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Sore throat represents one of the main causes of antibiotic overprescription in children. Its management is still a matter of debate, with countries considering streptococcal pharyngotonsillitis a benign and self-limiting condition and others advocating for its antibiotic treatment to prevent suppurative complications and acute rheumatic fever. Italian paediatricians frequently prescribe antibiotics on a clinical basis regardless of microbiological results. Moreover, broad-spectrum antibiotics are inappropriately prescribed for this condition. In this regard, an intersociety consensus conference was issued to promote the judicious use of antibiotic therapy in paediatric outpatient settings. A systematic review of the literature was performed, and updated recommendations were developed according to the GRADE methodology. Antibiotic treatment with amoxicillin (50 mg/kg/day) for 10 days is recommended in all children with proven streptococcal pharyngitis. Benzathine-penicillin could be prescribed in children with impaired intestinal absorption or inability to tolerate enteral intake and in those at high risk of suppurative complications with low compliance to oral therapy. In children with suspected amoxicillin allergy, third-generation cefalosporins for five days are recommended in low-risk patients, and macrolides are recommended in high-risk ones. Candidates for tonsillectomy due to recurrent pharyngitis could be treated with amoxicillin-clavulanic acid, clindamycin, or combined therapy with amoxicillin plus rifampicin for four days, in an attempt to avoid surgery., (© 2024. The Author(s).)

Community-acquired pneumonia (CAP) is an acute infection of the lung parenchyma acquired outside the hospital or other healthcare settings, typically affecting previously healthy individuals. This intersociety consensus aims to provide evidence-based recommendations for the antibiotic treatment of mild to moderate CAP in previously healthy children in Italy.A systematic review was conducted to identify the most recent and relevant evidence. Embase, Scopus, PubMed, and Cochrane databases were systematically screened, with a date restriction from 2012 to April 2024, but without language limitations. The review included studies conducted in high-income countries on antibiotic therapy in children over 3 months of age diagnosed with mild-moderate CAP. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods. The final recommendations were obtained through a Delphi consensus of an expert panel.Amoxicillin is the first-line treatment if the child is at least immunized against Haemophilus influenzae type b (low/very low quality of evidence, strong recommendations), while amoxicillin-clavulanate or second- or third-generation cephalosporins should be prescribed for those unimmunized or with incomplete immunization coverage for both H. influenzae type b and Streptococcus pneumoniae (low/very low quality of evidence, strong recommendations). Macrolides should be considered in addition to amoxicillin in children over 5 years old, if symptoms persist and the clinical condition remains good after 48 h of therapy (low/very low quality of evidence, strong recommendations). The dosage of amoxicillin is 90 mg/kg/day divided in three doses, although two doses could be considered to improve compliance (moderate quality of evidence, weak recommendations). A five-day duration of therapy is recommended, with clinical monitoring and re-assessment approximately 72 h after the start of antibiotic treatment to evaluate symptom resolution (moderate quality of evidence, strong recommendations).To improve the management of CAP in pediatric patients, we have developed this consensus based on a thorough review of the best available evidence and extensive discussions with an expert panel. However, further efforts are needed. Future research should focus on enhancing diagnostic accuracy, optimizing antibiotic utilization, comparing the efficacy of different antibiotic regimens, and determining the optimal dosage and duration of treatment in different setting., (© 2024. The Author(s).)

Purpose: To compare the clinical severity of Human Adenovirus (HAdV) infection with other viral diseases in a cohort of children, evaluating presentation, therapy, and outcome., Methods: We conducted a retrospective multicenter cohort study in Italian children hospitalized from January to December 2023 for respiratory symptoms. The study included children with HAdV infection presenting primarily with respiratory symptoms. Patients with isolated gastrointestinal involvement or coinfection with bacteria were excluded., Results: A total of 171 children were enrolled: 98 with HAdV infection (age 44.3 ± 37.9 months) and 73 with other viruses (age 20.4 ± 27.2 months). In the first group, 57.1% had a coinfection with one or more additional viruses. The most common symptoms were fever (89.8%), cough (73.5%) and sore throat (52%). Respiratory distress and hypoxemia were more frequent in the non-HAdV group. Children with HAdV infection demonstrated significantly higher C-reactive protein levels (50.8 ± 54.2 vs. 16.5 ± 33.8 mg/L, p < 0.001), experienced a longer duration of fever (4.9 ± 3.6 vs. 3.4 ± 2.3 days, p = 0.009) and were more likely to receive antibiotic treatment (77.6% vs. 27.4%, p < 0.001). No differences were observed in hospitalization stay, rate of complications, and ICU admission., Conclusions: Interestingly, our data suggests that HAdV-infected children exhibit a more pronounced inflammatory response despite experiencing less severe respiratory symptoms compared to other viruses. The presence of prolonged fever and a strong inflammatory response often leads to antibiotic overuse during the initial phase, when the viral etiology is yet to be confirmed. Early and accurate identification of HAdV infection is crucial to optimize treatment strategies and minimize unnecessary antibiotic use., (© 2024. The Author(s).)

