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Alessandra Scaparrotta, Marina Attanasi, Marianna I Petrosino, Paola Di Filippo, Sabrina Di Pillo, Francesco Chiarelli Department of Pediatrics, University of Chieti, Chieti, Italy Abstract: Allergic rhinitis is one of the most common diseases of adult and pediatric age, associated with grass pollen (GP) allergy in >50% cases, with a consistent impact on quality of life of affected patients. A grass allergen tablet, containing standardized extract derived from Timothy grass (Phleum pratense) pollen and ~15 µg major allergen P. pratense (rPhl p 5), may be the future of allergen-specific immunotherapy (IT) for GP allergy. The aim of this review was to critically evaluate the role of Timothy GP extract IT for the management of allergic rhinitis. For this purpose, we have tried to analyze potential mechanisms of action at the basis of Timothy GP extract, we have reviewed efficacy studies to establish potential benefits and clinical response, and we have also evaluated safety and tolerability profiles and patient focus perspective, such as quality of life, satisfaction and acceptability, and compliance to this IT. Keywords: Timothy grass pollen extract, allergic rhinitis, Grazax, efficacy, safety, compliance

Abstract International guidelines recommend the use of inhaled corticosteroids (ICSs) as the preferred therapy, with leukotriene receptor antagonists (LTRAs) as an alternative, for the management of persistent asthma in children. Montelukast (MLK) is the first LTRA approved by the Food and Drug Administration for the use in young asthmatic children. Therefore, we performed an analysis of studies that compared the efficacy of MLK versus ICSs. We considered eligible for the inclusion randomized, controlled trials on pediatric populations with Jadad score > 3, with at least 4 weeks of treatment with MLK compared with ICS. Although it is important to recognize that ICSs use is currently the recommended first-line treatment for asthmatic children, MLK can have consistent benefits in controlling asthmatic symptoms and may be an alternative in children unable to use ICSs or suffering from poor growth. On the contrary, low pulmonary function and/or high allergic inflammatory markers require the corticosteroid use.

Introduction: Although familial Mediterranean fever (FMF) is a relevant disease in countries surrounding the Mediterranean Sea, there are still few reports from Italy., Methods: We retrospectively evaluated patients with FMF diagnosed according to the EuroFever/PRINTO classification criteria in three pediatric rheumatology referral centers in central-southern Italy. Logistic regression analysis assessed the associations between age at disease onset and symptoms., Results: Overall, 48 patients were enrolled (28 females, 20 males), with a median age at onset of 3.3 [3.1] years, and a median follow-up period of 5.1 [10.8] years. The most common MEFV genotype was M694V/- (11 patients, 22.9%), followed by M694V/M694V (6 patients, 12.5%). At onset, recurrent fever was observed in 47 patients (97.9%), with a median time between attacks of 18 [11] days. Overall, recurrent fever was observed in all patients, abdominal pain in 44 (91.7%), and chest pain in 18 (37.5%). At the last follow-up visit, 24 patients were on colchicine (50%), 2 on biologic (4.2%), and 6 on both (12.5%). Canakinumab was the most used biologic drug, in 6 (12.5%) patients. MEFV genotype was associated with disease severity (p = 0.007) and the use of a biological drug (p = 0.01). FMF prevalence in the Abruzzo region was found highly than expected (at least 1:45,000). Differently, we found a relevant gap among FMF patients expected and observed in the Apulia and Sicily regions., Conclusions: FMF is a relevant issue in central-southern Italy. A large epidemiologic study should be performed to better define its prevalence in the country. Key Points • Italian children with familial Mediterranean fever tend to have an early age of onset, primarily manifesting with recurrent fever and characteristic associated symptoms. • Many MEFV gene variants are present in Italian children with familial Mediterranean fever, and these patients are most often heterozygous, exhibiting a mild to moderate phenotype. • The prevalence of familial Mediterranean fever in Italy is still unknown but recently estimated to be around 1:60,000, probably higher in central and southern Italy. • According to our cohort, the prevalence of FMF in the Abruzzo region is at least 1:45,000, higher than expected. Differently, we found lower prevalence rates of the disease in Apulia and Sicily., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Acute respiratory failure (ARF) is a sudden failure of the respiratory system to ensure adequate gas exchanges. Numerous clinical conditions may cause ARF, including pneumonia, obstructive lung diseases (e.g., asthma), restrictive diseases such as neuromuscular diseases (e.g., spinal muscular atrophy and muscular dystrophy), and albeit rarely, interstitial lung diseases. Children, especially infants, may be more vulnerable to ARF than adults due to anatomical and physiological features of the respiratory system. Assessing respiratory impairment in the pediatric population is particularly challenging as children frequently present difficulties in reporting symptoms and due to compliance and cooperation in diagnostic tests. The evaluation of clinical and anamnestic aspects represents the cornerstone of ARF diagnosis: first level exams (e.g., arterial blood gas analysis) confirm and evaluate the severity of the ARF and second level exams help to uncover the underlying cause. Prompt management is critical, with supplemental oxygen, mechanical ventilation, and the treatment of the underlying problem. The aim of this review is to provide a comprehensive summary of the current state of the art in diagnosing pediatric ARF, with a focus on pathophysiology, novel imaging applications, and new perspectives, such as biomarkers and artificial intelligence.

