Bacterial-like inflammatory response in children with adenovirus leads to inappropriate antibiotic use: a multicenter cohort study.

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

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.

Role of luteinizing hormone urinary levels in the diagnostic and therapeutic management of female central precocious puberty.

BACKGROUND: Diagnosing central precocious puberty (CPP) requires an integrated approach based on clinical, biochemical and instrumental data. The diagnostic gold standard is represented by GnRH (gonadotropin-releasing hormone) stimulation test. Some undoubted limitations of this procedure led the international scientific community to look for cheaper and less invasive alternative diagnostic methods, such as luteinizing hormone urinary levels (uLH) measurement. This study aims to define the reliability of urinary LH levels as a biomarker of pubertal development, both concerning the initial diagnostic management and the monitoring of patients with central precocious puberty undergoing therapy with GnRH analogues. Furthermore, the study plans to detect the potential association between LH peak serum (pLH) and urinary LH in patients undergoing diagnostic tests with GnRH and to identify a possible cut-off of uLH that may be suggestive of ensued successful hormonal stimulation. METHODS: The study includes 130 female patients with suspected precocious puberty or in follow-up during suppressive therapy. After the collection of the informed consent, the patients underwent clinical evaluation, auxological assessment, and hormone assays (basal levels of LH, FSH, and oestradiol; GnRH stimulating test in patients with suspected precocious puberty; urinary LH assay on the first-morning urine sample, collected after waking up). RESULTS: Two uLH cut-off values have been identified: the first of 0.25 UI/L [C.I. 95% 0.23-0.27], able to distinguish between pubertal and pre-pubertal patients, the second of 0.45 UI/L [C.I. 95% 0,20 - 0,70] suggestive of occurred hormonal stimulation in patients with diagnosis of CPP at GnRH test. All 30 patients with CPP in follow-up during suppressive therapy presented uLH values ≤ 0.45 IU/L (pU < 0.05), and uLH collected in prepubertal group control. CONCLUSIONS: uLH assays on the first morning urine specimen could be considered a low-cost and minimally invasive tool for precocious puberty diagnosing and monitoring, making possible to be easily performed even by a general pediatrician. Thus, this could help referring only selected patients to pediatric endocrinologists. After an appropriate validation, this approach could reasonably reduce hospital attendance and costs of performing more invasive procedures, with a more significant emotional impact on the pediatric patient.

Oxidative Stress, Environmental Pollution, and Lifestyle as Determinants of Asthma in Children.

Exposure to cigarette smoke, allergens, viruses, and other environmental contaminants, as well as a detrimental lifestyle, are the main factors supporting elevated levels of airway oxidative stress. Elevated oxidative stress results from an imbalance in reactive oxygen species (ROS) production and efficiency in antioxidant defense systems. Uncontrolled increased oxidative stress amplifies inflammatory processes and tissue damage and alters innate and adaptive immunity, thus compromising airway homeostasis. Oxidative stress events reduce responsiveness to corticosteroids. These events can increase risk of asthma into adolescence and prompt evolution of asthma toward its most severe forms. Development of new therapies aimed to restore oxidant/antioxidant balance and active interventions aimed to improve physical activity and quality/quantity of food are all necessary strategies to prevent asthma onset and avoid in asthmatics evolution toward severe forms of the disease.

46, XY Disorders of Sexual Development: a case report and theoretical framework.

