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.

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.

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.

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.

Viral rashes mimicking drug reaction with eosinophilia and systemic symptoms syndrome in children after ß-lactams intake: a diagnostic challenge.

In cases of skin eruptions over the course of antibiotic therapy and concomitant viral infection, differential diagnosis is often challenging. Confirming or ruling out drug hypersensitivity is not always a clear-cut question. Drug reaction with eosinophilia and systemic symptoms (DRESS) cases, for example, is classified as severe cutaneous adverse reactions due to drugs, but frequently the clinical manifestations do not completely fit into the diagnosis of DRESS. The aim of the present paper is to highlight similarities and differences among DRESS syndrome and DRESS-like rashes during viral infections and amoxicillin intake in children, in order to highlight those aspects that can help clinicians in early detection. We describe the dermatological, clinical, and laboratory characteristics of five patients hospitalized for DRESS-like skin rashes appearing roughly 1 week since the start of an amoxicillina course for upper respiratory tract infection (URTI) symptoms. The data are compared with those of 3 patients with early-onset DRESS syndrome. The absence of eosinophilia might be an initial marker to help identifying DRESS-like rashes; a quick clinical improvement and the confirmation of a viral infection able to explain the symptoms can help to finally rule out DRESS syndrome. Conclusion: A rapid, correct diagnosis of such DRESS-like rashes during viral infections allows more appropriate management and avoids unnecessary, life-long exclusion of useful and effective antibiotics because of a falsely "amoxicillin-allergy" labelling. What is Known: • Viral infections are common causes of skin rashes in children during antibiotic intake and may require differential diagnosis with drug reactions. • Early-onset DRESS syndrome is usually induced by antibiotics and appears ≤15 days after drug intake. What is New: • Prominent midface edema, maculopapular rash, and mild-to-moderate systemic symptoms may appear in children during viral illnesses treated with amoxicillin few days after drug intake, and may require differential diagnosis with early-onset DRESS. • In such cases, absence of eosinophilia, low (2-3) RegiSCAR score, confirmation of viral etiology, and a rapid resolution of the rash (2-5 days) might help to rule out DRESS; conversely, at an early stage, the presence of eosinophilia should suggest a diagnosis of DRESS.

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.

Tailored Sublingual Immunotherapy in a Monosensitized Child with Natural Rubber Latex Allergy.

Adverse reactions to natural rubber latex (NRL) represent a group of clinical manifestations that include non-allergic reactions and immediate-type or delayed-type allergic reactions. NRL sublingual immunotherapy (SLIT) has been demonstrated to be an effective and safe practice for latex clinical manifestations with good patient tolerance. A pediatric case of NRL allergy managed with an effective tailored SLIT is described. This case is compelling because the girl, who did not have an atopic background, suffered from NRL allergy with high reactivity and unique monosensitization. To the best of our knowledge, this is the first case with this characteristic described to date. Moreover, the SLIT follow-up time reported was unusually long, extending from childhood to adulthood. The case described highlights several problems of real-life management, and it demonstrates how the pediatric allergist plays a key role in the management of all these issues in order to succeed in guiding the patient through the immunotherapy process with a personalized approach, in line with the precision medicine principles. However, further long-term clinical studies are needed to better define the natural history of NRL allergy and find new potential biomarkers of response to NRL immunotherapy.

Kounis Syndrome: a pediatric perspective.

Kounis Syndrome is defined as a hypersensitivity coronary disorder constituted by the association of an acute coronary syndrome with a hypersensitivity, allergic, anaphylactic or anaphylactoid reaction, in a pathophysiologic context involving mast-cells, platelets, eosinophils and various interacting inflammatory cells. Currently, Kounis Syndrome is established in the literature, as accompanied by a plethora of clinical case reports that further elucidate its aspects. To the best of our knowledge, a specific analysis regarding the pediatric data of Kounis Syndrome has never been performed. The aim of this review was to reveal all the pediatric Kounis Syndrome cases in the literature, in an attempt to define its clinical implications in children. Moreover, based on the data of this analysis, a new classification for Kounis Syndrome is proposed, focusing mainly in the presence or the absence of allergic myocardial infarction, as the central clinical feature for the stratification of the patients' clinical manifestations.

Immunoglobulin E (IgE)-Mediated Food Allergy in Children: Epidemiology, Pathogenesis, Diagnosis, Prevention, and Management.

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.

Low-Dose Oral Food Challenge with Hazelnut: Efficacy and Tolerability in Children.

BACKGROUND: Hazelnut allergy (HA) is one of the more common food allergies (FAs) in Europe with a prevalence of 0.2%. The gold standard for diagnosing FA is oral food challenge (OFC) with the culprit food. Another purpose of OFC is to identify the "threshold level" of food as the dose that elicits symptoms. In this way it is possible to avoid a strict elimination diet and to determine the minimal quantity of the culprit food tolerated by the patient. OBJECTIVE: The aim of our study was to assess the efficacy and tolerability of hazelnut low-dose OFC (H-LDOFC) in children with HA. METHODS: From January 2015 to December 2016, we retrospectively analyzed the charts of patients referred to Allergy Unit of Meyer Children's Hospital, Florence, Italy for a history of HA. Prick by prick (PbP) and specific serum IgE (s-IgE) to hazelnut were performed. We proposed conducting an H-LDOFC to parents of children with HA. The H-LDOFC was considered completed when a cumulative dose of 2.5 g of hazelnut was reached. We divided the patients who underwent the H-LDOFC into an asymptomatic and a symptomatic group. For statistics we used SPSS for Windows version 16.0 and conducted a t test for comparing the averages, considering a p value of < 0.05 significant. RESULTS: Forty-three out of 70 patients (61.4%) with HA underwent an H-LDOFC. The PbP to hazelnut (mean ± SD) was 7.2 ± 2.9 mm and the s-IgE to hazelnut 25.3 ± 32.5 kU/L. Twenty-eight out of the 43 patients (65.1%) who underwent H-LDOFC reached the cumulative dose of 2.5 g of hazelnut. During the H-LDOFC, 20/43 patients (46.5%) had no reactions and 23/43 patients had a total of 55 reactions: 34 (61.8%) oral allergy syndrome, 8 (14.5%) rash, 6 (10.9%) abdominal pain, 2 (3.6%) urticaria, 2 (3.6%) angioedema, and 3 (5.4%) dyspnea. Atopic dermatitis was found to present the only statistically significant difference (p = 0.002) in patients with symptoms compared to asymptomatic patients during H-LDOFC. CONCLUSIONS: To our knowledge, this was the first study to assess the efficacy and tolerability of H-LDOFC in a pediatric population. Our study suggests that in children with HA, H-LDOFC is well accepted and safe because adverse reactions are mild and the majority are represented by localized symptoms (oral allergy syndrome) and efficient, especially in terms of improvement of quality of life. For these reasons it could be more extensively used in the treatment of HA.