Since January 2024, Italy experiences a pertussis outbreak, primarily affecting neonates and unvaccinated infants at high risk of severe complications and mortality; 11 major paediatric centres noted 108 hospitalisations and three deaths by 10 May. The outbreak reflects increased circulation of Bordetella pertussis and non-adherence to immunisation recommendations during pregnancy. Public health interventions, including maternal immunisation, vaccination of infants as early as possible and post-exposure prophylaxis, are critical for reducing the burden of pertussis and preventing further mortality.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: To investigate the specific role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in inducing elevation of marker of myocardial injury in infants with acute coronavirus disease 2019 (COVID-19)., Study Design: A prospective, multicentric 3-arm comparative study (March 2020 through March 2022) enrolling 152 infants hospitalized for COVID-19, 79 children with acute infections other than SARS-CoV-2, and 71 healthy controls. Determination of high-sensitivity cardiac troponin (hs-cTn) levels was the primary outcome., Results: The proportion of children with hs-cTn values above the upper limit of normal (44 [28.9%]), as well as with a 3-fold increased value (20 [13.2%]) were significantly higher in the COVID-19 group than those in both control groups. The risk of presenting a 3-fold increased hs-cTn value was higher in children with SARS-CoV-2 infection compared with either healthy children (OR, 5.23; 95% CI, 1.19-23.02) or those with other infections (OR, 11.89; 95% CI, 1.56-89.79). In children with COVID-19, hs-cTn elevation was associated with neither clinical nor biochemical characteristics, nor perinatal risk factors, but with an age of <3 months (P < .001). After adjustment for age, sex, and underlying clinical conditions, elevated hs-cTn was independently associated with COVID-19 in a multivariable regression model. All children showed a progressive reduction of hs-cTn until normalization over time, without clinical, ECG, or echocardiographic manifestations up to 1 year of follow-up., Conclusions: Infants with acute SARS-CoV-2 infection may show a subclinical and transient alteration of myocardial injury markers, especially in the first months of life. hs-cTn levels normalized during follow-up and were not associated with cardiac functional impairment; nevertheless, long-term consequences are unknown and should be followed carefully., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. This research was supported by EU funding within the NextGeneration EU-MUR PNRR Extended Partnership Initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT), with no role in study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication. No form of payment was given to anyone to produce the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Prolonged diarrhoea (ProD) refers to acute-onset diarrhoea that persists for longer than 1 week. As the aetiology, risk factors and management are poorly defined, we prospectively enrolled children hospitalised in a high-income setting to assess these outcomes and investigate the potential role of gut microbiota., Methods: All children aged 30 days to 14 years admitted for acute-onset diarrhoea lasting 7-14 days were included. Children consecutively admitted in the same period for acute diarrhoea (AD) served as controls. High-throughput sequencing of 16S rRNA gene amplicons was used to analyse stool samples from a subset of patients and healthy controls., Results: Sixty-eight with ProD and 104 with AD were enrolled. Intestinal infections were the main aetiology of diarrhoea in both groups (ProD 92.9% vs. AD 97.8%). ProD children showed a higher prevalence of bacterial infections compared to AD (30.8% vs. 8.9%, p = 0.024). Neither age, host-related factors, nor microbiome alterations were specifically linked to ProD. However, ProD children had a more severe initial clinical presentation than AD., Conclusion: ProD is often the result of an unusually severe intestinal infection that runs a course longer than expected but generally resolves without further problems. No specific management or therapies should be undertaken in most cases., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit. Compared to probiotics there are few studies with prebiotics in children. Most studies have been performed using infant formula supplemented with prebiotics, while add-on prebiotic supplementation as prevention or treatment of childhood gastrointestinal disorders has rarely been reported. The aim of this position paper was to summarize evidence and make recommendations for prebiotic supplementation in children with gastrointestinal diseases. Recommendations made are based on publications up to January 1, 2023. Within the scope of the European Society for Paediatric Gastroenterology Hepatology and Nutrition Special Interest Group on Gut Microbiota and Modifications, as in our previous biotic recommendations, at least two randomized controlled clinical trials were required for recommendation. There are some studies showing benefits of prebiotics on selected outcomes; however, we cannot give any positive recommendations for supplementing prebiotics in children with gastrointestinal disorders., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: In Italy Rotavirus vaccination (RVV) is provided free of charge from 2018, however, the coverage is scattered and suboptimal. The narrow time frame to complete the schedule is a barrier to uptake, and co-administration with other vaccines may potentially increase the coverage. Although the co-administration of RV vaccine and Meningococcal Group B vaccine (MenB) is not included in the product labels, we aimed at studying its impact on RVV coverage., Methods: This Surveillance study on Timing and cOverage of Rotavirus and MenB vaccine co-administration (STORM study) used the Regional Vaccination Registry to collect data about children born in Campania Region between January 2016 and December 2020, and receiving vaccines scheduled in the first year of life., Results: Among the 224,110 children enrolled, 60,614 (27.0%) completed the RVV schedule, with a vaccination rate that increased over time from 1.15% in 2016 to 56.92% in 2020. The first and last dose of RVV schedule were administered beyond the recommended time in 6% of the study population, respectively. Co-administration of RV vaccine with MenB vaccine increased from 0.7 % in 2016 to 46.85 % in 2020. Children receiving RV/MenB vaccines concomitantly had a significantly higher chance of completing the RV schedule compared to those receiving RVV alone during a specific appointment (94.78 % vs 72.26 %, Prevalence Ratio -PR- 1.275, 95 %CI 1.245-1.295p < 0.00001). The positive driving effect of RV/MenB co-administration was more evident for children receiving pentavalent (PR 1.288) than monovalent RVV (PR 1.115) which was confirmed when adjusted for confounding variables (i.e., year of vaccination, local district, gender)., Conclusions: Although still far from the target, RVV coverage has increased in recent years in Campania Region. Co-administration with MenB vaccine may aid in increasing RVV coverage, especially for pentavalent RVV. Further safety data are needed to support co-administration as a key tool to increase coverage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andrea Lo Vecchio reports financial support was provided by University of Naples Federico II. Andrea Lo Vecchio reports a relationship with University of Naples Federico II that includes: funding grants. The data presented in the present paper are part of the results of an Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. obtained by the Corresponding author Andrea Lo Vecchio. The opinions expressed in this paper are those of the authors and do not represent those of Merck Sharp & Dohme Corp., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acute infectious diarrhea (AID) is one of the most common diseases in pediatric age with relevant burden both in high and in low-income countries. Thanks to their direct action on enterocyte functions and indirect actions on the mucosal and systemic immune system and on intestinal microbiome, probiotics are an ideal intervention to treat AID in childhood. However, their efficacy is strictly related to strains and indications, and practitioners should take this information into account in clinical practice. This chapter summarizes the main mechanisms of action of probiotics in AID, with a focus on proof of efficacy supporting their use in prevention and treatment of childhood AID. The use of selected strains in appropriate doses is strongly recommended by guidelines of AID, based on compelling proofs of efficacy and safety. At present, therapy with probiotics of AID is probably the strongest indication for probiotic use in medicine. Their role in prevention of AID is however questionable in healthy population, whereas it should be considered in at-risk population. Evidence for prevention of diarrhea in day-care centers and communities is lacking, but consistent evidence supports efficacy in prevention of hospital acquired diarrhea. Finally, this chapter presents novelties on this topic, in particular the role of rotavirus immunization on probiotics effectiveness and the effect of probiotics and postbiotics on Covid-associated diarrhea.Overall: AID is the most convincing area for probiotic use in children with gastrointestinal disorders, and effective strains should be used early on after onset of symptoms., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: This study aimed to determine psychosocial differences between children with Long-COVID Syndrome (LCS) and two control groups (i.e., children who did not have COVID-19 and children who had previously had COVID-19 but did not develop LCS) from a bio-psycho-social and psychosomatic perspective. To classify children in these three groups, we examined the percentage of children meeting criteria for LCS, the type, frequency, perceived severity of symptoms, and their prevalence compared with children who never had SARS-CoV-2 infection., Methods: Data were collected from 198 Italian mothers of children aged 4 to 13 years using a cross-sectional web-based case-control survey. Of these, 105 were mothers of children who had contracted SARS-CoV-2 and 94 were mothers of children who had previously had COVID-19. Information was collected on the type and frequency of symptoms commonly referred to as "Long-COVID symptoms" and psychosocial dimensions (i.e., maternal and child health anxiety, COVID-19 anxiety, adjustment, and child deprivation). Descriptive analyses, chi-square tests, Student's T-Test, and analyses of variance were performed., Results: 29 children (15% of the total sample) developed LCS, mostly in the neurological/neuropsychiatric domain (59%), and of mild intensity. Regarding psychosocial and psychological dimensions, maternal health anxiety, child deprivation, and fear of SARS-CoV-2 infection differed between groups, with the first two dimensions higher in children with LCS than in controls and the latter lower in children with LCS than in controls., Conclusion: This study sheds light on the need of integrating a psychosocial approach into the medical care of children with LCS and their caregivers., Competing Interests: Declaration of Competing Interest The authors have no competing interests to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aims to provide a comparison of the current recommendations about the management of acute pharyngitis. A literature search was conducted from January 2009 to 2023. Documents reporting recommendations on the management of acute pharyngitis were included, pertinent data were extracted, and a descriptive comparison of the different recommendations was performed. The quality of guidelines was assessed through the AGREE II instrument. Nineteen guidelines were included, and an overall moderate quality was found. Three groups can be distinguished: one group supports the antibiotic treatment of group A β-hemolytic Streptococcus (GABHS) to prevent acute rheumatic fever (ARF); the second considers acute pharyngitis a self-resolving disease, recommending antibiotics only in selected cases; the third group recognizes a different strategy according to the ARF risk in each patient. An antibiotic course of 10 days is recommended if the prevention of ARF is the primary goal; conversely, some guidelines suggest a course of 5-7 days, assuming the symptomatic cure is the goal of treatment. Penicillin V and amoxicillin are the first-line options. In the case of penicillin allergy, first-generation cephalosporins are a suitable choice. In the case of beta-lactam allergy, clindamycin or macrolides could be considered according to local resistance rates.    Conclusion: Several divergencies in the management of acute pharyngitis were raised among guidelines (GLs) from different countries, both in the diagnostic and therapeutic approach, allowing the distinction of 3 different strategies. Since GABHS pharyngitis could affect the global burden of GABHS disease, it is advisable to define a shared strategy worldwide. It could be interesting to investigate the following issues further: cost-effectiveness analysis of diagnostic strategies in different healthcare systems; local genomic epidemiology of GABHS infection and its complications; the impact of antibiotic treatment of GABHS pharyngitis on its complications and invasive GABHS infections; the role of GABHS vaccines as a prophylactic measure. The related results could aid the development of future recommendations. What is Known: • GABHS disease spectrum ranges from superficial to invasive infections and toxin-mediated diseases. • GABHS accounts for about 25% of sore throat in children and its management is a matter of debate. What is New: • Three strategies can be distinguished among current GLs: antibiotic therapy to prevent ARF, antibiotics only in complicated cases, and a tailored strategy according to the individual ARF risk. • The impact of antibiotic treatment of GABHS pharyngitis on its sequelae still is the main point of divergence; further studies are needed to achieve a global shared strategy., (© 2023. The Author(s).)

