Machine learning-enhanced HRCT analysis for diagnosis and severity assessment in pediatric asthma.

OBJECTIVES: Chest high-resolution computed tomography (HRCT) is conditionally recommended to rule out conditions that mimic or coexist with severe asthma in children. However, it may provide valuable insights into identifying structural airway changes in pediatric patients. This study aims to develop a machine learning-based chest HRCT image analysis model to aid pediatric pulmonologists in identifying features of severe asthma. METHODS: This retrospective case-control study compared children with severe asthma (as defined by ERS/ATS guidelines) to age- and sex-matched controls without asthma, using chest HRCT scans for detailed imaging analysis. Statistical analysis included classification trees, random forests, and conventional ROC analysis to identify the most significant imaging features that mark severe asthma from controls. RESULTS: Chest HRCT scans differentiated children with severe asthma from controls. Compared to controls (n = 21, mean age 11.4 years), children with severe asthma (n = 20, mean age 10.4 years) showed significantly greater bronchial thickening (BT) scores (p < 0.001), airway wall thickness percentage (AWT%, p < 0.001), bronchiectasis grading (BG) and bronchiectasis severity (BS) scores (p = 0.016), mucus plugging, and centrilobular emphysema (p = 0.009). Using AWT% as the predictor in conventional ROC analysis, an AWT% ≥ 38.6 emerged as the optimal classifier for discriminating severe asthmatics from controls, with 95% sensitivity, specificity, and overall accuracy. CONCLUSION: Our study demonstrates the potential of machine learning-based analysis of chest HRCT scans to accurately identify features associated with severe asthma in children, enhancing diagnostic evaluation and contributing to the development of more targeted treatment approaches.

Invasive Streptococcal Infection in Children: An Italian Case Series.

Since October 2022, alerts have spread from several countries about the increase in invasive group A streptococcal (iGAS) and scarlet fever cases affecting young children. We aim to analyze the epidemiology of GAS infections in the last 12 years in our hospital and identify the clinical features of invasive cases observed in 2023. We conducted a retrospective study enrolling children and adolescents hospitalized at our pediatric clinic from January to December 2023 for a definitive diagnosis of iGAS infection. Clinical, laboratory, and imaging data were collected and analyzed. Comparing 2016 and 2023, we observed a similar number of GAS infections (65 vs. 60 cases). Five children with iGAS infection were hospitalized between March and April 2023. The median age was five years. At admission, all patients showed tachycardia disproportionate to their body temperature. Vomiting was a recurrent symptom (80%). Laboratory tests mostly showed lymphopenia, hyponatremia, and high inflammatory markers. The number of pediatric iGAS cases significantly increased in 2023. Clinical (pre-school-aged children with high fever, unexplained tachycardia, and vomiting) and laboratory parameters (high procalcitonin levels, hyponatremia, and lymphopenia) could help identify and suspect a potential iGAS infection.

Determinant factors for first-line treatment choice and effectiveness in pediatric eosinophilic esophagitis: an analysis of the EUREOS EoE CONNECT registry.

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed.  A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70-145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001). Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment.

Current state and advances in desensitization for peanut allergy in pediatric age.

Peanut allergy affects about 1%-3% of the pediatric population in the world, with an important increase in the last decades. Nowadays, international guidelines recommend the early introduction of peanuts in the infant diet, with poor information about the quantity and the frequency of the intake. Allergen immunotherapy may represent the only therapeutic strategy able to modify the natural history of peanut allergy. In particular, oral immunotherapy showed the most promising results in terms of efficacy, but with significant rates of adverse reactions, mostly gastrointestinal. In 2020, the Food and Drug Administration and the European Medicines Agency approved Palforzia®, an oral drug for patients aged 4-17 years. Several studies are ongoing to improve the tolerability of oral immunotherapy and standardize the desensitization protocols. Sublingual immunotherapy permits to offer much lower doses than oral immunotherapy, but fewer adverse events are shown. Subcutaneous immunotherapy is associated with the greatest systemic adverse effects. Epicutaneous immunotherapy, for which Viaskin® patch was approved, has the highest safety profile. Innovative studies are evaluating the use of biological drugs, such as omalizumab or dupilumab, and probiotics, such as Lactobacillus rhamnosus, in monotherapy or associated with oral immunotherapy. Therapy for peanut allergy is constantly evolving, and new perspectives are ongoing to develop.

