Immediate hypersensitivity reactions can pose a clinical and diagnostic challenge, mainly because of the multifarious clinical presentation and distinct underlying - frequently uncertain - mechanisms. Anaphylaxis encompasses all rapidly developing and life-threatening signs and may cause death. Evidence has accumulated that immediate hypersensitivity and anaphylaxis do not necessarily involve an allergen-specific immune response with cross-linking of specific IgE (sIgE) antibodies bound to their high-affinity IgE receptor (FcεRI) on the surface of mast cells (MCs) and basophils. Immediate hypersensitive and anaphylaxis can also result from alternative specific and nonspecific MC and basophils activation and degranulation, such as complementderived anaphylatoxins and off-target occupancy of MC and/or basophil surface receptors such as the Masrelated G protein-coupled receptor X2 (MRGPRX2). Degranulation of MCs and basophils results in the release of inflammatory mediators, which can be, depending on the underlying trigger, in a different spatiotemporal manner. In addition, hypersensitivity and anaphylaxis can occur entirely independently of MC and basophil degranulation, as observed in hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) that divert normal arachidonic acid metabolism by inhibiting the cyclooxygenase (COX)-1 isoenzyme. Finally, one should remember that anaphylaxis might be part of the phenotype of particular - sometimes poorly recognizable - conditions such as clonal MC diseases (e.g. mastocytosis) and MC activation syndrome (MCAS). This review provides a status update on the molecular mechanisms involved in both sIgE/FcεRI- and non-sIgE/FcεRIdependent immediate hypersensitivity and anaphylaxis. In conclusion, there is increasing evidence for alternative pathophysiological hypersensitivity and anaphylaxis endotypes that are phenotypically and biologically indistinguishable, which are frequently difficult to diagnose, mainly because of uncertainties associated with diagnostic tests that might not enable to unveil the underlying mechanism.

BACKGROUND: Drug hypersensitivity is increasing worldwide as the consumption of drug is increasing. Many clinical presentations of drug hypersensitivity are complex and take place in the setting of illness and/or polypharmacotherapy. OBJECTIVE: To review the most recent findings in the diagnosis and management of immediate drug hypersensitivity reactions. STUDY SELECTION: Studies were selected based on their relevance, originality and date of publication. MAIN FINDINGS: The understanding of endotypes, biomarkers and phenotypes has improved the categorization of immediate hypersensitivity reactions. In this review, we discussed the short- and long-term management of anaphylaxis with a special focus on in vivo and in vitro diagnostic methods. Moreover, the clinical management of drug-induced anaphylaxis, the role of hidden allergens and the importance of delabeling are discussed. CONCLUSIONS: Endophenotyping is crucial to correctly diagnose and treat patients with immediate drug hypersensitivity reactions, preventing future episodes through drug desensitization.

Anaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction. Yet, anaphylaxis is often difficult to diagnose, which in turn leads to a delay in the application of appropriate management. Epinephrine is the medication of choice for the immediate treatment of anaphylaxis. The rest of the actions to be taken during the acute episode of anaphylaxis, including the administration of other medications, will depend on the response to epinephrine. Epinephrine auto-injectors (EAI) are the preferred method for administration of treatment of anaphylaxis in the community setting. However, there are multiple potential barriers for the use of epinephrine during an anaphylactic reaction, related to the physicians and the patients themselves. Strategies to overcome gaps in the acute management of anaphylaxis include novel injection devices and research of new routes for the delivery of epinephrine. Electronic health solutions may also have a role at this level. Long-term management of anaphylaxis is focused on the prevention of new episodes. Etiologic diagnosis and patient education are key to this end. Application of health information technologies, such as telemedicine, social media, and mobile health can be helpful for the long-term management of anaphylaxis. Additionally, some patients may benefit from long-term immunomodulatory and etiologic treatments when allergen avoidance implies negative consequences. The aim of this review article is to address the most recent advances regarding the integral management of anaphylaxis, including pharmacological and non-pharmacological measures.

Although an increase in the incidence of childhood anaphylaxis has been reported, it remains underdiagnosed. Foods are the most common triggers for anaphylaxis, particularly cow's milk, hen's egg, and nuts. Other common causes of anaphylaxis in children and adolescents include venom and drugs. The skin is the most commonly affected organ, but approximately 10% of patients with anaphylaxis may present without skin symptoms, which can lead to misdiagnosis. Recognition of anaphylaxis is a great challenge in children, possibly due to a lack of vigilance among patients, caregivers, and healthcare professionals, but also in part due to discrepancies in the clinical definition of anaphylaxis. In addition, anaphylaxis in infants often poses a distinct challenge because the wide spectrum of clinical manifestations and the inability of infants to describe their symptoms may hinder prompt diagnosis and treatment. Given the rapid onset of anaphylaxis and its unpredictable severity, rapid assessment and appropriate treatment are critical. Although the morbidity and mortality associated with anaphylaxis are potentially preventable with the timely administration of life-saving epinephrine, anaphylaxis is still undertreated worldwide. Long-term management of pediatric anaphylaxis is a patient-centered, multidimensional approach that focuses on the recognition of anaphylaxis, the use of epinephrine auto-injectors, and prevention of recurrences. Therefore, close communication and collaboration between the child, caregivers, healthcare professionals, and schools is the cornerstone of long-term care. This paper is designed to provide a comprehensive overview of current perspectives and concepts related to anaphylaxis in the pediatric population in light of recent guidelines and literature.

Acute agitation is common in youths presenting to emergency departments, and, in some cases, may escalate into aggression and violence. Therefore, acute agitation in youths should be immediately and appropriately recognized and treated to avoid the consequences of its escalation. Agitation is widespread in youths, reported in around 7% of all youths admitted to emergency departments due to psychiatric reasons. Overall, the most frequent causes of youth acute agitation include the exacerbation of neurodevelopmental disorders, such as ADHD, autism, or intellectual disabilities, or the onset of mood and psychotic disorders. Substance abuse is also common in adolescents and young adults with acute agitation. Management of agitation should be individualized, multidisciplinary, and collaborative. Along with a diagnostic assessment, the needs of the young patients should be understood and addressed, and de-escalation strategies should be immediately prompted. Rapid recognition and management are warranted, in order to assure the safety of the patient and healthcare staff jeopardized by the acute crisis. Firstly, environmental and de-escalation strategies should be acted with the aim to reduce agitation and, if possible, avoid the use of physical restraint. In case these strategies fail to succeed, pharmacological treatment should be rapidly implemented. Although youth agitation and aggression is transdiagnostic, prior diagnosis of psychiatric disorder should guide the choice of the tranquilizing medication whenever possible. This review will examine these aspects in detail and provide guidance on how to recognize, manage, treat and resolve acute agitation in youths.