The Spike protein of SARS-CoV-2 acts as an enterotoxin able to induce chloride secretion and production of reactive oxygen species (ROS), involved in diarrhea pathogenesis. L. rhamnosus GG (LGG) is recommended in pediatric acute gastroenteritis guidelines as a therapy independent of infectious etiology. We tested a postbiotic preparation of LGG (mLGG) in an in vitro model of COVID-associated diarrhea. Caco-2 cell monolayers mounted in Ussing chambers were exposed to Spike protein, and electrical parameters of secretory effect ( Isc and TEER) were recorded in the Ussing chambers system. Oxidative stress was analyzed by measuring ROS production (DCFH-DA), GSH levels (DNTB), and lipid peroxidation (TBARS). Experiments were repeated after mLGG pretreatment of cells. The Isc increase induced by Spike was consistent with the secretory diarrhea pattern, which was dependent on oxidative stress defined by a 2-fold increase in ROS production and lipid peroxidation and variation in glutathione levels. mLGG pretreatment significantly reduced the secretory effect ( p = 0.002) and oxidative stress, namely ROS ( p < 0.001), lipid peroxidation ( p < 0.001), and glutathione level changes ( p < 0.001). LGG counteracts Spike-induced diarrhea by inhibiting the enterotoxic effect and oxidative stress. The LGG efficacy in the form of a postbiotic depends on metabolites secreted in the medium with antioxidant properties similar to NAC. Because SARS-CoV-2 is an enteric pathogen, the efficacy of LGG independent of etiology in the treatment of acute gastroenteritis is confirmed by our data.

This study aims to characterize the clinical and metabolic features of acute gastroenteritis in children with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A multicenter case-control study was conducted in 2022 including 200 children. Clinical data and laboratory tests were analyzed. Children with SARS-CoV-2 presented less frequently hyponatremia and metabolic acidosis, but more often systemic inflammation as compared with children without SARS-CoV-2., Competing Interests: D.B. has participated in a Pfizer-sponsored session on COVID vaccines at ESPID 2022. The other authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The outbreak of COVID-19 resulted in a decrease in tuberculosis notification rates globally. We compared tuberculosis incidence rates and disease severity in children seen in our centre prior and during COVID-19 pandemic.We performed a cohort study enrolling children aged under 18 years who received a diagnosis of tuberculosis (January 1st, 2010-December 31st, 2021) at our Pediatric Infectious Diseases Unit. Disease severity was evaluated based on: the classification proposed by Wiseman et al., smear positivity, presence of symptoms at presentation, lung cavitation, extrapulmonary disease, respiratory failure and need for intensive care support. Overall, 168 children (50.6% female, median age 69 months, IQR 95.4) received a diagnosis of tuberculosis, 156 (92.8%) between 2010-2019, before COVID-19 outbreak, and 12 (7.2%) between 2020-2021, during the pandemic. The annual tuberculosis notification rate dropped by 73% in 2021 (0.38/100000, 95%CI 0.1-0.96) compared with 2019 (1.46/100000, 95%CI 0.84-2.37). Compared to the pre-pandemic period, the proportion of children classified as severe was higher in 2020-2021 (5, 41.6% vs 23, 15.7%, p = 0.006) with a higher rate of respiratory failure (2, 16.7%, vs 4, 2.6%, p = 0.01) and an increased need for intensive care support (1, 8.3% vs 1, 0.6%, p = 0.01).   Conclusion: During COVID-19 pandemic we observed a reduction in tuberculosis notification rate in pediatric population and a significant increase in disease severity. This scenario may be the consequence of a delay in diagnosis and an underreporting of cases, rather than the effect of a reduced transmission of tuberculosis. Children reached health-care services only in the need of urgent medical attention. What is Known: • COVID-19 pandemic had a huge impact on national health care systems, resulting in a reduction of access to medical care. What is New: • In Campania Region, Italy, a low tuberculosis incidence country, we witnessed a 75% reduction in tuberculosis notification rate during pandemic. In parallel we demonstrated a significant increase in disease severity, suggesting that the reduction in notification rate may be attributed to an underreporting of cases and consequential diagnostic delay, rather than a reduced transmission of infection., (© 2023. The Author(s).)