BACKGROUND AND AIM: Disorders of sexual differentiation (DSD) with karyotype 46,XY include gonadal developmental differences such as complete gonadal dysgenesis, partial gonadal dysgenesis, testicular regression and ovotesticular sexual differentiation disorder, differences in androgen synthesis or action, such as androgen synthesis deficiency, androgen action deficits, LH receptor deficiency, AMH synthesis or action deficits, and other conditions such as severe hypospadias, cloaca estrophy, etc. Methods: A 17 years-old girl came to our attention for hirsutism, clitoral hypertrophy, primary amenorrhea, and bilateral mammary hypoplasia. According to clinical features and anamnesis, the diagnosis of 46, XY DSD was made. For diagnostic purposes, she underwent an extensive genetic analysis, hormone dosage and instrumental examinations. After a clitoridoplasty and hormone replacement treatment, the patient performs appropriate multidisciplinary follow-up and regular psychotherapy. RESULTS: The clinical case reported falls, according to the recent classification developed by the Chicago Consensus, within the scope of DSD with karyotype 46, XY. About 160 cases of patients with 17ß-HSD3 deficiency, diagnosed at a mean age of 12 years, are described in the literature, most of them coming from Western Asia and Europe and only three cases from Eastern Asia. Clinically, about 30% of patients showed virilization, 20% clitoromegaly, ambiguous genitalia, inguinal/labial mass, 16% primary amenorrhea, and 5% absence of mammary development, features that are partly traced in the case described here. CONCLUSIONS: This case underscores the complexity of managing individuals with DSD. Having acquired the concept that irreversible surgery should be avoided, except in cases where failure to do so would determine health risks, the primary objective of the medical decision lies in meeting conditions aimed at harmonious sexual identification, especially regarding sexual activity and fertility, involving a team of experienced professionals (psychologists, pediatricians, surgeons, endocrinologists, radiologists), capable of promptly identifying suggestive clinical signs.

Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Efficacy, immunogenicity, and safety of available vaccines in children on biologics: A systematic review and meta-analysis.

Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics. Response to immunizations in this group is not well known. OBJECTIVE: A systematic review was performed to evaluate three primary outcomes: efficacy; immunogenicity; and safety of vaccines in children with chronic conditions treated with biologics. METHODS: The protocol for our systematic review and meta-analysis was registered and published with PROSPERO. We searched electronic bibliographic databases for studies published from 2009 to 2019, focusing on vaccinations in children with chronic conditions treated with biologics. RESULTS: We retrieved 532 records. Thirty-one full-text articles were selected, and 14 were included in the meta-analysis. No significant publication bias was found. EFFICACY: limited data are available regarding the efficacy of vaccination, as most studies have focused on immunogenicity as surrogate outcome for efficacy. Immunogenicity: patients receiving anti-TNF-alpha therapy had a statistically significant risk of poor seroconversion (p = 0.028) and seroprotection by the serotype B influenza vaccine [inflammatory bowel disease (IBD) p = 0.013; juvenile idiopathic arthritis (JIA) p = 0.004]. We found adequate responses with H1N1 and H3N2 serotypes. Few studies existed for pneumococcal, hepatitis A virus, hepatitis B virus, varicella-zoster virus, Measles Mumps Rubella virus, and multiple vaccine administration. SAFETY: vaccine administration was not associated with serious side effects, but JIA patients on anti-TNF alpha therapy had a statistically significant risk of presenting with myalgia or arthralgia postinfluenza vaccine (p = 0.014). CONCLUSIONS: More evidence concerning efficacy, immunogenicity, and safety of vaccinations is needed to guide physicians in the vaccine decision process for this pediatric population.

Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies.

Advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, cells or tissue engineering. After clear successes in adults, the nascent technology now sees increasing pediatric application. For many still untreatable disorders with pre- or perinatal onset, timely intervention is simply indispensable; thus, prenatal and pediatric applications of ATMPs hold great promise for curative treatments. Moreover, for most inherited disorders, early ATMP application may substantially improve efficiency, economy and accessibility compared with application in adults. Vindicating this notion, initial data for cell-based ATMPs show better cell yields, success rates and corrections of disease parameters for younger patients, in addition to reduced overall cell and vector requirements, illustrating that early application may resolve key obstacles to the widespread application of ATMPs for inherited disorders. Here, we provide a selective review of the latest ATMP developments for prenatal, perinatal and pediatric use, with special emphasis on its comparison with ATMPs for adults. Taken together, we provide a perspective on the enormous potential and key framework parameters of clinical prenatal and pediatric ATMP application.

Asthma-Related Knowledge and Practices among Mothers of Asthmatic Children: A Latent Class Analysis.

