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Abstract Idiopathic anaphylaxis (IA) remains a frustrating challenge for both patients and physicians. The aim of this paper is to focus on IA in pediatric ages and suggest possible diagnostic algorithms according to specific age ranges (infants, children, and adolescents). In fact, in a variable percentage of patients, despite extensive diagnostic tests, the cause of anaphylactic episodes cannot be identified. Moreover, the lack of a unanimous IA definition requires a careful and detailed diagnostic workup. Prompt recognition of signs and symptoms, especially in younger children, and an accurate clinical history often allow a choice of the most appropriate diagnostic tests and a correct differential diagnosis.

Food protein-induced enteropathy (FPE) belongs to non-IgE gastrointestinal mediated food allergies. FPE is a syndrome characterized by diarrhea, weight loss and failure to thrive in young infants. Cow milk is the culprit food that most frequently causes FPE. The prevalence of FPE has not been fully estimated, but it is relatively rare. The diagnosis is based on the clinical manifestations and histological findings through colonoscopy. Laboratory tests are somewhat helpful in the diagnosis, although there are no disease-specific findings. Allergy testing for food specific IgE is not routinely recommended. The cornerstone of the management of FPE is the removal of culprit food from the diet. FPE is usually a transient condition that resolves in most cases by 1–2 years of life. This review addresses the latest findings on FPE, including a practical guide to assist pediatricians treating children with FPE.

Abstract Exercise-induced bronchoconstriction (EIB) is characterized by the narrowing of airways during or after physical activity, leading to symptoms such as wheezing, coughing, and shortness of breath. Distinguishing between EIB and exercise-induced asthma (EIA) is essential, given their divergent therapeutic and prognostic considerations. EIB has been increasingly recognized as a significant concern in pediatric athletes. Moreover, studies indicate a noteworthy prevalence of EIB in children with atopic predispositions, unveiling a potential link between allergic sensitivities and exercise-induced respiratory symptoms, underpinned by an inflammatory reaction caused by mechanical, environmental, and genetic factors. Holistic management of EIB in children necessitates a correct diagnosis and a combination of pharmacological and non-pharmacological interventions. This review delves into the latest evidence concerning EIB in the pediatric population, exploring its associations with atopy and sports, and emphasizing the appropriate diagnostic and therapeutic approaches by highlighting various clinical scenarios.

Abstract Imported allergens are involved in many allergic reactions, with unexpected and unusual implications. They can be involved in developing asthma, allergic rhinoconjunctivitis, Hymenoptera venom allergies and food allergies. Imported allergens can be implied in respiratory allergies attributable to commercial practices and accidental diffusion through air currents that have introduced non-native species in new geographical contexts. Ambrosia artemisiifolia L., a plant native to North America and currently in the western part of Lombardy, represents an example. Moreover, a variation in the pollen concentration in the Northwest Tuscany area and Trentino Alto-Adige was observed. Cannabis sativa is another imported allergen used frequently by adolescents. Regarding potential imported food allergens, there is no validated list. Imported food allergens derive from ethnic foods, referring to Mexican/Latin American, Chinese/Japanese, Southeast Asian, Arab/Middle Eastern and African cuisine. Four insect flours were recently introduced to the European and Italian markets (Acheta domesticus, Alphitobius diaperinus, Tenebrio molitor and Locusta migratoria). The association between the accidental introduction through commercial traffic, climate change, and the absence of natural enemies in the destination ecosystem is related to the introduction of a specific Hymenoptera, Vespa velutina, in Italy and Europe. External events attributable to human activities, such as climate change and the introduction of non-native plants, foods and Hymenoptera through trade, have contributed to the issue of imported allergens. Making the correct diagnosis and guiding the diagnostic and therapeutic path in this particular context represent the concerns of the pediatric allergist.

Abstract Anaphylaxis is a life-threatening reaction characterized by the acute onset of symptoms involving different organ systems and requiring immediate medical intervention. The incidence of fatal food anaphylaxis is 0.03 to 0.3 million/people/year. Most fatal food-induced anaphylaxis occurs in the second and third decades of life. The identified risk factors include the delayed use of epinephrine, the presence of asthma, the use of recreational drugs (alcohol, nicotine, cannabis, etc.), and an upright position. In the United Kingdom (UK) and Canada, the reported leading causal foods are peanuts and tree nuts. In Italy, milk seems to be the most common cause of fatal anaphylaxis in children

The majority of viral rashes occurring during an antibiotic therapy are considered as a drug hypersensitivity reaction (DHR). Differentiating a viral rash versus a DHR is difficult or even impossible. In delayed DHRs the interplay between viruses and drugs is summarized according to the recent literature. The question is if the same reaction will again occur in case of drug re-exposure in absence of the concomitant viral infection because of persistent immune reactivity. Epstein Barr Virus (EBV) and Human Herpes virus 6 (HHV-6) models are analyzed in case of maculopapular exanthemas (MPEs) and drug reaction with eosinophilia and systemic symptoms (DRESS) over a course of drug therapy. MPEs are the most common skin manifestation during a viral infection and a concomitant drug therapy. In type IVb reactions to drugs a hapten/pro-hapten mechanism and a pharmacological interaction (p-i mechanism) are described as the 2 major ways to make T cells response functional. Rarely the altered repertoire model is involved. The Human Leukocyte Antigen (HLA) predisposition is an additional essential factor that can facilitate DHR. In MPEs rarely a DHR is confirmed by allergy testing. Severity and duration of MPEs, the presence of eosinophilia and systemic symptoms make more reliable the persistent nature of the reaction. Research on this topic is needed in order to provide the clinicians with instruments to decide when to suspect future reactions upon drug re-exposure even in the absence of a viral infection, because those patients should be investigated by a complete drug allergy work up.

