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Background The role of allergic sensitization seems to be protective against SARS CoV2 infection. The aim of this study was to evaluate, using online surveys, the impact of COVID-19 on Italian allergic children, comparing the prevalence of AR and asthma symptoms between the first and second pandemic wave. Methods Both surveys were emailed to Italian pediatricians in April 2020 (first survey) and in March 2021 (second survey). The first one was related to the impact of COVID-19 and the most frequently reported symptoms. The second one was superimposed on the previous one, taking into account some additional aspects in the management of disease. Results A total of 99 pediatricians participated in the first survey and 267 in the second one. The first survey showed that, asthma and allergic rhinoconjunctivitis prevalence was mostly between 0 and 20% throughout the country. The second survey showed a lower prevalence of both diseases nationwide in comparison to the first one. Comparing the two surveys, statistically significant differences were reported only in the distribution of asthma prevalence in Southern Italy while no differences were highlighted in the North and in the Center. Finally regarding allergic rhinoconjunctivitis prevalence, no differences were noticed nationwide. Conclusions Allergic rhinoconjunctivitis and asthma, if under control, did not represent risk factors for the susceptibility to SARS CoV2. Therefore, it is strongly recommended to continue therapies during COVID-19 outbreak, according to the international guidelines. However, being COVID-19 a new disease, actual knowledge will undergo continuous improvements over time.

Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are potentially severe and complex disease in its management among the various allergic eye diseases. In this regard, studies clarified the etiopathogenetic mechanisms. The workup should be multidisciplinary. The treatment includes topical and systemic medications with anti-inflammatory and immunosuppressant activity. However, a definition of nationally- and internationally-shared diagnostic protocols would also be needed and validated access to therapeutic options of proven safety and efficacy to avoid the use of galenic preparations, up to now still essential in the management of moderate-severe VKC. Finally, recognizing VKC and AKC, among rare diseases, at a national and international level would be an essential step to allow the management of VKC with adequate timings and settings within the National Health System.

The clinical spectrum of SARS‐CoV‐2 infection is mixed. It ranges from asymptomatic cases, medium‐intensity forms with mild to moderate symptoms, to severe ones with bilateral lung involvement and respiratory distress, which can require transfer to ICUs and intubation. In most cases, the clinical picture is characterized by a persistent fever, cough, dyspnoea, expectoration, myalgias, arthralgias, headache, gastrointestinal symptoms, nasal congestion, and pharyngodynia. The spread of COVID‐19 in Europe has highlighted an atypical presentation of disease involving upper airways and, above all, dysfunction of olfactory and gustatory senses. There is ample evidence that COVID‐19 is significantly less severe in children than in adults. However, due to difficulties in assessing the disorder in children, especially among very young patients, the olfaction and gustatory dysfunctions remain open issues. This article sheds light on the upper airway involvement in pediatric COVID‐19 subjects.

Background In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. Methods Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. Results The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. Conclusions We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research.

Since the outbreak of novel influenza A (H1N1) in 2009, various neurologic complications have been cited.1 A 2-month-old girl died of a rapidly progressive encephalopathy after influenza infection. MRI, performed after 12 hours from the onset of symptoms, showed bilateral and symmetric lesions including the thalamus, the cortical–subcortical regions of the occipital and parietal lobes, and brainstem tegmentum …

Background Multipotent progenitor cells have been harvested from different human tissues, including the bone marrow, adipose tissue, and umbilical cord blood. Previously, we identified a population of mesenchymal progenitor cells (MPCs) isolated from the traumatized muscle of patients undergoing reconstructive surgery following a war-related blast injury. These cells demonstrated the ability to differentiate into multiple mesenchymal lineages. While distal radius fractures from a civilian setting have a much lower injury mechanism (low-energy trauma), we hypothesized that debrided traumatized muscle near the fracture site would contain multipotent progenitor cells with the ability to differentiate and regenerate the injured tissue. Methods The traumatized muscle was debrided from the pronator quadratus in patients undergoing open reduction and internal fixation for a distal radius fracture at the Walter Reed National Military Medical Center. Using a previously described protocol for the isolation of MPCs from war-related extremity injuries, cells were harvested from the low-energy traumatized muscle samples and expanded in culture. Isolated cells were characterized by flow cytometry and q-RT-PCRs and induced to adipogenic, osteogenic, and chondrogenic differentiation. Downstream analyses consisted of lineage-specific staining and q-RT-PCR. Results Cells isolated from low-energy traumatized muscle samples were CD73+, CD90+, and CD105+ that are the characteristic of adult human mesenchymal stem cells. These cells expressed high levels of the stem cell markers OCT4 and NANOG 1-day after isolation, which was dramatically reduced over-time in monolayer culture. Following induction, lineage-specific markers were demonstrated by each specific staining and confirmed by gene expression analysis, demonstrating the ability of these cells to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Conclusions Adult multipotent progenitor cells are an essential component for the success of regenerative medicine efforts. While MPCs have been isolated and characterized from severely traumatized muscle from high-energy injuries, here, we report that cells with similar characteristics and multipotential capacity have been isolated from the tissue that was exposed to low-energy, community trauma.

BACKGROUND Vernal keratoconjunctivitis (VKC) is a rare chronic conjunctivitis characterized by a predominantly eosinophil-mediated inflammatory disorder that could develop critical complications such as blindness. Oxidative stress plays a pivotal role in the pathogenesis of several allergic diseases. The role of oxidative stress has been hypothesized in VKC, but no study explored this issue. Furthermore, cyclosporine A (CsA) exerts an anti-inflammatory and antioxidant action on the conjunctiva. This study aimed to assess the oxidative stress in VKC patients and controls and to study the effect of CsA on oxidative stress in these subjects. METHODS Thirty-six consecutive children, including 12 VKC (nine males, 75%; mean age 10.17; SD ± 2.48) patients without treatment, 12 VKC patients treated with CsA (nine males, 75%; mean age 9.08; SD ± 2.75), and 12 controls (CT) (seven males, 58%; mean age 8.58; SD ± 1.78), were recruited. A cross-sectional study was performed to compare H2 O2 in the serum with that in the tears of these children. RESULTS Compared with CT and VKC children treated with CsA, VKC untreated children had significantly higher values of hydrogen peroxide (H2 O2 ) in the serum and the tears. No significant differences were observed between CT and VKC treated with CsA. A significant correlation was found at the linear regression analysis between serum and tear H2 O2 levels. CONCLUSION This study provides the first report attesting that patients with VKC have high oxidative stress; furthermore, it suggests that CsA could have an anti-inflammatory and antioxidant action that could be useful to prevent the poor VKC outcome.

The persistence of symptoms after recovery from Coronavirus 2019 (COVID-19) is defined as long COVID, an entity that had occurred among adults but which is not yet well characterized in pediatric ages. The purpose of this work was to present some of the data from a survey addressed to Italian pediatricians concerning the impact of long-COVID among children who recovered from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The questionnaire was designed and pre-tested in February 2021 by a working group of experts from the Italian Pediatric Society for Allergy and Immunology (SIAIP). The survey was emailed once in March 2021 to a sample of Italian pediatricians. A total 267 Italian pediatricians participated in our survey. According to most pediatricians (97.3%), the persistence of symptoms is found in less than 20% of children. Specifically, with regard to the symptoms that persist even after swab negativization, fatigue was the most mentioned one (75.6%). Long-COVID would seem to be a phenomenon of limited occurrence in pediatric ages, affecting less than 20% of children. Among all of the symptoms, the one that was most prevalent was fatigue, a pathological entity that is associated with many viral diseases.

