The importance of clinical history in the diagnosis of drug hypersensitivity in children.

BACKGROUND: In case of suspected hypersensitivity reactions (HRs) to drugs, a challenging area for pediatricians is detecting relevant elements in the parent-reported history, in order to reach a definite diagnosis. We analyzed the concordance between the description of the HR and the medical reports documented at the time of the event. Furthermore, we studied any correlation between clinical history variables and the prediction of true allergy. METHODS: We retrospectively collected 50 charts of children referred to our Allergy Unit, after a previous access to the Emergency Department. We compared the description of the HR at acute phase to the history told by parents. Type and timing of the HR and culprit drug were classified as "known" or "unknown." The diagnosis was confirmed or excluded at the end of the investigations. Logistic regression analysis was performed to find any significant association. RESULTS: The type of the HR was known in 74%, the timing in 28%, and the culprit drug in 98%. We showed that having had a severe HR had an increased odds of remembering the timing; being older >6 years and having had an immediate HR had an increased odds of remembering the type; time to diagnostic was lower in patients whose parents remembered the type of HR. CONCLUSION: Our paper underlines the importance of an accurate anamnesis at the time of the event. Providing the physicians with a standardized Case Report Form could be a useful tool to simplify the diagnostic work-up and minimize mistakes due to lack of memory.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

Appearance of food-dependent exercise-induced anaphylaxis as an inflammatory disease: a pediatric case report and differential diagnosis.

Anaphylaxis is the most serious of all allergic reactions. Despite advances in the knowledge of anaphylaxis, its clinical manifestations continue to be under-recognized. Indeed, proper diagnosis of anaphylaxis is often missed, and the treatment is delayed. The underlying causes are still under investigation globally. Inflammation represents the cornerstone of pathophysiology of anaphylaxis. Food-dependent exercise-induced anaphylaxis (FDEIA) is a rare clinical manifestation characterized by a chronological sequence in which food ingestion followed by physical exercise leads to anaphylaxis. Its mechanisms are yet to be fully explained. We report the case of a 14-year-old Chinese male who lost consciousness while undergoing physical activity at school. Several differential diagnoses were considered such as hypovolemic shock, septic shock, anaphylactic shock or neurological adverse event. Finally, the diagnosis of FDEIA was made. This case highlights the difficulties in diagnosing FDEIA and its management, especially when the clinical history is not complete and detailed.

IgE-mediated Anisakis allergy in children.

Anisakids are nematodes responsible for different clinical patterns in humans. The well-known human-infecting Anisakis species include members of the Anisakis simplex (AS) complex. Humans usually contract anisakiasis through ingestion of raw or undercooked seafood containing Anisakis larvae. Once Anisakis has been ingested, patients may develop disease driven directly by Anisakis larvae and/or by allergic reaction due to this nematode. The capability of inducing allergic reactions depends on the expression of specific antigens by nematodes and host factors. This study aims to resume actual knowledge about AS and Anisakiasis with regard to epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment. Particular attention is paid to Anisakis allergens and their cross-reactivity on available diagnostic methods, and defining a diagnostic pathway for Anisakis allergy. Because only a few data are available in the literature about pediatric population, we focus on this group of patients specifically.

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.

Simplifying the drug provocation test in non-immediate hypersensitivity reactions to amoxicillin in children: The experience of a tertiary care allergy unit.

BACKGROUND: Mild non-immediate reactions (NIR) to beta-lactams (ßLs) are the most common manifestation of adverse drug reactions in children, and the drug provocation test (DPT) remains the gold standard for diagnosis. However, there are still controversies about the protocol that should be used, especially regarding the administration of doses and the DPT length. OBJECTIVE: This study aimed to evaluate a pediatric population with a history of mild NIR to amoxicillin (AMX) or to amoxicillin-clavulanic acid (AMX/CL) who underwent a diagnostic workup including a DPT with the culprit drug, to understand if a graded DPT or, instead, a single full dose could be the most appropriate way of administration in clinical practice. METHODS: The data of children were retrospectively analyzed for a 5-year period, with demographic and clinical characteristics collected. We reported the allergy workup and the results of the DPT performed with the administration of incremental doses and a prolonged DPT at home for a total of 5 days. RESULTS: Three hundred fifty-four patients were included. Overall, 23/354 (6.5%) DPTs were positive: 11/23 patients showed a reaction after 2-8 h after the last dose on the 1st or 2nd day (1 reacted 30 min after the last dose), 1/23 reacted with urticaria 30 min after the first dose, 11/23 reacted at home on the 5th day of the DPT. CONCLUSION: This paper indirectly suggests that a single therapeutic dose administered on the 1st day of a DPT could be safe in the diagnostic workup of mild NIR to AMX/CL. Moreover, this could be less time-consuming as patients would spend less time in the hospital, also considering the public health restrictions imposed during the COVID-19 pandemic.