Breastfeeding is the most important nutrition source for infants. However, managing breastfed infants with signs and symptoms related to food allergy can be difficult. Many studies have shown the presence of different food allergens in breast milk, but the clinical role of these antigens in human milk is still much debated. Milk is the main suspect in exclusively breastfed infants with signs and symptoms attributable to food allergy, even if other foods may be responsible. This narrative review analyzes the recommendations provided by international guidelines to determine the diagnosis and management of IgE-mediated and non-IgE-mediated food allergies in exclusively breastfed infants. Dietary restrictions in lactating mothers of infants with suspected FA are usually not necessary. Only in the very few cases where significant allergy signs and symptoms occur in the infant during exclusive breastfeeding should the lactating mother follow an elimination diet for the suspected food for a short period.

Treatment of IgE-mediated food allergy involves avoiding the food causing the allergic reaction. In association, an action plan for allergic reactions is indicated, sometimes including self-injectable adrenaline. In addition to these dietary and medical implications, there are two equally important ones: nutritional and psychosocial. From a nutritional point of view, it is known that children suffering from food allergy have a growth delay in height and weight compared to their non-allergic peers. Specifically, this condition is directly related to the specific food excluded from the diet, the number of foods excluded and the duration of the elimination diet. From a psychosocial point of view, the child often cannot eat the foods other guests eat. Children with food allergy may perceive an aura of parental anxiety around their mealtime and may be afraid that what they eat could have harmful consequences for their health. Furthermore, children’s and their parents’ quality of life appears to be affected. The need to manage the allergy and the nutritional and psychosocial problems positions the pediatric nutritionist and the child neuropsychiatrist as support figures for the pediatric allergist in managing the child with food allergy.

Shellfish is defined as any edible marine invertebrate and refers to crustaceans and mollusks. Crustaceans belong to the phylum Arthropods. Mollusks belong to the phylum Mollusca. This report illustrates a rare case of a 6-year-old girl with challenge-proven acute food protein–induced enterocolitis syndrome (FPIES) to cuttlefish (phylum Mollusca, class Cephalopoda), anaphylaxis to crustaceans (phylum Arthropoda), and tolerance to other mollusks, including clams and mussels (phylum Mollusca, class Bivalvia). The association of IgE-mediated food allergy and acute FPIES seen in this case is rare. To our knowledge, this is the first case of FPIES to cuttlefish reported in a child. This challenge highlights the need for further research into the allergens and mechanisms underpinning FPIES at a molecular level, enabling a better understanding of cross-reactivity patterns and the development of diagnostic and predictive tests to assist in clinical practice.

Abstract Hypersensitivity pneumonitis (HP) is a rare disease in childhood with the prevalence of 4 cases per 1 million children and an incidence of 2 cases per year. The average age of diagnosis at pediatric age is approximately 10 years. The pathogenesis of HP is characterized by an immunological reaction caused by recurrent exposure to triggering environmental agents (mostly bird antigens in children). The clinical picture of HP is complex and variable in children, often presenting in subacute forms with cough and exertion dyspnea. A diagnosis of HP should be considered in patients with an identified exposure to a triggering antigen, respiratory symptoms, and radiologic signs of interstitial lung disease. Blood tests and pulmonary function tests (PFT) support the diagnosis. Bronchoscopy (with bronchoalveolar lavage and tissue biopsy) may be needed in unclear cases. Antigen provocation test is rarely required. Of note, the persistence of symptoms despite various treatment regimens may support HP diagnosis. The avoidance of single/multiple triggers is crucial for effective treatment. No evidence- based guidelines for treatment are available; in particular, the role of systemic glucocorticoids in children is unclear. With adequate antigen avoidance, the prognosis in children with HP is generally favorable.

Chronic urticaria (CU) is one of the most common skin disorders worldwide. Among the inducible subgroup of CU, cold urticaria (ColdU) can affect both children and adults and is the only type associated with the risk of anaphylaxis without cofactors. In the scientific literature, data about cold anaphylaxis (ColdA) are poor, especially at pediatric age, and little is known about risk factors associated with the onset of systemic reactions and about the criteria for prescribing adrenaline auto-injectors (AAIs) in these patients. We describe the clinical characteristics and management of a case series of 21 patients with a history of ColdA, and we compare them with the pediatric case reports and case series published so far. On the basis of the scientific literature and of our case series of patients, we suggest that AAI should be prescribed to all high-risk patients: those with urticaria caused by cold-water immersion, oropharyngeal reactions, and with a previous history of systemic symptoms or anaphylaxis.