Background There is ample evidence that COVID-19 is significantly less severe in children than in adults and asthma and allergy, the most common chronic disorders in children, are not included in the top 10 comorbidities related to COVID-19 fatalities. Nevertheless, concerns about asthma and allergy are still high.. In order to evaluate the impact of paediatric COVID-19 among Italian paediatricians, we sent a 20-questions anonymous internet-based survey to 250 Italian paediatricians with particular address to allergic symptoms and those affecting the upper airways. Methods The questionnaire was conceived and pretested in April 2020, by a working group of experts of the Italian Paediatric Society for Allergy and Immunology (SIAIP), and structured into different sections of 20 categorized and multiple choice questions. The first part included questions about epidemiological data follows by a second part assessing the way to manage a suspected COVID-19 infection and personal experiences about that. The third part concerned questions about patients’ clinical characteristics and clinical manifestations. The survey was emailed once between April and mid-May 2020. Results A total 99 participants had participated in our survey and provided responses to our electronic questionnaire. The distribution of patients reported per month varies significantly according to the geographical area (P = 0.02). Data confirmed that in the North part of Italy the rate of patients referred is higher than in the rest of Italy. Almost all respondents (98%) reported caring for up to a maximum of 10 infected children and the last 2% more than twenty. Among these patients, according to the 75% of responders, a maximum rate of 20% were affected by allergic rhino-conjunctivitis and in particular in the North of Italy while in the Centre and in the South there was a higher incidence (P = 0.09). Almost the same applies for asthma, 83% of responders declared that up to a maximum of 20% of affected children were asthmatic, from 20 to 40% for the 13,5% of responders and from 40 to 60% for the last 3,5%. As for the allergic conjunctivitis also for asthma, we found a higher incidence in the Centre and in South than in the North (P = 0.03). Conclusions This study is the first to provide a comprehensive review of COVID-19 knowledge and impact among paediatricians in Italy about allergic asthma and upper airway involvement. From our point of view, it provides important information clearly useful for improving a good practice.

Background SARS-CoV-2 outbreak pushed the Italian government to start a strict lockdown, replacing school attendance with long-distance learning. This caused reduced exposure to sunlight but increased exposure to screens. Vernal keratoconjunctivitis (VKC) is a chronic inflammatory ocular condition in which exposure to light plays a cardinal role. We conducted an online survey to evaluate the impact of screen exposure in children with VKC during the lockdown. Methods We performed a survey-based observational study, asking patients followed at the Allergology of Meyer Children’s University Hospital in Florence and of Policlinico Umberto I in Rome to provide grading on 6 subjective ocular clinical manifestations presented during the lockdown and to give an estimate of the hours/day of screen exposure. Results Mean scores of signs and symptoms increased homogeneously when studying patients exposed to longer screen time. When comparing scores collected in 2019 versus 2020, there was not a significant reduction in clinical manifestations, although the situation differed between the two centres due to geographical differences in sunlight exposure. Conclusion During the lockdown, there was a reduction of sunlight exposure but conversely an increase in the time spent in front of screens that correlated with the worsening of VKC signs symptoms in direct proportion to the hours/day of screen exposure. Our results also showed a statistically significant difference in the relative impact of long-distance learning on VKC clinical manifestations in the different Italian regions.

Background Hypertrophic cardiomyopathy (HCM) in newborns is a rare and pathological condition with heterogeneous etiologies. Among all the different causes of HCM, hyperinsulinism is not generally reported but the relationship between hyperinsulinism and cardiac hypertrophy (CH) is known. Case presentation We report the case of cardiac hypertrophy (CH) in an Extremely Low Birth Weight (ELBW) infant who underwent insulin therapy after the onset of a persistent hyperglycemia due to parenteral nutrition (PN); the finding supports the hypothesis of a newborn’s iatrogenic hyperinsulinemia in cardiac involvement. Despite the effects of hyperglycemia on myocardial cells are well known and infants of diabetic mother may develop cardiac malformations, the consequences of an early administration of insulin in preterm infants have never been fully clarified and are often underestimated. The present case underlines the importance of a close cardiological follow-up in infants undergoing insulin infusion for an alteration in the glucose metabolism PN-related, that is a common finding in preterm infants. Conclusion: This case report, also considering the scientific literature, reiterates the importance of taking into account hyperinsulinism in the differential diagnosis of cardiac hypertrophy.

Background: Probiotics may prevent the allergic response development due to their anti-inflammatory and immunomodulatory effects. The aim of this study is to determine if the prophylactic treatment with a mixture of Bifidobacterium animalis subsp. Lactis BB12 and Enterococcus faecium L3 would reduce symptoms and need for drug use in children with allergic rhinitis (AR). Methods: The study included 250 children aged from 6 to 17 years, affected by AR. Patients were randomly assigned to the intervention group (150) or to the placebo group (100). Patients in the intervention group, in addition to conventional therapy (local corticosteroids and/or oral antihistamines), were treated in the 3 months preceding the onset of symptoms related to the presence of the allergen to which the children were most sensitized, with a daily oral administration of a probiotic mixture containing the Bifidobacterium animalis subsp. Lactis BB12 DSM 15954 and the Enterococcus faecium L3 LMG P-27496 strain. We used Nasal Symptoms Score (NSS) to evaluate AR severity before and after the treatment with probiotics or placebo. Results: the patients in the intervention group had a significant reduction in their NSS after probiotic treatment (p-value = 2.2 × 10−10. Moreover, for the same group of patients, we obtained a significant reduction in the intake of pharmacological therapy. In particular, we obtained a reduction in the use of oral antihistamines (p-value = 2.2 × 10−16), local corticosteroids (p-value = 2.2 × 10−13), and of both drugs (p-value 1.5 × 10−15). Conclusions: When administered as a prophylactic treatment, a mixture of BB12 and L3 statistically decreased signs and symptoms of AR and reduced significantly the need of conventional therapy.

The objective of the study was to develop a multiparametric oximetry indicator (IMp-SpO2) to diagnose obstructive sleep apnea in adults. This was an observational, retrospective study of diagnostic accuracy. We included adults who had had a diagnostic polysomnography with few artifacts and a total sleep time of at least 180 min in the sleep laboratory. Obstructive sleep apnea (OSA) was defined as an apnea-hypopnea index (AHI) ≥ 5. The database was randomly divided into an experimental (Exp-G) and validation (Val-G) group. The program calculated several parameters of oxygen saturation variability (Par-VarSpO2): (a) oxygen desaturation index (ODI ≥ 3, 4%) and (b) 90, 95, and 97.5 percentiles of both the number of oxygen desaturations ≥ 3 and 4% (P90–97.5 OD3/4 W5-60) and SpO2 standard deviations in moving windows from 5 to 60 min (P90–P97.5 SDSpO2 W5-10). Area under the ROC curve (AUC-ROC), sensitivity, specificity, positive/negative likelihood ratios, and accuracy were calculated. Of 1141 adults included in the study, experimental (571) and validation group (570) were similar (women 47% vs 45%, BMI 27.5 kg/m2 vs 27.2 kg/m2, and AHI 11.7 vs 12, p NS). The IMp-SpO2 developed in the experimental group consisted of a combination of 10 parameters of oxygen saturation variability. The presence of at least one IMp-SpO2 variable had a high diagnostic performance for OSA (sensitivity/specificity/accuracy: Exp-G: 92.8/94/93.2%; Val-G: 93/95.2/93.7%). The IMp-SpO2 AUC-ROC was higher (Exp-G 0.934, Val-G 0.941) than most of the Par-VarSpO2 (0.898–0.929, p 90% accuracy for OSA diagnosis in adults.

