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Claudia Carmassi,1 Martina Corsi,1 Carlo Antonio Bertelloni,1 Barbara Carpita,1 Camilla Gesi,1 Virginia Pedrinelli,1 Gabriele Massimetti,1 Diego Giampietro Peroni,2 Alice Bonuccelli,2 Alessandro Orsini,2 Liliana Dell’Osso1 1Psychiatric Clinic, 2Pediatric Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Background: Post-traumatic stress disorder (PTSD) and post-traumatic stress spectrum have been recently applied to understand the impact of life-threatening disease or injury in one’s child; nevertheless, scant data are available on a particular chronic illness such as epilepsy whose phenotypic expression is seizures, which are acute, sudden, and unpredictable manifestations. Subjects with bipolar disorders or with mood spectrum symptoms demonstrated to be more vulnerable to develop PTSD in the aftermath of a trauma. Objectives: The main aim of this study was to evaluate post-traumatic symptoms among 134 parents of children with a diagnosis of epilepsy, followed at the outpatient neurologic unit of Department of Pediatrics in Santa Chiara Hospital in Pisa, as well as gender differences. The second aim of this study was to estimate the impact of lifetime mood spectrum on post-traumatic stress symptoms in the same study sample after fulfillment of the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Mood Spectrum-Self Report (MOODS-SR) lifetime version. Results: Results showed 10.4% and 37.3% of PTSD full and partial, respectively. Demographic characteristics and clinical features of the study sample did not show any impact on stress symptomatology. Mothers presented higher rates at all Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 PTSD symptoms’ clusters except avoidance. Nevertheless, noteworthy correlations between post-traumatic symptomatology and mood spectrum symptoms detected with the self-report tools, emerged only in the subgroup of the fathers. Conclusion: These findings corroborate the need to provide assistance to caregivers of pediatric patients and confirm the hypothesis that lifetime mood spectrum may have an impact on reaction to traumas. Keywords: PTSD, post-traumatic stress spectrum, mood spectrum, DSM-IV, DSM-5, caregivers, children with epilepsy

Matteo Gelardi,1 Diego G Peroni,2 Cristoforo Incorvaia,3 Nicola Quaranta,1 Concetta De Luca,1 Salvatore Barberi,4 Ilaria Dell'Albani,5 Massimo Landi,6 Franco Frati,5 Olivier de Beaumont7 1Otolaryngology Unit, Department of Neuroscience and Sensory Organs, University of Bari, Bari, Italy; 2Department of Pediatrics, University of Verona, Verona, Italy; 3Allergy/Pulmonary Rehabilitation, ICP Hospital, Milan, Italy; 4Department of Pediatrics, San Paolo Hospital, Milan, Italy; 5Medical and Scientific Department, Stallergenes, Milan, Italy; 6Department of Pediatrics, National Healthcare System, ASL TO1, Turin, Italy; 7Medical Affairs Department, Stallergenes, Antony, France Background: House dust mites (HDMs) are a major cause of allergic rhinitis (AR) and asthma worldwide. Recent studies suggested that the allergen load presents seasonal modifications, giving rise to seasonal variation in nasal inflammation and symptoms. The aim of this study was to evaluate by nasal cytology whether nasal inflammation in mite-allergic patients changes with the seasons of the year. Methods: The study included 16 patients (seven males and nine females, mean age 38.1 years) with persistent AR caused by monosensitization to HDMs. Nasal cytology was performed in all patients once monthly for 1 year. Results: Nasal cytology showed that the cells most commonly detected in the nasal mucosa were neutrophils. During the period from October to April, a peak in the number of neutrophils and also the presence of significant numbers of eosinophils, mast cells, and lymphocytes/plasma cells were found, which shows the occurrence of more intense inflammation during these months. Conclusion: Nasal cytology provides useful data in detecting nasal inflammation and its association with the clinical stage of AR. The seasonal variations in nasal cytology are likely to be induced by the fluctuations in the HDM allergen that have been uncovered in recent investigations. Keywords: allergens, allergic rhinitis, house dust mite, nasal inflammation

Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pediatric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neurological involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.

The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.

Background: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections., Methods: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC., Results: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts., Conclusions: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants., (© 2024. The Author(s).)

