Descriptive bias in the clinical history of adverse drug reactions in children.

Descriptive bias in the clinical history of adverse drug reactions in children. | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 27 June 2025 V1 Latest version Share on Descriptive bias in the clinical history of adverse drug reactions in children. Authors : Giacomo Gagliardi 0000-0003-3839-583X [email protected] , Leonardo Tomei 0000-0002-7177-7939 , Giulia Liccioli 0000-0002-5216-0423 , Simona Barni 0000-0001-5598-2740 , Mattia Giovannini 0000-0001-9568-6882 , Lucrezia Sarti 0000-0001-8055-3788 , Benedetta Pessina , Erika Paladini , Anna Ariano , Salvatore Grosso , and Francesca Mori 0000-0001-7483-0128 Authors Info & Affiliations https://doi.org/10.22541/au.175102207.77676696/v1 266 views 171 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background De-labeling suspected adverse drug reactions (ADRs) is a critical goal in clinical practice, as misdiagnosed allergies lead to unnecessary medicalization and unwarranted restrictions on available medications. In children, high-risk factors for ADR, such as immediate urticaria, often overlap with common viral rashes, complicating risk stratification. This challenge is compounded by caregiver-reported histories, which can distort symptom timing and severity. This case-control study evaluated the reliability of caregivers and the influence of non-clinical factors in predicting the risk. Methods Patients and caregivers referred to the Allergy Units of two tertiary care hospitals for suspected hypersensitivity reactions (HSRs) were included. Questionnaires were offered to caregivers and patients aged 7-17. Participants were divided into two groups: patients with suspected HSRs and controls without a history of HSR. Enrolled subjects were asked to recognize pictures of maculopapular, micropapular, and urticaria via a multiple-choice questionnaire. Results Data from 405 participants were collected between September 2023 and August 2024. Statistical analysis showed that a higher caregiver education and a positive personal or familiar history of HSR and/or urticaria significantly improved recognition accuracy. Nevertheless, over 50% of participants with suspected HSR history misidentified urticaria with micropapular rash, underscoring the low reliability of caregiver reports. In addition, rash recognition skills did not differ significantly between healthcare and non-healthcare caregivers. Conclusions These findings highlight the need for systematic approaches beyond descriptive histories. Integrating non-clinical factors into diagnostic frameworks could enhance risk stratification and support safer and more effective allergy workup for de-labeling suspected HSR in pediatric patients. Title : jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Descriptive bias in the clinical history of adverse drug reactions in children. Authors : Giacomo Gagliardi* 1,2 ; Leonardo Tomei 1 ; Giulia Liccioli 1 ; Simona Barni 1 ; Mattia Giovannini 1,2 ; Lucrezia Sarti 1 ; Benedetta Pessina 1,2 ; Erika Paladini 3 ; Anna Ariano 3 ; Salvatore Grosso 3 ; Francesca Mori 1 Giacomo Gagliardi https://orcid.org/0000-0003-3839-583X [email protected] Leonardo Tomei https://orcid.org/0000-0002-7177-7939 [email protected] Giulia Liccioli https://orcid.org/0000-0002-5216-0423 [email protected] Simona Barni https://orcid.org/0000-0001-5598-2740 [email protected] Mattia Giovannini https://orcid.org/0000-0001-9568-6882 [email protected] Lucrezia Sarti https://orcid.org/0000-0001-8055-3788 [email protected] Benedetta Pessina https://orcid.org/0000-0002-1387-3463 [email protected] Erika Paladini https://orcid.org/0000-0001-7116-0325 [email protected] Anna Ariano [email protected] Salvatore Grosso https://orcid.org/0000-0002-0974-0596 [email protected] Francesca Mori https://orcid.org/0000-0001-7483-0128 [email protected] jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Affiliations: 1 Allergy Unit, Meyer Children’s Hospital IRCCS, Florence, Italy; 2 Department of Health Sciences, University of Florence, Florence, Italy. 3 Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy *Corresponding author: Giacomo Gagliardi; Allergy Unit, Meyer Children’s Hospital IRCCS, Viale Pieraccini 24, 50139, Florence, Italy. Email address: [email protected] Phone number: +39 055 566 2472 Running title: Descriptive bias in pediatric ADRs. World count for text : 2707 Number of tables : 4 Number of figures : 2 (1 graphical abstract) Data sharing and data accessibility: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Conflict of interest : MG reports personal fees from Sanofi, Thermo Fisher Scientific. All other authors declare that they have no conflicts of interest to disclose in relation to this paper. Financial support : The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Ethical approval and trial registration : The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board Statement of Meyer Children’s Hospital IRCCS. Consent for publication : Written informed consent was obtained from the children’s caregivers for all procedures performed and for publication. Abstract: Background De-labeling suspected adverse drug reactions (ADRs) is a critical goal in clinical practice, as misdiagnosed allergies lead to unnecessary medicalization and unwarranted restrictions on available medications. In children, high-risk factors for ADR, such as immediate urticaria, often overlap with common viral rashes, complicating risk stratification. This challenge is compounded by caregiver-reported histories, which can distort symptom timing and severity. This case-control