration of fever.

Congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) infection is a serious health problem. The obstacles for limiting this infection are the lack of public awareness on this issue, especially owing to the asymptomatic nature of CMV infections, the inefficacy of therapy, and the unsuccessful vaccine trials to date. It is therefore important to organize the current data to estimate the results and to report that the development of a vaccine against CMV must be of the highest priority.