Convergence and divergence in Kawasaki disease and multisystem inflammatory syndrome in children: results from the COVASAKI survey.

OBJECTIVES: To compare Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS-C) in children. METHODS: Prospective collection of demographics, clinical and treatment data. Assessment of type 1 interferon (IFN) score, CXCL9, CXCL10, Interleukin (IL)18, IFNγ, IL6, IL1b at disease onset and at recovery. RESULTS: 87 patients (43 KD, 44 MIS-C) were included. Age was higher in MIS-C compared to KD group (mean 31±23 vs. 94±50 months, p<0.001). Extremities abnormalities (p=0.027), mucosal involvement (p<0.001), irritability (p<0.001), gallbladder hydrops (p=0.01) and lymphadenopathy (p=0.07) were more often recorded in KD. Neurological findings (p=0.002), gastrointestinal symptoms (p=0.013), respiratory involvement (p=0.019) and splenomegaly (p=0.026) were more frequently observed in MIS-C. Cardiac manifestations were higher in MIS-C (p<0.001), although coronary aneurisms were more frequent in KD (p=0.012). In the MIS-C group, the multiple linear regression analysis revealed that a higher IFN score at onset was related to myocardial disfunction (p<0.001), lymphadenopathy (p=<0.001) and need of ventilation (p=0.024). Both CXCL9 and CXCL10 were related to myocardial disfunction (p<0.001 and p=0.029). IL18 was positively associated to PICU admission (0.030) and ventilation (p=004) and negatively associated to lymphadenopathy (0.004). IFNγ values were related to neurological involvement and lymphadenopathy (p<0.001), IL1b to hearth involvement (0.006). A negative correlation has been observed between IL6 values, heart involvement (p=0.013) and PICU admission (p<0.001). CONCLUSIONS: The demographic and clinical differences between KD e MIS-C cohorts confirm previous reported data. The assessment of biomarkers levels at MIS-C onset could be useful to predict a more severe disease course and the development of cardiac complications.

IgE to cyclophilins in pollen-allergic children: Epidemiologic, clinical, and diagnostic relevance of a neglected panallergen.

BACKGROUND: Cyclophilins are ubiquitous panallergens whose epidemiologic, diagnostic, and clinical relevance is largely unknown and whose sensitization is rarely examined in routine allergy practice. OBJECTIVE: We investigated the epidemiologic, diagnostic, and clinical relevance of cyclophilins in seasonal allergic rhinitis and its comorbidities. METHODS: We examined a random sample of 253 (25%) of 1263 Italian children with seasonal allergic rhinitis from the Panallergens in Pediatrics (PAN-PED) cohort with characterized disease phenotypes. Nested studies of sensitization prevalence, correlation, and allergen extract inhibition were performed in patients sensitized to birch pollen extract but lacking IgE to Bet v 1/2/4 (74/1263) or with highest serum level of IgE to Bet v 1 (26/1263); and in patients with sensitization to various extracts (ragweed, mugwort, pellitory, Plantago, and plane tree), but not to their respective major allergenic molecule, profilins, and polcalcins. IgE to cyclophilin was detected with recombinant Bet v 7, and extract inhibition tests were performed with the same rBet v 7. RESULTS: IgE to rBet v 7 was detected in 43 (17%) of 253 patients. It was associated with asthma (P < .028) and oral allergy syndrome (P < .017) in univariate but not multivariate analysis adjusted for IgE to profilins (Phl p 12), PR-10s (Bet v 1), and lipid transfer proteins (Pru p 3). IgE to rBet v 7 was also highly prevalent (47/74, 63%) among patients with unexplained sensitization to birch pollen extract. In patients with unexplained sensitization to ragweed, mugwort, pellitory, Plantago and plane tree pollen, the levels of IgE to those extracts correlated with the levels of IgE to rBet v 7, and they were also significantly inhibited by rBet v 7 (inhibition range 45%-74%). CONCLUSIONS: IgE sensitization to cyclophilin is frequent in pollen-allergic patients living in temperate areas and can produce "false" positive outcomes in skin prick and IgE tests to pollen extracts. Molecular diagnostic guidelines should include this panallergen family.

IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins.

BACKGROUND: IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. Their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood. METHODS: We examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (Panallergen in Paediatrics, PAN-PED), as well as with a longitudinal approach in 612 German children (Multicenter Allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. The presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA). RESULTS: IgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. Children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. Among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period. CONCLUSIONS: Our results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction.

Hyper IgE Syndromes.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Asymptomatic CMV infection at birth following maternal primary infection despite valacyclovir treatment and a subsequent negative amniocentesis. Case report.

Valacyclovir is currently the only pharmacological intervention demonstrated to reduce the risk of vertical CMV congenital infection within a randomized clinical trial in case of primary infection during pregnancy. So far, no data are available on the prognosis of children with congenital CMV infection diagnosed at birth after a negative amniocentesis whose mother were treated with valacyclovir during pregnancy, therefore it is essential to carry out a rigorous neurocognitive follow-up in these children in order to investigate the potential clinical consequence.

IgE-Mediated and Non-IgE-Mediated Fish Allergy in Pediatric Age: A Holistic Approach-A Consensus by Diagnostic Commission of the Italian Society of Pediatric Allergy and Immunology.

Fish is one of the "big nine" foods triggering allergic reactions. For this reason, fish allergens must be accurately specified on food labels. Fish allergy affects less than 1% of the world population, but a higher prevalence is observed in pediatric cohorts, up to 7%. Parvalbumin is the main fish allergen found in the muscles. In childhood, sensitization to fish allergens occurs most frequently through the ingestion of fish, rarely transcutaneously or by inhalation. Fish allergy symptoms usually appear within two hours of the allergen contact. The diagnosis begins with the collection of the history. If it is suggestive of fish allergy, prick tests or the measurement of serum-specific IgE should be performed to confirm the suspicion. The oral food challenge is the gold standard for the diagnosis. It is not recommended in case of a severe allergic reaction. It is important to make a differential diagnosis with anisakiasis or scombroid poisoning, which have overlapping clinical features but differ in pathogenesis. Traditionally, managing fish allergy involves avoiding the triggering species (sometimes all bony fish species) and requires an action plan for accidental exposures. The present review will analyze IgE- and non-IgE-mediated fish allergy in children from epidemiology, pathogenesis to clinical features. Moreover, clinical management will be addressed with a particular focus on potential nutritional deficiencies.

Are Babies Born Preterm High-Risk Asthma Candidates?

Among preterm infants, the risk of developing asthma is a matter of debate. This review discusses the state of the art of poorly understood prematurity-associated asthma. Impaired pulmonary function is common in children born prematurely. Preterm infants are prone to developing viral respiratory tract infections, bronchiolitis in the first year of life, and recurrent viral wheezing in preschool age. All of these conditions may precede asthma development. We also discuss the role of both atopic sensitization and intestinal microbiome and, consequently, immune maturation. Diet and pollution have been considered to better understand how prematurity could be associated with asthma. Understanding the effect of factors involved in asthma onset may pave the way to improve the prediction of this asthma phenotype.

An Overview of Off-Label Use of Humanized Monoclonal Antibodies in Paediatrics.

In recent years, off-label and unlicensed drug use has extensively developed in the paediatric population. For a long time, clinical trials in the paediatric population were considered complicated to perform because of ethical problems, causing frequent off-label use. Off-label drug use remains an important public health issue, especially for children with rare conditions or with diseases not responsive to conventional treatments. The present paper is a narrative review of the literature of off-label drug use in children. The aim of our study is to summarize the main works dealing with the off-label use of biological drugs in paediatrics. Further studies analyzing their efficacy, safety, and cost-benefit ratios are needed to extend the use of biological therapies to the paediatric population.

Steroid-sparing effect of mepolizumab in children with severe eosinophilic nonallergic asthma.