study evaluated the reliability of caregivers and the influence of non-clinical factors in predicting the risk. Methods Patients and caregivers referred to the Allergy Units of two tertiary care hospitals for suspected hypersensitivity reactions (HSRs) were included. Questionnaires were offered to caregivers and patients aged 7-17. Participants were divided into two groups: patients with suspected HSRs and controls without a history of HSR. Enrolled subjects were asked to recognize pictures of maculopapular, micropapular, and urticaria via a multiple-choice questionnaire. Results Data from 405 participants were collected between September 2023 and August 2024. Statistical analysis showed that a higher caregiver education and a positive personal or familiar history of HSR and/or urticaria significantly improved recognition accuracy. Nevertheless, over 50% of participants with suspected HSR history misidentified urticaria with micropapular rash, underscoring the low reliability of caregiver reports. In addition, rash recognition skills did not differ significantly between healthcare and non-healthcare caregivers. Conclusions These findings highlight the need for systematic approaches beyond descriptive histories. Integrating non-clinical factors into diagnostic frameworks could enhance risk stratification and support safer and more effective allergy workup for de-labeling suspected HSR in pediatric patients. Key message: This case-control study analyzes the reliability of caregiver-reported histories in suspected pediatric drug hypersensitivity reactions. The findings suggest that caregiver descriptions are often influenced by recall bias and subjective misinterpretation of symptoms, particularly in the identification of skin manifestations such as urticaria and micropapular rashes. Higher educational attainment and a personal or family history of previous cutaneous reactions are associated with better recognition accuracy. This study highlights the need to move beyond purely descriptive anamnesis of cutaneous drug hypersensitivity reactions; non-clinical factors should be considered in order to improve risk stratification and optimize resource allocation. Keywords: Adverse drug reactions, Bias, Skin rash, Maculopapular Drug Eruption, Urticaria, Risk assessment, Caregivers. jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Main text: jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Introduction An adverse drug reaction (ADR) is a noxious, unintended response to a drug. While some are relatively minor, others can be life-altering or even fatal. 1 ADRs are often grouped into two types: Type A reactions are predictable and dose-dependent, while Type B reactions are unpredictable, not dose-related and typically immune-mediated. 2 Only approximately 5% of Type B reactions are allergic reactions, 3 which although rare require a proper diagnosis to prevent incorrect labelling, particularly in children. The classification of ADRs based on the Gell and Coombs system includes four types of immune mechanisms (Types I-IV), each with distinct pathophysiological and clinical presentations. 4,5 However, this classification has limitations in capturing the overlapping mechanisms of ADRs. Recent advances in immunology have prompted the development of updated classification systems. Among them, the model proposed by Doña et al. integrates immunologic and non-immunologic mechanisms with clinical phenotypes, endotypes and potential biomarkers. This model allows for the inclusion of IgE-mediated, non-IgE-mediated, mixed reactions and delayed-type T-cell mediated hypersensitivity reactions. 6 Cutaneous manifestations represent the most frequent clinical expression of hypersensitivity reactions (HSRs) with a broad spectrum of presentations ranging from urticaria and mild maculopapular rashes to severe life-threatening conditions. 7,8 Diagnosis of HSRs requires a stepwise approach, starting with a detailed clinical history, targeted skin and in vitro testing and often concluding with a supervised drug provocation test (DPT). 9 DPT remains the gold standard for confirming or excluding drug HSRs in the absence of clear immunologic markers. 10,11 Recent studies have focused on how to identify low-risk patients with suspected HSR who may safely undergo direct DPT without prior skin testing. 12 The EAACI/ENDA 2023 position paper underscores the importance of a proper risk stratification to ensure patient safety and reduce unnecessary testing and resource utilization. 13 One of the key high-risk indicators is the onset of urticaria within one hour of drug intake, which suggests an immediate-type HSR. In such cases, skin testing is mandatory, and if negative, DPT should be performed in a hospital setting with at least three incremental steps and prolonged observation. Pediatric patients exhibit unique vulnerabilities due to the immaturity of pharmacokinetic processes involved in drug metabolism and clearance, as well as the frequent off-label use of drugs due to the lack of pediatric-specific pharmacological data. 14 Whereas adult risk stratification protocols classify acute urticaria occurring after drug intake as a high-risk manifestation suggestive of IgE-mediated hypersensitivity, the EAACI Pediatric Task Force Report adopts a less stringent classification, considering acute urticaria in children without systemic symptoms a low-risk manifestation. 15 Data from pediatric cohorts show that DPT performed without prior skin testing is usually well tolerated in children with a history of mild non-immediate cutaneous HSRs, with only 2% of cases yielding a mild, self-limited positive reaction. 