Extrauterine Growth Restriction (EUGR) refers to inadequate growth during hospitalization. Current definitions for EUGR are varied and can be classified as cross-sectional (weight at a given t-time 1SD). Different t-times are also considered in literature, such as 36 weeks of gestational age (GA) or age at discharge. The aim of this study is to investigate whether EUGR could predict the auxological outcome at 24–30 months, and to evaluate the agreement between cross-sectional and longitudinal definitions. In total, 1589 infants with GA <30 weeks or birthweight ≤ 1500 g and without major congenital anomalies were included in this study. Cross-sectional and longitudinal EUGR were calculated at 36 and 40 weeks of GA, at discharge, and at 28 days. The concordance between the two definitions was estimated by Kappa coefficient. At 24–30 months, 803 infants were measured again. The agreement between the two definitions of EUGR was low. Both EUGR and not-EUGR groups were at lower centiles for weight, but at higher centiles for head circumference at 24–30 months than at birth. Longitudinal EUGR was associated with a poorer growth outcome for weight and height circumference than cross-sectional EUGR. No differences were observed for length. An agreed definition of EUGR is highly desirable in clinical practice to assess medical and nutritional interventions in preterm neonates. Based on the results of this study, we recommend the use of the longitudinal evaluation, that proved to better predict the auxological long-term outcome with respect to the cross-sectional one.

Background: Long COVID-19 syndrome is a complex of symptoms that occurs after the acute SARS-CoV-2 infection, in the absence of other possible diagnoses. Studies on Long COVID-19 in pediatric population are scanty and heterogeneous in design, inclusion criteria, outcomes, and follow-up time. The objective of the present study is to assess the prevalence of Long COVID-19 syndrome in a cohort of Italian pediatric primary care patients, observed for a period of time of 8 to 36 weeks from healing. Prevalence was also assessed in a cohort of pediatric patients hospitalized during acute infection. Methods: Data concerning 629 primary care patients with previous acute SARS-CoV-2 infection were collected by a questionnaire filled in by Primary Care Pediatrician (PCP). The questionnaire was administrated to patients by 18 PCPs based in 8 different Italian regions from June to August 2021. Data concerning 60 hospitalized patients were also collected by consultation of clinical documents. Results: Cumulative incidence of Long COVID-19 resulted to be 24.3% in primary care patients and 58% in hospitalized patients. The most frequently reported symptoms were abnormal fatigue (7%), neurological (6.8%), and respiratory disorders (6%) for the primary care cohort. Hospitalized patients displayed more frequently psychological symptoms (36.7%), cardiac involvement (23.3%), and respiratory disorders (18.3%). No difference was observed in cumulative incidence in males and females in both cohorts. Previous diseases did not influence the probability to develop Long COVID-19. The prevalence of Long COVID-19 was 46.5% in children who were symptomatic during acute infection and 11.5% in asymptomatic ones. Children aged 0 to 5 years had a greater risk to develop respiratory symptoms, while adolescents (aged 11–16 years) had a greater risk to develop neurological and psychological Long COVID-19 symptoms. Conclusions: Our study demonstrates that Long COVID-19 is a reality in pediatric age and could involve even patients with mild or no acute symptoms. The results stress the importance of monitoring primary care pediatric patients after acute COVID-19 infection and the relevance of vaccination programs in pediatric population, also in order to avoid the consequences of Long COVID-19 syndrome.