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.

Netherton syndrome (NS) is a rare and potentially life-threatening genetic skin disease responsible for skin inflammation and scaling, hair abnormalities and severe allergic manifestations. NS is caused by loss-of-function variants in Serine Peptidase Inhibitor Kazal-Type 5 (SPINK5), encoding the serine protease inhibitor LEKTI. NS patients have a profound skin barrier defect caused by unopposed kallikrein-related proteases activity (KLKs). They develop severe skin inflammation with eczematous-like lesions and high serum IgE levels. Multiomics studies have revealed that the IL-17/IL-36 pathway is the most predominant upregulated pathway in NS. It is associated with a Th2 signature with complement activation in the ichthyosis linearis circumflexa subtype, and with interferon and Th9 activation in the scaly erythrodermic form. Several case reports proved the efficacy of different biotherapies targeting IL-17A, IL-12/IL-23, IL-4R and IL-13R, TNF-a and IL-1β in pediatric NS patients. Intravenous immunoglobulins (IVIG) have also shown efficacy. These studies showed no severe side effects. At present, IL-17 blockade seems to be the most efficient treatment, but case reports remain limited with small numbers of patients and no placebo-control. Additional pathways must also be explored, and more efficient strategies could be used to block IL-17 and IL-23 pathways. In the future, the combination of specific strategies aiming at repairing the initial skin barrier defect could potentiate the efficacy of biologics. The current reports suggest that biological therapy is safe and often effective at pediatric age. However, controlled clinical trials that include a larger number of patients need to be conducted to reach more reliable conclusions.

Abstract Available guidelines for asthma management represent an important and suitable tool to make the entire medical process evidence-based, effective, and safe for patients. Their purpose is to help doctors and patients formulate the best decisions in regard to asthma management by choosing the most appropriate strategies in each specific clinical situation. The Global Initiative for Asthma (GINA) document, together with other national and international recommendations, is one of the main documents used for asthma prevention and management in Italy, but several studies reported that these recommendations are often not applied in real-life clinical practice, which consequently results in inadequate asthma control. In this context, a substantial simplification of the GINA document and asthma guidelines may represent a feasible strategy to be pursued to ameliorate the knowledge among GPs, primary care pediatricians, and specialists taking care of children and adults with asthma. On the other hand, another critical factor that may explain unsatisfactory control of asthma is the limited importance that all recommendations place on asthma heterogeneity. In the era of personalized medicine and target therapies, phenotype-driven asthma management may become a desirable approach for optimizing the management of asthmatic patients. In addition, digital health strategies have been investigated in the literature to improve asthma monitoring and may represent a promising tool in the future from this point of view. Relevant stakeholders should continue to investigate how to optimize real-life asthma control to propose novel solutions to translate into clinical practice.

Abstract Eosinophilic esophagitis (EoE) is a chronic clinical-pathologic disease characterized by eosinophilic infiltration of the esophageal epithelium with esophageal dysfunction symptoms. EoE can occur at any age and has different clinical manifestations depending on the age onset. To date, esophago-gastroduodenal endoscopy (EGD) with biopsy is the gold-standard for EoE diagnosis. According to the recent consensus guidelines, proton pump inhibitors, corticosteroids and elimination diets could be a first-line therapy option. The aim of the treatment is clinical and histological remission for preventing long-lasting untreatable fibrosis. A multidisciplinary approach (allergist, gastroenterology, dietitian, and pathologist) is recommended for managing patients affected by EoE, given the complexity of its treatment. This review will provide a practical guide to assist pediatricians treating children with EoE. Moreover, it highlights the unmet needs in diagnosis and treatment that require urgent attention from the scientific community in the aim of improving the management of patients with EoE.

Allergic proctocolitis (AP) is a benign condition, frequent in childhood, that is classified as a non-IgE-mediated food allergy. The prevalence is unknown; however, its frequency appears to be increasing, especially in exclusively breastfed infants. Clinical manifestations typically begin in the first few months of life with the appearance of bright red blood (hematochezia), with or without mucus, in the stool of apparently healthy, thriving infants. Most cases of AP are caused by cow’s milk proteins; however, other allergens, such as soy, egg, corn, and wheat, may be potential triggers. Diagnosis is based on the patient’s clinical history and on the resolution of signs and symptoms with the elimination of the suspected food antigen from the diet and their reappearance when the food is reintroduced into the diet. The treatment of AP is based on an elimination diet of the trigger food, with resolution of the symptoms within 72–96 h from the beginning of the diet. The prognosis of AP is good; it is a self-limiting condition, because most children can tolerate the trigger food within one year of life, with an excellent long-term prognosis. The purpose of this review is to provide an update on the current knowledge and recommendations in epidemiological, diagnostic, and therapeutic terms to the pediatricians, allergists, and gastroenterologists who may find themselves managing a patient with AP.