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the implementation of restrictive measures led to a dramatic reduction in respiratory syncytial virus (RSV) occurrence together with rare and mild bronchiolitis induced by SARS-CoV-2. We described the respiratory picture of SARS-CoV-2 infection and evaluated the frequency and the severity of SARS-CoV-2 bronchiolitis comparing it with other respiratory viral infections in children less than two years of age. The severity of respiratory involvement was evaluated based on the need for oxygen therapy, intravenous hydration, and the length of hospital stay. A total of 138 children hospitalized for respiratory symptoms were enrolled: 60 with SARS-CoV-2 and 78 with RSV. In the group of SARS-CoV-2-infected children, 13/60 (21%) received a diagnosis of co-infection. Among the enrolled children, 87/138 (63%) received a diagnosis of bronchiolitis. The comparative evaluation showed a higher risk of the need for oxygen therapy and intravenous hydration in children with RSV infection and co-infection compared to children with SARS-CoV-2 infection. In the children with a diagnosis of bronchiolitis, no differences in the main outcomes among the groups were observed. Although children with SARS-CoV-2 infection have less severe respiratory effects than adults, the pediatrician should pay attention to bronchiolitis due to SARS-CoV-2, which could have a severe clinical course in younger children.

Telemedicine has entered the daily lives of doctors, although the digital skills of healthcare professionals still remain a goal to be achieved. For the purpose of a large-scale development of telemedicine, it is necessary to create trust in the services it can offer and to favor their acceptance by healthcare professionals and patients. In this context, information for the patient regarding the use of telemedicine, the benefits that can be derived from it, and the training of healthcare professionals and patients for the use of new technologies are fundamental aspects. This consensus document is a commentary that has the aim of defining the information on and training aspects of telemedicine for pediatric patients and their caregivers, as well as pediatricians and other health professionals who deal with minors. For the present and the future of digital healthcare, there is a need for a growth in the skills of professionals and a lifelong learning approach throughout the professional life. Therefore, information and training actions are important to guarantee the necessary professionalism and knowledge of the tools, as well as a good understanding of the interactive context in which they are used. Furthermore, medical skills can also be integrated with the skills of various professionals (engineers, physicists, statisticians, and mathematicians) to birth a new category of health professionals responsible for building new semiotics, identifying criteria for predictive models to be integrated into clinical practice, standardizing clinical and research databases, and defining the boundaries of social networks and new communication technologies within health services.

Background: Probiotics, defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, are widely used despite uncertainty regarding their efficacy and discordant recommendations about their use. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Gut Microbiota and Modifications provides updated recommendations for the use of probiotics for the management of selected pediatric gastrointestinal disorders., Methods: All systematic reviews and/or meta-analyses, as well as subsequently published randomized controlled trials (RCTs) (until December 2021), that compared the use of probiotics in all delivery vehicles and formulations, at any dose, with no probiotic (ie, placebo or no treatment), were eligible for inclusion. The recommendations were formulated only if at least 2 RCTs on a similar well-defined probiotic strain were available. The modified Delphi process was used to establish consensus on the recommendations., Results: Recommendations for the use of specific probiotic strains were made for the management of acute gastroenteritis, prevention of antibiotic-associated diarrhea, nosocomial diarrhea and necrotizing enterocolitis, management of Helicobacter pylori infection, and management of functional abdominal pain disorders and infant colic., Conclusions: Despite evidence to support the use of specific probiotics in some clinical situations, further studies confirming the effect(s) and defining the type, dose, and timing of probiotics are still often required. The use of probiotics with no documented health benefits should be discouraged., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: Changes of routine disease management associated with COVID-19 lockdown might have potentially affected the clinical course of juvenile idiopathic arthritis (JIA). The aim of our study was to assess the rate of disease flare before and during COVID-19 lockdown to investigate its impact on disease course in children with JIA., Methods: A single-center retrospective study was conducted, including patients presenting with inactive JIA between September 1, 2018 and March 9, 2019 (group A) and between September 1, 2019 and March 9, 2020 (group B). For each patient, demographic and clinical data were collected. The rate of JIA flare from March 10, 2019 to June 30, 2019 for group A and from March 10, 2020 to June 30, 2020 for group B was compared., Results: Group A included 126 patients, and group B 124 patients. Statistical analysis did not show significant differences among the 2 cohorts with respect to age, sex, age at JIA onset, JIA subtype, co-occurrence of uveitis, antinuclear antibody positivity, and past or ongoing medications. The rate of disease flare during lockdown at the time of the first COVID-19 pandemic wave was significantly higher in comparison to the previous year (16.9% versus 6.3%; P = 0.009)., Conclusion: Our study showed that COVID-19 lockdown was associated with a higher rate of joint inflammation in children with JIA. This finding has a considerable clinical implication, as restrictive measures may be necessary in order to contain pandemics. Our data highlight the need for rearrangement in the home and health care management of children with JIA during lockdowns., (© 2021 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Telemedicine is considered an excellent tool to support the daily and traditional practice of the health profession, especially when referring to the care and management of chronic patients. In a panorama in which chronic pathologies with childhood onset are constantly increasing and the improvement of treatments has allowed survival for them into adulthood, telemedicine and remote assistance are today considered effective and convenient solutions both for the chronic patient, who thus receives personalized and timely assistance, and for the doctors, who reduce the need for direct intervention, hospitalizations and consequent management costs. This Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, has the objectives to propose an organizational model based on the relationships between the actors who participate in the provision of a telemedicine service aimed at minors with chronic pathologies, identifying specific project links between the areas of telemedicine in the developmental age from the first 1000 days of life to the age adult. The future scenario will have to be able to integrate digital innovation in order to offer the best care to patients and citizens. It will have to be able to provide the involvement of patients from the very beginning of the design of any care pathway, increasing where possible the proximity of the health service to citizens.

Technological innovation can contribute to a reorganization of healthcare, particularly by supporting the shift in the focus of care from the hospital to the territory, through innovative citizen-centered models, and facilitating access to services in the territory. Health and social care delivery modalities, enabled by telemedicine, are crucial in this regard. The objective of this Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, is to define a standard for its use at the territorial level in various declinations in the pediatric field; this paper also identifies priority areas for its application and the types of services that most require intervention and investment. The changes that are underway in digital transformation in all sectors are unstoppable, and for the digital transformation to take place in a productive sense, the contribution of not only all health professionals, but also of patients, is necessary. From this perspective, authors from different backgrounds were involved in the drafting of this Consensus and, in the future, other figures, primarily patients, are expected to be involved. In fact, this belongs to the vision of connected care, in which the citizen/patient actively participates in the treatment path so that they are assisted in a personalized, predictive and preventive way. The future scenario must be able to provide for the involvement of patients from the initial stages of planning any treatment path, even in the pediatric age, and increasing, where possible, the proximity of the health service to the families.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen with enteric tropism. We compared the clinical, biochemical and radiological features of children hospitalized for acute SARS-CoV-2 infection, classified in two groups based on the presence of diarrhea. Logistic regression analyses were used to investigate the variables associated with diarrhea. Overall, 407 children were included in the study (226 males, 55.5%, mean age 3.9 ± 5.0 years), of whom 77 (18.9%) presented with diarrhea, which was mild in most cases. Diarrhea prevalence was higher during the Alpha (23.6%) and Delta waves (21.9%), and in children aged 5-11 y (23.8%). Other gastrointestinal symptoms were most commonly reported in children with diarrhea ( p < 0.05). Children with diarrhea showed an increased systemic inflammatory state (higher C-reactive protein, procalcitonin and ferritin levels, p < 0.005), higher local inflammation as judged by mesenteric fat hyperechogenicity (adjusted Odds Ratio 3.31, 95%CI 1.13-9.70) and a lower chance of previous immunosuppressive state (adjusted Odds Ratio 0.19, 95%CI 0.05-0.70). Diarrhea is a frequent feature of pediatric COVID-19 and is associated with increased systemic inflammation, which is related to the local mesenteric fat inflammatory response, confirming the implication of the gut not only in multisystem inflammatory syndrome but also in the acute phase of the infection.