Giulia Brindisi,1,* Valentina De Vittori,1,* Rosalba De Nola,2,3 Antonio Di Mauro,4 Giovanna De Castro,1 Maria Elisabetta Baldassarre,4 Ettore Cicinelli,2 Bianca Cinicola,1 Marzia Duse,1 Anna Maria Zicari1 1Pediatrics Department, Umberto I Hospital, Sapienza University, Rome, 00161, Italy; 2Department of Biomedical Science and Human Oncology, Gynecology and Obstetrics Section, “Aldo Moro” University of Bari, Bari, 70124, Italy; 3Department of Tissues and Organs Transplantation and Cellular Therapies, “Aldo Moro” University of Bari, Bari, 70124, Italy; 4Department of Biomedical Sciences and Human Oncology-Neonatology and Neonatal Intensive Care Unit, “Aldo Moro” University of Bari, Bari, 70124, Italy*These authors contributed equally to this workCorrespondence: Giulia BrindisiPediatrics Department, Umberto I Hospital, Sapienza University, Viale Regina Elena 324, Rome, 00161, ItalyTel +39 06 49979333Email giulia.brindisi@gmail.comBackground: Allergic rhinitis (AR) and asthma are two common atopic diseases, often associated with a common ethiopathogenesis characterized by a Th2 inflammatory response with the release of many biomarkers, such as nitric oxide (NO).Purpose: To evaluate and compare inflammatory (nFeNO and eFeNO) and functional (mNF and FEV1) parameters in AR children with or without asthma in comparison to controls. Secondly, we aimed to identify nFeNO cut-off values and verify their reliability to predict the presence of rhinitis or asthma alone or in combination.Patients and Methods: We enrolled 160 children (6– 12 years of age) with AR and/or asthma divided into four groups: controls, AR, asthma, and AR + asthma. All children underwent the following inflammatory and functional measurements: nFeNO, eFeNO, mNF and FEV1.Results: We observed that levels of nFeNO were extremely higher in children with AR and even more in those with AR + asthma in respect to controls. Notably, all the pathological conditions, especially AR + asthma, showed significantly lower values of mNF compared to healthy children. A negative correlation linked mNF and nFeNO. Then, we found eFeNO values significantly higher in all the pathological groups compared to controls, with major values of this marker in patients affected by asthma and AR + asthma, as well as FEV1 values significantly lower in all the disease groups, especially in children with asthma and AR+ asthma. ROC curve analysis showed that nFeNO was a great predictor for rhinitis alone or with asthma, revealing an accurate cut-off of 662 ppb.Conclusion: nFeNO measurement is non-invasive, easy to perform, economic and a valuable test in case of AR alone or in association with asthma. Thus, it should be used in patients with rhinitis, together with anterior active rhinomanometry (AAR) to diagnose and estimate the degree of nasal obstruction but also in children with asthma to assess their nasal involvement and improve the therapeutic management.Keywords: nasal nitric oxide, exhaled nitric oxide, anterior active rhinomanometry, allergic rhinitis, asthma, children

Hypoalbuminemia is considered a predictor of adverse outcomes in critically ill children1 and in adults affected by COVID-192, 3 . This article is protected by copyright. All rights reserved.

Background: Pollen-related seasonal allergic rhinoconjunctivitis (SAR) is a very frequent pediatric disease in Westernized countries. Risk factors and disease phenotypes have been thoroughly examined in several cross-sectional studies. By contrast, only a few studies have examined disease evolution in patient cohorts. We investigated predictive biomarkers of disease evolution in a large cohort of children with SAR. Methods: During 2015-2017 (follow-up), we re-examined 401 patients from those enrolled in 2009-2011 (baseline) by the “Panallergens in Pediatrics” study, a large multicenter survey of Italian children with SAR. Information on clinical history (standard questionnaire, AllergyCARD®; TPS, Italy) and skin prick tests for inhalant and foods extracts (ALK-Abelló, Hørsholm, Denmark) was acquired as at baseline visit. Evolution in clinical and sensitization data of patients was analyzed over time, as well as their association with the main baseline characteristics and atopy risk factors. Results: The average age of participants was 10.4±3.4years at baseline and 16.2±3.6years at follow-up. SAR persisted in 93.3% of patients at follow-up and became more frequently associated with asthma (from 36.7% at baseline to 48.6% at follow-up) and oral allergy syndrome (OAS, from 23.4% to 37.7%). Compared to baseline, the prevalence of skin sensitization to some pollens (Phleum pratense, Corylus avellana, Platanus acerifolia, Artemisia vulgaris) and vegetables (hazelnut, wheat, and apple) significantly decreased at follow-up. Earlier onset of SAR and polysensitization at baseline were associated with incident asthma at follow-up. The presence at baseline of serum IgE to the following allergen molecules was identified as biomarkers of clinical evolution: (a) Phl p 1, for persistence of SAR; (b) Phl p 5, for persistence of both rhinitis and asthma; (c) Pru p 3, for new onset of asthma; (d) Bet v 1, for persistence of OAS. Conclusions: Seasonal allergic rhinoconjunctivitis is clinically heterogeneous in its evolution from childhood to adolescence. The detection of serum IgE to specific molecules (Phl p 1, Phl p 5, Bet v 1, Pru p 3) may be useful as biomarkers to predict SAR persistence and future onset of comorbidities, such as asthma and/or OAS.

Background: Vernal keratoconjunctivitis (VKC) is a rare chronic conjunctivitis characterized by a predominantly eosinophil-mediated inflammatory disorder that could develop critical complications such as blindness. Oxidative stress plays a pivotal role in the pathogenesis of several allergic diseases. The role of oxidative stress has been hypothesized in VKC, but no study explored this issue.Furthermore, cyclosporine A (CsA) exerts an anti-inflammatory and antioxidant action on the conjunctiva. This study aims to assess oxidative stress in VKC patients and controls and to study the effect ofCsA on oxidative stress in these subjects. Methods:Thirty-six consecutive children, including 12 VKC(9 males, 75%; mean age 10,17; SD ± 2.48) patients without treatment,12 VKC treated with CsA(9 males, 75%; mean age 9,08; SD± 2.75) and 12 controls (CT) (7males,58%; mean age8,58; SD ±1,78) were recruited. A cross-sectional study was performed to compare H2O2 in the serum and the tears ofthese children. Results: Compared with CT and VKC children treated with CsA, VKCuntreated children had significantly higher values ofHydrogen peroxide (H2O2) in theserum and the tears.No significant differences were observed between CT and VKC treated with CsA. A significant correlation was found at the linear regression analysis between serum and tear H2O2 levels. Conclusion: This study provides the first report attesting that patients with VKC have high oxidative stress; furthermore, it suggests that CsA could have an anti-inflammatory and antioxidant action that could be useful to prevent the poor VKC outcome.