Shellfish, including various species of mollusks (e.g., mussels, clams, and oysters) and crustaceans (e.g., shrimp, prawn, lobster, and crab), have been a keystone of healthy dietary recommendations due to their valuable protein content. In parallel with their consumption, allergic reactions related to shellfish may be increasing. Adverse reactions to shellfish are classified into different groups: (1) Immunological reactions, including IgE and non-IgE allergic reactions; (2) non-immunological reactions, including toxic reactions and food intolerance. The IgE-mediated reactions occur within about two hours after ingestion of the shellfish and range from urticaria, angioedema, nausea, and vomiting to respiratory signs and symptoms such as bronchospasm, laryngeal oedema, and anaphylaxis. The most common allergenic proteins involved in IgE-mediated allergic reactions to shellfish include tropomyosin, arginine kinase, myosin light chain, sarcoplasmic calcium-binding protein, troponin c, and triosephosphate isomerase. Over the past decades, the knowledge gained on the identification of the molecular features of different shellfish allergens improved the diagnosis and the potential design of allergen immunotherapy for shellfish allergy. Unfortunately, immunotherapeutic studies and some diagnostic tools are still restricted in a research context and need to be validated before being implemented into clinical practice. However, they seem promising for improving management strategies for shellfish allergy. In this review, epidemiology, pathogenesis, clinical features, diagnosis, and management of shellfish allergies in children are presented. The cross-reactivity among different forms of shellfish and immunotherapeutic approaches, including unmodified allergens, hypoallergens, peptide-based, and DNA-based vaccines, are also addressed.

Linear Immunoglobulin A Bullous Disease (LABD) is a rare dermatosis whose pathomechanisms are not yet completely understood. LABD has different features characterizing adults and children in terms of potential triggers, clinical manifestations, and prognosis. The aim of the present study is to review all neonatal and pediatric cases of LABD and summarize the major characteristics. Childhood LABD is mainly idiopathic with a benign prognosis. Neonatal cases are difficult to differentiate from infectious diseases and usually have a poor prognosis. Drugs are one of the possible triggers that can activate autoimmune responses through antigen mimicry and epitope spreading as well as different stimuli (e.g., infections, inflammatory diseases, trauma). The gold standard for the diagnosis is based on direct immunofluorescence. Prognosis is generally favorable but often depends on the prompt dermatological diagnosis, treatment and follow-up guaranteed by a multidisciplinary team, including pediatricians for this group of age.

Angioedema (AE) is a vascular reaction of subcutaneous and submucosal tissues that identifies various clinical pictures and often is associated with wheals. AE without wheals (AEwW) is infrequent. The ability to distinguish between AEwW mediated by mast cells and bradykinin-mediated or leukotriene-mediated pathways is often crucial for a correct diagnostic–therapeutic and follow-up approach. AEwW can be hereditary or acquired. Factors typically correlated with hereditary angioedema (HAE) are a recurrence of episodes, familiarity, association with abdominal pain, onset after trauma or invasive procedures, refractoriness to antiallergic therapy, and lack of pruritus. The acquired forms of AE can present a definite cause based on the anamnesis and diagnostic tests. Still, they can also have an undetermined cause (idiopathic AE), distinguished according to the response to antihistamine in histamine-mediated and non-histamine-mediated forms. Usually, in childhood, AE responds to antihistamines. If AEwW is not responsive to commonly used treatments, it is necessary to consider alternative diagnoses, even for pediatric patients. In general, a correct diagnostic classification allows, in most cases, optimal management of the patient with the prescription of appropriate therapy and the planning of an adequate follow-up.

In food allergy management, the avoidance of the allergen that caused the reaction plays a fundamental role. Nevertheless, that can be thwarted in case of accidental exposure to a rare or hidden allergen, causing the adoption of a monotonous diet and a consequent reduction in the quality of life of the patient and their family. The identification of a rare and hidden allergen is an important diagnostic challenge, taking into account that a significant proportion of all food reactions is in reality due to them. The aim of the present review is to provide the pediatric allergist an overview of the possible sources of rare and hidden food allergens, taking into consideration the routes of exposure to these potential allergens with the main examples published in the scientific literature and the distinction between types of direct or cross-contamination. The identification of the allergen responsible for the reaction and the provision of a dietary advice customized for the specific individual’s dietary habits is essential to improve quality of life of the familiar nucleus and to reduce the risk of further allergic reactions.

Acute asthma remains one of the most frequent causes of children's access to healthcare. Asthma exacerbation is an essential defining characteristic of its severity, and respiratory infections entail increased risks of exacerbations with potential hospitalization. In the literature, contradictory findings have been reported about the risk and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients affected by asthma, with several implications for its management. Anti-IgE monoclonal antibody therapy is meant for patients affected by severe persistent allergic asthma without adequate control with other treatments. Indeed, biological therapies, such as omalizumab, are used as add-on treatments (step 5 in the Global Initiative for Asthma report) for severe asthma with several benefits, including a reduction in the frequency of exacerbations. To the best of our knowledge, we hereby report the first case in which an adolescent with severe allergic asthma treated with omalizumab has switched to self-administration at home during SARS-CoV-2 infection. Based on our peculiar experience, physicians may consider switching to self-administration of omalizumab at home, even during the coronavirus disease 2019 pandemic. However, more extensive research data from future studies are needed to confirm these first findings.