Background: Even though the incidence of Multisystem Inflammatory Syndrome in children (MIS-C) is decreasing cases are still reported across the world. Studying the consequences of MIS-C enhances our understanding of the disease's prognosis. The objective of this study was to assess short- and medium-term clinical outcomes of MIS-C., Methods: Prospective observational cohort study at Municipal Children's Hospital Morozovskaya, Moscow, Russia. All children meeting the Royal College of Paediatrics and Child Health (RCPCH), Centers for Disease Control and Prevention (CDC), or the World Health Organization (WHO) MIS-C case definition admitted to the hospital between 17 May and 26 October 2020 were included in the study. All survivors were invited to attend a clinic at 2 and 6 weeks after hospital discharge., Results: 37 children median age 6 years (interquartile range [IQR] 3.3-9.4), 59.5% (22/37) boys were included in the study. 48.6% (18/37) of patients required ICU care. One child died. All children had increased levels of systemic inflammatory markers during the acute event. Echocardiographic investigations identified abnormal findings in 35.1% (13/37) of children. 5.6% (2/36) of children were presenting with any symptoms six weeks after discharge. By six weeks the inflammatory markers were within the reference norms in all children. The echocardiographic evaluation showed persistent coronary dilatation in one child., Conclusions: Despite the severity of their acute MIS-C, the majority of children in our cohort fully recovered with none having elevated laboratory markers of inflammation at 6 weeks, few (< 10%) reporting persistent symptoms at 6 weeks, and only one with persistent echocardiographic abnormalities., (© 2023. The Author(s).)

Background: Alterations in plantar soft tissues are often reported in adults with diabetes, whereas data on children are conflicting. Also, the extent of foot damage caused by excess body fat in children has not been fully characterized yet. This study aimed to address the relationship between body mass and structural changes of the foot in children and adolescents with and without diabetes., Methods: In a case-control study, 43 participants (age 13 ± 2.6 years) were recruited, 29 (67%) with type 1 diabetes (T1D) and 14 (33%) controls. Anthropometric parameters [body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)], foot posture index-6 (FPI-6) for static foot posture, and navicular drop test (NDT) for medial longitudinal arch height (MLA) were measured in all participants. The thickness of the midfoot plantar fascia (MPF) and medial midfoot fat pad (MMFP) were quantified using ultrasound., Results: No differences in clinical and ultrasonographical parameters were observed between the study groups. MMFP thickness was correlated with MPF thickness ( p = 0.027). MMFP and MPF thicknesses were positively associated with BMI ( p < 0.001 and p = 0.013, respectively), WC ( p < 0.001 and p = 0.013), and WHtR ( p < 0.001 and p = 0.026). The NDT measured on the right and left foot correlated with WHtR ( p = 0.038 and p = 0.009, respectively), but not with WC and BMI., Conclusions: Children with T1D show structural alterations of plantar soft tissues which seem related to body mass increase rather than diabetes pathology. Ultrasound is a valuable tool to assess early structural changes of the foot in young people with an elevated BMI.

The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, β-hydroxybutyrate, and acetone, which are utilized as energy substrates. This dietary approach impacts several biochemical processes, resulting in improved clinical management of various disorders, particularly in childhood. However, the exact mechanisms underlying the efficacy of KD remain unclear. Interestingly, KD may also impact the gut microbiota, which plays a pivotal role in metabolism, nutrition, and the development of the immune and nervous systems. KD has gained popularity for its potential benefits in weight loss, blood sugar control, and certain neurological conditions. This narrative review sums up KD-related studies published over 30 years. While short-term studies have provided valuable insights into the effects of KD on the gut microbiota, persistent uncertainties surround its long-term efficacy and potential for inducing dysbiosis. The significant influence of KD on epigenetic mechanisms, intracellular pathways, and gut microbial composition underscores its potential as a therapeutic choice. However, a judicious consideration of the potential risks associated with the strict adherence to a low-carbohydrate, high-fat, and high-protein regimen over prolonged periods is imperative. As KDs gain popularity among the adolescent and young adult demographic for weight management, it becomes imperative to undertake additional research to comprehensively assess their impact on nutritional status and gut microbiota, ensuring a holistic and sustainable approach to medical nutrition.