16 In children, acute urticaria occurs at an annual incidence of approximately 1%. 17 Infections are recognized as the leading cause of acute urticaria in the pediatric population, more commonly identified than drug HSRs or food-related triggers. 18,19 The diagnostic distinction between viral rashes and drug-induced skin reactions remains complex, given their frequent temporal overlap. 20 Furthermore, evidence indicates that the concomitant presence of viral infections and drug administration may synergistically contribute to the onset of urticaria. 21,22 Diagnostic workups are contingent upon an accurate and reliable clinical history, which is often lacking, especially in pediatric cases. Despite widespread reporting, more than 90% of individuals who self-report a drug allergy actually tolerate the drug upon re-exposure through a DPT. 23 These findings underscore the overreporting of drug allergies, reinforcing the importance of accurate diagnostic pathways. Moreover, most scoring systems and risk assessment algorithms have been studied in adults, and their applicability have not been adequately validated in children. 12 In addition, caregiver-reported ADR histories are frequently unreliable due to recall bias, emotional distortion and limited medical vocabulary. This is further supported by evidence that reactions described by parents as “immediate” are later found to be mostly delayed viral rashes or unrelated conditions, with only about 8% of ADRs confirmed by testing. 24 In a study conducted in a large sample of adult patients with history of HSR to penicillin, 21.1% of patients were unable to provide a detailed description of the time interval between drug administration and reaction, and therefore could not distinguish immediate from late reactions on the basis of history. 25 Reliability of caregivers’ anamnesis is further affected by socioeconomic and educational factors, as shown by a study which revealed that only 35% of caregivers accurately recalled their child’s past hospitalizations, and 25% failed to recall any at all. 26 This diagnostic inaccuracy can result in unnecessary avoidance of first-line treatments, increased antimicrobial resistance, and higher healthcare costs. The literature currently lacks comprehensive studies that examine how non-clinical variables influence the reliability of drug allergy histories in pediatric populations. Caregiver education level, previous exposure to similar events or a family history of a drug allergy may impact the accuracy of reported symptoms, yet these aspects are rarely included in clinical algorithms. The aim of this study is, therefore, to evaluate how well caregivers and pediatric patients can visually recognize drug-related skin manifestations and to analyze how factors such as caregiver’s educational attainment, personal history of urticaria and family history of drug HSR influence the reliability of the anamnesis. By quantifying these descriptive biases, this study seeks to help identify specific limitations in current pediatric risk stratification tools and underline the need for a more nuanced approach in the diagnostic workup of drug HSRs in children. Methods This case-control study was conducted between September 2023 and August 2024 at the Allergy Units of two specialized Italian centers: Meyer Children’s Hospital IRCCS, Florence, and Santa Maria alle Scotte University Hospital, Siena. Participants enrolled were caregivers and patients divided into two clusters according to age (7–13 years and 14–17 years). Recruitment criteria ensured age-matching between case and control groups. We assessed participants’ ability to discriminate among drug-related skin rashes via a structured questionnaire, showing three pictures of patients with different cutaneous HSRs on their back: micropapular rash, urticaria and maculopapular rash (Figure 1). High-resolution pictures were selected and validated by a panel of pediatric allergologists and confirmed by a dermatologist to ensure they represented typical features of these reactions. Participants were asked to identify each rash type in a standardized multiple-choice format. Before answering, the study purpose was explained to all participants. Responses to the questionnaire were recorded alongside personal data. Educational attainment, healthcare-related experience, and history of drug hypersensitivity or dermatological conditions were recorded for each participant to evaluate their potential influence on rash recognition accuracy. Both descriptive and inferential statistics were employed to analyze response accuracy rates for each rash type. Chi-square tests were used to examine associations between participant characteristics and rash identification accuracy. Logistic regression models were employed to quantify the impact of educational attainment and previous HSR or urticaria episodes, reporting odds ratios with 95% confidence intervals. All analyses were conducted using an R-based statistical software. Results A sample of 276 caregivers and 129 patients was recruited. The study population was divided into two cohorts: an arm consisting of 202 patients and their parents, selected on the basis of a suspected history of drug HSR posed after careful clinical and anamnestic evaluation, and a control group, consisting of 203 subjects without a history of previous suspected HSR with other disorders (allergic rhinitis, atopic dermatitis, food allergy, asthma, acute or chronic urticaria, Hymenoptera venom allergy). The two arms also had a uniform distribution in both age and educational level (Table 1). Analysis of