Background and study aims  The ability to perform endoscopy procedures safely and effectively is a key aspect of quality clinical care in Pediatric Gastroenterology, Hepatology and Nutrition (PGHN). The aim of this survey, which was part of a global survey on PGHN training in Europe, was to assess endoscopy training opportunities provided across Europe. Methods  Responses to standardized questions related to endoscopy training were collected from training centers across Europe through the presidents/representatives of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition National Societies from June 2016 to December 2019. Results  A total of 100 training centers from 19 countries participated in the survey. In 57 centers, the endoscopy suit was attached to the PGHN center, while in 23, pediatric endoscopies were performed in adult endoscopy facilities. Ninety percent of centers reported the availability of specialized endoscopy nurses and 96 % of pediatric anesthetists. Pediatric endoscopies were performed by PGHN specialists in 55 centers, while 31 centers reported the involvement of an adult endoscopist and 14 of a pediatric surgeon. Dividing the number of procedures performed at the training center by the number of trainees, ≤ 20 upper, lower, or therapeutic endoscopies per trainee per year were reported by 0 %, 23 %, and 56 % of centers, respectively, whereas ≤ 5 wireless capsule endoscopies per trainee per year by 75 %. Only one country (United Kingdom) required separate certification of competency in endoscopy. Conclusions  Differences and deficiencies in infrastructure, staffing, and procedural volume, as well as in endoscopy competency assessment and certification, were identified among European PGHN training centers limiting training opportunities in pediatric endoscopy., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which, since 2019 in China, has rapidly become a worldwide pandemic. The aggressiveness and global spread were enhanced by the many SARS-CoV-2 variants that have been isolated up to now. These mutations affect mostly the viral glycoprotein Spike (S), the capsid protein mainly involved in the early stages of viral entry processes, through the recognition of specific receptors on the host cell surface. In particular, the subunit S1 of the Spike glycoprotein contains the Receptor Binding Domain (RBD) and it is responsible for the interaction with the angiotensin-converting enzyme 2 (ACE2). Although ACE2 is the primary Spike host receptor currently studied, it has been demonstrated that SARS-CoV-2 is also able to infect cells expressing low levels of ACE2, indicating that the virus may have alternative receptors on the host cells. The identification of the alternative receptors can better elucidate the pathogenicity and the tropism of SARS-CoV-2. Therefore, we investigated the Spike S1 interactomes, starting from host membrane proteins of non-pulmonary cell lines, such as human kidney (HK-2), normal colon (NCM460D), and colorectal adenocarcinoma (Caco-2). We employed an affinity purification-mass spectrometry (AP-MS) to pull down, from the membrane protein extracts of all cell lines, the protein partners of the recombinant form of the Spike S1 domain. The purified interactors were identified by a shotgun proteomics approach. The lists of S1 potential interacting proteins were then clusterized according to cellular localization, biological processes, and pathways, highlighting new possible S1 intracellular functions, crucial not only for the entrance mechanisms but also for viral replication and propagation processes., Competing Interests: II, VM, LC, FB, FC, MZ, and MM were affiliated with the company CEINGE Advanced Biotechnologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Iacobucci, Monaco, Canè, Bibbò, Cioffi, Cozzolino, Guarino, Zollo and Monti.)

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

Background and Aims: The pathophysiology of SARS-CoV-2-associated diarrhea is unknown. Using an experimental model validated for rotavirus-induced diarrhea, we investigated the effects of SARS-CoV-2 on transepithelial ion fluxes and epithelial integrity of human intestinal cells. The effect of the antidiarrheal agent diosmectite on secretion was also evaluated following its inclusion in COVID-19 management protocols., Methods: We evaluated electrical parameters (intensity of short-circuit current [ Isc ] and transepithelial electrical resistance [TEER]) in polarized Caco-2 cells and in colonic specimens mounted in Ussing chambers after exposure to heat-inactivated (hi) SARS-CoV-2 and spike protein. Spectrofluorometry was used to measure reactive oxygen species (ROS), a marker of oxidative stress. Experiments were repeated after pretreatment with diosmectite, an antidiarrheal drug used in COVID-19 patients., Results: hiSARS-CoV-2 induced an increase in Isc when added to the mucosal (but not serosal) side of Caco-2 cells. The effect was inhibited in the absence of chloride and calcium and by the mucosal addition of the Ca 2+ -activated Cl - channel inhibitor A01, suggesting calcium-dependent chloride secretion. Spike protein had a lower, but similar, effect on Isc . The findings were consistent when repeated in human colonic mucosa specimens. Neither hiSARS-CoV-2 nor spike protein affected TEER, indicating epithelial integrity; both increased ROS production. Pretreatment with diosmectite inhibited the secretory effect and significantly reduced ROS of both hiSARS-CoV-2 and spike protein., Conclusions: SARS-CoV-2 induces calcium-dependent chloride secretion and oxidative stress without damaging intestinal epithelial structure. The effects are largely induced by the spike protein and are significantly reduced by diosmectite. SARS-CoV-2 should be added to the list of human enteric pathogens., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