Background: Artificial intelligence (AI) has become a popular tool for clinical and research use in the medical field. The aim of this study was to evaluate the accuracy and reliability of a generative AI tool on pediatric familial Mediterranean fever (FMF)., Methods: Fifteen questions repeated thrice on pediatric FMF were prompted to the popular generative AI tool Microsoft Copilot with Chat-GPT 4.0. Nine pediatric rheumatology experts rated response accuracy with a blinded mechanism using a Likert-like scale with values from 1 to 5., Results: Median values for overall responses at the initial assessment ranged from 2.00 to 5.00. During the second assessment, median values spanned from 2.00 to 4.00, while for the third assessment, they ranged from 3.00 to 4.00. Intra-rater variability showed poor to moderate agreement (intraclass correlation coefficient range: -0.151 to 0.534). A diminishing level of agreement among experts over time was documented, as highlighted by Krippendorff's alpha coefficient values, ranging from 0.136 (at the first response) to 0.132 (at the second response) to 0.089 (at the third response). Lastly, experts displayed varying levels of trust in AI pre- and post-survey., Conclusions: AI has promising implications in pediatric rheumatology, including early diagnosis and management optimization, but challenges persist due to uncertain information reliability and the lack of expert validation. Our survey revealed considerable inaccuracies and incompleteness in AI-generated responses regarding FMF, with poor intra- and extra-rater reliability. Human validation remains crucial in managing AI-generated medical information., (© 2024. The Author(s).)

Introduction: Recent works in the scientific literature reported the role of C reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) as biomarkers of disease activity in rheumatic diseases., Objectives: To investigate the role of CAR, PLR and NLR as potential markers of disease activity in children with non-systemic JIA (nsJIA) and their correlation with the risk of persistent disease activity of flare during follow up., Methods: Our prospective, cross-sectional study involved 130 nsJIA patients (74 with active disease and 56 with inactive disease according to Wallace criteria) and 62 healthy controls. Demographic, clinical and laboratory data were collected at baseline (T0) and at 3 (T1), 6 (T2), 12 (T3) and 18 months (T4) during follow up. Disease activity was evaluated through Juvenile Arthritis Disease Activity Score (JADAS-27)., Results: At baseline, CRP and CAR were higher in patients than in controls (p = 0.046), while no differences were found for NLR and PLR. However, there was no positive correlation between CAR, NLR, PLR and JADAS-27 in JIA patients. To better investigate the role of CAR, NLR and PLR as markers of disease activity, we used a generalized estimating equation (GEE) model, applied to all patients either with or without active disease. According to this analysis, CAR and NLR baseline levels were predictive of higher risk of disease activity at 6 months follow up (p < 0.001)., Conclusions: CAR and NLR could indicate persistent disease activity in patients with JIA. Their predictive value could be increased by their combined use and by the observation of their trend during follow up, since increasing CAR values over time could predict a disease flare in the brief time., (© 2024. The Author(s).)

This study, conducted by searching keywords such as "maternal lupus", "neonatal lupus", and "congenital heart block" in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants., Competing Interests: The authors declare no conflict of interest. No part of the review, including its graphics, are copied or published elsewhere in whole or in part.

Background: The SARS-CoV-2 pandemic has significantly affected the pediatric population. Long-term sequelae (Long COVID-19) may particularly involve the central nervous system, with possible effects on psychological well-being and quality of life (QoL), aspects that were already influenced by the restrictive measures and general social impact of the pandemic., Methods: We conducted a cross-sectional survey that aims at investigating the neuropsychological effects and the QoL impairment of SARS-CoV-2 on a cohort of children and adolescents in the Abruzzo region (Italy). A questionnaire was submitted to caregivers with the help of the PEDIATOTEM platform. A control group of healthy subjects was also included to distinguish between the effects of infection from the general influence of the pandemic., Results: A total of 569 subjects responded: 396 COVID-19 patients (99 of whom had Long COVID-19) and 111 controls. After the pandemic, when compared with the COVID-19 group, the controls reported significantly increased appetite, sleeping habits, and time spent remotely with friends and a reduction in physical activity and time spent in person with friends. A significant higher rate of controls asked for psychological/medical support for emotional problems. On the other hand, the Long COVID-19 group showed more fatigue and emotional instability with respect to non-Long-COVID-19 subjects. No differences in QoL results (EuroQOL) were found between the COVID-19 patients and controls, while the Long-COVID-19 subgroup showed significantly higher rates of pain/discomfort and mood instability, as confirmed by the analysis of variation of responses from the pre-COVID-19 to the post-COVID-19 period., Conclusions: Among COVID-19 patients, neuropsychological and QoL impairment was more evident in the Long COVID-19 subgroup, although emotional and relational issues were also reported by uninfected patients, with a growing request for specialist support as a possible consequence of social restriction.