The alpha-gal syndrome is an allergic syndrome that comprises two clinical pictures: an immediate hypersensitivity to drugs containing alpha-gal and a delayed hypersensitivity to the ingestion of red mammalian meat. This allergic syndrome is often under-recognized, and patients are mislabeled with diagnosis as spontaneous urticaria or idiopathic anaphylaxis. Even though less frequently, children could also be of interest, especially in tick-endemic areas. In most cases, a positive anamnesis for tick bites months before the onset of symptoms is recorded. The clinical manifestations could range from asymptomatic cases to severe anaphylaxis. The most frequently used diagnostic test is the determination of specific IgE for alpha-gal. Oral provocation test is usually reserved to unclear cases or to verify tolerance after diet. No long-term follow-up studies have been published, although an elimination diet could lead to a decrease of specific IgE for alpha-gal and a possible reintroduction of some avoided foods. This paper provides a literature review, focused on pediatric age, and an evaluation of available diagnostic tests. We analyze the correlation between tick bites and symptom onset and unfold the different clinical pictures to help clinicians to promptly recognized this syndrome. Lastly, we address unmet needs in this specific allergy.

Hymenoptera stings are generally well-tolerated and usually cause limited local reactions, characterized by self-resolving erythema and edema associated with pain. However, Hymenoptera stings can induce immediate and delayed hypersensitivity reactions. In addition to these manifestations, unusual reactions to Hymenoptera stings have been reported. The latter are defined as unusual because of their atypical characteristics. They may differ from classical hypersensitivity reactions due to the stings' particular localization and the unusual involvement of one or more specific organs. Although unusual reactions to Hymenoptera stings are infrequent, it is essential for clinicians to know the possible related clinical manifestations. Here, we review the available literature and propose a diagnostic and management algorithm. At present, there are no defined guidelines for most of the unusual reactions to Hymenoptera stings, which should be managed in a tailored way according to the specifical clinical manifestations presented by the patients. Further studies are needed to better define these conditions and the underlying pathogenetic mechanisms to improve the diagnostic and therapeutic approach.

The prevalence of food allergy has increased in recent years, especially in children. Allergen avoidance, and drugs in case of an allergic reaction, remains the standard of care in food allergy. Nevertheless, increasing attention has been given to the possibility to treat food allergy, through immunotherapy, particularly oral immunotherapy (OIT). Several OIT protocols and clinical trials have been published. Most of them focus on children allergic to milk, egg, or peanut, although recent studies developed protocols for other foods, such as wheat and different nuts. OIT efficacy in randomized controlled trials is usually evaluated as the possibility for patients to achieve desensitization through the consumption of an increasing amount of a food allergen, while the issue of a possible long-term sustained unresponsiveness has not been completely addressed. Here, we evaluated current pediatric OIT knowledge, focusing on the results of clinical trials and current guidelines. Specifically, we wanted to highlight what is known in terms of OIT efficacy and effectiveness, safety, and impact on quality of life. For each aspect, we reported the pros and the cons, inferable from published literature. In conclusion, even though many protocols, reviews and meta-analysis have been published on this topic, pediatric OIT remains a controversial therapy and no definitive generalized conclusion may be drawn so far. It should be an option provided by specialized teams, when both patients and their families are prone to adhere to the proposed protocol. Efficacy, long-term effectiveness, possible role of adjuvant therapies, risk of severe reactions including anaphylaxis or eosinophilic esophagitis, and impact on the quality of life of both children and caregivers are all aspects that should be discussed before starting OIT. Future studies are needed to provide firm clinical and scientific evidence, which should also consider patient reported outcomes.

Vaccination is a well-known trigger for mast cell degranulation in subjects affected by mastocytosis. Nevertheless, there is no exact standardized protocol to prevent a possible reaction after a vaccine injection, especially for patients who have already presented a previous vaccine-related adverse event, considering that these patients frequently tolerate future vaccine doses. For this reason, we aim to share our experience at Meyer Children’s University Hospital in Florence to raise awareness on the potential risk for future vaccinations and to discuss the valuable therapeutic strategies intended to prevent them, taking into account what is proposed by experts in literature. We describe the case of an 18-month-old female affected by a polymorphic variant of maculopapular cutaneous mastocytosis that presented an extensive bullous cutaneous reaction 24 hours after the second dose (booster dose) of inactivated-tetravalent influenza vaccine, treated with a single dose of oral corticosteroid therapy with betamethasone (0.1 mg/kg) and an oral antihistamine therapy with oxatomide (1 mg/kg/daily) for a week, until resolution. To the best of our knowledge, in the literature, no documented case of reaction to influenza vaccine in maculopapular cutaneous mastocytosis is described. Subsequently, the patient started a background therapy with ketotifen daily (0.05 mg/kg twice daily), a non-competitive H1-antihistamine, and a mast cell stabilizer (dual activity). A non-standardized pharmacological premedication protocol with an H1-receptor antagonist (oxatomide, 0.5 mg/kg) administered 12 hours before the immunizations, and a single dose of betamethasone (0.05 mg/kg) together with another dose of oxatomide (0.5 mg/kg) administered 2 hours before the injections was followed to make it possible for the patient to continue with the scheduled vaccinations. Indeed, no reactions were subsequently reported. Thus, in our experience, a background therapy with ketotifen associated with a premedication protocol made by two doses of oxatomide and a single dose of betamethasone was helpful to make possible the execution of the other vaccines. We suggest how in these children, it could be considered the idea of taking precaution when vaccination is planned, regardless of the kind of vaccine and if a dose of the same vaccine was previously received. However, international consensus needs to be reached to manage vaccinations in children with mastocytosis and previous adverse reactions to vaccines.