Objectives/background: Disease-related malnutrition is common in patients with chronic diseases and has detrimental effects, therefore, skills in nutrition care are essential core competencies for paediatric digestive medicine. The aim of this survey, conducted as part of a global survey of paediatric gastroenterology, hepatology and nutrition (PGHN) training in Europe, was to assess nutrition care-related infrastructure, staff, and patient volumes in European PGHN training centres., Methods: Standardized questionnaires related to clinical nutrition (CN) care were completed by representatives of European PGHN training centres between June 2016 and December 2019., Results: One hundred training centres from 17 European countries, Turkey, and Israel participated in the survey. Dedicated CN clinics exist in 66% of the centres, with fulltime and part-time CN specialists in 66% and 42%, respectively. Home tube feeding (HTF) andhome parenteral nutrition (HPN) programmes are in place in 95% and 77% of centres, respectively. Twenty-four percent of centres do not have a dedicated dietitian and 55% do not have a dedicated pharmacist attached to the training centre. Even the largest centres with >5000 outpatients reported that 25% and 50%, respectively do not have a dedicated dietitian or pharmacist. Low patient numbers on HTF and HPN of <5 annually are reported by 13% and 43% of centres, respectively., Conclusions: The survey shows clear differences and deficits in Clinical Nutrition training infrastructure, including staff and patient volumes, in European PGHN training centres, leading to large differences and limitations in training opportunities in Clinical Nutrition., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Pediatric gastrointestinal motility disorders present significant challenges for diagnosis and management, emphasizing the need for appropriate training in Pediatric Neurogastroenterology and Motility (PNGM). The aim of this survey, part of a comprehensive survey on training in pediatric gastroenterology, hepatology and nutrition, was to evaluate training related to PNGM across European training centers., Method: Standardized questionnaires were collected from training centers through the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), from June 2016 to December 2019., Results: In total, 100 training centers from 19 countries participated in the survey. Dedicated PNGM clinics were available in 22 centers; pH-monitoring in 60; pH/impedance in 66; standard manometry in 37; and high-resolution manometry in 33. If all motility studies were performed partially or fully by the trainees, the median (range) annual numbers/per trainee were as follows: pH-monitoring 30 (1-500); pH/impedance 17 (1-131); standard manometries 10 (1-150); and high-resolution manometries 8 (1-75). The motility assessment was performed by pediatric gastroenterologists (43 centers); adult gastroenterologists (10 centers); pediatric surgeons (5 centers); and both pediatric gastroenterologists and pediatric surgeons (9 centers). Annual numbers ≤10 for pH-monitoring, pH/impedance, standard manometries and high-resolution manometries were reported by 7 (12%), 15 (23%), 11 (30%) and 14 (42%) centers, respectively., Conclusions: Significant differences exist in PNGM-related infrastructure, staff and procedural volumes at training centers across Europe. ESPGHAN and the National Societies should take initiatives to ensure the acquisition of competence in PNGM-related knowledge and skills, and develop strategies for assessment and accreditation.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic-AG6486.pdf., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background: This survey evaluated the effects of the recognition of pediatric gastroenterology, hepatology and nutrition (PGHN) on European PGHN training centers., Method: Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, from June 2016 to December 2019., Results: A total of 100 training centers from 19 countries participated in the survey: 55 from 12 countries where PGHN is formally recognized (Group 1) and 45 from 7 countries where it is not (Group 2). Training centers in Group 2 were less likely to have an integrated endoscopy suite, a written training curriculum and a training lead (P=0.059, P<0.001 and P=0.012, respectively). Trainees in Group 2 were less likely to be exposed to an adequate number of diagnostic endoscopies, while no differences were found in relation to liver biopsies. Half of the training centers in both Groups do not have dedicated beds for PGHN patients, while in 64% and 58%, respectively, trainees do not participate in on-call programs for PGHN emergencies. Research training is mandatory in 26% of the centers. The duration of training, as well as the assessment and accreditation policies, vary between countries., Conclusions: This study has revealed significant discrepancies and gaps in infrastructure and training programs, training leadership, and assessment of training and certification across European training centers in PGHN. Strategies to support the recognition of PGHN and to standardize and improve training conditions should be developed and implemented.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic&#95;AG-6496.pdf., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: A higher prevalence of celiac disease (CD) has been reported in patients with juvenile idiopathic arthritis (JIA) compared to the general population. Factors related to the increased risk of co-occurrence and associated disease course have not been fully elucidated. Aims of this study were to determine the prevalence of CD in a large Southern Italian cohort of children with JIA, describe their clinical features and disease course and investigate risk factors associated with their co-occurrence., Findings: Demographic, clinical and laboratory data of all patients with JIA admitted to our Pediatric Rheumatology Unit from January 2001 to June 2019, who underwent CD screening, were retrospectively extracted from clinical charts and analyzed. Eight of 329 JIA patients were diagnosed with CD, resulting in a prevalence higher than the general Italian population (2.4% vs 0.93%, p < 0.05). Familiarity for autoimmunity was reported by 87.5% patients with JIA and CD compared to 45.8% of those without CD (p < 0.05). 87.5% patients with JIA and CD required both a conventional Disease Modifying Anti-Rheumatic Drug (DMARD) and a biological DMARD over time compared to 36.4% of those without CD (p < 0.05)., Conclusion: A higher CD prevalence was found in a large JIA cohort, supporting the need for CD screening in all JIA children, especially those with a family history of autoimmunity, found to be associated with the co-occurrence of the two diseases. This is clinically relevant since patients with CD and JIA more often required a step-up therapy, suggesting a more severe JIA clinical course., (© 2022. The Author(s).)

Background: Administration of Lacticaseibacillus rhamnosus GG (LGG) to children with gastroenteritis is recommended by universal guidelines. Rotavirus (RV) causes diarrhea through combined cytotoxic and enterotoxic effects. Aim of this study was to evaluate the mechanisms of efficacy of LGG in an in-vitro model of RV diarrhea in its viable form (LGG) and conditioned medium (mLGG)., Methods: Ion secretion corresponding to the NSP4 enterotoxic effect, was evaluated by short circuit current ( Isc ) and the cytotoxic effect by transepithelial electrical resistance (TEER) in Ussing chambers, upon exposure to RV in Caco-2 enterocyte monolayers treated or not with living probiotic or its culture supernatant. Mechanisms of enterotoxic and cytotoxic damage were evaluated including oxidative stress measured by reactive oxygen species, apoptosis evaluated by DAPI and nuclear staining, NFkβ immunofluorescence., Results: RV induced Isc increase and TEER decrease, respectively indicating ion secretion and epithelial damage, the two established pathways of diarrhea. Both probiotic preparations reduced both diarrheal effects, but their potency was different. Live LGG was equally effective on both enterotoxic and cytotoxic effect whereas mLGG was highly effective on ion secretion and showed minimal protective effects on cytoskeleton, apoptosis and NFkβ., Conclusions: LGG counteracts RV-induced diarrhea by inhibiting both cytotoxic and enterotoxic pathogenic mechanisms. Namely, LGG inhibits chloride secretion by specific moieties secreted in the medium with a direct pharmacologic-like action. This is considered a postbiotic effect. Subsequently, live bacteria exert a probiotic effect protecting the enterocyte structure., Competing Interests: The study was in part supported by Dicofarm S.p.A. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. All authors declare no other competing interests., (Copyright © 2022 Buccigrossi, Poeta, Cioffi, Terranova, Nunziata, Lo Vecchio and Guarino.)

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burbelo, Castagnoli, Shimizu, Delmonte, Dobbs, Discepolo, Lo Vecchio, Guarino, Licciardi, Ramenghi, Rey-Jurado, Vial, Marseglia, Licari, Montagna, Rossi, Montealegre Sanchez, Barron, Warner, Chiorini, Espinosa, Noguera, Dropulic, Truong, Gerstbacher, Mató, Kanegaye, Tremoulet, Pediatric Emergency Medicine Kawasaki Group, Eisenstein, Su, Imberti, Poli, Burns, Notarangelo and Cohen.)

Background: Two sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed., Main Findings: Although the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type., Conclusions: Pediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue., (© 2022. The Author(s).)

