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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.

Abstract Drug hypersensitivity reactions are common in children. Risk factors predisposing to IgE-mediated drug allergies and delayed drug reactions are a matter of debate. Gender, age, previous reactions to the same drug or to another drug, reduced drug metabolism, chronic diseases, polypharmacy, drug doses are linked with the onset of hypersensitivity reactions in some children. Novel advances in genetic polymorphisms can rapidly change the approach to the prevention of reactions since gene testing can be a useful screening test for severe cutaneous adverse reactions. Viral infections may act as cofactors in susceptible individuals. Polypharmacy, high doses, repeated doses and parental route of administration are also risk factors. Clinicians should take into account risk factors to allow the risk–benefit balance to be maintained.

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

Drug-induced anaphylaxis in children is less common than in adults and primarily involves beta-lactams and nonsteroidal anti-inflammatory drugs. Epidemiological studies show variable prevalence, influenced by age, gender, and atopic diseases. The pathophysiology includes IgE-mediated reactions and non-IgE mechanisms, like cytokine release reactions. We address drug-induced anaphylaxis in children, focusing on antibiotics, nonsteroidal anti-inflammatory drugs, neuromuscular blocking agents, and monoclonal antibodies. Diagnosis combines clinical criteria with in vitro, in vivo, and drug provocation tests. The immediate management of acute anaphylaxis primarily involves the use of adrenaline, coupled with long-term strategies, such as allergen avoidance and patient education. Desensitization protocols are crucial for children allergic to essential medications, particularly antibiotics and chemotherapy agents.

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.

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.

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.

Acute Viral Bronchiolitis is one of the leading causes of hospitalization in the first 12–24 months of life. International guidelines on the management of bronchiolitis broadly agree in recommending a minimal therapeutic approach, not recommending the use of bronchodilators. Guidelines, generally, consider bronchiolitis as a “unique disease” and this runs the risk of not administering therapy in some patients who could benefit from the use of bronchodilators, for instance, in those who will develop asthma later in their life and face first episode in the age of bronchiolitis. Today, there is growing evidence that bronchiolitis is not a single illness but can have different “endotypes” and “phenotypes,” based on age, personal or family history of atopy, etiology, and pathophysiological mechanism. There is evidence that some phenotypes of bronchiolitis are more strongly associated with asthma features and are linked to higher risk for asthma development. In these populations, possible use of bronchodilators might have a better impact. Age seems to be the main feature to suggest a good response to a bronchodilator-trial, because, among children > 6 months old with bronchiolitis, the presence of a subset of patients with virus-induced wheezing or the first episode of asthma is more likely. While waiting for new research to define the relationship between therapeutic options and different phenotypes, a bronchodilator-trial (using short-acting β2 agonists with metered-dose inhalers and valved holding chambers) seems appropriate in every child with bronchiolitis and age > 6 months.

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.

Intravenous iron is widely used for the treatment of iron deficiency anemia when adherence to oral iron replacement is poor. Acute hypersensitivity reactions during iron infusions are very rare but can be life threatening. Major risk factors for hypersensitivity reactions include a previous reaction to an iron infusion, a fast iron infusion rate, multiple drug allergies, atopic diseases, high serum tryptase levels, asthma, and urticaria. The management of iron infusions requires meticulous observation, and, in the event of an adverse reaction, prompt recognition and severity-related interventions by well-trained medical and nursing staff. Avoidance of IV iron products in patients with iron hypersensitivity reactions may not be considered as a standard practice.

Hypersensitivity reactions to radiocontrast media seem to be rare in children. Furthermore, the use of radiocontrast media in children remains quite safe in terms of the severity of reactions. Since pediatric guidelines are lacking, the diagnostic workup employed in adults could be adapted to children, taking into account that results have not yet been validated in this age group. Specific protocols for risk stratification and management of severe reactions have been proposed so far.