Abstract Severe asthma has a substantial epidemiological impact on children and biological treatments can be an option to take into account, as they target specific molecules and pathways involved in its pathogenesis. Modern medicine is continuously and progressively oriented towards tailored treatments designed specifically for the pathology patterns observed in individual patients and identified as endotypes with associated biomarkers. In this regard, biologic treatments in asthma are one of the best examples. Among the biological drugs currently available, omalizumab is the one with the greatest amount of data on efficacy and safety, and the one we have more real-life clinical experience with. However, mepolizumab will likely be accessible soon globally for clinical use. Moreover, research on biological drugs for the treatment of severe asthma is expanding rapidly, with some molecules currently used in adult patients that could be registered also for pediatric use and new molecules that could be available in the future. On the other hand, due to this potential abundance of therapeutic options, new criteria could become necessary to guide clinicians through an evidence-based choice between omalizumab and these new drugs. For the same reason, more data collected specifically from pediatric clinical trials are necessary. In this review we aim to analyze the factors that could help clinicians make their choice and to highlight the unmet need for a more evidence-based choice.

Abstract Background The therapeutic strategy for children with cow’s milk allergy (CMA) consists in the elimination of cow’s milk (CM) from their diet. Donkey’s milk (DM) has been reported to be an adequate alternative, mainly to his nutritional similarities with human milk (HM) and excellent palatability. The aim of present prospective study was to evaluate the nutritional impact of DM on the diet of children with CMA in term of children growth. Methods Before the nutritional trial on children and during the study the health and hygiene risks and nutritional and nutraceuticals parameters of DM were monitored. Children with CMA were identified by the execution of in vivo and in vitro tests for CM and subsequent assessment of tolerability of DM with oral food challenge (OFC). Finally, we prescribed DM to a selected group of patients for a period of 6 months during which we monitored the growth of children. A total of 81 children, 70 with IgE mediated cow’s milk protein allergy (IgE-CMPA) and 11 with Food Protein Induced Enterocolitis Syndrome to CM (CM-FPIES), were enrolled. Results Seventy-eight out of 81 patients underwent the OFC with DM and only one patient with IgE-CMPA (1.5 %) reacted. Twenty-two out of 81 patients took part of the nutritional trial. All the 22 patients took and tolerated the DM, moreover DM did not change the normal growth rate of infants. Conclusions In conclusion, DM resulted safe in term of health and hygiene risks and nutritionally adequate: no negative impact on the normal growth rate of children was assessed. Therefore, it may be a suitable alternative for the management of IgE mediated CMA and FPIES, also in the first 6 months of life, if adequately supplemented.

Abstract Drug hypersensitivity reactions (DHRs) in childhood are mainly caused by betalactam or non-betalactam antibiotics, and non-steroidal anti-inflammatory drugs (NSAIDs). Laboratory tests for identifying children who are allergic to drugs have low diagnostic accuracy and predictive value. The gold standard to diagnose DHR is represented by the drug provocation test (DPT), that aims of ascertaining the causative role of an allergen and evaluating the tolerance to the suspected drug. Different protocols through the administration of divided increasing doses have been postulated according to the type of drug and the onset of the reaction (immediate or non immediate reactions). DPT protocols differ in doses and time interval between doses. In this position paper, the Italian Pediatric Society for Allergy and Immunology provides a practical guide for provocation test to antibiotics and NSAIDs in children and adolescents.

Netherton syndrome (NS) is a genetic, multisystemic disease classically distinguished by a triad of clinical manifestations: congenital ichthyosiform erythroderma, hair shaft abnormalities, and immune dysregulation. Due to the complex pathogenesis of the disease, there are no specific therapies currently accessible for patients with NS. An early diagnosis is crucial to start the correct management of these patients. A multidisciplinary approach, including specialists in immunology, allergology, and dermatology, is necessary to set up the best therapeutic pathway. We conducted a review with the aim to summarize the different therapeutic strategies currently accessible and potentially available in the future for children with NS. However, given the limited data in the literature, the best-tailored management should be decided upon the basis of the specific clinical characteristics of the patients with this rare clinical condition. Further comprehension of the pathophysiology of the disease could lead to more efficacious specific therapeutic options, which could allow a change in the natural history of NS.