Record of strep throat infections in Italy: what is needed to know about penicillin allergy? The point of view from the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Notifications of invasive group A streptococcal (iGAS) infections have significantly increased in many European Countries compared to the previous season. In Italy, there has been an increase in streptococcal pharyngitis and scarlet fever cases since January 2023, which sparked concerns about a GAS epidemic in the pediatric population. This rise may be ascribed to the GAS infection season that began earlier than usual (off-season outbreak) and the increase in the spread of respiratory viruses and viral coinfections that raised the risk of iGAS disease. Moreover, this phenomenon was also facilitated by increased travel after reduced GAS circulation during the COVID-19 pandemic.The increase in cases of GAS disease has raised some critical issues regarding the potential reactions to administering amoxicillin, the first-line antibiotic therapy, many of which have been erroneously labeled as "allergy."For these reasons, the Italian Society of Pediatric Allergy and Immunology (SIAIP) intends to provide simple clinical indications to help pediatricians manage GAS pharyngitis, discerning the allergic from non-allergic drug hypersensitivity.

A Practical Update on Pediatric Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is an emerging atopic disease of unknown etiology limited to the esophagus. The pathogenesis is still understood and is likely characterized by type 2 inflammation. Food allergens are the primary triggers of EoE that stimulate inflammatory cells through an impaired esophageal barrier. In children and adolescents, clinical presentation varies with age and mainly includes food refusal, recurrent vomiting, failure to thrive, abdominal/epigastric pain, dysphagia, and food impaction. Upper-gastrointestinal endoscopy is the gold standard for diagnosing and monitoring EoE. EoE therapy aims to achieve clinical, endoscopic, and histological ("deep") remission; prevent esophageal fibrosis; and improve quality of life. In pediatrics, the cornerstones of therapy are proton pump inhibitors, topical steroids (swallowed fluticasone and viscous budesonide), and food elimination diets. In recent years, much progress has been made in understanding EoE pathogenesis, characterizing the clinical and molecular heterogeneity, and identifying new therapeutic approaches. Notably, clinical, molecular, endoscopic, and histological features reflect and influence the evolution of inflammation over time and the response to currently available treatments. Therefore, different EoE phenotypes and endotypes have recently been recognized. Dupilumab recently was approved by FDA and EMA as the first biological therapy for adolescents (≥12 years) and adults with active EoE, but other biologics are still under consideration. Due to its chronic course, EoE management requires long-term therapy, a multidisciplinary approach, and regular follow-ups.

Selective IgM Deficiency: Evidence, Controversies, and Gaps.

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies.

Clinical and immunological phenotypes of selective IgM deficiency in children: Results from a multicenter study.

BACKGROUND: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available. METHODS: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years. RESULTS: Forty-eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long-term follow-up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM. CONCLUSIONS: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work-up to obtain a comprehensive clinical and immunological characterization of the patient. The follow-up of these patients is fundamental to define the disease evolution and appropriate management.

Severe pediatric asthma endotypes: current limits and future perspectives.

INTRODUCTION: Although rare, pediatric severe therapy-resistant asthma (STRA) is a highly heterogeneous, resource-demanding disease that differs significantly from severe adult asthma and whose pathogenesis is still poorly understood. AREAS COVERED: This review summarizes the latest 10 years of English-written studies defining pediatric STRA endotypes using lung-specific techniques such as bronchoalveolar lavage and endobronchial biopsy. Results of the studies and limits on the field are discussed, together with some future perspectives. EXPERT OPINION: Over the years, it has become increasingly clear that 'one size does not fit all" in asthma. However, "Does an extremely tailored size fit more than one?'. Only using multicentric, longitudinal pediatric studies, will we be able to answer. Three issues could be particularly critical for future research. First, to provide, if existing, a distinction between prepuberal STRA and puberal STRA endotypes to understand the transition from pediatric to adult STRA and to design effective, tailored therapies in adolescents, usually suffering from poorer asthma control. Second, design early treatments for pediatric airway remodeling to preserve lifelong good lung function. Finally, to better characterize inflammation before and during biological therapies, to provide clues on whether to stop or change treatments.

Food allergy: cause or consequence of pediatric eosinophilic esophagitis? Potential implications of ultraprocessed foods in prevention and management.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by eosinophilic infiltration, leading to esophageal dysfunction, inflammation, and fibrotic remodeling. In the last few decades, there has been an increased prevalence of EoE at an alarming rate in the pediatric age. The pathogenesis of EoE is still largely undefined, and this limits the definition of effective strategies for the prevention and management of this condition. EoE is considered a multifactorial disease arising from a negative interaction between environmental factors and genetic background, causing an impaired esophageal epithelial barrier with subsequent abnormal allergen exposure activating type 2 (Th2) inflammation. Food antigens have been suggested as key players in Th2 inflammation in pediatric patients with EoE, but emerging evidence suggests a potential role of other dietary factors, including ultraprocessed foods, as possible triggers for the occurrence of EoE. In this paper, we discuss the potential role of these dietary factors in the development of the disease, and we propose a new approach for the management of pediatric patients with EoE.