Background: Allergic diseases are a major public health burden worldwide. Evidence suggests that early nutrition might play a key role in the future development of allergies and the use of hydrolyzed protein formulas have been proposed to prevent allergic disease, mainly in term infants with risk factors. Aim: To evaluate the preventive effect of a hydrolyzed protein formula vs. an intact protein formula on allergy development in preterm infants with or without risk factors. Methods: We performed a 3-year follow-up study of a previous triple-blind, placebo-controlled randomized trial. Evidence of atopic dermatitis, asthma and IgE-mediated food allergies were evaluated according to a validated parental questionnaire (Comprehensive Early Childhood Allergy Questionnaire). Food sensitization was also investigated by skin prick test at 3 years of chronological age. Results: Of the 30 subjects in the intact protein formula group and 30 in the extensively hydrolyzed formula group, respectively 18 and 16 completed the 3-year follow-up and entered the final analysis. No group differences in the incidence of atopic dermatitis, asthma, IgE-mediated food allergies, and food sensitization were found. Conclusion: Despite the small number of cases, extensively hydrolyzed protein formula seems to be ineffective in allergic diseases prevention in preterm neonates. Further adequately powered, randomized controlled trials evaluating hydrolyzed protein formula administration to prevent allergic diseases in preterm neonates are needed.

Background Allergic rhinitis (AR) and adenoidal hypertrophy (AH) are the most frequent causative disorders of nasal obstruction in children, leading to recurrent respiratory infections. Both nasal cavities are colonized by a stable microbial community susceptible to environmental changes and Staphylococcus aureus seems to play the major role. Furthermore, nasal microbiota holds a large number and variety of viruses with upper respiratory tract infections. This local microbiota deserves attention because its modification could induce a virtuous cross-talking with the immune system, with a better clearance of pathogens. Although AR and AH present a different etiopathogenesis, they have in common a minimal chronic inflammation surrounding nasal obstruction; hence it would be challenging to evaluate the effect of an immunomodulator on this minimal chronic inflammation with possible clinical and microbiological effects. The aim of this study is therefore to evaluate the efficacy of an immunomoldulator (Pidotimod) on nasal obstruction in children with AR and/or AH and whether its action involves a variation of nasal microbiota. Methods We enrolled 76 children: those with allergic rhinitis (AR) sensitized to dust mites entered the AR group, those with adenoidal hypertrophy (AH) the AH group, those with both conditions the AR/AH group and those without AR ± AH as controls (CTRL). At the first visit they performed: skin prick tests, nasal fiberoptic endoscopy, anterior rhinomanometry, nasal swabs. Children with. AR ± AH started treatment with Pidotimod. After 1 month they were re-evaluated performing the same procedures. The primary outcome was the evaluation of nasal obstruction after treatment and the secondary outcome was the improvement of symptoms and the changes in nasal microflora. Results All patients improved their mean nasal flow (mNF) in respect to the baseline. In AR children mNF reached that one of CTRL. In AH children±AR the mNF was lower in respect to CTRL and AR group. We did not find any differences among all the groups at the two different time points in nasal microflora. Conclusions Pidotimod is able to give an improvement in nasal obstruction, especially in AR children but this effect seems to be not mediated by changes in nasal microbiota.

Background. Neurodegenerative diseases (ND) as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2α (8-iso-PGF2α), serum H2O2, and LPS in patients with ND compared to controls. Methods. One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum H2O2, and LPS in these two groups. Serum zonulin was used to assess gut permeability. Results. Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2α, H2O2, and LPS. Simple linear regression analysis showed that sNOX2-dp was significantly correlated with serum LPS (Rs=0.441; p<0.001), zonulin (Rs=0.411; p<0.001), serum H2O2 (Rs=0.329; p<0.001), and 8-iso-PGF2α (Rs=0.244; p=0.006). LPS significantly correlated with serum zonulin (Rs=0.818; p<0.001) and 8-iso-PGF2α (Rs=0.280; p=0.001). A multiple linear regression analysis was performed to define the independent predictors of sNOX2-dp. LPS (SE, 0.165; standardized coefficient β, 0.459; p<0.001) and 8-iso-PGF2α (SE, 0.018; standardized coefficient β, 0.220; p=0.005) emerged as the only independent predictive variables associated with sNOX2-dp (R2=57%). Conclusion. This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation.

Background: The European Academy of Allergy and Clinical Immunology guidelines, strongly recommended allergen immunotherapy (AIT) as an effective treatment to achieve long-term clinical benefits and to modify the natural history of allergic diseases. Sublingual immunotherapy (SLIT) offers the possibility of home administration, which improves patient comfort and compliance. Objective: The primary outcome of this study was to assess the change in nasal reactivity after grass-pollen AIT treatment. Methods: This was a monocentric, prospective, observational study conducted in Rome from September 2016 to June 2018, in the Pediatric Department of Policlinico Umberto I. We enrolled children, ages between 6 and 12 years, with persistent allergic rhinitis (AR), sensitized to grass pollen. At the first visit (V0, September 2016), one group received the first dose of oral immunotherapy for grass-pollen spray buccal and the other group continued only standard therapy. All the patients had nasal specific immunoglobulin I (IgE) assay (Phl p1, Phl p5), active anterior rhinomanometry with a nasal provocation test (NPT), and spirometry. The patients attended two follow-up visits, in May 2017 (V1) and May 2018 (V2), with the same examinations as at V0. Results: During the treatment, we observed, in the treated group, a significant increase in the mean nasal flow compared with untreated children (p Conclusion: Analysis of our data provided evidence for a clinical effect of SLIT in inducing clinical changes and allergen tolerance in children with AR.

The Italian Society of Paediatric Allergy and Immunology has developed the project "ControL'Asma," a nationwide study involved ten third-level pediatric allergy clinics across Italy. The first findings of the "ControL'Asma" project showed that asthma was more frequent in males, had an early onset and allergic phenotype with very frequent rhinitis comorbidity, uncontrolled, and partly controlled asthma affected about the half of subjects, and the assessment of asthma symptom perception by VAS could be a reliable tool in the asthma management.

(1) Background: Preterm birth exposes the infant to the known risk factors for atopic diseases. We aimed to study the neonatal risk factors and to describe the clinical manifestations of atopy, including the march of symptoms, in a cohort of preschool children born preterm. (2) Methods: We enrolled neonates with gestational age &lt, 32 weeks or birth weight &lt, 1500 g. We classified patients in cases and controls according to the presence of at least one atopic manifestation. (3) Results: We observed 72 cases and 93 controls. Multivariate models showed that the administration of more than one cycle of antibiotics (B 0.902, p = 0.026) and gestational diabetes (B 1.207, p = 0.035) influence the risk of atopy in babies born preterm. In addition, risk of atopic dermatitis was influenced by gestational age &lt, 29 weeks (B −1.710, p = 0.025) and gestational diabetes (B 1.275, p = 0.027). The risk of wheeze was associated with familiarity for asthma (B 1.392, p = 0.022) and the administration of more than one cycle of antibiotics (B 0.969, p = 0.025). We observed a significant reduction in the rate of atopic manifestation after 2 years of life (33.9% vs. 23.8%, p &lt, 0.05). (4) Conclusions: Modifiable (gestational diabetes, antibiotics use) and unmodifiable (familiarity for asthma) conditions influence the risk of atopy in babies born preterm. Extreme prematurity reduces the risk of atopic dermatitis. Preterm babies showed a peculiar atopic march.