BACKGROUND: Asthma is characterized by a chronic airway inflammation, usually sustained by type 2 immunity. Bronchial and peripheral eosinophilia are biomarkers for type 2 asthma. Biologicals are the most effective treatment for severe asthma at present. Mepolizumab is an antagonist of interleukin-5 (IL-5), the most relevant cytokine involved in eosinophilia. OBJECTIVE: This case report evaluated the effectiveness of mepolizumab in two girls with severe eosinophilic non-allergic asthma. MATERIALS AND METHODS: Two female children with severe eosinophilic nonallergic asthma were treated with mepolizumab for two years. Clinical findings, lung function, peripheral eosinophils, asthma control, and bronchial endoscopy were performed. RESULTS: Biologicals reduced the eosinophilia, asthma exacerbations, and improved lung function in both patients. The treatment was also safe and well-tolerated. CONCLUSION: Mepolizumab represents an effective therapeutic option in the management of severe pediatric asthma.

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.

Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic.

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic.Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases.

Human Microbiome and Allergic Diseases in Children: Pathogenetic Role and Therapeutic Options.

The recent and extensive study of the microbiome has provided an enormous amount of data concerning the type and possible functions of microorganisms present in the gut, airways, genital tract, and skin. These data showed interpersonal differences in the composition of the microbiome and these differences suggest a link between the microbiome, the immune modulation, and the pathogenesis of allergic diseases. This research is particularly relevant in paediatrics, since allergic diseases are constantly increasing and there is evidence in the paediatric age that shows that the composition of the microbiome in the foetal and neonatal period plays a key role in the development of the immune system: vaginal delivery, breastfeeding, childhood spent in rural environments and/or in contact with animals result in a greater biodiversity of the microbiome with the presence of protective species that reduce the activation of Th2 lymphocytes, involved in allergic reactions. Further studies are necessary to better understand the microbiota role in the pathogenesis of atopy in order to understand if specific probiotics and prebiotics, administered orally or topically, can affect the microbiota composition and modulate immune system functions, producing a therapeutic effect in the treatment of allergic diseases. This narrative review analysed the available literature regarding the correlation between the microbiome and the development of allergic diseases and with special focus on paediatric studies. The skin, gut or lung dysbiosis can be a cofactor in the pathogenesis of allergies and the remodulation of the microbiome becomes an important therapeutic challenge.

Management of chronic urticaria in children: a clinical guideline.

The aim of this guidance is to provide recommendations to clinicians and other interested parties on chronic urticaria in children. The Italian Society for Pediatrics (SIP), the Italian Society for Allergy and Immunology (SIAIP), the Italian Society for Pediatric dermatology (SIDerP) convened a multidisciplinary panel that prepared clinical guidelines for diagnosis and management of chronic urticaria in childhood. Key questions on epidemiology, natural history, diagnosis, and management were developed. The literature was systematically searched and evaluated, recommendations were rated and algorithms for diagnosis and treatment were developed. The recommendations focus on identification of diseases and comorbidities, strategies to recognize triggering factors, improvement of treatment by individualized care.

Management of the child with allergy to non-antibiotic drugs.

Non-steroidal anti-inflammatory drugs, perioperative drugs, radio contrast media and chemotherapeutics drugs are, after the non-antibiotic drugs, the drugs most commonly responsible for allergic reactions in children. Management is different depending on the drug involved.

A practical management of children with antibiotic allergy.

About 10% of the parents reported that their children are allergic to one drug and the betalactam antibiotics are the most frequently suspected. Even if most of the adverse events following antibiotic prescriptions to children are considered allergic, after a full allergy work-up only a few of the suspected reactions are confirmed. For this reason, many children are incorrectly labelled as "allergic" and this represents an important challenge for the choice of the antibiotic therapy in these "labelled" children, who are frequently improperly deprived of narrow-spectrum antibiotics because considered as allergic. When an allergic reaction is suspected a precise diagnosis and a choice of a safe and effective alternative is essential for the future antibiotic option. In the light of this, the main aim of this paper is to try to provide a practical approach to managing the individuals who have reported adverse reactions to antibiotics.