Importance: Population-based data on the 4-component recombinant protein-based (4CMenB) vaccine effectiveness and reduction in incidence rate ratios (IRRs) are continuously needed to assess vaccine performance in the prevention of serogroup B invasive meningococcal disease (IMD)., Objective: To assess the effectiveness and reduction in IRRs associated with the 4CMenB vaccine in the pediatric population in 6 regions in Italy., Design, Setting, and Participants: This retrospective cohort screening study and case-control study included data from children aged younger than 6 years in 6 highly populated Italian regions from January 1, 2006, to January 1, 2020. Participants included children younger than 6 years diagnosed with serogroup B IMD without predisposing factors. Data were collected from regional surveillance and vaccination registries and were analyzed from September 2021 to January 2022., Exposures: Routine 4CMenB vaccination, per regional vaccination programs., Main Outcomes and Measures: The main outcome was the effectiveness of the 4CMenB vaccine in the prevention of serogroup B IMD in the population of children aged younger than 6 years in 6 Italian regions. The percentages of vaccine effectiveness (VE) were obtained through the concomitant use of a screening method and a case-control study. Secondary outcomes were the comparison of effectiveness results obtained using the 2 different computational methods, the description of serogroup B IMD incidence rates, and reduction in IRRs before and after 4CMenB introduction, as a proxy for vaccine impact., Results: The cohort screening study included a resident population of 587 561 children younger than 6 years in 3 regions with similar surveillance protocols, and the matched-case controls study assessed a resident population of 1 080 620 children younger than 6 years in 6 regions. Analyses found that 4CMenB VE in fully immunized children was 94.9% (95% CI, 83.1%-98.4%) using the screening method and 91.7% (95% CI, 24.4%-98.6%) using the case-control method. Overall reduction in IRR was 50%, reaching 70% in regions with early-start vaccination schedules. The case-control method involving 6 highly-populated Italian regions included 26 cases and 52 controls and found an estimated VE of 92.4% (95% CI, 67.6%-97.9%) in children old enough for the first vaccine dose and 95.6% (95% CI, 71.7%-99.1%) in fully immunized children. VE was more than 90% for partially immunized children. Even in regions where the first dose was administered at age 2 months, almost 20% of unvaccinated cases were among infants too young to receive the first 4CMenB dose., Conclusions and Relevance: This screening cohort study and matched case-controls study found high effectiveness of 4CMenB vaccination and greater reduction in IRR for early-start vaccination schedules in preventing invasive serogroup B meningococcal disease. The high proportion of children too young to be vaccinated among unvaccinated cases suggests that starting the vaccination even earlier may prevent more cases. Screening and case-control methods provided similar estimates of VE: either method may be used in different study settings, but concomitant use can provide more robust estimates.

Background: Intestinal parasitic infections are common in humans, especially among young children. These conditions are often asymptomatic and self-limiting, and diagnosis is mainly based on the search for ova and parasites in the stools since serology may be biased due to cross reactivity between parasites. Pinworm is common in children and is not usually associated with hypereosinophilia; adhesive-tape test is the gold standard testing for the microscopic detection of Enterobious vermicularis (Ev) eggs., Case Presentation: A 13-year-old boy was referred due to a self-resolving episode of vomiting and palpebral oedema after dinner, together with a history of chronic rhinitis, chronic cough, absolute IgA deficiency and Hashimoto's thyroiditis and hypereosinophilia (higher value = 3140/µl). On evaluation we detected only palpable thyroid and hypertrophic nasal turbinates. Food allergy was excluded, but skin prick tests showed sensitization to house dust mites and cat epithelium and spirometry showed a marked obstructive pattern with positive bronchodilation test prompting the diagnosis of asthma for which maintenance inhaled treatment was started. Chest x-ray and abdomen ultrasound were negative. Further blood testing showed positive IgG anti-Echinococcus spp. and Strongyloides stercoralis and positive IgE for Ascaris, while Ev were detected both by the adhesive tape test and stool examination, so that we made a final diagnosis of pinworm infection. Three months after adequate treatment with pyrantel pamoate the adhesive-tape test turned out negative and blood testing showed a normal eosinophil count. The child later developed also type 1 diabetes., Conclusions: We suggest the need to investigate for enterobiasis in children with hypereosinophilia and to consider autoimmunity as a potential confounding factor when interpreting serology for helminths., (© 2023. The Author(s).)

Neurovisual involvement has been reported in a number of patients with severe SARS-CoV-2 disease (COVID-19), mainly among adult patients. In children, such involvement has been reported in rare cases, often in those presenting with severe forms of COVID-19. The aim of this work is to explore the association between mild COVID-19 and neurovisual manifestations. We report the cases of three previously healthy children who developed neurovisual manifestations following mild acute COVID-19, analysing the clinical phenotype, the latency between the onset of acute COVID-19 and neurovisual involvement, and the kinetic of resolution. Our patients developed different clinical patterns, including visual impairment and ophthalmoplegia. In two cases, these clinical features occurred during acute COVID-19, while in the third patient their development was delayed after 10 days from disease onset. Furthermore, the dynamics of resolution were different, with one patient showing remission after 24 hours, the second after 30 days, and the third showing persistence of the strabismus after 2 months of follow-up. The spreading of COVID-19 among the paediatric population will probably lead to an increase of atypical disease forms, including those presenting with neurovisual involvement. Therefore, a better knowledge of the pathogenic and clinical features of these manifestations is warranted., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 Taylor & Francis Group, LLC.)