Allergic rhinitis (AR) is a common pediatric disease, that involves up to the 25% of children worldwide. Environmental pollution, passive smoke, and many viruses are actively involved in the chronic inflammation of the nasal mucosa.As described previously in the literature, novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in children is uncommon and often asymptomatic or mild.

This study explored oxidative stress, nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox2) activity and endothelial function in children exposed or not to passive smoking. Compared with controls (n=57), Nox2 activity and isoprostanes were higher in children exposed to passive smoking (n=57); conversely, nitric oxide (NO) bioavailability and flow-mediated dilation were lower in children exposed to passive smoking. A bivariate analysis showed that Nox2 activity correlated with flow-mediated dilation, NO bioavailability and isoprostanes. A multivariate analysis showed that Nox2 activity was significantly associated with serum isoprostanes and cotinine levels; flow-mediated dilation was associated with isoprostanes and carotid intima-media thickness.In children exposed to passive smoking, Nox2-derived oxidative stress is upregulated and inversely associated with impaired artery dilation.

Rhinitis is a common, under-diagnosed condition in childhood and adolescence. Pathogenic classification of rhinitis includes allergic rhinitis (AR) and non-allergic rhinitis (NAR); the latter is characterized by non-infectious and infectious subtypes; non-infectious subtype is by far the most prevalent in infancy. Endotyping may help to predict chronic rhinosinusitis (CRS) risk factors, as well as disease progression and response to different treatments. The validation of pediatric algorithms and the implementation of novel biotherapeutics in the endotype-driven integrated pathways of CRS will lead in the next future to more successful disease management.

Objective: Cardiac involvement in PANS has not been clarified relying on the scientific literature available until today. It is known that streptococcal infections play a role in the etiology of a great number of diseases including Sydenham chorea and rheumatic fever, among others. Based on the suspected pathogenesis of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) reported in the medical literature, we decided to investigate the cardiologic involvement in children with a recent PANS/PANDAS diagnosis. Methods: The study population satisfies PANS (1) and PANDAS (2) criteria of diagnoses. Cardiologic assessment was performed through clinical examination, electrocardiography, and echocardiography. Results: In the selected pediatric population, a significant number of children presented mitral valve involvement, systolic murmurs and electrocardiographic abnormalities. High ASLOT levels did not seem to be associated to a cardiac involvement. Conclusions: Often PANS is difficult to diagnose because it is little known by physicians and most of the cardiologic findings described in this study are common among the healthy pediatric population. Also, ASLOT levels seems not to be predictive of cardiac involvement. Furthermore, the existence of PANDAS as a clinical entity is associated with a group of anti-neuronal autoantibodies found in Sydenham chorea is still controversial. We recommend a complete cardiologic evaluation in those children who meet the PANS/PANDAS diagnostic criteria.

Background Bronchial asthma and rhinitis are among the most common diseases in children and frequently coexist in the patient. The primary aim of anti-asthmatic therapy is disease control. Several questionnaires can be used in pediatrics to assess asthma control and the Children Asthma Control Test (C-ACT) is one of the most used. Objective To evaluate the percentage of asthma control in our cohort of patients with asthma and correlate C-ACT with bronchial and nasal function tests. Methods We enrolled all children ages between 5 and 11 years with persistent bronchial asthma, sensitized to dust mite, and who presented to our center during an 8-month period. All the children had skin-prick tests, spirometry, measurement of fractional exhaled nitric oxide levels, active anterior rhinomanometry, measurement of nasal nitric oxide level, and C-ACT. Results Sixty patients were enrolled; 80% of these children had rhinitis. According to C-ACT, 31% of our patients had uncontrolled asthma. Nasal flow values were significantly lower in patients with uncontrolled asthma, who also had higher nasal inflammation. Conclusion The disease is not controlled in a significant percentage of children with asthma. In patients with uncontrolled asthma, worse nasal flow was detected. These results supported the relationship between upper and lower airways, and highlighted the importance of performing nasal function tests in all patients with asthma, which could be useful to determine whether better control of asthma symptoms can be reached through an appropriate treatment of rhinitis.

Background The relationship between the tissue injury healing response and development of heterotopic ossification (HO) is poorly understood. Here we compare a rat blast model and human traumatized muscle from a blast injury to study the early signatures of osteogenesis and fibrosis during the formation of HO. Methods Rat and human tissues were characterized using histology, scanning electron microscopy, immunohistochemistry, as well as gene and protein expression analysis. Additionally, animals and humans were assessed radiographically for HO formation following injury. Results Markers of bone formation were dramatically increased in tissue samples from both humans and rats, and both displayed increased fibroproliferative regions within the injured tissues and elevated expression of markers of tissue fibrosis such as TGF-β1, Fibronectin, SMAD3 and PAI-1. Markers of inflammation and fibrosis (ACTA, TNFα, BMP1 and BMP3) were elevated at the RNA level in both rat and human samples. By day 42, bone formation in the rat blast model appeared similar in radiographs compared to human patients who progressed to develop post-traumatic HO. Conclusions Our data demonstrates that a similar early fibrotic response is evident in both the rat blast model and the human tissues following a traumatic injury and demonstrates the relevance of this animal model for future translational studies.

Background The purpose of this report was to present the results of eye movement desensitisation and reprocessing (EMDR) therapy associated with parent management training (PMT) in a child with paediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS), who had previously only been treated with pharmacological treatment. Case presentation The case concerns an 11-year-old boy who presented with simple and complex vocal tics, motor tics, obsessive-compulsive traits and irritability from the age of 6 years, in addition to a positive result for streptococcal infection. The course of symptoms followed a relapsing-remitting trend with acute phases that were contingent on the infectious episodes. Conclusions Following eight sessions of EMDR, preceded by training sessions with the parents, the child showed a significant reduction in symptoms and disappearance of the exacerbation. These results indicate the possibility of improving the treatment outcomes of patients with PANDAS by a combined approach using both antibiotic and EMDR therapies.