Background: The widely recognized burden of liver diseases makes training in pediatric hepatology (PH) imperative. The aim of this survey, which was part of a global survey on training in pediatric gastroenterology, hepatology and nutrition (PGHN) across Europe, was to assess the PH and liver transplantation (LT) infrastructure, staff and training programs in PGHN training centers., Method: Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) from June 2016 to December 2019., Results: A total of 100 PGHN training centers participated in the survey (14/100 were national referral centers in PH and/or LT). Dedicated PH clinics were available in 75%, but LT clinics in only 11%. Dedicated beds for PGHN inpatients were available in 47/95 (49%) centers. Full-time or part-time specialists for PH care were available in 31/45 (69%) and 11/36 (31%) centers, respectively. Liver biopsies (LB) were performed in 93% of centers by: a PGHN specialist (35%); an interventional radiologist (26%); a pediatric surgeon (4%); or a combination of them (35%). Dividing the annual number of LBs in the centers performing LBs by the number of trainees gave a median (range) of 10 (1-125) per trainee. Transient elastography was available in 60/92 (65%) of centers., Conclusions: The survey highlighted the differences and shortcomings in PH training across Europe. ESPGHAN should take initiatives together with National Societies to ensure the acquisition of PH knowledge and skills according to the ESPGHAN curriculum.An infographic is available for this article at: http://www.annalsgastro.gr/files/journals/1/earlyview/2022/Infographic-Hepatology-training-paper.pdf., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Importance: Severe gastrointestinal (GI) manifestations have been sporadically reported in children with COVID-19; however, their frequency and clinical outcome are unknown., Objective: To describe the clinical, radiological, and histopathologic characteristics of children with COVID-19 presenting with severe GI manifestations to identify factors associated with a severe outcome., Design, Setting, and Participants: A multicenter retrospective cohort study (February 25, 2020, to January 20, 2021) enrolled inpatient and outpatient children (aged <18 years) with acute SARS-CoV-2 infection, confirmed by positive real-time reverse-transcriptase-polymerase chain reaction on nasopharyngeal swab or fulfilling the US Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children (MIS-C). The study was conducted by pediatricians working in primary care or hospitals in Italy participating in the COVID-19 Registry of the Italian Society of Pediatric Infectious Diseases., Main Outcomes and Measures: The occurrence of severe GI manifestations, defined by a medical and/or radiological diagnosis of acute abdomen, appendicitis (complicated or not by perforation and/or peritonitis), intussusception, pancreatitis, abdominal fluid collection, and diffuse adenomesenteritis requiring surgical consultation, occurring during or within 4 to 6 weeks after infection with SARS-CoV-2 infection. Logistic regression was used to estimate odds ratios (ORs) with 95% CIs of factors potentially associated with severe outcomes., Results: Overall, 685 children (386 boys [56.4%]; median age, 7.3 [IQR, 1.6-12.4] years) were included. Of these children, 628 (91.7%) were diagnosed with acute SARS-CoV-2 infection and 57 (8.3%) with MIS-C. The presence of GI symptoms was associated with a higher chance of hospitalization (OR, 2.64; 95% CI, 1.89-3.69) and intensive care unit admission (OR, 3.90; 95% CI, 1.98-7.68). Overall, 65 children (9.5%) showed severe GI involvement, including disseminated adenomesenteritis (39.6%), appendicitis (33.5%), abdominal fluid collection (21.3%), pancreatitis (6.9%), or intussusception (4.6%). Twenty-seven of these 65 children (41.5%) underwent surgery. Severe GI manifestations were associated with the child's age (5-10 years: OR, 8.33; 95% CI, 2.62-26.5; >10 years: OR, 6.37; 95% CI, 2.12-19.1, compared with preschool-age), abdominal pain (adjusted OR [aOR], 34.5; 95% CI, 10.1-118), lymphopenia (aOR, 8.93; 95% CI, 3.03-26.3), or MIS-C (aOR, 6.28; 95% CI, 1.92-20.5). Diarrhea was associated with a higher chance of adenomesenteritis (aOR, 3.13; 95% CI, 1.08-9.12) or abdominal fluid collection (aOR, 3.22; 95% CI, 1.03-10.0)., Conclusions and Relevance: In this multicenter cohort study of Italian children with SARS-CoV-2 infection or MIS-C, 9.5% of the children had severe GI involvement, frequently associated with MIS-C. These findings suggest that prompt identification may improve the management of serious complications.

Human Immunodeficiency Virus (HIV) infected children have a 30-70% chance of being incompletely immunized and may not respond serologically with the same magnitude or durability as uninfected children. The aim of the study was to describe the rate of protective antibodies titre and the persistence of the response against four recommended vaccinations in HIV infected children and adolescents. A two-phase observational study was performed in which protective IgG antibodies to measles, mumps, rubella and hepatitis B were determined and monitored for 12 and 24 months, in 26 perinatally HIV-infected children. The rate of protection for rubella and hepatitis B was significantly lower in the HIV group compared to the control group (92% vs. 65% for rubella and 78.4% vs. 45.4% for hepatitis B; p < 0.05). Children who received primary vaccination after initiating combination antiretroviral therapy (cART) had a higher rate of response. Seronegative patients who received a booster dose of vaccine had a good immunological response. HIV infection is associated with a lower response to vaccines against rubella and hepatitis. The beginning of cART before vaccination may be associated with a better response. The evaluation of the serological response is crucial in children with HIV infection in order to evaluate the protection of vaccine preventable diseases.

SARS-CoV-2 enters the intestine by the spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors in enterocyte apical membranes, leading to diarrhea in some patients. Early treatment of COVID-19-associated diarrhea could relieve symptoms and limit viral spread within the gastrointestinal (GI) tract. Diosmectite, an aluminomagnesium silicate adsorbent clay with antidiarrheal effects, is recommended in some COVID-19 management protocols. In rotavirus models, diosmectite prevents pathogenic effects by binding the virus and its enterotoxin. We tested the trapping and anti-inflammatory properties of diosmectite in a SARS-CoV-2 model. Trapping effects were tested in Caco-2 cells using spike protein receptor-binding domain (RBD) and heat-inactivated SARS-CoV-2 preparations. Trapping was assessed by immunofluorescence, alone or in the presence of cells. The effect of diosmectite on nuclear factor kappa B (NF-kappaB) activation and CXCL10 secretion induced by the spike protein RBD and heat-inactivated SARS-CoV-2 were analyzed by Western blot and ELISA, respectively. Diosmectite bound the spike protein RBD and SARS-CoV-2 preparation, and inhibited interaction of the spike protein RBD with ACE2 receptors on the Caco-2 cell surface. Diosmectite exposure also inhibited NF-kappaB activation and CXCL10 secretion. These data provide direct evidence that diosmectite can bind SARS-CoV-2 components and inhibit downstream inflammation, supporting a mechanistic rationale for consideration of diosmectite as a management option for COVID-19-associated diarrhea., (© 2021. The Author(s).)

Competing Interests: None disclosed.