Micronutritional deficiencies are common in atopic children suffering from atopic dermatitis, food allergy, rhinitis, and asthma. A lack of iron, in particular, may impact immune activation with prolonged deficiencies of iron, zinc, vitamin A, and vitamin D associated with a Th2 signature, maturation of macrophages and dendritic cells (DCs), and the generation of IgE antibodies. In contrast, the sufficiency of these micronutrients establishes immune resilience, promotion of regulatory cells, and tolerance induction. As micronutritional deficiencies mimic an infection, the body's innate response is to limit access to these nutrients and also impede their dietary uptake. Here, we summarize our current understanding of the physiological function of iron, zinc, and vitamins A and D in relation to immune cells and the clinical consequences of deficiencies in these important nutrients, especially in the perinatal period. Improved dietary uptake of iron is achieved by vitamin C, vitamin A, and whey compounds, whereas zinc bioavailability improves through citrates and proteins. The addition of oil is essential for the dietary uptake of beta-carotene and vitamin D. As for vitamin D, the major source comes via sun exposure and only a small amount is consumed via diet, which should be factored into clinical nutritional studies. We summarize the prevalence of micronutritional deficiencies of iron, zinc, and vitamins in the pediatric population as well as nutritional intervention studies on atopic diseases with whole food, food components, and micronutrients. Dietary uptake via the lymphatic route seems promising and is associated with a lower atopy risk and symptom amelioration. This review provides useful information for clinical studies and concludes/emphasizes that a healthy, varied diet containing dairy products, fish, nuts, fruits, and vegetables as well as supplementing foods or supplementation with micronutrients as needed is essential to combat the atopic march., Competing Interests: FR-W declares inventorship of EP2894478 (Roth-Walter et al. method and means for diagnosing and treating allergy) (applicant Biomedical International R+D GmbH, Vienna, Austria). FR-W received research funding from Biomedical International R+D GmbH, Vienna, Austria, Bencard Allergie GmbH, Munich, Germany and Vienna, Austria, and Allergy Therapeutics, Worthing, United Kingdom. Moreover, she received lecture honoraria by FOMF, VAEM, Bencard Allergie GmbH, Munich, Germany and Vienna, Austria, and Allergy Therapeutics, Worthing, United Kingdom. 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 © 2023 Peroni, Hufnagl, Comberiati and Roth-Walter.)

Electroencephalography (EEG) is pivotal in the clinical assessment of epilepsy, and sleep is known to improve the diagnostic yield of its recording. Sleep-EEG recording is generally reached by either partial deprivation or by administration of sleep-inducing agents, although it is still not achieved in a considerable percentage of patients. We conducted a double-blind placebo-controlled study, involving a hundred patients between 1 and 6 years old, randomized into two groups: Group 1 received liposomal melatonin (melatosome) whereas Group 2 received a placebo. Sleep latency (SL), defined as the time span between the onset of a well-established posterior dominant rhythm, considered as a frequency of 3 to 4 Hz, increasing to 4-5 Hz by the age of 6 months, to 5-7 Hz by 12 months, and finally to 8 Hz by 3 years, and the first EEG sleep figures detected, were measured for each patient. A significant difference in SL was observed (10.8 ± 5 vs. 18.1 ± 13.4 min, p -value = 0.002). Within each group, no differences in sleep latency were detected between genders. Furthermore, no difference in EEG abnormality detection was observed between the two groups. Our study confirmed the efficacy and safety of melatonin administration in sleep induction. Nonetheless, liposomal melatonin presents a greater bioavailability, ensuring a faster effect and allowing lower dosages. Such results, never before reported in the literature, suggest that the routine employment of melatonin might improve clinical practice in neurophysiology, reducing unsuccessful recordings.

Background: Previous studies assessing the prevalence of COVID-19 sequelae in adults and children were performed in the absence of an agreed definition. We investigated prevalence of post-COVID-19 condition (PCC) (WHO definition), at 6- and 12-months follow-up, amongst previously hospitalised adults and children and assessed risk factors., Methods: Prospective cohort study of children and adults with confirmed COVID-19 in Moscow, hospitalised between April and August, 2020. Two follow-up telephone interviews, using the International Severe Acute Respiratory and Emerging Infection Consortium survey, were performed at 6 and 12 months after discharge., Results: One thousand thirteen of 2509 (40%) of adults and 360 of 849 (42%) of children discharged participated in both the 6- and 12-month follow-ups. PCC prevalence was 50% (95% CI 47-53) in adults and 20% (95% CI 16-24) in children at 6 months, with decline to 34% (95% CI 31-37) and 11% (95% CI 8-14), respectively, at 12 months. In adults, female sex was associated with PCC at 6- and 12-month follow-up (OR 2.04, 95% CI 1.57 to 2.65) and (OR 2.04, 1.54 to 2.69), respectively. Pre-existing hypertension (OR 1.42, 1.04 to 1.94) was associated with post-COVID-19 condition at 12 months. In children, neurological comorbidities were associated with PCC both at 6 months (OR 4.38, 1.36 to 15.67) and 12 months (OR 8.96, 2.55 to 34.82) while allergic respiratory diseases were associated at 12 months (OR 2.66, 1.04 to 6.47)., Conclusions: Although prevalence of PCC declined one year after discharge, one in three adults and one in ten children experienced ongoing sequelae. In adults, females and persons with pre-existing hypertension, and in children, persons with neurological comorbidities or allergic respiratory diseases are at higher risk of PCC., (© 2022. The Author(s).)