Background Offspring of patients with early myocardial infarction have a higher risk to develop cardiovascular events; the underlying physiopathology is still unclear. Several lines of evidence support a role for oxidative stress in atherogenesis and NADPH oxidase-2 (NOX-2) is considered a major source of O2– in human. Furthermore, oxidative stress regulates arachidonic acid metabolism via activation of platelet phospholipase-A2. The aim of this study was to address NOX-2 activity as well as serum thromboxane B2 (TXB2) and 8-isoPGF2-alpha in offspring of patients with premature myocardial infarction. Methods Ninety-two consecutive subjects, including 46 offspring of patients with premature myocardial infarction and 46 healthy subjects (HS) matched for age and gender, were recruited. A cross sectional study was performed to compare serum activity of soluble NOX-2-dp (sNOX-2-dp), blood levels of isoprostanes and serum TXB2 in these two groups. Results Compared with HS, offspring of patients with early myocardial infarction had higher values of serum TxB2, isoprostanes and sNOX-2-dp. Bivariate analysis in the overall population showed that serum sNOX-2-dp levels were significantly associated with serum isoprostanes and TXB2. A multiple linear regression analysis was performed to define the independent predictors of sNOX-2-dp. Serum isoprostanes (SE: 0.07; standardized coefficient β: 0.579; P Conclusion This study shows that Nox-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance that is first diagnosed during pregnancy. Maternal adipose tissue and fetal membranes secrete various molecules that are relevant players in the pathogenesis of GDM. This pilot study aimed to examine whether the expression of the high mobility group box 1 protein (HMGB1) and its receptor for advanced glycation end products (RAGE), and the vasoactive intestinal peptide (VIP) and its receptors (VPAC-1,-2) were modified in pregnant women with GDM. Fetal membranes (FMs), omental adipose tissue (VAT) explants, and serum samples were obtained from 12 women with GDM and 12 with normal glucose tolerance (NGT) at delivery. The expression of HMGB1, RAGE and VIP, VPAC-1,-2 was detected by Western Blotting in explants; circulating levels and “in vitro” release of HMGB1 and VIP were measured by ELISA tests. HMGB1 tissue expression was higher in FMs obtained from GDM women (p = 0.02) than in FMs from NGT women. VPAC2 (p = 0.03) and RAGE (p = 0.03) tissue expressions were significantly increased in VAT from GDM subjects. Only FMs of NGT released detectable levels of HMGB1, which was not observed in samples obtained from GDM. VAT of GDM released lower levels of VIP (p = 0.05) than NGT samples. This study indicates that a fine tuned regulation exists between FMs and VAT throughout pregnancy to maintain immune metabolic homeostasis. In GDM a balance between inflammatory and anti-inflammatory mediators has been observed. Further studies are needed to establish their exact role on fetal and maternal outcomes in GDM.

Background: During the lockdown period caused by the SARS-CoV-2 pandemic, we monitored via online survey the trend of allergic symptoms and the therapeutic compliance in patients followed at our center. Material and methods: In June 2020, we selected children followed at the Allergy and Immunology Service of Umberto I Hospital, aged between 6 and 16 years old, diagnosed with asthma and/or rhinitis and sensitized to grass pollen or dust mite. We sent an email with 12 multiple-choice questions investigating several areas: type of disease and sensitization, recurrence of symptoms, medication use during lockdown compared to the same period of the previous year. Results: The results of 82 questionnaires showed that 17.8% of patients suffered from asthma, 24.4% from rhinitis, and 57.8% from both. Within the group of asthmatic children, most of them presented an improvement of their symptoms. Likewise, with regard to allergic rhinitis, most of them reported better clinical conditions. Regarding treatment, we observed a global decrease in the use of on-demand therapies (salbutamol, nasal corticosteroid, and antihistamine) for both pathologies. In addition, there was a reduction in the use of basal therapy for asthma and rhinitis from 2019 (23.3%) to 2020 (15.5%). Conclusions: Our data show a general trend of clinical improvement and a reduction in the use of on-demand and basal therapy in allergic children during the lockdown.

Immune checkpoint blockaders (ICBs) act by unbalancing the immune system, thus favoring the development of an immune-mediated antitumor effect. ICBs targeting the programmed cell death receptor-1 (PD-1) have recently been investigated in a number of advanced tumors, including non-small cell lung cancer (NSCLC). Nivolumab, a fully human IgG4 kappa directed against PD-1, has been the first ICB to be approved for second-line treatment of advanced NSCLC. Areas covered: In this review we focus on the clinical development of nivolumab for the treatment of advanced NSCLC, with an emphasis on its safety profile. In addition, we summarize the most common types of immune-related adverse events (irAEs) associated with nivolumab, mainly due to organ inflammation secondary to autoimmunity. Expert opinion: Nivolumab is the preferred treatment option for platinum-pretreated advanced NSCLC, having convincingly shown higher efficacy compared with standard docetaxel chemotherapy in phase III trials. The same trials showed far less incidence of either any grade and severe treatment-related AEs with nivolumab compared with chemotherapy. IrAEs associated with nivolumab are rarely severe in intensity, and often resolve with prompt management. Future studies will explore nivolumab in combination strategies with either platinum-based chemotherapy or other ICBs in treatment-naïve advanced NSCLC patients.

Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease. Patients with CGD experience recurrent life-threatening infections. Lack of large interventional trials generated several doubts for the treatment of infections in CGD. Objective To evaluate the effect of interferon gamma, antifungal drugs, and antibiotics in patients with CGD undergoing prophylaxis of infections. Methods A meta-analysis of the interventional trials was performed. The studies were identified by searching MEDLINE, ISI Web of Science, SCOPUS, and Cochrane database. The last search was run on January 2016. Reference lists of all studies included in the present systematic review were screened for potential additional eligible studies. Results Two studies with 163 patients with CGD were included in the interferon gamma analysis. Severe infections occurred in 17 of 73 patients (23%) treated with interferon gamma and in 49 of 90 patients (54%) not undergoing treatment with interferon gamma. Compared with control, severe infections were significantly reduced in patients treated with interferon gamma (relative risk, 0.46; 95% confidence interval, 0.29–0.73; P = .001). Interferon gamma treatment was associated with an absolute risk reduction of 31% and a number needed to treat of 3. Furthermore, compared with control, interferon gamma treatment reduced pulmonary infections (relative risk, 0.43; 95% confidence interval, 0.19–0.96; P = .04). Two studies with 172 patients with CGD were included in the antifungal drug analysis. Infections occurred in 4 of 69 patients (6%) treated with antifungals and in 17 of 103 patients (16%) not receiving treatment with antifungals. Compared with control, Aspergillus infections were not significantly reduced in patients treated with antifungals. No randomized prospective clinical trials of antibacterial prophylaxis in patients with CGD have been performed. Conclusion Despite the fact that interferon gamma prophylaxis seems to have a positive effect on severe infections, small sample sizes preclude definite conclusions. Further trials with interferon gamma and/or antifungal and antibiotics are necessary to optimize the treatment of CGD.

Background: No consensus has ever been reached about the correlation between nasal resistance and the subjective sensation of nasal patency. The aim of the present study was to better de ne whether primary school and secondary school aged children correctly estimate their nasal obstruction. Materials and methods: Two hundred eighty four children (168 males and 116 female) aged between 6 and 14 years (9.5+2.9 years) affected by Pediatric Allergic Rhinitis underwent Rhinomanometry and they were considered as correctly estimating their nasal obstruction when the grade of nasal patency corresponded to the severity of the NOSE score, overestimating when the grade of nasal patency was 1 when compared to the severity of the score. Results: Correlation between NOSE score and nasal patency was statistically significant (r -0.74; p12 overestimate (34.7%) their symptoms more frequently than children among other age ranges (p

Hypothesis Virchow-Robin spaces (VRS) are perivascular spaces in the brain and can normally be visualized in Magnetic Resonance Imaging (MRI). Dilated VRS (dVRS) are defined on the basis of their shape, and can rarely be observed in healthy subjects, or found in various diseases. A judgement of their role may derive from the appearance of the adjacent cerebral tissue and from the clinical context. Objective To define a correlation between the presence of dVRS and the clinical, EEG and MRI features in children with seizures. Materials and methods We retrospectively analyzed the clinical, electroencephalographic and additional neuroradiological features of a group of 30 children with seizures and dVRS. Six patients repeated the MRI because of persistent drug-refractory seizures. Results 26/30 patients had epilepsy, 4/30 patients had febrile seizures. dVRS were localized in basal ganglia in 10/30 cases and in supratentorial white matter in 16/30 cases. In 4/30 cases dilated VRS were present in both the zones. Associated MRI anomalies were reported in 11/30 patients, not necessary involving the adjacent tissue. A correlation between epileptic focus and side of VRS was present in 5/30 patients only. Unmodified VRS were observed in the 6 patients who underwent a second MRI. Conclusion In children with seizures, dVRS may be observed in basal ganglia or, mainly, in supratentorial white matter. However, also in this class of patients dVRS appear to be a non-progressive findings and not connected with the main seizures-related features of the patients.