Introduction: The transmission rates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from children to adults are unclear due to a lack of controlled conditions. Materials and Methods: We investigated the occurrence of SARS-CoV-2 transmission among 12 discordant child-parent pairs in our ward. In each hospital isolation room, caregivers and children lived in close contact during the entire hospitalization period. Results: A total of 136 swab-positive children (mean age, 3.6 ± 4.9 median age, 1; IQR 0-6.2, range 0.1-17) attended by their caregivers were hospitalized. Of those, 12/136 (8.8%, mean age, 6.1 ± 5.3 median age, 4.5) were attended by caregivers who were swab and serology negative at admission despite previous close contact with positive children at home. Three children were completely dependent on their mothers, one of whom was being breastfed. The mean duration of overall exposure to the index case was 20.5 ± 8.2 days. Conclusion: None of the infected children transmitted SARS-CoV-2 infection to their caregivers, raising the hypothesis of a cluster of resistant mothers or of limited transmission from children to adults despite prolonged exposure and close contact. These data might provide reassurance regarding school openings and offer the chance of investigating SARS-CoV-2 variants in the future under the same quasi-experimental conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nunziata, Poeta, Vassallo, Continisio, Lo Vecchio, Guarino and Bruzzese.)

Background: Worldwide medical authorities recommend vitamin A supplementation for severe measles requiring hospitalization; however, evidence supporting its use in high-income countries is lacking. A nationwide vitamin A shortage reported in concomitance with a recent measles outbreak in Italy provided an opportunity to test the effectiveness of vitamin A in a high-income setting, approximating an unbiased allocation., Methods: We conducted a prospective controlled cohort study involving children admitted for measles to a tertiary-care hospital in Southern Italy. The primary outcome was the duration of fever. Secondary outcomes included the length of hospitalization, rate of complications, need for antibiotic treatment and body temperature., Results: A total of 108 inpatient children (36% female, median age 16.3 months) were enrolled; 36 received 2 doses of oil-based vitamin A according to age, and 72 matched controls received standard care. There were no significant differences between the study groups in the duration of fever (7.03 ± 2.67 vs. 6.82 ± 3.27, P = 0.72), length of hospitalization (median, 5.0 vs. 5.0 days, P = 0.50), maximum body temperature (median, 39°C in both groups, P = 0.23), rate of organ (69.4% vs. 63.9%, P = 0.72) and hematologic complications (41.7% vs. 59.7%, P = 0.12), or need for antibiotic treatment (66.7% vs. 61.1%, P = 0.72). Overall, vitamin A supplementation did not reduce the risk of any complications (relative risk, 1.33; 95% confidence intervals: 0.59-2.96)., Conclusion: Vitamin A does not change the clinical course of measles infection or the rate of complications in children hospitalized in a high-income country., Study Registration Number: EU PAS 31805., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Importance: Chilblain-like lesions have been one of the most frequently described cutaneous manifestations during the COVID-19 pandemic. Their etiopathogenesis, including the role of SARS-CoV-2, remains elusive., Objective: To examine the association of chilblain-like lesions with SARS-CoV-2 infection., Design, Setting, and Participants: This prospective case series enrolled 17 adolescents who presented with chilblain-like lesions from April 1 to June 30, 2020, at a tertiary referral academic hospital in Italy., Main Outcomes and Measures: Macroscopic (clinical and dermoscopic) and microscopic (histopathologic) analysis contributed to a thorough understanding of the lesions. Nasopharyngeal swab, serologic testing, and in situ hybridization of the skin biopsy specimens were performed to test for SARS-CoV-2 infection. Laboratory tests explored signs of systemic inflammation or thrombophilia. Structural changes in peripheral microcirculation were investigated by capillaroscopy., Results: Of the 17 adolescents (9 [52.9%] male; median [interquartile range] age, 13.2 [12.5-14.3] years) enrolled during the first wave of the COVID-19 pandemic, 16 (94.1%) had bilaterally localized distal erythematous or cyanotic lesions. A triad of red dots (16 [100%]), white rosettes (11 [68.8%]), and white streaks (10 [62.5%]) characterized the dermoscopic picture. Histologic analysis revealed a remodeling of the dermal blood vessels with a lobular arrangement, wall thickening, and a mild perivascular lymphocytic infiltrate. SARS-CoV-2 infection was excluded by molecular and serologic testing. In situ hybridization did not highlight the viral genome in the lesions., Conclusions and Relevance: This study delineated the clinical, histologic, and laboratory features of chilblain-like lesions that emerged during the COVID-19 pandemic, and its findings do not support their association with SARS-CoV-2 infection. The lesions occurred in otherwise healthy adolescents, had a long but benign course to self-resolution, and were characterized by a microvascular remodeling with perivascular lymphocytic infiltrate but no other signs of vasculitis. These results suggest that chilblain-like lesions do not imply a concomitant SARS-CoV-2 infection. Ongoing studies will help clarify the etiopathogenic mechanisms.

Objectives: The paucity of symptoms and the difficulties in wearing personal protective equipment make children a potential source of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for health care workers (HCWs). Previous experience in pediatric settings reported high rate of intrahospital SARS-CoV-2 transmission in HCWs caring for children. We aimed at investigating the rate and determinants of SARS-CoV-2 infection among HCWs working in a regional reference center in the Southern Italy., Methods: A prospective observational study was conducted to monitor the occurrence of SARS-CoV-2 infections among HCWs and investigate the relation between the infection rate and hours of exposure or number and characteristics of procedures, including nasopharyngeal swab, high-flow oxygen delivery, suctioning of airway secretions, sputum induction, and nebulizer administration., Results: After 5 months of monitoring, 425.6 hours of SARS-CoV-2 exposure (18.5 hours per person), and 920 hospital procedures, no case of nosocomial transmission was reported among the 23 HCWs enrolled in the study., Conclusions: The application of stringent preventive measures, also outside the area dedicated to patients' care, can effectively control infection spreading also in pediatric settings., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

We tested the hypothesis that a narrative approach may enhance a bio-psycho-social model (BPS) in caring for chronically ill children. Forty-eight narratives were collected from 12 children with six different medical conditions, their mothers, physicians, and nurses. By a textual analysis, narratives were classified on their predominant focus as disease (biological focus), illness (psychologic focus), or sickness (social focus). Sixty-one percent of narrative' text were classified as illness, 28% as disease and 11% as sickness. All narratives had a degree of illness focus. Narratives by patients and physicians on the one hand, and nurses' and mothers' on the other were disease focused. Narratives were also evaluated with respect to the type of medical condition: Illness was largely prevalent in all but Crohn's disease and HIV infection, the latter having a predominance of sickness most probably related to stigma. Narrative exploration proved a valuable tool for understanding and addressing the needs of children with complex conditions. Narrative approaches allow identification of the major needs of different patients according to health conditions and story tellers. In the narratives, we found a greater illness and disease focus and surprisingly a low sickness focus, except with HIV stories. Narrative medicine provides a tool to strengthen the BPS model in health care., (© 2020 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)