Patients with inborn errors of immunity (IEI) are susceptible to developing a severe infection-related clinical phenotype, but the clinical consequences of immune dysregulation, expressed with autoimmunity, atopy, and lymphoproliferation could represent the first sign in a significant percentage of patients. Therefore, during the diagnostic work-up patients with IEI are frequently addressed to different specialists, including endocrinologists, rheumatologists, and allergologists, often resulting in a delayed diagnosis. In this paper, the most relevant non-infectious manifestations of IEI are discussed. Particularly, we will focus on the potential presentation of IEI with autoimmune cytopenia, non-malignant lymphoproliferation, severe eczema or erythroderma, autoimmune endocrinopathy, enteropathy, and rheumatologic manifestations, including vasculitis and systemic lupus erythematosus. This paper aims to identify new warning signs to suspect IEI and help in the identification of patients presenting with atypical/non-infectious manifestations., 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 Costagliola, Peroni and Consolini.)

Introduction: Stroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (≥500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However, many issues are still open on the underlying pathogenesis, clinical, and therapeutic management and long-term outcome., Materials and Methods: We retrospectively analyzed clinical, radiological and laboratory records of all patients diagnosed with SLS between 2011 and 2021 at 4 National referral centers for Pediatric Onco-Hematology. Patients with a latency period that was longer than 3 weeks between the last MTX administration of MTX and SLS onset were excluded from the analysis, as were those with unclear etiologies. We assessed symptom severity using a dedicated arbitrary scoring system. Eleven patients were included in the study., Results: The underlying disease was acute lymphoblastic leukemia type B in 10/11 patients, while fibroblastic osteosarcoma was present in a single subject. The median age at diagnosis was 11 years (range 4-34), and 64% of the patients were women. Symptoms occurred after a mean of 9.45 days (± 0.75) since the last MTX administration and lasted between 1 and 96 h. Clinical features included hemiplegia and/or cranial nerves palsy, paraesthesia, movement or speech disorders, and seizure. All patients underwent neuroimaging studies (CT and/or MRI) and EEG. The scoring system revealed an average of 4.9 points (± 2.3), with a median of 5 points (maximum 20 points). We detected a linear correlation between the severity of the disease and age in male patients., Conclusions: SLS is a rare, well-characterized complication of MTX administration. Despite the small sample, we have been able to confirm some of the previous findings in literature. We also identified a linear correlation between age and severity of the disease, which could improve the future clinical management., 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 Santangelo, Bartolini, Nuzzi, Foiadelli, Michev, Mina, Trambusti, Fichera, Bonuccelli, Massimetti, Peroni, De Marco, Coccoli, Luti, Bernasconi, Nardi, Menconi, Casazza, Pruna, Mura, Marra, Zama, Striano, Cordelli, Battini and Orsini.)

Few data are currently available on the effects of aeroallergens in triggering respiratory symptoms in children. To evaluate the potential effects of daily outdoor aeroallergens loads on childhood admissions, in this case-crossover study, we analyzed data from 85 children hospitalized at the University Hospital of Pisa, Italy, for asthma or asthma-like symptoms without respiratory infection, between 2010 and 2019. Data were linked to outdoor allergens, temperature, nitrogen dioxide, and relative humidity observed during the same period. A 10-grains/m 3 increase in the total aeroallergen concentration was associated with an increased risk of admission at lag 0 (OR = 1.054, 95% CI: 1.011-1.098), with a smaller effect at lag 1 (OR = 1.037, 95% CI: 1.008-1.067) and lag 2 (OR = 1.021, 95% CI: 1.003-1.039). Trends to larger effects were observed in children with sensitization to one or more aeroallergens (OR = 1.085, 95% CI: 1.004-1.173 at lag 0), in males (OR = 1.069, 95% CI: 1.009-1.132 at lag 0) and in older children (OR = 1.065, 95% CI: 1.007-1.127 at lag 0). Our study shows an association between increased outdoor allergens loads and asthma or asthma-like symptoms in children up to at least two days prior to hospitalization, suggesting that tracking aeroallergen counts may be useful to improve the management of respiratory allergic diseases.

Asthma is the most common chronic non-communicable disease in children, the pathogenesis of which involves several factors. The increasing burden of asthma worldwide has emphasized the need to identify the modifiable factors associated with the development of the disease. Recent research has focused on the relationship between dietary factors during the first 1000 days of life (including pregnancy)-when the immune system is particularly vulnerable to exogenous interferences-and allergic outcomes in children. Specific nutrients have been analyzed as potential targets for the prevention of childhood wheeze and asthma. Recent randomized controlled trials show that vitamin D supplementation during pregnancy, using higher doses than currently recommended, may be protective against early childhood wheezing but not school-age asthma. Omega-3 fatty acid supplementation during pregnancy and infancy may be associated with a reduced risk of childhood wheeze, although the evidence is conflicting. Data from observational studies suggest that some dietary patterns during pregnancy and infancy might also influence the risk of childhood asthma. However, the quality of the available evidence is insufficient to allow recommendations regarding dietary changes for the prevention of pediatric asthma. This review outlines the available high-quality evidence on the role of prenatal and perinatal nutritional interventions for the primary prevention of asthma in children and attempts to address unmet areas for future research in pediatric asthma prevention.

