Diagnostic evaluation of hypersensitivity reactions to arylpropionic acid derivatives: a descriptive observational study focusing on clinical characteristics and potential risk factors in children.

BACKGROUND: Arylpropionic acid derivatives (APs) are the main triggers of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. Data on clinical patterns and risk factors for AP hypersensitivity in children are quite limited. AIM: To assess the clinical characteristics and potential risk factors for proven AP hypersensitivity in children. METHOD: Patients with a history of AP hypersensitivity were retrospectively assessed using a standardized diagnostic algorithm. Children with confirmed hypersensitivity were defined as selective responders or cross-intolerants based on the result of drug provocation tests and further categorized according to the EAACI/ENDA classification. A multivariable logistic regression analysis was performed to analyze the potential risk factors for proven AP hypersensitivity. RESULTS: A total of 166 patients (51.2% male, median age of six years) with a history of AP hypersensitivity were included. Ibuprofen (89.2%) was the most frequently reported AP in the patients' histories. The reported hypersensitivity of 40 (22.4%) patients was confirmed by diagnostic testing: eight (13.6%) patients with a history of reaction only to APs and 32 (29.9%) patients with a history of reactions to multiple NSAIDs, including chemically unrelated NSAIDs in addition to APs. Five (12.5%) patients were classified as selective responders and 35 (87.5%) were cross-intolerants. Overall, five (12.5%) of the confirmed cases could not be categorized according to the EAACI/ENDA classification. Older age (aOR: 1.11, 95% CI 1.02-1.21, p = 0.015), chronic urticaria as an underlying disease (aOR: 2.87, 95% CI 1.09-7.54, p = 0.033) and a history of anaphylaxis (aOR: 7.84, 95% CI 1.86-33.04, p = 0.005) were related to confirmed AP hypersensitivity. CONCLUSION: Almost a quarter of children and adolescents were confirmed to have AP hypersensitivity. Older age, the presence of chronic urticaria and a history of anaphylaxis were potential risk factors for proven AP hypersensitivity.

Toxic Skin Reactions Should Be Differentiated from Allergic Reactions to Chemotherapeutic Drugs in Children: A Case Series and Review of the Literature.

Background: Chemotherapeutic drugs can lead to a wide spectrum of cutaneous findings, ranging from nonimmune toxic reactions to severe immune-mediated hypersensitivity reactions. The aim of this study was to evaluate the clinical, histopathological features, and prognosis of toxic skin reactions to chemotherapeutic drugs and to compare them with characteristics of immune-mediated reactions in children with malignancies. Methods: The medical records of all children with cancer who experienced skin reactions after chemotherapy administration and diagnosed as a toxic skin reaction between 2010 and 2022 were retrospectively analyzed. The diagnosis was re-evaluated and differentiated from other similar disorders by using clinical manifestations, photodocumentation, and histopathological findings. Results: A total of 17 children aged 2-17 years were involved: toxic erythema of chemotherapy (TEC) in 14 children, methotrexate-induced epidermal necrosis in 2 children, and toxic epidermal necrolysis (TEN)-like TEC in 1 child. The most commonly implicated drug was methotrexate. Most patients recovered rapidly after drug cessation and supportive measures. In 10 of the 17 patients, reintroduction of the culprit chemotherapeutic drug at reduced doses or increased dosage intervals was possible without any recurrence. Six patients could not receive further doses since they deceased due to sepsis and other complications. Conclusions: Cutaneous toxic eruptions to chemotherapeutic drugs may present with a severe phenotype resembling Stevens-Johnson syndrome/TEN. An accurate diagnosis prevents potentially harmful therapeutic interventions, withholding of chemotherapy, and erroneous assignment of drug allergies.

Evaluation of different protocols for classification of pediatric hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: Children with underlying allergic disease should be a separate subgroup.