The history of the drug-induced enterocolitis syndrome.

The diagnosis of drug-induced enterocolitis syndrome (DIES), resembling the typical findings of a well-known disease, the food protein-induced enterocolitis syndrome (FPIES), was acknowledged in the first publication on the topic in 2014. Ten cases of DIES have been described so far. Unanswered questions concerning DIES include its pathogenetic mechanism, natural history, the possible presence of predisposing genetic factors, and the potential existence of its atypical forms. DIES is a recently defined and intriguing clinical entity, similar to FPIES but triggered by drugs. It seems well-defined from the clinical point of view, but its pathogenetic mechanisms are not known. DIES deserves more attention among allergists, especially among the professionals who work with children, and all efforts should be conceived to improve its correct recognition and accurate management.

De Novo Food Allergy in Pediatric Recipients of Liver Transplant.

ABSTRACT: Allergic and atopic conditions, including food allergy, asthma, eczema and eosinophilic disease of the gastrointestinal tract after liver transplant in previously non-allergic children have been increasingly described. After a liver transplant, children can present mild to severe reactions to food allergens (ie, from urticaria-angioedema to life-threatening anaphylactic reactions). De novo post-transplant food allergy may become clinically evident in children who undergo liver transplant between a few months and a few years of transplant. The present narrative review aims to describe the spectrum of de novo post-transplant food allergy development, the current theories of pathogenesis, risk factors and to suggest possible clinical management strategies.

Relapse or worsening of chronic spontaneous urticaria during SARS-CoV-2 infection and vaccination in children: A telemedicine follow-up.

BACKGROUND: Chronic urticaria (CU), characterized by daily wheals and/or angioedema lasting more than 6 weeks, is a common skin disease. CU is classified as spontaneous or inducible. Because of Coronavirus Disease-19 (COVID-19) pandemic, face-to-face visits were reduced, and many centers started remote consultations to minimize hospital admissions and risk for viral diffusion. Telemedicine became a valuable tool for evaluating and monitoring patients with chronic diseases, such as CU. This study aims to evaluate the effectiveness of telemedicine as a means for the follow-up of patients with chronic spontaneous urticaria (CSU) during the COVID-19 pandemic. In particular, we collected data related to CSU evolution and treatment by remote consultation. Moreover, we specifically investigated the impact of SARS-CoV-2 infection or vaccination on CSU in relapsing or worsening of such a disease. METHODS: The electronic charts were reviewed for patients diagnosed with CSU, who were referred to the allergy unit of Meyer Children's Hospital, Florence. For each patient, a review of demographic characteristics, diagnostic workup, efficacy, and tolerability of the treatment was performed. Patients with a physical agent triggering CU were excluded from the study. Disease activity was monitored using the Urticaria Activity Score (UAS7). In addition, when the COVID-19 pandemic started, follow-up continued through telemedicine after an initial face-to-face visit when possible. Approximately 1 year after the diagnosis of CSU, patients were recontacted to investigate whether they had experienced a relapse or worsening of urticaria during a possible COVID-19 or immediately after receiving a COVID-19 vaccine. RESULTS: From January 2020 to March 2021, 84 cases of CSU were identified, with 71 (84.5%) of these being evaluated via televisit (remote consultation). During the remote follow-up period, 38/71 (53.5%) patients who were evaluated via televisit recovered completely from CSU, while 24 (33.8%) made therapy adjustments, and 9 (12.7%) had to discontinue follow-up through remote visits and return to face-to-face visits. In February 2022, we recontacted the 71 patients with CSU, and 50 (70.4%) of them answered by phone call interview. Four (19.2%) of the 26 patients who had COVID-19 showed CSU relapse, while 1 (3.8%) had a CSU worsening. Instead, 1 (3.8%) patient of the 26 who were vaccinated had a relapse of CSU, and 1 (3.8%) had a worsening of CSU, both after the first dose. CONCLUSION: Our data showed that telemedicine can be an effective tool for the follow-up of patients with CSU. Moreover, COVID-19, as well as COVID-19 vaccination, may trigger CSU relapse or worsening, but both are unspecific triggers, and urticaria shows a very short duration in most cases.