COVID-19 and autoimmune diseases: is there a connection?

PURPOSE OF REVIEW: This review summarizes current evidence on the potential link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and autoimmunity. RECENT FINDINGS: Several viral infections are potential triggers of reactive and autoimmune diseases by inducing type II and type IV hypersensitivity reactions. Recent evidence demonstrated that SARS-CoV-2 infection is not an exception, triggering the production of tissue-specific autoantibodies during the acute phase of coronavirus disease 2019 (COVID-19) and leading to autoimmune diseases development as long-term complication. The significant immune dysregulation with cytokine storm and organ damage observed in patients with severe to critical COVID-19 is considered the main mechanism explaining the high levels of autoantibodies, which are also implicated in disease severity and the need for an intensive care assessment. Multisystem inflammatory syndrome in children (MIS-C) is an immune-mediated disease where the recent viral infection leads to systemic inflammation, as already observed in other reactive and autoimmune diseases. SUMMARY: Autoimmunity may be a complication of SAR-CoV-2 infection. Understanding the pathogenesis of autoimmune manifestations in COVID-19 might help prevent the incidence or exacerbation of autoimmune disorders and design better and more efficient treatment strategies in children and adult populations.

Eosinophilic Gastrointestinal Diseases in Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are disorders mostly caused by mutations in genes involved in host defense and immune regulation. Different degrees of gastrointestinal (GI) involvement have been described in IEI, and for some IEI the GI manifestations represent the main and characteristic clinical feature. IEI also carry an increased risk for atopic manifestations. Eosinophilic gastrointestinal diseases (EGIDs) are emerging disorders characterized by a chronic/remittent and prevalent eosinophilic inflammation affecting the GI tract from the esophagus to the anus in the absence of secondary causes of intestinal eosinophilia. Data from the U.S. Immunodeficiency Network (USIDNET) reported that EGIDs are more commonly found in patients with IEI. Considering this element, it is reasonable to highlight the importance of an accurate differential diagnosis in patients with IEI associated with mucosal eosinophilia to avoid potential misdiagnosis. For this reason, we provide a potential algorithm to suspect an EGID in patients with IEI or an IEI in individuals with a diagnosis of primary EGID. The early diagnosis and detection of suspicious symptoms of both conditions are fundamental to prevent clinically relevant complications.

Evaluation of diagnostic time in pediatric patients with eosinophilic gastrointestinal disorders according to their clinical features.

Eosinophilic gastrointestinal disorders (EGIDs) are chronic/remittent inflammatory diseases associated with a substantial diagnostic delay, often attributable to misdiagnosis and variable clinical presentation in adults. In the pediatric population, few studies have been conducted worldwide reporting EGID diagnostic delay and its consequences on patients. This study aims to analyze and identify potential clinical factors and complications associated with a longer diagnostic time. We performed a retrospective analysis of pediatric patients with EGIDs followed at the Center for Pediatric EGIDs in Pavia, Italy. A total of 60 patients with EGIDs were enrolled. Thirty-nine (65%) patients had EoE, and 21 (35%) non-esophageal EGIDs. EGID diagnosis was achieved about 2 years after the symptom onset, and the median diagnostic time was 12 months (IQR 12-24 months). Diagnostic time was 12 months (IQR 12-69) in non-esophageal EGIDs and 12 months (IQR 4-24 months) in EoE patients. EoE patients presenting with FTT and feeding issues experienced a longer diagnostic time (p = 0.02 and p = 0.05, respectively) than children without growth and feeding impairments.In this study, symptoms appeared about 2 years before the definitive EGID diagnosis was reached, and this diagnostic time was shorter than the delay observed in other published studies. Especially in EoE children, the diagnostic time is significantly associated with impaired child growth, highlighting the importance of an early diagnosis to prevent esophageal stenosis and failure to thrive.

Omalizumab and allergen immunotherapy for respiratory allergies: A mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Although currently approved to treat severe asthma and chronic spontaneous urticaria, omalizumab has also been an effective and safe add-on treatment for other allergic diseases. Namely, omalizumab has been proposed to be used as add-on therapy in patients with allergic rhinitis and asthma and undergoing specific allergen immunotherapy (AIT). AIT is the only treatment that modifies the natural history of IgE-mediated diseases. This brief review summarizes the available evidence and controversies on the efficacy and safety of omalizumab combined with specific AIT.