The benefits of human milk are mediated by multiple nutritional, trophic, and immunological components, able to promote infant’s growth, maturation of its immature gut, and to confer protection against infections. Despite these widely recognized properties, breast-feeding represents an important mother-to-child transmission route of some viral infections. Different studies show that some flaviviruses can occasionally be detected in breast milk, but their transmission to the newborn is still controversial. The aim of this study is to investigate the antiviral activity of human milk (HM) in its different stages of maturation against two emerging flaviviruses, namely zika virus (ZIKV) and Usutu virus (USUV) and to verify whether HM-derived extracellular vesicles (EVs) and glycosaminoglycans (GAGs) contribute to the milk protective effect. Colostrum, transitional and mature milk samples were collected from 39 healthy donors. The aqueous fractions were tested in vitro with specific antiviral assays and EVs and GAGs were derived and characterized. HM showed antiviral activity against ZIKV and USUV at all the stages of lactation with no significant differences in the activity of colostrum, transitional or mature milk. Mechanism of action studies demonstrated that colostrum does not inactivate viral particles, but it hampers the binding of both flaviviruses to cells. We also demonstrated that HM-EVs and HM-GAGs contribute, at least in part, to the anti-ZIKV and anti-USUV action of HM. This study discloses the intrinsic antiviral activity of HM against ZIKV and USUV and demonstrates the contribution of two bioactive components in mediating its protective effect. Since the potential infectivity of HM during ZIKV and USUV infection is still unclear, these data support the World Health Organization recommendations about breast-feeding during ZIKV infection and could contribute to producing new guidelines for a possible USUV epidemic. ZIKV and USUV are emerging flaviviruses that cause conditions ranging from mild febrile diseases to more sever outcomes. ZIKV is associated with microcephaly in newborns and USUV neurotropism represents a growing concern for human health. We studied these viruses in the context of breast-feeding. Breast-milk is a complex biofluid to nourish infants, support their growth and to protect them from numerous diseases, but it also represents a transmission route of several infections. It has been reported that flaviviruses can occasionally be detected in breast-milk, with limited information existing about their possible transmission through breast-feeding. We therefore explored the intrinsic protective role of human milk against ZIKV and USUV infections in vitro and we also assessed the contribution of specific components in mediating this activity. We demonstrated that human milk is endowed with anti-ZIKV and anti-USUV activity at all maturation stages and that it acts by altering virus attachment to the host cell. This activity is mostly due to non-specific bioactive factors, including extracellular vesicles and glycosaminoglycans. Our findings support the use of fresh milk (or from donor banks) as the food of choice for nutrition and protection of newborns in a possible context of ZIKV or USUV epidemics.

Fortification of human milk (HM) for preterm and very low-birth weight (VLBW) infants is a standard practice in most neonatal intensive care units. The optimal fortification strategy and the most suitable protein source for achieving better tolerance and growth rates for fortified infants are still being investigated. In a previous clinical trial, preterm and VLBW infants receiving supplementation of HM with experimental donkey milk-based fortifiers (D-HMF) showed decreased signs of feeding intolerance, including feeding interruptions, bilious gastric residuals and vomiting, with respect to infants receiving bovine milk-based fortifiers (B-HMF). In the present ancillary study, the urinary metabolome of infants fed B-HMF (n = 27) and D-HMF (n = 27) for 21 days was analyzed by ¹H NMR spectroscopy at the beginning (T0) and at the end (T1) of the observation period. Results showed that most temporal changes in the metabolic responses were common in the two groups, providing indications of postnatal adaptation. The significantly higher excretion of galactose in D-HMF and of carnitine, choline, lysine and leucine in B-HMF at T1 were likely due to different formulations. In conclusion, isocaloric and isoproteic HM fortification may result in different metabolic patterns, as a consequence of the different quality of the nutrients provided by the fortifiers.

Here we present the Authors’ answer to the Letter written by Dr. Garazzino and Colleagues with reference to our article “Long COVID-19 in children: an Italian cohort study”.

Background: Symptoms of SARS-CoV-2 infection in children are nonspecific and shared with other common acute viral illnesses (fever, respiratory or gastrointestinal symptoms, and cutaneous signs), thus making clinical differential diagnosis tricky. In Italy, first line management of pediatric care is handed over to Primary Care Pediatricians (PCPs), who were not allowed to directly perform diagnostic tests during the recent COVID-19 outbreak. Without a confirmatory diagnosis, PCPs could only collect information on “COVID-19 like symptoms” rather than identify typical COVID-19 symptoms. Aim: To evaluate the prevalence of COVID-19 like symptoms in outpatient children, during Italian lockdown. To provide PCPs a risk score to be used in clinical practice during the differential diagnosis process. Methods: A survey was submitted to 50 PCPs (assisting 47,500 children) from 7 different Italian regions between the 4 ^th of March and the 23 ^rd of May 2020 (total and partial lockdown period). COVID-19 like symptoms in the assisted children were recorded, as well as presence of confirmed/suspected cases in children’s families, which was taken as proxy of COVID-19. Multivariable logistic regression was accomplished to estimate the risk of having suspected/confirmed cases in families, considering symptoms as potential determinants. Results: 2,300 children (4.8% of overall survey population) fell ill with COVID-19 like symptoms, 3.1% and 1.7% during total and partial lockdown period respectively. The concurrent presence of fatigue, cough, and diarrhea in children, in absence of sore throat/earache and abnormal skin signs, represents the maximum risk level of having a suspected/confirmed case of COVID-19 at home. Conclusions: The percentage of children presenting COVID-19 like symptoms at home has been remarkable also during the total lockdown period. The present study identified a pattern of symptoms which could help, in a cost-effective perspective, PCPs in daily clinical practice to define priorities in addressing children to the proper diagnostic procedure.