Background: The long-term sequelae of coronavirus disease 2019 (COVID-19) in children remain poorly characterised. This study aimed to assess long-term outcomes in children previously hospitalised with COVID-19 and associated risk factors., Methods: This is a prospective cohort study of children (≤18 years old) admitted to hospital with confirmed COVID-19. Children admitted between 2 April 2020 and 26 August 2020 were included. Telephone interviews used the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 Health and Wellbeing Follow-up Survey for Children. Persistent symptoms (>5 months) were further categorised by system(s) involved., Results: 518 out of 853 (61%) eligible children were available for the follow-up assessment and included in the study. Median (interquartile range (IQR)) age was 10.4 (3-15.2) years and 270 (52.1%) were girls. Median (IQR) follow-up since hospital discharge was 256 (223-271) days. At the time of the follow-up interview 126 (24.3%) participants reported persistent symptoms, among which fatigue (53, 10.7%), sleep disturbance (36, 6.9%) and sensory problems (29, 5.6%) were the most common. Multiple symptoms were experienced by 44 (8.4%) participants. Risk factors for persistent symptoms were: older age "6-11 years" (OR 2.74, 95% CI 1.37-5.75) and "12-18 years" (OR 2.68, 95% CI 1.41-5.4), and a history of allergic diseases (OR 1.67, 95% CI 1.04-2.67)., Conclusions: A quarter of children experienced persistent symptoms months after hospitalisation with acute COVID-19 infection, with almost one in 10 experiencing multisystem involvement. Older age and allergic diseases were associated with higher risk of persistent symptoms at follow-up., Competing Interests: Conflict of interest: J. Genuneit reports working as a project manager of unrestricted research grants on the composition of breast milk to Ulm University and Leipzig University with funding from Danone Nutricia Research. M.G. Semple reports grants from the Dept of Health and Social Care National Institute of Health Research UK, grants from the Medical Research Council UK, grants from the Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, outside the submitted work; he also reports a minority ownership at Integrum Scientific LLC (Greensboro, NC, USA), outside the submitted work. T. Vos reports personal fees for work on the Global Burden of Disease Study from the Bill and Melinda Gates Foundation, outside the submitted work. C. Apfelbacher has received lecture fees from AstraZeneca, and is a member of a group developing a core outcome set for long COVID, outside the submitted work. All other authors report no relevant conflict of interests., (Copyright ©The authors 2022.)

Nasal polyps (NPs) are benign inflammatory masses causing chronic nasal obstruction, usually associated with underlying chronic rhinosinusitis (CRS), which are rarely reported in childhood. The interest in NPs has recently increased due to new therapeutic options, namely biological agents, such as dupilumab, and an update of the European position paper on this topic was released in 2020, providing a detailed classification for these lesions and also discussing diagnostic and therapeutic approaches also in children. In childhood, NPs usually represent red flags for systemic diseases, such as cystic fibrosis and immunodeficiencies. This review outlines the recent data on NPs in childhood, focusing on predisposing factors for CRS as well as on the potential endotypes in this particular age group, for which further studies are required in order to better clarify their pathogenesis and to identify molecular biomarkers that could help achieve more personalized treatments.

(1) Background: Children with chronic medical conditions may be at increased risk for severe complications related to vaccine-preventable infections. Therefore, additional booster doses or supplementary vaccines are recommended, over and above the routine immunization schedule for healthy children. The aim of this study was to investigate attitude, knowledge, and practices toward additional vaccinations for children affected by chronic conditions among pediatricians and parents. (2) Methods: This study is based on two surveys: (i) a national cross-sectional survey, targeting pediatrician working in hospitals or in the primary health sector; (ii) a local cross-sectional survey, targeting parents of children with a previous diagnosis of chronic disease. (3) Results: Despite the fact that most of the health professionals and parents interviewed had an overall positive vaccine attitude, most pediatricians did not show an adequate knowledge of additional vaccinations for children affected by chronic diseases. Moreover, the coverage of additional recommended vaccinations in chronic pediatric patients was low. (4) Conclusions: This research highlighted important existing challenges hampering optimal vaccination coverage among pediatric chronic patients, including knowledge gaps on tailored vaccination schedules among pediatricians and organizational issues. The ongoing review of the Italian national immunization plan is a not-to-be-missed-opportunity to include evidence-based, detailed, and comprehensive recommendations on vaccinations for children affected by chronic conditions.