Background: Identifying predictive factors of long COVID syndrome (LCS) is essential to preventing and managing this condition. We investigated the prevalence, symptoms, and risk factors of LCS in a cohort of Italian children and adolescents., Methods: We carried out a cross-sectional survey on demographic characteristics and clinical data related to COVID-19 phase and LCS in a cohort of children and adolescents, sending a questionnaire by using the PEDIATOTEM platform., Results: The prevalence of LCS was 25% (99/396). The most frequent symptoms of LCS included nasal congestion, diarrhea, headache, and fatigue. We found no association between demographic data (gender, age, and ethnicity) and LCS. Additionally, we showed that patients with concurrent allergic rhinitis, atopic dermatitis, respiratory disease, gastrointestinal disease, and rheumatologic disease had a higher risk of LCS than patients without those comorbidities. Patients experiencing fatigue, muscle, and abdominal pain in COVID-19 showed a higher risk of LCS than patients complaining of other symptoms. We found no association between vaccination and LCS., Conclusions: Specific comorbidities or symptoms during acute illness were identified as being risk factors for LCS. Understanding which are the risk factors for LCS could yield a clearer picture of its pathogenesis.

Introduction: A significant percentage of patients who survived the Coronavirus Infection Disease 2019 (COVID-19) showed persistent general and respiratory symptoms even months after recovery. This condition, called Post-Acute Sequelae of COVID-19 or Long-Covid syndrome (LCS), has been described also in children with positive history for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Little is known about the pathophysiologic mechanisms underlying this syndrome. The aim of this study was to investigate any difference between children with LCS and asymptomatic peers with previous COVID-19 in terms of lung function and lung ultrasound (LUS) patterns. Secondly, we tested associations between lung function abnormalities and LUS findings with Long-Covid., Methods: We carried out a prospective, descriptive, observational study including 58 children aged 5-17 years: 28 with LCS compared to 30 asymptomatic children with previous COVID-19. We collected demographic data, history of asthma, allergy or smoke exposure, and acute COVID-19 symptoms. After a median period of 4.5 months (1%-95% range 2-21) since the infection, lung function was assessed by spirometry, body plethysmography, diffusion lung capacity for carbon monoxide (DLCO). Airways inflammation was investigated by fractional exhaled nitric oxide (FeNO). LUS was performed independently by two experienced clinicians., Results: We found that children with LCS were older than controls (mean (SD) 12 (4.1) vs. 9.7 (2.6); p = .04). Children with LCS complained more frequently fatigue (46.4%), cough (17.9%), exercise intolerance (14.3%) and dyspnea (14.3%). Lung function was normal and similar between the two groups. The frequency of LUS abnormalities was similar between the two groups (43.3% children with LCS vs. 56.7% controls; p = .436). Children with LCS showed lower FeNO values (log difference -0.30 (CI 95% -0.50, -0.10)), but no association of LCS with a lower lung function and abnormal LUS findings was found., Conclusions: LCS seems to be more frequent in older age children. Lung functional and structural abnormalities were not different between children with LCS and asymptomatic subjects with previous COVID-19. In addition, children with LCS showed lower FeNO values than controls, suggesting its potential role as a marker in LCS. However, further and larger studies are needed to confirm our findings., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Objectives: The aim of our study was to investigate the role of serum calprotectin (SC) and muscle-skeletal ultrasound (MSUS) as predictive markers of relapse in patients with juvenile idiopathic arthritis (JIA)., Methods: Sixty non-systemic (ns) JIA patients in clinical remission were recruited to evaluate the risk of disease relapse. SC levels and JIA disease activity were assessed at every visit (3, 6, 12 and 18 months). Joint synovitis, characterised by both synovial effusion (SE) and synovial hyperplasia (SH), was measured by US score (sum of SE, SH, power Doppler and bone erosions) given to each examined joint and US ratio (US score/number of joints examined) at every visit. Associations of SC, US score and US ratio with relapse prevalence was studied longitudinally by using generalised estimating equations model., Results: Thirty-one (51.6%) patients relapsed within 18 months. Patients with higher baseline US scores showed higher risk of relapse at 6 months (OR (95% confidence interval (CI)): 1.96 (1.09-3.52)). Additionally, patients with higher SC values at baseline showed higher risk of relapse at 18 months (1.66 (1.13-2.44)). Patients with higher baseline SC values showed an increased overall odds of relapse up to 18 months of follow-up (1.21 (1.08-1.36)). Furthermore, patients with higher US scores showed an increased overall odds of relapse up to 18 months of follow-up (1.96 (1.56-2.46)). Similarly, patients with higher US ratio showed an increased overall odds of relapse up to 18 months of follow-up (16.62 (7.17-38.54))., Conclusions: SC was able to identify JIA patients with unstable remission and increased risk of relapse. MSUS represents an interesting additional tool to the clinical evaluation, especially in predicting early relapse.