Chronic spontaneous urticaria (CSU) is a mast cell-driven disease that is often associated with autoimmune or autoinflammatory conditions. Omalizumab is recommended in the treatment of refractory CSU in patients over 12 years of age who do not respond to four standard doses of antihistamines. Omalizumab blocks the mast cells’ degranulation, thus interrupting the resulting inflammatory cascade driven by T-helper 2 (Th2) cytokines. The efficacy of omalizumab in controlling CSU and possible associated diseases has been studied in few patients so far. In particular, some case reports describe adults with CSU and concomitant inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) or ulcerative colitis (UC). Although the treatment of CD with anti-tumor necrosis factors-α (TNF-α) seems to be effective in controlling CSU, no cases of the utility of omalizumab in patients with both conditions have been described so far. At the moment, there is no evidence that the pathogenetic mechanisms underlying CD are linked to the same pathways that are inhibited by omalizumab for the treatment of CSU. We present the first pediatric case of refractory CSU and CD in which omalizumab led to CSU remission, even if the follow-up period was limited. In conclusion, our experience shows how CSU could be associated with CD and successfully treated with the monoclonal anti-IgE antibody in a patient on immunosuppressive therapy. However, more data is needed from a larger population.

Peach allergy is emerging as a common type of fresh-fruit allergy in Europe, especially in the Mediterranean area. The clinical manifestations of peach allergy tend to have a peculiar geographical distribution and can range from mild oral symptoms to anaphylaxis, depending on the allergic sensitization profile. The peach allergen Pru p 7, also known as peamaclein, has recently been identified as a marker of peach allergy severity and as being responsible for peculiar clinical features in areas with high exposure to cypress pollen. This review addresses the latest findings on molecular allergens for the diagnosis of peach allergy, the clinical phenotypes and endotypes of peach allergy in adults and children, and management strategies, including immunotherapy, for peach allergy.

Background: Nut allergies are an increasingly frequent health issue in the pediatric population. Tree nuts (TN) and peanuts are the second cause of food anaphylaxis in Italy. Unfortunately, knowledge of the clinical characteristics of a TN allergy in Italian children is limited. Our study aimed to identify the clinical and allergological characteristics of Italian children with a nut allergy (TN and peanut). Methods: A retrospective observational analysis was performed on the clinical charts of children with a history of nut reaction referred to the allergy unit of the hospital from 2015 to 2019. The studied population was represented by children with a confirmed nut allergy based on positive prick by prick and/or serum-specific IgE to nut plus a positive nut oral food challenge. Demographic, clinical, and allergological features were studied and compared among different nuts. Results: In total, 318 clinical charts were reviewed. Nut allergy was confirmed in 113 patients. Most patients (85/113, 75%) had a familial history of allergy and/or a concomitant allergic disorder (77/113, 68%). Hazelnut and walnut were the more common culprit nuts observed in allergic children. Anaphylaxis was the first clinical manifestation of nut allergy in a high percentage of children (54/113, 48%). The mean age of the first nut reaction was statistically higher with pine nuts. Over 75% of children reported a single nut reaction. During the OFCs, the signs and symptoms involved mainly the gastrointestinal system (82/113, 73%) and resolved spontaneously in most cases. Severe reactions were not frequent (22/113, 19%). Conclusion: To our knowledge, this is the first Italian study that provided a comprehensive characterization of children with a nut allergy. These results are important for clinicians treating children with a nut allergy.

Abstract Background The basophil activation test (BAT), has been proposed as a possible assay for the diagnosis of immediate-type allergy to beta-lactams (BLs). The aim of this study was to assess the utility of BAT in the diagnosis of amoxicillin (AMX) or AMX-clavulanate (AMX-C) IgE-mediated hypersensitivity in children and adults. Material and methods Eighteen children and 21 adults, with clinical history of immediate reactions to AMX or AMX-C, were referred to Anna Meyer Children’s Hospital and San Giovanni di Dio Hospital, respectively. They underwent in vivo tests (skin prick test and intradermal test). Moreover, BAT with AMX or AMX-C was performed within 6 months from the reaction. Results In the pediatric group, the concordance between the skin tests (ST) and BAT results was 83.3%. Upon comparing the symptom grades and ST results to the BAT results, we found that the reaction severity and ST positivity did not correlate with BAT results in children. In the adult group, the concordance between the ST and BAT results was 61.9%. Upon comparing patients with severe reactions and patients with mild reactions in terms of BAT results, we found a BAT sensitivity of 38.5% and a specificity of 100%. When comparing the symptom grades to the BAT results, we found that no patients with mild symptoms had a positive BAT result, whereas 38.5% of patients with severe symptoms had a positive BAT result. Conclusions BAT does not seem to be a useful tool to increase the sensitivity of an allergy work-up to diagnose immediate hypersensitivity to AMX or AMX-C.