Routine vaccination is among the most effective clinical interventions to prevent diseases as it is estimated to save over 3 million lives every year. However, the full potential of global immunization programs is not realised because population coverage is still suboptimal. This is also due to the inadequate immune response and paucity of informative correlates of protection upon immunization of vulnerable individuals such as newborns, preterm infants, pregnant women, and elderly individuals as well as those patients affected by chronic and immune compromising medical conditions. In addition, these groups are undervaccinated for a number of reasons, including lack of awareness of vaccine-preventable diseases and uncertainty or misconceptions about the safety and efficacy of vaccination by parents and healthcare providers. The presence of these nonresponders/undervaccinated individuals represents a major health and economic burden to society, which will become particularly difficult to address in settings with limited public resources. This review describes innovative and experimental approaches that can help identify specific genomic profiles defining nonresponder individuals for whom specific interventions might be needed. We will provide examples that show how such information can be useful to identify novel biomarkers of safety and immunogenicity for future vaccine trials. Finally, we will discuss how system biology “OMICs” data can be used to design bioinformatic tools to predict the vaccination outcome providing genetic and molecular “signatures” of protective immune response. This strategy may soon enable identification of signatures highly predictive of vaccine safety, immunogenicity, and efficacy/protection thereby informing personalized vaccine interventions in vulnerable populations. This work was supported by Associazione Volontari Bambino Gesù and Ricerca Corrente Ospedale Pediatrico Bambino Gesù 2017/2018. The Precision Vaccines Program is supported in part by NIH/NIAID Human Immunology Project Consortium U19 AI118608 and an internal award from the Boston Children’s Hospital Department of Pediatrics SI

Objective The relation between nasal flow and malocclusion represents a practical concern to pediatricians, otorhinolaryngologists, orthodontists, allergists and speech therapists. If naso-respiratory function may influence craniofacial growth is still debated. Chronic mouth-breathing is reported to be associated also with a characteristic pattern of dental occlusion. On the other hand, also malocclusion may reduce nasal air flows promoting nasal obstruction. Hereby, the aim of this review was to describe the relationship between rhinitis and malocclusion in children. Methods An electronic search was conducted using online database including Pubmed, Web of Science, Google Scholar and Embase. All studies published through to January 30, 2017 investigating the prevalence of malocclusion in children and adolescents (aged 0-20 years) affected by rhinitis and the prevalence of rhinitis in children with malocclusion were included. The protocol was registered at PROSPERO - International prospective register of systematic reviews under CRD42016053619. Results Ten studies with 2733 patients were included in the analysis. The prevalence of malocclusion in children with rhinitis was specified in four of the studies ranging from as high as 78.2% to as low as 3%. Two out of the studies reported the prevalence of rhinitis in children with malocclusion with a rate ranging from 59.2 to 76.4%. Conclusion The results of this review underline the importance of the diagnosis and treatment of the nasal obstruction at an early age to prevent an altered facial growth, but the data currently available on this topic do not allow to establish a possible causal relationship between rhinitis and malocclusion.

It is unknown whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) activation is early associated with endotoxemia and liver damage in nonalcoholic fatty liver disease (NAFLD). To address this issue, we evaluated Nox2 activation, oxidative stress, gut permeability, and lipopolysaccharide (LPS) serum levels in 67 children with biopsy-proven NAFLD and 73 controls. Compared with controls, NAFLD patients had higher Nox2 activity, isoprostane, zonulin, and LPS levels. Multivariate linear regression analysis showed that triglycerides, high-density lipoprotein (HDL), homeostatic model assessment-estimated insulin resistance (HOMA-IR), LPS, and isoprostanes were independently associated with Nox2-derivative peptide (sNox2-dp) levels. Within the NAFLD group, patients with nonalcoholic steatohepatitis (NASH) had significant higher levels of sNox2-dp, isoprostanes, LPS, triglycerides, HOMA-IR, fasting glucose and insulin, and lower HDL than those without NASH. Furthermore, sNox2-dp levels were linearly associated with the histological grading of steatosis, inflammation, ballooning, fibrosis, and NAFLD activity score. This study provides evidence that children with NAFLD have Nox2 overactivation compared with controls and significant association with the degree of liver damage. The close relationship between Nox2 and LPS serum levels leads to hypothesize a potential role for gut-derived LPS in eliciting systemic Nox2 activation.

Background & aims It is uncertain whether non-alcoholic steatohepatitis (NASH) is a risk factor for low bone mineral density (BMD). Our aim was to investigate: (a) associations between NASH and BMD values and (b) associations between PNPLA3 I148M genotypes and BMD, in children with histologically proven non-alcoholic fatty liver disease (NAFLD). Methods BMD area (g/cm2 ) was measured using dual-energy X-ray absorptiometry (DEXA). NASH was diagnosed by a Steatosis, Activity and Fibrosis (SAF) score and FLIP algorithm. Genotyping for patatin-like phospholipase domain containing-3 (PNPLA3) I148M genotype (rs738409) (CC, CG and GG) was undertaken using the TaqMan SNP genotyping allelic discrimination method. Logistic regression was used to test associations [OR (95% CIs)] between low BMD, and both NASH and PNPLA3 I148M genotypes. Results Thirty-four adolescents (mean age 13.8 ± 1.1 years) with histologically confirmed NAFLD were studied. Subjects with NASH (n = 25) had a lower BMD (means (SDs) 0.87 ± 0.06 vs 0.97 ± 0.12, P = 0.005), compared to subjects without NASH. Subjects with PNPLA3 CG+GG genotypes had a lower BMD compared with subjects with PNPLA3-CC genotype (means (SDs) 0.79 ± 0.20 vs 0.92 ± 0.10, P = 0.009). PNPLA3 CG+GG genotypes were independently associated with NASH [OR (95% CIs 1.78, 1.24, 2.99)], and low BMD was associated with both PNPLA3 CG+GG (OR 3.62 (95% CIs 1.21, 5.53), P = 0.028) and with SAF score (OR 2.76 (95% CIs 1.12, 5.41), P = 0.045). Conclusions Taken together the independent associations between: (a) low BMD and PNPLA3 CG+GG genotype; (b) low BMD and NASH; and (c) PNPLA3 CG+GG genotype and NASH, provide support for a causal relationship between NASH and low BMD.