Background: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive-compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection., Methods: In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study., Results: The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0-9.5) years, and the median age at diagnosis was 8.0 (3.0-10.4) years. The median follow-up period was 16.0 (6.0-72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin., Conclusions: Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Introduction: The health consequences of lactose intolerance remain unclear. We studied the association of lactose intolerance with growth in children., Methods: In this prospective case-control study, we compared Caucasian prepubertal children with lactose intolerance (LI) [ n  = 30, median age = 7.87 years (3.00-12.75)] to healthy controls [( n  = 75, median age = 2.25 years (2.00-7.25)]. A lactose tolerance test was performed for lactose intolerance diagnosis. The gastrointestinal symptom score was administered at baseline and after a lactose-free diet for a median period of 9.0 months [range 5%-95% (6.0-24.0)]. The anthropometric parameters were measured at baseline and follow-up. All the anthropometric data were converted into standard deviation scores (SDS). A linear regression model was used to investigate the association of lactose intolerance with growth parameters., Results: We found no difference in height velocity SDS between the LI and control groups [SDS difference (95% CI): 0.52 (-1.86 to 2.90)]. In addition, we found a significant reduction in the clinical score of the LI group after a lactose-free diet [median (5%-95%): 7.5 (4.0-15.0) and 3 (0.0-8.0); p- value <0.001]., Conclusions: The LI group exhibited no difference in height velocity compared with the control group. Nonetheless, due to the small sample size, the results on the anthropometric profile of the LI group require careful interpretation. More large-scale studies in the pediatric population are required to better understand the association of LI with anthropometric and metabolic profiles., 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., (© 2023 Lizzi, Sgrazzutti, Porreca, Di Filippo, Cauzzo, Di Pillo, Chiarelli and Attanasi.)

Long COVID syndrome has emerged as a long-lasting consequence of acute SARS-CoV-2 infection in adults. In addition, children may be affected by Long COVID, with potential clinical issues in different fields, including problems in school performance and daily activities. Yet, the pathophysiologic bases of Long COVID in children are largely unknown, and it is difficult to predict who will develop the syndrome. In this multidisciplinary clinical review, we summarise the latest scientific data regarding Long COVID and its impact on children. Special attention is given to diagnostic tests, in order to help the physicians to find potential disease markers and quantify impairment. Specifically, we assess the respiratory, upper airways, cardiac, neurologic and motor and psychological aspects. Finally, we also propose a multidisciplinary clinical approach.

Drug-Induced Enterocolitis Syndrome (DIES) is a drug-induced hypersensitivity reaction non-IgE mediated involving the gastrointestinal system that occurs 2 to 4 h after drug administration. Antibiotics, specifically amoxicillin or amoxicillin/clavulanate, represent the most frequent drugs involved. Symptoms include nausea, vomiting, abdominal pain, diarrhea, pallor, lethargy, and dehydration, which can be severe and result in hypovolemic shock. The main laboratory finding is neutrophilic leukocytosis. To the best of our knowledge, 12 cases of DIES (9 children-onset and 3 adult-onset cases) were described in the literature. DIES is a rare clinically well-described allergic disease; however, the pathogenetic mechanism is still unclear. It requires to be recognized early and correctly treated by physicians.

A Nasal Provocation Test allows the differentiation of allergic and non-allergic rhinitis, but it is difficult and expensive. Therefore, nasal cytology is taking hold as an alternative. We carried out a cross-sectional study, including 29 patients with persistent rhinitis according to ARIA definition and negative skin prick tests. Nasal symptoms were scored from 0 to 5 using a visual analogue scale, and patients underwent blood tests to investigate blood cell count (particularly eosinophilia and basophilia), to analyze serum total and specific IgE and eosinophil cationic protein (ECP), and to perform nasal cytology. We performed a univariate logistical analysis to evaluate the association between total serum IgE, serum eosinophilia, basophils, and ECP and the presence of eosinophils in the nasal mucosa, and a multivariate logistic model in order to weight the single variable on the presence of eosinophils to level of the nasal mucosa. A statistically significant association between serum total IgE levels and the severity of nasal eosinophilic inflammation was found (confidence interval C.I. 1.08-4.65, odds ratio OR 2.24, p value 0.03). For this reason, we imagine a therapeutic trial with nasal steroids and oral antihistamines in patients with suspected LAR and increased total IgE levels, reserving nasal cytology and NPT to non-responders to the first-line therapy.