Infants affected by Heiner syndrome (HS) display chronic upper or lower respiratory tract infections, including otitis media or pneumonia. Clinically, gastrointestinal signs and symptoms, anemia, recurrent fever and failure to thrive can be also present. Chest X-rays can show patchy infiltrates miming pneumonia. Clinical manifestations usually disappear after a milk-free diet. The pathogenetic mechanism underlying HS remains unexplained, but the formation of immune complexes and the cell-mediated reaction have been proposed. Patients usually outgrow this hypersensitivity within a few years. The aim of this review is to provide an updated overview on the current evidence on HS in children, with a critical approach on the still undefined points of this interesting disease. Finally, we propose the first structured diagnostic approach for HS.

The food industry commonly uses milk ingredients as technological aids in an uncounted number of products. On the other hand, milk contains allergenic proteins causing adverse allergic reactions in sensitized/allergic individuals. This work intends to evaluate the effect of autoclaving and in vitro digestion on the allergenicity of milk proteins incurred in meat products. Protein profiles of raw and autoclaved sausages without and with the addition of 10% of milk protein concentrates were analyzed by gel electrophoresis and liquid chromatography–mass spectrometry. Additionally, residual IgE-reactivity was evaluated by immunoblot analysis using pooled sera of cow’s-milk-allergic individuals followed by bioinformatic analysis. Results showed that autoclaving led to an increase in protein fragmentation (higher number of short peptides) and consequently to a higher digestion rate, that was found to be more pronounced in β-casein. The IgE-binding capacity of milk proteins seems to be reduced after autoclaving prior to digestion, with a residual reactivity in caseins, but was eliminated following digestion. This study highlights the importance of autoclaving as a processing strategy to produce hypoallergenic formulas.

Fish allergy constitutes a severe problem worldwide. Its prevalence has been calculated as high as 7% in paediatric populations, and in many cases, it persists into adulthood with life-threatening signs and symptoms. The following review focuses on the epidemiology of Immunoglobulin E (IgE)-mediated fish allergy, its pathogenesis, clinical manifestations, and a thorough approach to diagnosis and management in the paediatric population. The traditional approach for managing fish allergy is avoidance and rescue medication for accidental exposures. Food avoidance poses many obstacles and is not easily maintained. In the specific case of fish, food is also not the only source of allergens; aerosolisation of fish proteins when cooking is a common source of highly allergenic parvalbumin, and elimination diets cannot prevent these contacts. Novel management approaches based on immunomodulation are a promising strategy for the future of these patients.

A food allergy is an immunoglobulin E (IgE)-mediated hypersensitive reaction to food, which consists in the appearance of allergic symptoms; it can vary from common urticaria to even fatal anaphylaxis. The prevalence of food allergies has been increasing in the past twenty years and it represents a major public health problem in industrialized countries. The mechanism that leads to food allergies is the lack of immunologic and clinical tolerance to food allergens. The diagnosis of IgE-mediated food allergies is based on the combined use of a detailed medical history, in-vivo, and in-vitro research of specific IgE, the elimination diet, and the double-blind placebo-controlled food challenge. The only currently available treatment for allergies is the strict elimination diet. This type of attitude, which we could define as “passive”, does not overcome the risk of accidental reactions due to involuntary intake of the culprit food. For food allergy management, an “active” approach is urgently needed, such as specific allergen immunotherapy, which is currently under development and only used for research purposes. This article aims to give an updated review of IgE-mediated food allergies in pediatric populations in terms of epidemiology, pathogenesis, prevention, diagnosis, and management.

Unsuccessful Desensitization in a Child with Hypersensitivity to Diazoxide

Oral Immunotherapy (OIT), a promising allergen-specific approach in the management of Food Allergies (FA), is based on the administration of increasing doses of the culprit food until reaching a maintenance dose. Each step should be adapted to the patient, and OIT should be considered an individualized treatment. Recent studies focused on the standardization and identification of novel biomarkers in order to correlate endotypes with phenotypes in the field of FA.

Cow’s milk is considered the best wholesome supplement for children since it is highly enriched with micro and macro nutrients. Although the protein fraction is composed of more than 25 proteins, only a few of them are capable of triggering allergic reactions in sensitive consumers. The balance in protein composition plays an important role in the sensitization capacity of cow’s milk, and its modification can increase the immunological response in allergic patients. In particular, the heating treatments in the presence of a food matrix have demonstrated a decrease in the milk allergenicity and this has also proved to play a pivotal role in developing tolerance towards milk. In this paper we investigated the effect of thermal treatment like baking of cow’s milk proteins that were employed as ingredients in the preparation of muffins. A proteomic workflow was applied to the analysis of the protein bands highlighted along the SDS gel followed by western blot analyses with sera of milk allergic children in order to have deeper information on the impact of the heating on the epitopes and consequent IgE recognition. Our results show that incorporating milk in muffins might promote the formation of complex milk−food components and induce a modulation of the immunoreactivity towards milk allergens compared to milk baked in the oven at 180 °C for ten minutes. The interactions between milk proteins and food components during heating proved to play a role in the potential reduction of allergenicity as assessed by in vitro tests. This would help, in perspective, in designing strategies for improving milk tolerance in young patients affected from severe milk allergies.