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.

Dupilumab treatment of trichothiodystrophy in a child.

Trichothiodystrophy (TTD) is a rare congenital disorder caused by genetic mutations, leading to hair and skin abnormalities. We report successful treatment of a TTD case using dupilumab, a monoclonal antibody targeting IL-4Rα. The patient, a 7-year-old boy, exhibited significant improvement in skin and hair conditions, suggesting the potential of dupilumab as a therapeutic option for TTD. Further research is needed to elucidate its mechanism and efficacy in TTD treatment.

Drug provocation tests in children: All that glitters is not gold.

A proper allergy work-up, based on the gold standard drug provocation test (DPT), usually rules out suspected drug hypersensitivity in children. These tests are generally open, given their high efficiency compared with double-blind placebo-controlled DPTs. Although their negative predictive value is excellent, no studies have calculated their positive predictive value, highly dependent on the prevalence of the disease. Most studies have found a rate of <5%-10% of true beta-lactam hypersensitivity in children. Given this low prevalence (pre-test probability), a few false-positive results can significantly reduce the estimated positive predictive value. False positives may arise from the nocebo effect during the test, including nocebo by proxy, or from observer bias, which depends on professional expertise and organizational circumstances. Some studies have found a high rate of tolerance on a second DPT in children who failed the first, but these results may be affected by the interval between the two tests, of a year or more in most cases, reflecting a loss of hypersensitivity over time. Taking into account the low rate of positive DPTs, with commonly mild reactions, we suggest confirming nonsevere positive DPTs with a second provocation performed soon after the first, especially in the case of beta-lactam antibiotics, in order to improve the diagnostic accuracy, de-label more patients, and achieve a better estimation of true drug hypersensitivity prevalence. In case of mild immediate reactions, the potential benefits of a second DPT should be carefully weighed against the risk of anaphylaxis.

In vitro diagnostic testing for drug allergy in children.

Diagnosing Drug Hypersensitivity Reactions (DHRs) could be a complicated process especially in children, since allergic-like manifestation at this age is more often the expression of concomitant infections rather than a actual DHRs. In vivo tests are usually suggested as a first step; however, prick and intradermal tests could be painful and have shown different sensitivity and specificity among published studies. In some cases, in vivo tests such as Drug Provocation test (DPT) could be even contraindicated. Therefore, the need for in vitro testing is compelling, to add useful information along the diagnostic pathway and to limit the need of DPT. In this review, we analyze the different types of in vitro tests, focusing on those used more widely such as specific IgE and on those that are still for research settings, such as basophil activation test and lymphocyte transformation test, but that have shown some useful diagnostic potential.

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.

Allergies and COVID-19 vaccines: An ENDA/EAACI Position paper.

BACKGROUND: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized. METHOD: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed. RESULTS: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable. CONCLUSIONS: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated.

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.

Hypersensitivity reactions to vaccines in children: from measles to SARS-CoV-2.

Allergic individuals at risk for hypersensitivity reactions to measles vaccine marketed for a long time are well established. On the other hand, risk factors for hypersensitivity reactions to the new mRNA COVID-19 vaccines currently include a history of allergy, allergy to excipient of the vaccine, or hypersensitivity reactions to the first dose of COVID-19 vaccine. In the last two cases, the recipient should be assessed by an allergist before vaccination to share a decision on the choice of vaccination. Studies on skin testing accuracy and desensitization protocols to the COVID-19 vaccines and the efficacy of potential alternatives in patients with confirmed hypersensitivity reactions to the first COVID-19 vaccine are necessary to improve the safety of COVID-19 vaccines.

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.

Radiocontrast Media Hypersensitivity Reactions in Children.

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.

'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.

An EAACI Task Force report on allergy to beta-lactams in children: Clinical entities and diagnostic procedures.

Beta-lactam (BL) allergy suspicion is common in children and constitutes a major public health problem, with an impact on patient's health and on medical costs. However, it has been found that most of these reactions are not confirmed by a complete allergic workup. The diagnostic value of the currently available allergy tests has been investigated intensively recently by different groups throughout the world. This has led to major changes in the management of children with a suspected BL allergy. Particularly, it is now well accepted that skin tests can be skipped before the drug provocation test in children with a benign non-immediate reaction to BL. However, there is still a debate on the optimal allergic workup to perform in children with a benign immediate reaction. In addition, management of children with severe cutaneous adverse drug reactions remains difficult. In this review, based on a selection of the most relevant studies found in the literature, we will review and discuss the diagnosis of different forms of BL allergy in children.

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.

Delayed hypersensitivity to antiepileptic drugs in children.

BACKGROUND: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy, but they can be associated with the development of mainly delayed/non-immediate hypersensitivity reactions (HRs). Although these reactions are usually cutaneous, self-limited, and spontaneously resolve within days after drug discontinuation, sometime HR reactions to AEDs can be severe and life-threatening. AIM: This paper seeks to show examples on practical management of AED HRs in children starting from a review of what it is already known in literature. RESULTS: Risk factors include age, history of previous AEDs reactions, viral infections, concomitant medications, and genetic factors. The diagnostic workup consists of in vivo (intradermal testing and patch testing) and in vitro tests [serological investigation to exclude the role of viral infection, lymphocyte transformation test (LTT), cytokine detection in ELISpot assays, and granulysin (Grl) in flow cytometry. Treatment is based on a prompt drug discontinuation and mainly on the use of glucocorticoids. CONCLUSION: Dealing with AED HRs is challenging. The primary goal in the diagnosis and management of HRs to AEDs should be trying to accurately identify the causal trigger and simultaneously identify a safe and effective alternative anticonvulsant. There is therefore an ongoing need to improve our knowledge of HS reactions due to AED medications and in particular to improve our diagnostic capabilities.

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.