Asthma, chronic urticaria, and atopic dermatitis are some of the most numerous allergic diseases affecting children. Recent advances in the understanding of their specific intracellular molecular pathways have led to the approval of monoclonal antibodies targeting definite inflammatory molecules in order to control symptoms and improve quality of life. Less is known about other allergic and immunologic disorders such as rhinosinusitis with nasal polyps, eosinophilic esophagitis, anaphylaxis, and food allergy undergoing allergen immunotherapy. The increasing evidence of the molecular mechanisms underlying their pathogeneses made it possible to find in children new indications for known biological drugs, such as omalizumab and dupilumab, and to develop other ones even more specific. Promising results were recently obtained, although few are currently approved in the pediatric population. In this review, we aim to provide the latest evidence about the role, safety, and efficacy of biologic agents to treat allergic and immunologic diseases in children.

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive ( p = 0.0016) and vs. controls ( p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels ( p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL ( p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 ( p = 0.0001). Log rank test showed significant differences up to 10 ng/mL ( p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

Background: There is limited information available on fast and safe bedside tools that could help clinicians establish whether the pathological process underlying cases of wheezing is due to asthmatic exacerbation, asthmatic bronchitis, or pneumonia. The study's aim was to characterize Lung Ultrasound (LUS) in school-aged children with wheezing and evaluate its use for their follow-up treatment., Materials and Methods: We carried out a cross-sectional study involving 68 consecutive outpatients (mean age 9.9 years) with wheezing and suggestive signs of an acute respiratory infection. An expert sonographer, blinded to all subject characteristics, clinical course, and the study pediatrician's diagnosis, performed an LUS after spirometry and before BDT. The severity of acute respiratory symptoms was determined using the Pediatric Respiratory Assessment Measure (PRAM) score., Results: The LUS was positive in 38.2% (26/68) of patients [12 (46.1%) with multiple B-lines, 24 (92.3%) with consolidation, and 22 (84.6%) with pleural abnormalities]. In patients with pneumonia, asthmatic bronchitis, and asthma, the percentages of those patients with a positive LUS were 100%, 57.7%, and 0%, respectively. Of note, patients with a positive LUS were associated with an increased need for hospital admission (30.8% vs. 2.4%, p  = 0.001), administration of oxygen therapy (14.6% vs. 0%, p  = 0.009), oral corticosteroids (84.6% vs. 19.0%, p  < 0.001), and antibiotics (88.5% vs. 11.9%, p  < 0.001); and a higher median value of PRAM score (4.0 (2.0-7.0) vs. 2.0 (1.0-5.0); p  < 0.001)., Conclusions: Our findings would suggest the use of LUS as a safe and cheap tool used by clinicians to define the diagnosis of school-aged children with wheezing of unknown causes., 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., (© 2023 Attanasi, Sferrazza Papa, Porreca, Sferrazza Papa, Di Filippo, Piloni, Dodi, Sansone, Di Pillo and Chiarelli.)

Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (<2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the “DRESS hypothesis” and the “cytokine plasticity hypothesis”. Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.

Children with medical complexity (CMCs) represent a subgroup of children who may have congenital or acquired multisystemic disease. CMCs are frequently predisposed to respiratory problems and often require long-term mechanical ventilation (LTMV). The indications for LTMV in CMCs are increasing, but gathering evidence about indications, titration, and monitoring is currently the most difficult challenge due to the absence of validated data. The aim of this review was to examine the clinical indications and ethical considerations for the initiation, continuation, or withdrawal of LTMV among CMCs. The decision to initiate long-term ventilation should always be based on clinical and ethical considerations and should be shared with the parents.

Background: The gold standard to diagnose food allergy (FA) is a double-blind, placebo-controlled food challenge (OFC), even if it shows potential risk of severe allergic reactions for the patient and is time-consuming. Therefore, easier, and less invasive methods are needed to diagnose FA and predict the tolerance, changing the clinical practice., Aim: The main aim of this study was to assess whether the total IgE values at the diagnosis of FA were associated with the duration of the tolerance acquisition and thus of the food elimination diet., Methods: We retrospectively analyzed the medical records of 40 patients allergic to milk or egg who performed an OFC for the reintroduction of the causal food at the Pediatric Allergy and Respiratory Unit of the University of Chieti from January 2018 to December 2020., Results: We found a positive association of total serum IgE with the elimination diet duration ( β  = 0.152; CI, 95% 0.04-0.27) after adjusting for age, sex, and type of allergy (milk or egg). We also showed a significant correlation ( r  = 0.41 and p -value = 0.007) between the total IgE values and the duration of the elimination diet and a significant correlation between the casein specific IgE values at diagnosis of FA and the severity of the clinical presentation ( r  = 0.66; p -value 0.009)., Conclusion: Total serum IgE at baseline, along with the downward trend of food-specific IgE levels (to milk or egg), may be useful in the prognostication of natural tolerance acquisition., 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., (© 2022 Dodi, Di Filippo, Di Pillo, Chiarelli and Attanasi.)