Mothers' knowledge about childhood asthma influences management practices and disease control, but validating knowledge/practice questionnaires is difficult due to the lack of a gold standard. We hypothesized that Latent Class Analysis (LCA) could help identify underlying mother profiles with similar knowledge/practices. A total of 438 mothers of asthmatic children answered a knowledge/practice questionnaire. Using answers to the knowledge/practice questionnaire as manifest variables, LCA identified two classes: Class 1, "poor knowledge" (33%); Class 2, "good knowledge" (67%). Classification accuracy was 0.96. Mothers in Class 2 were more likely to be aware of asthma-worsening factors and indicators of attacks. Mothers in Class 1 were more likely to prevent exposure to tobacco smoke (91.1% vs. 78.8%, p = 0.005). For attacks, mothers in Class 2 were more likely to go to the emergency department and follow the asthma action plan. Mothers in Class 2 more frequently had a high education level (79.5% vs. 65.2%, p = 0.004). Children in Class 2 more frequently had fully controlled asthma (36.7% vs. 25.9%, p = 0.015) and hospitalizations for attacks in the previous 12 months (24.2% vs. 10.7%, p = 0.003). LCA can help discover underlying mother profiles and plan targeted educational interventions.

Type 2 inflammation in cystic fibrosis: New insights.

Recently, type 2 inflammation has been recognized as one of the most critical factors participating in the pathogenesis of cystic fibrosis (CF). On the one hand, type 2 inflammation restores tissue homeostasis and contributes to the resolution of inflammation following an injury. On the other hand, type 2 response-activated immune cells may become dysregulated or chronically activated, causing tissue fibrosis. Among the type 2 cytokine-driven inflammatory pathways, the transforming growth factor ß (TGFß), interleukin (IL)-17, IL-33, and IL-13 have been identified as essential mediators in patients suffering from CF. Given their critical role, we firmly believe that an adequate comprehension of the type 2-mediated pathways can identify attractive targets to decrease pharmacologically the inflammation and fibrosis occurring in the pulmonary tissue of patients suffering from CF.

ARIA-ITALY multidisciplinary consensus on nasal polyposis and biological treatments.

In the recent years, it was recognized that type-2 inflammation links many forms of nasal polyposis with severe asthma. Thus, some biological drugs developed for severe asthma appeared to exert an effect on nasal polyposis. So far, there are several trials supporting this concept; therefore, some monoclonal antibodies for severe asthma were assessed also in polyposis, with promising results. Since different specialists are involved in the management of nasal polyposis (eg, pulmonologists, ENT, allergists), it was felt that an educational and informative document was needed to better identify the indications of biologicals in nasal polyposis. We collected the main Italian Scientific Societies, and prepared (under the Allergic Rhinitis and its Impact on Asthma, ARIA) a document endorsed by all Societies, to provide a provisional statement for the future use of monoclonal antibodies as a medical treatment for polyposis. It is the first nationwide endorsed document on this aspect. The current pathogenic knowledge and the experimental evidence are herein reviewed, and some suggestions for a correct prescription and follow-up are provided.

Tailored therapies for primary immunodeficiencies.

Primary immunodeficiency disorders (PIDs) are rare inherited monogenic disorders of the immune system, characterized by an increased risk of infection, immune dysregulation and malignancies. To date, more than 420 PIDs have been identified. The recent introduction of high throughput sequencing technologies has led to identifying the molecular basis of the underlying aberrant immune pathway, and candidate targets to develop precision treatment, aimed at modifying the clinical course of the disease. In PID, targeted therapies are especially effective to manage immune dysregulation and autoimmunity, also reducing the incidence of side effects compared to conventional treatments, sparing the use of steroids and immunosuppressive drugs. Moreover, in the last years, the approach of conventional treatments such as immunoglobulin replacement therapies has evolved and the indication has expanded to new diseases, leading to individualized strategies to both improve infection control and quality of life.  Similarly, the new advent of gene therapy in selected PIDs has introduced the benefit to correct the immunological defect, reducing at the same time the complications related to the hematopoietic stem cell transplantation. Here, we illustrate the most recent findings on tailored treatments for PIDs.

Non-invasive biomarkers of eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an emerging allergen-mediated disease characterized by symptoms of esophageal dysfunction and eosinophilic inflammation. EoE diagnosis requires 15 eosinophils per high power field (eos/HPF) in tissue biopsies endoscopically obtained. The need for several endoscopies to monitoring the disease and the absence of validated non-invasive biomarkers or tools are the main reasons for the significant burden on affected patients and the healthcare system. There is a critical need for non-invasive or minimally invasive biomarkers. In the last years, several efforts have been made to identify potential biomarkers for diagnosing and monitoring the disease that we summarized in this review. The future of EoE is exciting from both a diagnostic and therapeutic standpoint. Further research is required to confirm phenotypes and histological or serological biomarkers to provide a novel endotype classification based on different cytokine or genetic signatures relevant to precision medicine.