Background. Vernal keratoconjunctivitis (VKC) is a rare ocular surface inflammatory disease that affects mainly boys in the first decade of life. Clinical observations show that it generally regresses spontaneously with the onset of puberty, but therapeutic measures must be taken before then to control the course of the disease. Purpose.To evaluate the role of the lacrimal mucous component in VKC patients and compare tear ferning test (TFT) modifications, MUC5AC levels in tears, and density of conjunctival goblet cells to clinical characteristics before and after treatment with cyclosporine A (CY) in eye drops. Methods. Forty-seven patients affected by VKC and 30 healthy subjects aged between 3 and 16 years of life were enrolled. All individuals were submitted to complete eye examination and skin prick test (SPT) for the most common allergens. Then, they were subjected to collection of the tears and to impression cytology to evaluate TFT, MUC5AC levels, and conjunctival goblet cell density, before and after treatment with CY in eye drops. Results. Comparing the VKC group vs. the control group at baseline, a significant alteration in the degree of the ferns was found, indicating a pathological condition of the lacrimal mucous layer. In addition, an increased number of goblet cells were observed in the patients. The concentration of lacrimal secretory mucins (MUC5AC) did not show significant differences between the 2 groups. Patients treated with CY have reported improvements of some signs and symptoms of disease activity, including TFT, and a tendency of conjunctival goblet cell density to normalise. Conclusions. The results obtained demonstrated for the first time a significant alteration of the lacrimal mucin component evaluated in the VKC group, and an improvement of the latter after CY therapy.

Background. Vernal keratoconjunctivitis (VKC) is a rare inflammatory disease involving the ocular surface, with seasonally exacerbated symptoms. Both type-1 and type-4 hypersensitivity reactions play a role in the development of VKC. Purpose. The aim of the present study was to assess the presence and evaluate the concentration of the vascular endothelial growth factor (VEGF) in tear and blood samples from patients with VKC, during the acute phase, based on the histopathological vasculostromal structure of the tarsal papillae. Methods. Two groups of children aged between 6 and 16 years of life were enrolled: 21 patients (16 males, 76%) affected by VKC, tarsal or mixed form, and 13 healthy children (5 males, 38%) used as controls. Blood and tear samples were obtained from all patients, in order to specifically assess the presence of VEGF. Statistical analyses were performed with one-way ANOVA, followed by post hoc comparisons with the Bonferroni tests. Pearson’s correlation was chosen as statistical analysis to assess the relationship between the expression levels of VEGF in tears and blood and the clinical parameters measured. Results. Comparing the 2 groups for VEGF concentration, a statistically significant difference was found in tear samples: the mean value was 12.13 pg/mL (±5.54 SD) in the patient group and 7 pg/ml (±4.76 SD) in controls (p<0.05). However, no statistically significant difference was found when comparing VEGF concentration in blood samples (p>0.05), with a mean value of 45.17 pg/mL (±18.67 SD) in VKC patients and 38.08 pg/mL (±19.43 SD) in controls. Conclusions. This pilot study highlights the importance of lacrimal and vascular inflammatory biomarkers that can be detected in VKC patients during the acute phase, but not in healthy children. The small group of patients warrants additional studies on a larger sample, not only to further investigate the role of VEGF but also to evaluate the angiogenic biomarkers before and after topical treatment.

Objective To characterize nicotinamide-adenine dinucleotide phosphate oxidase isoform 2 (NOX2), oxidative stress, and endothelial function in children with and without allergic rhinitis and to ascertain the effect of passive smoke exposure on these factors, because there is an established association between allergic rhinitis and increased cardiovascular risk in adults. Methods We recruited 130 children—65 with persistent allergic rhinitis and 65 healthy controls. A cross-sectional study was performed to compare endothelial function by flow-mediated dilation, blood levels of isoprostanes, serum activity of soluble NOX2-dp (sNOX2-dp), and nitric oxide bioavailability, in these 2 groups of children. Serum cotinine levels were assessed to measure exposure to passive smoking. Results Compared with healthy controls, children with persistent allergic rhinitis had significantly higher sNOX2-dp and isoprostanes levels, lower flow-mediated dilation, and reduced nitric oxide bioavailability. Multivariable linear regression analysis showed that flow-mediated dilation, isoprostanes, and cotinine were independently associated with sNOX2-dp levels. Of note, sNOX2-dp serum levels were significantly higher in children with allergic rhinitis exposed to smoke, as compared with unexposed children with allergic rhinitis. Conclusion NOX2 is activated in children with persistent allergic rhinitis and passive smoke exposure exacerbates this effect. We further demonstrate an association between higher sNOX2-dp and oxidative stress and endothelial dysfunction.

Bronchiolitis is the most common acute lower respiratory tract infection in infants and the first cause of hospitalization in this age group. Despite it has been studied for over 70 years, its management remains controversial and nowadays the treatment is only supportive. Pediatricians should be well acquainted with the clinical course of the disease. In particular, they should know that the severity of respiratory symptoms peaks between days 3-7 of the disease and dehydration is a key sign to consider for the management. In this review, we will discuss the most controversial points in the management of bronchiolitis according to six evidence-based guidelines, six clinical practice guidelines and five consensus-based reviews.

The aim of the study was to identify which groups of women contribute to interinstitutional variation of caesarean delivery (CD) rates and which are the reasons for this variation. In this regard, 15,726 deliveries from 11 regional centers were evaluated using the 10-group classification system. Standardized indications for CD in each group were used. Spearman’s correlation coefficient was used to calculate (1) relationship between institutional CD rates and relative sizes/CD rates in each of the ten groups/centers; (2) correlation between institutional CD rates and indications for CD in each of the ten groups/centers. Overall CD rates correlated with both CD rates in spontaneous and induced labouring nulliparous women with a single cephalic pregnancy at term (P=0.005). Variation of CD rates was also dependent on relative size and CD rates in multiparous women with previous CD, single cephalic pregnancy at term (P<0.001). As for the indications, “cardiotocographic anomalies” and “failure to progress” in the group of nulliparous women in spontaneous labour and “one previous CD” in multiparous women previous CD correlated significantly with institutional CD rates (P=0.021,P=0.005, andP<0.001, resp.). These results supported the conclusion that only selected indications in specific obstetric groups accounted for interinstitutional variation of CD rates.

Intranasal steroids are recognized as an effective treatment for allergic rhinitis (AR) although their effect on nasal patency has never been evaluated with an objective instrument such as anterior rhinomanometry in children. Moreover this effect has been widely assessed with total Nasal Symptom Scores (NSS) including all symptoms of allergic rhinitis and not with scores specifically focused on nasal obstruction such as the Nasal Obstruction Symptom Evaluation score (NOSE).Sixty children (42 males and 18 female) aged 6-10 years, affected by persistent AR, were randomized and divided in two groups of 30 children to be included in an unblinded trial: one group treated with intranasal budesonide and isotonic nasal saline for 2 weeks and the other group treated only with isotonic nasal saline for 2 weeks. Each child underwent rhinomanometry and completed the NSS and the NOSE scores before and after treatment.At the baseline nasal patency and NSS total score, NOSE total scores were correlated (r=-0.29, p0.001; r=-60, p0.001). After 2 weeks of treatment improvements in nasal patency, NSS and NOSE were seen (Δ NSS 4.13 ± 1.38 vs 1.33 ± 1.93, p0.001; Δ NOSE 34 ± 17.97 vs 9 ± 18.21, p0.001; Δ nasal patency -26.13 ± 25.25 vs -11.83 ± 11.31, p0.001). Correlations were found between rhinitis duration and Δ nasal patency and Δ NOSE (r=-0.84, p0.001; r=0.43, p0.01).Intranasal budesonide is effective in increasing nasal patency in children. Moreover the NOSE score was strongly correlated with nasal flow and, hence, this score should be regarded as a valid and reliable instrument in children.