High-flow nasal cannula (HFNC) therapy is a non-invasive ventilatory support that has gained interest over the last ten years as a valid alternative to nasal continuous positive airway pressure (nCPAP) in children with respiratory failure. Its safety, availability, tolerability, and easy management have resulted its increasing usage, even outside intensive care units. Despite its wide use in daily clinical practice, there is still a lack of guidelines to standardize the use of HFNC. The aim of this review is to summarize current knowledge about the mechanisms of action, safety, clinical effects, and tolerance of HFNC in children, and to propose a clinical practices algorithm for children with respiratory failure., Competing Interests: All authors disclose no personal or financial support or author involvement with organizations with financial interest in the subject. All authors approved the final version and its submission to the journal. The authors report no conflicts of interest in this study.

Background: Despite recent neonatal care improvements, mechanical ventilation still remains a major cause of lung injury and inflammation. There is growing literature on short- and long-term respiratory outcomes in infants born prematurely in the post-surfactant era, but the exclusive role of mechanical ventilation at birth in lung function impairment is still unclear. The aim of this study was to assess the effect of neonatal mechanical ventilation on lung function parameters in children born ≤ 32 weeks of gestational age at 11 years of age., Materials and Methods: In total, 55 ex-preterm children born between January 1, 2006 and December 31, 2007 were enrolled at 11 years of age. Neonatal information was obtained from medical records. Information about family and personal clinical history was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. In addition, an allergy evaluation by skin prick test and eosinophil blood count were performed. A multivariable linear or logistic regression analysis was performed to examine the associations of mechanical ventilation with respiratory outcomes, adjusting for confounders (maternal smoking during pregnancy, gestational age, surfactant replacement therapy, and BMI)., Results: No difference in lung function evaluation between ventilated and unventilated children were found. No association was also found between mechanical ventilation with lung function parameters., Conclusion: Mechanical ventilation for a short period at birth in preterm children was not associated with lung function impairment at 11 years of age in our study sample. It remains to define if ventilation may have a short-term effect on lung function, not evident at 11 years of age., 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 Di Filippo, Dodi, Di Pillo, Chiarelli and Attanasi.)

Background: Breastfeeding is associated with a lower risk of wheezing in early childhood, but its effect later in childhood remains unclear. We investigated the association of breastfeeding and respiratory outcomes in children aged 11 years., Materials and Methods: We performed an observational longitudinal study including 110 prepubertal children. Information about breastfeeding duration, wheezing and asthma was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. We used logistic and linear regression models to examine the associations of breastfeeding duration with the odds of asthma and lung function measures. All multivariable analyses were adjusted for sex, smoking during pregnancy, gestational age at birth, twins, and mode of delivery (confounder model)., Results: Breastfeeding duration was associated with FEV 1 z-score [β = 0.04, CI 95% (0.02-0.09)], FEF75 z-score [β = 0.06, CI 95% (0.03-0.09)] and FEV 1 /FVC z-score [β = 0.03, CI 95% (0.00-0.07)], but not with diffusing lung capacity and fractional exhaled nitric oxide. No association of breastfeeding duration with preschool wheezing, ever asthma and current asthma was documented., Conclusion: We showed that children breastfed for longer time presented higher FEV 1 , FEV 1 /FVC, and FEF75 z-score values at 11 years of age compared to children breastfed for shorter time, suggesting a protective effect of breastfeeding on airways, and not on lung parenchyma (lung volumes and alveolar capillary membrane) or allergic airway inflammation. The positive effect of breastfeeding duration on lung function lays the foundation to promote breastfeeding more and more as effective preventive measure., 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 Di Filippo, Lizzi, Raso, Di Pillo, Chiarelli and Attanasi.)

The clinical, functional, and structural pattern of chronic lung disease of prematurity has changed enormously in last years, mirroring a better perinatal management and an increasing lung immaturity with the survival of increasingly premature infants. Respiratory symptoms and lung function impairment related to prematurity seem to improve over time, but premature birth increases the likelihood of lung function impairment in late childhood, predisposing to chronic obstructive pulmonary disease (COPD). It is mandatory to identify those individuals born premature who are at risk for developing long-term lung disease through a better awareness of physicians, the use of standardized CT imaging scores, and a more comprehensive periodic lung function evaluation. The aim of this narrative review was to provide a systematic approach to lifelong respiratory symptoms, lung function impairment, and lung structural anomalies in order to better understand the specific role of prematurity on lung health.