Use of remdesivir in children with COVID-19 infection: a quick narrative review.

SARS-CoV-2 infection has a severe course in a small percentage of children. Remdesivir has shown promising results in reducing hospitalisation time in adults, but data on mortality rate are conflicting and few studies are available on its use use in antivirals in children. We performed a quick narrative review of the available literature data regarding the usage of remdesivir in children and neonates. In children, remdesivir showed good safety profile, however bradicardia events have been reported in children. Remdesivir is currently recommended by several guidelines in some subgroups of children with severe COVID-19, and should also be considered in critically ill patients, always in the context of the overall clinical picture and drug availability.

Atypical erythema annulare centrifugum in a child with celiac disease.

Herpetiformis dermatitis is the best characterized extraintestinal manifestation of celiac disease (CD). However, other chronic heterogeneous skin lesions have been associated with CD and should be considered in the differential diagnosis.

Novel therapeutic approaches targeting endotypes of severe airway disease.

Introduction: Severe asthma and chronic rhinosinusitis (CRS), with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP), are heterogeneous diseases characterized by different mechanistic pathways (endotypes) and variable clinical presentations (phenotypes).Areas covered: This review provides the clinician with an overview of the prevalence and clinical impact of severe chronic upper and lower airways disease and suggests a novel therapeutic approach with biological agents with possible biomarkers. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed database, using terms 'severe airways disease' AND 'endotype' AND 'treatment.' The literature review was performed for publication years 2010-2020, restricting the articles to humans and English language publications.Expert opinion: The coronavirus disease (COVID-19) pandemic has brought forth many challenges for patients with severe airway disease and healthcare practitioners involved in care. These patients could have an increased risk of developing severe SARS-CoV-2 disease, although treatment with biologics is not associated with a worse prognosis. Eosinopenia on hospital admission plays a key role as a diagnostic and prognostic biomarker.

Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases.

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.

Eosinophilic colitis in children: a new and elusive enemy?

PURPOSE: Eosinophilic gastrointestinal disorders are rare in children and present with a broad spectrum of non-specific symptoms. To date, no guidelines for diagnosis, therapy and follow-up are validated. Aim of our study is to focus on eosinophilic colitis (EC), to determine a possible correlation between associated disorders, macroscopic findings and treatment/follow up. METHODS: Retrospective study from 2015 to 2019 including all colonoscopies performed at our Institution. Eosinophilic colitis was defined according to the threshold identified by Collins: > 100 Eo/Hpf: right colon, > 84 Eo/Hpf transverse and left colon, > 64 Eo/Hpf sigma and rectum. We excluded colonoscopy in patients with IBD or other diseases causing hypereosinophilia (i.e., parasite infection, GVHD). RESULTS: Among 399 colonoscopies performed in 355 patients, we made 50 diagnosis of EC, 36 males, 14 females, median age 8.5 (3-17). Symptoms leading to endoscopy were recurrent abdominal pain (66%), chronic diarrhea (64%), and chronic constipation (8%). Two patients presented with GI bleeding and one with weight loss. Macroscopic findings were mostly normal or lymphoid nodular hypertrophy presenting different endoscopic features. In seven children (14%) we found history of allergy and atopy. 22 children present a diagnosis of autistic spectrum disorder (ASD) with a prevalence higher than in the overall population (44% vs 28.5%, p = 0.03). According to symptoms, treatment consist variably of steroids, six food elimination diet, mesalamine. For patients with available follow-up, we found histological persistence of Eosinophils in 75%, even in patients with symptoms relief. CONCLUSION: This study focus attention on EC as a new challenging pathology. Multicentric randomized clinical trials are needed to understand physiopathological mechanisms to validate a possible endoscopic score and related histological threshold, and to standardize therapy according to clinical features and instrumental findings. The high prevalence of EC in ASD need further specific research.

An immune-based biomarker signature is associated with mortality in COVID-19 patients.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

An asymptomatic mediastinal cyst in a young child: Case report and summary of the literature.

Bronchogenic cyst is a rare congenital chest malformation that mainly presents with wheeze and feeding issues in early life. A multidisciplinary approach and follow-up are pivotal for the improvement of lung function, mostly in cases of mediastinal complications.