Background: It has been recognized that microbiota plays a key role in shaping immune system maturation and activity. Since probiotic administration influences the microbiota composition and acts as a biological response modifier, the efficacy of an adjuvant for boosting vaccine-specific immunity is investigated., Methods: A review of the literature was performed, starting from the mechanisms to laboratory and clinical evidence., Results: The mechanisms, and in vitro and animal models provide biological plausibility for microbiota use. Probiotics have been investigated as adjuvants in farm conditions and as models to understand their potential in human vaccinations with promising results. In human studies, although probiotics were effective in ameliorating seroconversion to vaccines for influenza, rotavirus and other micro-organisms, the results for clinical use are still controversial, especially in particular settings, such as during the last trimester of pregnancy., Conclusion: Although this topic remains controversial, the use of probiotics as adjuvant factors in vaccination represents a strategic key for different applications. The available data are deeply influenced by heterogeneity among studies in terms of strains, timing and duration of administration, and patients. Although these do not allow us to draw definitive conclusions, probiotics as adjuvants in vaccination should be considered in future studies, especially in the elderly and in children, where vaccine effectiveness and duration of immunization really matter.

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.

In the last decade, the role of nutritional management in pediatric gastrointestinal diseases has gained increasing popularity. Disease-specific diets have been introduced as conventional treatments by international guidelines. Patients tend to more willingly accept food-based therapies than drugs because of their relatively "harmless" nature. Apart from a diet's therapeutic role, nutritional support is crucial in maintaining growth and improving clinical outcomes in pediatric patients. Despite the absence of classical "side effects", however, it should be emphasized that any dietary modification might have negative consequences on children's growth and development. Hence, expert supervision is always advised, in order to support adequate nutritional requirements. Unfortunately, the media provide an inaccurate perception of the role of diet for gastrointestinal diseases, leading to misconceptions by patients or their caregivers that tends to overestimate the beneficial role of diets and underestimate the potential adverse effects. Moreover, not only patients, but also healthcare professionals, have a number of misconceptions about the nutritional benefits of diet modification on gastrointestinal diseases. The aim of this review is to highlight the role of diet in pediatric gastrointestinal diseases, to detect misconceptions and to give a practical guide for physicians on the basis of current scientific evidence.

A growing number of Italian families are adopting a vegan diet (VD) for their offspring from infancy for various reasons, with health benefits and ethics being the most common reasons. Barriers to effective communication with primary care pediatricians (PCPs) are perceived by many parents and, depending on the actors involved and the environment, a VD may affect social interactions in everyday life. A national cross-sectional survey was conducted between July and September 2020. Parents of children following a VD completed an online questionnaire. Data from 176 Italian parents were collected. About 72% (71.8%) of the children included in this study had been on a VD since weaning. Parents did not inform their primary care pediatricians (PCP) about the VD in 36.2% of the cases. In 70.8% of the cases, PCPs were perceived as skeptical or against a VD. About 70% (71.2%) of the parents relied on medical dietitians, and 28.2% on nutritionists/dietitians for dietary counseling. Parents administered an individual B12 supplement in 87.2% of the cases. To the best of our knowledge, this survey is the first which explores the relationship between vegan parents and their PCPs, the parental management of their children's diet and problems regarding the implementation of a VD in everyday life.

Asthma and other allergic disorders, such as atopic dermatitis and food allergies, are common chronic health problems in childhood. The rapid rise in the prevalence of these conditions registered over the last few decades has stressed the need to identify the modifiable risk factors associated with the development of these diseases. Breast milk, recognized as the gold standard for healthy growth and development of the newborn, is one of the major factors associated with a lower incidence of allergic and infectious diseases in childhood and young adulthood. Although the underlying mechanisms for these effects are not well understood, breastfeeding leads to immune system maturation. In this narrative review, we summarize existing evidence on breastfeeding and human milk composition in relation to allergic disease prevention or development.

Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions, resulting in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. The management of a newborn with suspected 46,XY DSD remains challenging. Newborns with 46,XY DSD may present with several phenotypes ranging from babies with atypical genitalia or girls with inguinal herniae to boys with micropenis and cryptorchidism. A mismatch between prenatal karyotype and female phenotype is an increasing reason for presentation. Gender assignment should be avoided prior to expert evaluation and possibly until molecular diagnosis. The classic diagnostic approach is time and cost-consuming. Today, a different approach may be considered. The first line of investigations must exclude rare life-threatening diseases related to salt wasting crises. Then, the new genetic tests should be performed, yielding increased diagnostic performance. Focused imaging or endocrine studies should be performed on the basis of genetic results in order to reduce repeated and invasive investigations for a small baby. The challenge for health professionals will lie in integrating specific genetic information with better defined clinical and endocrine phenotypes and in terms of long-term evolution. Such advances will permit optimization of counseling of parents and sex assignment. In this regard, society has significantly changed its attitude to the acceptance and expansion beyond strict binary male and female sexes, at least in some countries or cultures. These management advances should result in better personalized care and better long-term quality of life of babies born with 46,XY DSD., 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 Bertelloni, Tyutyusheva, Valiani, D'Alberton, Baldinotti, Caligo, Baroncelli and Peroni.)