Susceptibility to asthma is complex and heterogeneous, as it involves both genetic and environmental insults (pre- and post-birth) acting in a critical window of development in early life. According to the Developmental Origins of Health and Disease, several factors, both harmful and protective, such as nutrition, diseases, drugs, microbiome, and stressors, interact with genotypic variation to change the capacity of the organism to successfully adapt and grow in later life. In this review, we aim to provide the latest evidence about predictive risk and protective factors for developing asthma in different stages of life, from the fetal period to adolescence, in order to develop strategic preventive and therapeutic interventions to predict and improve health later in life. Our study shows that for some risk factors, such as exposure to cigarette smoke, environmental pollutants, and family history of asthma, the evidence in favor of a strong association of those factors with the development of asthma is solid and widely shared. Similarly, the clear benefits of some protective factors were shown, providing new insights into primary prevention. On the contrary, further longitudinal studies are required, as some points in the literature remain controversial and a source of debate.

Atopic dermatitis and urticaria are two invalidating skin disorders that are very common in children. Recent advances in the understanding of their specific intracellular molecular pathways have permitted the development of precise biological molecules, targeting inflammatory mediators and arresting the pathogenetic pathways of skin diseases. Many biologics with promising results have been studied, although few are currently approved in children. In this review, we aim to provide the latest evidence about the use, indications, efficacy and safety of biologic therapies to treat atopic dermatitis and chronic urticaria in children and adolescents.

Introduction: The aim of this study was to compare the number of the Pediatric Emergency Department (PED) visits for young allergic patients with respiratory or cutaneous symptoms during the first wave of the coronavirus disease 19 (COVID-19) pandemic in 2020 with the same period in 2019, evaluating the percentage of positive cases to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We carried out a retrospective analysis using data from young patients who visited the PED with cutaneous or respiratory symptoms in the period from 20 th February to 12 th May of the years 2020 and 2019. Data on allergy and COVID-19 nasal swab were also collected. We observed eleven (28.2%) PED visits for allergic patients with respiratory or cutaneous symptoms for the period from 20 th February to 12 th May of the year 2020 and ninety-three (31.8%) PED visits for the same time frame of the year 2019 (p=0.645). Only a two-month-old child out of 39 patients with non-allergic respiratory or cutaneous symptoms resulted positive for SARS-CoV-2. Specifically, we found for all the PED visits: 21 (7.2%) in 2019 vs 2 (5.1%) in 2020 for patients with urticaria/angioedema or atopic dermatitis (p=0.634); 3 (1.0%) in 2019 vs 3 (7.7%) in 2020 for patients with anaphylaxis (p=0.003); 19 (6.5%) in 2019 vs 2 (5.1%) in 2020 for those with asthma (p=0.740); 11(3.8%) in 2019 vs 1(2.6%) in 2020 for those with lower respiratory diseases, excluding asthma (p=0.706); 39(13.4%) in 2019 vs 3 (7.7%) in 2020 for those with upper respiratory diseases (URDs) (p=0.318). We also showed a substantial decrease (~80%) in all PED visits compared with the same time frame in 2019 (absolute number 263 vs 1,211, respectively). Among all the PED visits a significant reduction was mostly found for URDs [155 (12.8%) in 2019 vs 17 (6.5%) in 2020; p=0.045)]. The total number of PED visits for allergic patients with respiratory or cutaneous symptoms dropped precipitously in 2020. It is very tricky to estimate whether it was a protective action of allergy or the fear of contagion or the lockdown or a reduction in air pollution that kept children with allergy from visiting the PED. Further studies are needed to better understand the impact of underlying allergies on COVID-19 susceptibility and disease severity., (©Copyright: the Author(s).)

Respiratory infection diseases are among the major causes of morbidity and mortality in children. Diagnosis is focused on clinical presentation, yet signs and symptoms are not specific and there is a need for new non-radiating diagnostic tools. Among these, lung ultrasound (LUS) has recently been included in point-of-care protocols showing interesting results. In comparison to other imaging techniques, such as chest X-ray and computed tomography, ultrasonography does not use ionizing radiations. Therefore, it is particularly suitable for clinical follow-up of paediatric patients. LUS requires only 5-10 min and allows physicians to make quick decisions about the patient's management. Nowadays, LUS has become an early diagnostic tool to detect pneumonia during the COVID-19 pandemic. In this narrative review, we show the most recent scientific literature about advantages and limits of LUS performance in children. Furthermore, we discuss the major paediatric indications separately, with a paragraph fully dedicated to COVID-19. Finally, we mention potential future perspectives about LUS application in paediatric respiratory diseases.

Severe asthma is a heterogeneous, complex and chronic disease widespread in the pediatric population. According to the recent findings about the different endotypes of asthma in children, each one characterized by specific intracellular molecular pathways, several innovative biologic therapies have been developed. Due to their precise ability to target specific inflammatory type 2 mediators, biologics have revolutionized the care of chronic allergic diseases in the pediatric and adult population. In this review, we aim to provide the latest evidence about the use, indications, efficacy and safety of biologic therapies to treat severe asthma in children and adolescents.