'Diagnosing food protein-induced enterocolitis syndrome'.

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES.

Allergy to Gibberellin-Regulated Proteins (Peamaclein) in Children.

BACKGROUND: Gibberellin-regulated proteins (GRPs, Peamaclein) are allergens recently identified in plant-derived food allergy (FA), and little is known about the clinical manifestations of this allergic condition in the European population, especially in children. OBJECTIVE: Our study aimed to identify and characterize pediatric patients with pollen-FA due to GRP sensitization. METHODS: We retrospectively analyzed the charts of patients referred to the Allergy Unit of the Meyer Children's Hospital in Florence for suspected FA. Three main eligibility criteria based on the actual knowledge of GRP allergy were used to select patients deserving further investigations: (1) systemic reactions after consumption of fruit or an unknown culprit food, (2) positive skin prick tests to both cypress pollen and Pru p 3-enriched peach peel extracts, (3) negative in vitro test results for Pru p 3 serum-specific Immunoglobulin E (sIgE). We performed the in vitro test to determine the anti-rPru p 7 (Peamaclein) sIgE levels in the selected patients. RESULTS: We identified 10 pediatric patients with Pru p 7 allergy and described their characteristics. The use of our eligibility criteria showed a high accuracy in identifying these patients: 100% of the selected patients had positive in vitro results for Pru p 7. We therefore proposed a diagnostic algorithm for Pru p 7 allergy. CONCLUSION: This is the first case series of European pediatric patients with a demonstrated Peamaclein allergy. These findings broaden our knowledge on GRP allergy in pediatric populations and could help clinicians to suspect, diagnose, and manage this recently discovered plant-derived FA.

Efficacy and tolerability of the updosing of second-generation non-sedating H1 antihistamines in children with chronic spontaneous urticaria.

BACKGROUND: Chronic urticaria (CU), daily wheals or angioedema that lasts more than 6 weeks, is a common skin disease; CU is classified as spontaneous (no specific eliciting factor involved) or inducible (specific eliciting factor involved). Recent EAACI guidelines for management of CSU recommend second-generation non-sedating H1 antihistamines (sgAH1 s) as initial treatment in children (weight-adjusted) as in adults, followed by increased doses (up to 4 times) if the standard dose is not effective. The efficacy and tolerability of fourfold updosing in adults are known, but there is little documentation regarding updosing in the pediatric population. This retrospective study evaluates the efficacy and tolerability of the updosing of sgAH1 s in children with CSU in a tertiary care pediatric hospital. METHODS: The electronic charts of patients diagnosed with CSU and referred to the Allergy Unit of Meyer Children's University hospital were reviewed during a period of 4 years. For each patient, an examination of demographic characteristics, diagnostic workup, efficacy, and tolerability of the treatment was performed. Disease activity was monitored using UAS7. RESULTS: Sixty-six cases of CSU were identified, and all of them were treated initially with a standard dose of sgAH1 s, followed by increased doses up to fourfold when standard dosing was not effective. 44/66 patients (66.7%) treated with sgAH1 s responded: 25 with a standard dose, 16 with a double, 2 with threefold dose, and 1 with fourfold dose. 12/66 (18.2%) patients began a therapy with omalizumab. As for the remaining patients, 10/66 (15.1%), they are still undergoing therapy with sgAH1 s because of the relapse of the symptoms after the stepped-down dosage. Regarding tolerability, 9/66 (13.6%) patients treated with sgAH1 s experienced side effects: three that required treatment change and six that did not. CONCLUSION: Our data were consistent with the tolerability of updosing of sgAH1 s in children with CSU, although the efficacy appears to be limited to double the standard dose.