The current systematic review presented and discussed the most recent studies on acute cough in pediatric age. After that, the Italian Society of Pediatric Allergy and Immunology elaborated a comprehensive algorithm to guide the primary care approach to pediatric patients, such as infants, children, and adolescents, with acute cough. An acute cough is usually consequent to upper respiratory tract infections and is self-resolving within a few weeks. However, an acute cough may be bothersome, and therefore remedies are requested, mainly by the parents. An acute cough may significantly affect the quality of life of patients and their family.Several algorithms for the management of acute cough have been adopted and validated in clinical practice; however, unlike the latter, we developed an algorithm focused on pediatric age, and, also, in accordance to the Italian National Health System, which regularly follows the child from birth to all lifelong. Based on our findings, infants from 6 months, children, and adolescents with acute cough without cough pointers can be safely managed using well-known medications, preferably non-sedative agents, such as levodropropizine and/or natural compounds, including honey, glycerol, and herb-derived components.

The current systematic review presented and discussed the most recent studies on pediatric chronic cough. In addition, the Italian Society of Pediatric Allergy and Immunology elaborated a comprehensive algorithm to guide the primary care approach to a pediatric patient with chronic cough.Several algorithms on chronic cough management have been adopted and validated in clinical practice; however, unlike the latter, we developed an algorithm focused on pediatric age, from birth until adulthood. Based on our findings, children and adolescents with chronic cough without cough pointers can be safely managed, initially using the watchful waiting approach and, successively, starting empirical treatment based on cough characteristics. Unlike other algorithms that suggest laboratory and instrumental investigations as a first step, this review highlighted the importance of a "wait and see" approach, consisting of parental reassurance and close clinical observation, also due to inter-professional collaboration and communication between general practitioners and specialists that guarantee better patient management, appropriate prescription behavior, and improved patient outcome. Moreover, the neonatal screening program provided by the Italian National Health System, which intercepts several diseases precociously, allowing to treat them in a very early stage, helps and supports a "wait and see" approach.Conversely, in the presence of cough pointers or persistence of cough, the patient should be tested and treated by the specialist. Further investigations and treatments will be based on cough etiology, aiming to intercept the underlying disease, prevent potentially irreversible tissue damage, and improve the general health of patients affected by chronic cough, as well as the quality of life of patients and their family.

In recent years, the role of human microbiota as a short- and long-term health promoter and modulator has been affirmed and progressively strengthened. In the course of one's life, each subject is colonized by a great number of bacteria, which constitute its specific and individual microbiota. Human bacterial colonization starts during fetal life, in opposition to the previous paradigm of the "sterile womb". Placenta, amniotic fluid, cord blood and fetal tissues each have their own specific microbiota, influenced by maternal health and habits and having a decisive influence on pregnancy outcome and offspring outcome. The maternal microbiota, especially that colonizing the genital system, starts to influence the outcome of pregnancy already before conception, modulating fertility and the success rate of fertilization, even in the case of assisted reproduction techniques. During the perinatal period, neonatal microbiota seems influenced by delivery mode, drug administration and many other conditions. Special attention must be reserved for early neonatal nutrition, because breastfeeding allows the transmission of a specific and unique lactobiome able to modulate and positively affect the neonatal gut microbiota. Our narrative review aims to investigate the currently identified pre- and peri-natal factors influencing neonatal microbiota, before conception, during pregnancy, pre- and post-delivery, since the early microbiota influences the whole life of each subject.

Background: The role of the immune system and inflammatory response in the pathogenesis of the severe manifestations of coronavirus disease 2019 (COVID-19) is well known. Currently, different therapies active on the immune system are used for the management of COVID-19. The involvement of the immune system also opens the opportunity for the use of nutritional supplements with antimicrobial and immunomodulatory activity., Main Aspects: Nutritional supplements with antimicrobial and immunomodulatory activity are promising therapeutic adjuvants for the treatment of COVID-19, and also for the prevention of viral spreading. In particular, the role of vitamin D, probiotics, lactoferrin, and zinc is of significant clinical interest, although there are only a few data on their use in COVID-19 patients. Their molecular actions, together with the results of studies performed on other respiratory infections, strongly suggest their potential utility in COVID-19. This article discusses the main properties of these nutritional supplements and their potential applicability in the prevention and treatment of COVID-19., Conclusion: The supplementation with vitamin D, probiotics, lactoferrin and zinc could have a role both in preventing SARS-CoV-2 infection and in mitigating the clinical course in infected patients, contributing in the prevention of immune-mediated organ damage.