More recently, increasing attention has been directed to exploring the function of the global virome in health and disease. Currently, by new molecular techniques, such as metagenomic DNA sequencing, the virome has been better unveiled. By investigating the human lung virome, we could provide novel insights into respiratory diseases. The virome, as a part of the microbiome, is characterized by a constant change in composition related to the type of diet, environment, and our genetic code, and other incalculable factors. The virome plays a substantial role in modulating human immune defenses and contributing to the inflammatory processes. Anelloviruses (AVs) are new components of the virome. AVs are already present during early life and reproduce without apparently causing harm to the host. The role of AVs is still unknown, but several reports have shown that AVs could activate the inflammasomes, intracellular multiprotein oligomers of the innate immune system, which show a crucial role in the host defense to several pathogens. In this narrative revision, we summarize the epidemiological data related to the possible link between microbial alterations and chronic respiratory diseases in children. Briefly, we also describe the characteristics of the most frequent viral family present in the lung virome, Anelloviridae. Furthermore, we discuss how AVs could modulate the immune system in children, affecting the development of chronic respiratory diseases, particularly asthma, the most common chronic inflammatory disease in childhood.

Objective: The aim of this study was to evaluate sleep quality and psychological effects on pediatric healthcare workers during the first wave of COVID-19 epidemic in Italy and to evaluate differences between primary and secondary care operators. Pediatric healthcare workers were involved in an online survey to assess sleep quality, stress and anxiety level, self-efficacy and social support in Italian pediatric healthcare workers during COVID-19 pandemic., Results: We found that 67.4% of our sample suffered from sleep disturbance and 19.4% of subjects suffered from anxiety. Lower values of anxiety and social support were found in primary care staff compared to secondary care one. The associations between healthcare professional figures (being primary or secondary care operators) and mental health outcomes were not statistically significant. However, sex, age and having a SARS-CoV-2 infected relative/friend had an independent effect on mental health outcomes. It is crucial to provide social and psychological support to pediatric healthcare workers. A tailored psychological screening would be desirable for female healthcare workers and for those who have a SARS-CoV-2 infected relative/friend.

Asthma and type 1 diabetes mellitus (T1DM) are two of the most frequent chronic diseases in children, representing a model of the atopic and autoimmune diseases respectively. These two groups of disorders are mediated by different immunological pathways, T helper (Th)1 for diabetes and Th2 for asthma. For many years, these two groups were thought to be mutually exclusive according to the Th1/Th2 paradigm. In children, the incidence of both diseases is steadily increasing worldwide. In this narrative review, we report the evidence of the potential link between asthma and T1DM in childhood. We discuss which molecular mechanisms could be involved in the link between asthma and T1DM, such as genetic predisposition, cytokine patterns, and environmental influences. Cytokine profile of children with asthma and T1DM shows an activation of both Th1 and Th2 pathways, suggesting a complex genetic-epigenetic interaction. In conclusion, in children, the potential link between asthma and T1DM needs further investigation to improve the diagnostic and therapeutic approach to these patients. The aim of this review is to invite the pediatricians to consider the potential copresence of these two disorders in clinical practice.

Background: There is increasing evidence of prematurity being a risk factor for long-term respiratory outcomes regardless the presence of bronchopulmonary dysplasia (BPD). Aim: To assess the effect of prematurity on respiratory outcomes in children born ≤32 weeks of gestational age at 11 years of age. Materials and Methods: Fifty five ex-preterm children (≤ 32 weeks of gestational age), born in Chieti between January 1, 2006 and December 31, 2007, performed lung function and diffusing capacity test (DLCO) at 11 years of age. Furthermore, allergy evaluation by skin prick test (SPT), eosinophil blood count and assessment of eosinophilic airways inflammation by exhaled nitric oxide (FeNO) were performed. The ex-preterm group was compared to an age- and sex-matched group of term children. Results: No difference for atopic and respiratory medical history was found between ex-preterm children and term controls, except for preschool wheezing that resulted more frequent in ex-preterm children. No difference neither in school-aged asthma frequency nor in lung function assessment at 11 years of age was found between the two groups. Lower DLCO values in ex-preterm children compared to term controls regardless the presence of BPD were found; furthermore, we showed a positive association between DLCO and gestational age. Eosinophil blood count, positive SPTs and FeNO values were similar between the two groups. Conclusions: Diffusing lung capacity was decreased in ex-preterm children at 11 years of age in the absence of lung function impairment and eosinophil airway inflammation, suggesting a non-eosinophilic pattern underlying pulmonary alterations. It could be desirable to include the diffusing capacity assessment in follow-up evaluation of all ex-preterm children., 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 Di Filippo, Giannini, Attanasi, Dodi, Scaparrotta, Petrosino, Di Pillo and Chiarelli.)