Background: Different recommendations for the classification of nonsteroidal anti-inflammatory drug hypersensitivity reactions (NSHSR) in children have been reported but a shortage still exists. Objective: The aim of the present study was to evaluate the inclusivity of two European Academy of Allergy and Clinical Immunology (EAACI) position paper classifications and to characterize the factors that underlie classification discordance in children. Methods: Patients with a history of NSHSR were evaluated with a standardized diagnostic protocol according to EAACI/ European Network for Drug Allergy (ENDA) recommendations. Children were classified and compared according to the EAACI 2013 and the pediatric EAACI/ENDA 2018 classifications. Subjects who were unclassified and those who were classified were compared. Results: Of 232 patients (median [interquartile range] age 6 years (4-11 years) with a history of NSHSR, 52 (22.4%) were confirmed with diagnostic tests. Thirty-six (69.2%) were classified as having cross-intolerance, whereas 16 patients (30.8%) were classified as selective responders. Eleven of the confirmed cases (21.2%) could not be categorized according to the 2013 EAACI classification, whereas this number was six adolescents (11.5%) when the 2018 EAACI/ENDA pediatric classification was used. Patients who were unclassified and who were all cross-intolerant were more likely to have atopic sensitization (p = 0.001) and asthma as an underlying disease (p = 0.03), higher serum eosinophil count (p = 0.022), and total immunoglobulin E levels (p = 0.007) compared with those who fit well into the classification. In multivariate regression analysis, the presence of atopic sensitization (adjusted odds ratio 20.36 [95% confidence interval, 2.14-193.48]; p = 0.009) was found to be the only significant underlying factor for an unclassified and/or blended phenotype. Conclusion: The 2013 EAACI classification resulted in a high rate of subjects who were unclassified. Despite better clinical utility, the recent pediatric EAACI/ENDA classification system still has shortcomings in terms of inclusivity for adolescents. Mostly, children with underlying allergic diseases could not be classified by the current guidelines. We propose to classify them as a separate pediatric cross-intolerance subgroup because the underlying mechanism may involve more than cyclooxygenase 1 inhibition.

A combined risk modeling strategy for clinical prediction of beta-lactam allergies in children.

Background: Drug provocation test (DPT) without skin tests is increasingly recommended in the evaluation of children with low-risk beta-lactam (BL) allergies. However, risk definitions are unclear. Objective: The aim of this study was to compose a clinical predictive model that could identify the children at low risk who could safely undergo direct DPT. Methods: The clinical data of 204 children who underwent a full diagnostic algorithm for suspected BL allergy were analyzed. Clinical data were used to construct mathematical predictive model for confirmed BL allergies. A prospective new sample was used for external validation of the final model. Results: The presentations during the index reaction were anaphylaxis in 5.9% and cutaneous reactions in the majority. BL allergy was confirmed in 15.7% of suspected cases. A backward multiple logistic regression model showed that a family history of drug allergy (adjusted odds ratio [aOR], 5.52), anaphylaxis (aOR, 5.14), any atopic disease other than asthma (aOR, 4.38), and a reaction interval of 0-6 hours during the index reaction (aOR, 5.32) were significantly associated with a confirmed BL allergy. A mathematical combined model based on these factors showed a sensitivity of 77.8% and a negative predictive value (NPV) of 94.3%. The validation study replicated sensitivity and NPV values of the main cohort. Conclusion: The risk definition in BL allergies should depend on population-specific predictive models, including a combination of significant risk factors rather than empiric risk approaches. This may help to accurately determinate children at low risk who may safely proceed to direct DPT.

A novel whole blood based method for lymphocyte transformation test in drug allergies.

Drug allergies pose a great deal of danger for the patients. It hinders effective treatment procedures in hospitalized patients. Moreover, it complicates the symptoms due to the allergic reactions of the immune system. Allergic reactions may arise against any medication including antibiotics and chemotherapeutics. Therefore, it is crucial to assess the sensitization pattern of the patients to culprit drug(s) before retreatment with the same or similar drug, or in order to confirm/exclude a suspected drug hypersensitivity reaction. In vivo and in vitro tests are performed in the evaluation of patients. Current methods of in vitro drug allergy evaluations rely on time consuming and expensive methods. Ficoll separation of peripheral blood mononuclear cells, their activation with stimulants in the presence of the drug of interest, CD69 or CD25 or BrdU or radioactive thymidine analysis of the cells after a couple of days of incubation is an excessively elaborate work and also uneconomical. Moreover, it requires a great deal of expertise to interpret the results. Here, we are reporting a new whole blood based lymphocyte transformation test method that does not require ficoll separation, CD69, CD25, BrdU and radioactive thymidine analysis. Thanks to the color change in the whole blood itself one can easily determine the allergic reaction to a certain drug. This new method is less time consuming, more economical and easy to apply.