Drug-induced enterocolitis syndrome: Similarities and differences compared with food protein-induced enterocolitis syndrome.

In 2014, drug-induced enterocolitis syndrome (DIES) was described for the first time. It is still a poorly known disease with symptoms that typically resemble those of food protein-induced enterocolitis syndrome (FPIES). To date, six more cases of DIES have been described and new clinical diagnostic criteria have been proposed based on those in the international guidelines for FPIES. In this paper, the authors describe three more cases of DIES. In addition, similarities and differences with FPIES have been deeply analyzed. To date, several unanswered questions need to be addressed, but clinicians must be instructed how to identify DIES, in order to make an allergy workup and give definite therapeutic indications to patients, especially in children where DIES seems to be more frequent.

Food protein-induced enterocolitis syndrome oral food challenge: Time for a change?

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. DATA SOURCES: PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E-mediated food allergy and FPIES. STUDY SELECTIONS: Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. RESULTS: We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. CONCLUSION: International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient's reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

Hypersensitivity to Rituximab in Children.

Biological agents have had an increased usage during the past years, also in pediatric population. Monoclonal antibodies can cause adverse drug reactions with different pathomechanisms, including type I IgE-mediated hypersensitivity reactions (HR). In this report, we describe 2 children who had a diagnosis of anaphylaxis to rituximab (RTX), confirmed by positive in vivo tests in both cases and elevated tryptase value in one case. We also made a review of the few cases of HR to RTX in pediatric population reported in literature and discuss differential diagnosis and utility of allergy investigations.

Managing food allergy immunotherapy in children during the COVID-19 pandemic.

Food allergy immunotherapy is a promising allergen-specific approach to manage food allergy in children, although it is not exempt from adverse events, even severe. The adverse events are not predictable and furthermore cofactors can play a role in triggering them. During the COVID-19 pandemic, patients on food allergy immunotherapy should be provided with suggestions on how to proceed in the event of COVID-19 infection occurring or is suspected. These recommendations would be of support to clinical practitioners dealing with patients on food allergy immunotherapy since there is little data in the literature on the topic.

Frequency of positive oral food challenges and their outcomes in the allergy unit of a tertiary-care pediatric hospital.

INTRODUCTION AND OBJECTIVE: The oral food challenge (OFC) is the gold standard to diagnose food allergy (FA); however, it is not a procedure free from the risk of having significant allergic reactions, even life-threatening.The aims of our study were to evaluate the frequency of positive OFCs performed in children with a suspected diagnosis of IgE- and non-IgE-mediated (food protein-induced enterocolitis syndrome (FPIES)) FA and how the failed challenges were managed. MATERIALS AND METHODS: A retrospective chart review was done on all children who have had OFCs in a tertiary-care pediatric allergy unit from 2017 to 2019. RESULTS: 682 patients were enrolled and 2206 challenges were performed: 2058 (93%) for IgE-mediated FA and 148 (7%) for FPIES. There were 262 (11.8%) challenge failures. The transfer to the emergency department was required 3 times (1.1%). None of the failed challenges resulted in death or hospitalization and 13.3% challenges did not require any treatment. CONCLUSIONS: Our findings confirm that food challenges can be performed safely in a specialized setting by well-trained personnel; all food challenge reactions, even the most serious, were reversible, thanks to a prompt recognition and treatment that generally did not worsen over time.

IgE-Mediated Fish Allergy in Children.

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.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. OBJECTIVE: The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. METHODS: From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. RESULTS: Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. CONCLUSIONS: In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Role of in vitro testing in food allergy.

Oral food challenges remain the gold standard for the diagnosis of food allergy. Nevertheless, the allergy workup is based on the presence of a clinical history, which is evocative of an immune-allergic reaction, and the first assessment is usually the performance of skin prick tests. Based on these results, allergists are used to evaluate the presence of serum-specific IgE, which are today the most commonly prescribed in vitro test for the evaluation of a possible food allergy. Other in vitro tests include the basophil activation test, that is becoming more and more employed by clinicians and not only by researchers, and the evaluation of serum IgG4, which is still an issue of debate in the allergy community. The present paper reviews the use of these in vitro tests for the diagnosis of food allergy.