the test results of the study subjects shows that the participants performed significantly better in recognizing the maculopapular rash than the other proposed rash types. However, it was significantly difficult for participants to correctly recognize both micropapular rash and urticaria (Table 2). Comparative analysis of the test results showed no statistically significant differences in skin rash proper recognition between health care workers and the remaining study sample (p > 0.05) (Table 3). The hypothesis that a personal history of urticaria, whether occasional or recurrent/persistent, predisposes to visual recognition of this condition was strongly supported by the data collected: statistical analysis showed a highly significant association (p < 0.001) between a positive history of urticaria and better ability to identify images of urticarial lesions. Similarly, subjects with a positive history had significantly higher scores on the overall questionnaire (p = 0.002). Analyzing the responses given to the picture of maculopapular rash between the two study groups, no statistically significant differences in the results emerged (p > 0.05). Although a significant difficulty in recognizing urticaria and micropapular rash has already been found in the analyzed sample, a statistically significant disparity emerges in the ability to discriminate urticaria from micropapular rash (p < 0.01) and vice versa (p < 0.01) among the participants: in fact, the group with a negative history of HSRs showed a more pronounced propensity to confuse the two types of rash, as opposed to the group with previous history of HSRs, although approximately in the latter group 50% of the subjects still confused the two types of rash (Table 4). Considering the unsatisfactory results obtained in the recognition of picture 3 (“maculopapular rash”), we opted to simplify the model by excluding this variable. We then adopted ordinal logistic regression to evaluate the performance of the model based on an ordinal dependent variable indicating the number of correct responses given for picture 1 (“micropapular rash”) and 2 (“urticaria”) (Table 4). This methodological choice allowed us to sort the outcomes into three categories, defined as follows: • Value 0: none of the answers given for images 1 and 2 were correct (0/2). This indicates that the subject was unable to identify either type of rash under consideration correctly. • Value 1: only one of the answers given for images 1 and 2 was correct (1/2). This means that the subject correctly identified one of the two types of rash but made a mistake in identifying the other. • Value 2: both answers given for images 1 and 2 were correct (2/2). This indicates that the subject correctly identified both types of rash. In order to minimize the influence of external factors, such as parental intervention in providing the answers to the questionnaires, we further restricted the study sample of the model to the adult population only: the inclusion of underage subjects could have introduced a bias in the data, as the test responses might have been mediated or influenced by parental opinions. A further reason for excluding minors concerns the potential bias related to educational qualification: all minors would necessarily have been classified as ”non-college graduates,” underestimating the actual impact of educational qualification on the dependent variable and thus reducing possible bias in the data analysis. The purpose of limiting the study to the adult population, in exchange for a net reduction in the sample analyzed, is to ensure greater variability of educational qualification in the population and consequently a more accurate estimation of its effect, greater autonomy in completing the questionnaires and consequently reliability of the results and homogeneity of the population in terms of cognitive ability and socioeconomic factors. In order to investigate the association between educational qualification, membership in the healthcare category, the presence of a positive history of HSR, a positive history of urticaria and the outcome of the dependent variable, we considered the following nonparametric categories: non-college graduates and college graduates, non-healthcare workers and healthcare professionals, negative or positive history of a previous HSR, and absence and presence of previous urticaria. Ordinal logistic regression analysis revealed that both educational level and the presence of a prior drug reaction were significantly associated with a higher test score. More specifically, college-educated subjects were significantly (p = 0.01) more likely (p = 0.01) to score about twice as high as nongraduates. Similarly, subjects with a history of urticaria (p = 0.022) and parents of children with prior HSR had a significantly higher probability (p = 0.042) of scoring higher on the questionnaire by about 85% (p = 0.0022) and 67% (p = 0.042) respectively (Table 4). When analyzing caregivers working in health care versus the rest of the sample, the odds ratio is very close to 1 and the confidence interval includes 1: this indicates that based on these data we cannot conclude that there is a significant difference between the health care and non-health care groups in terms of rash recognition ability. Discussion This study highlights the impact of descriptive biases in the caregiver-reported histories when evaluating suspected HSRs in children. The visual recognition of drug-related eruptions, particularly urticaria, maculopapular and micropapular rashes, significantly varies among caregivers and patients, with maculopapular rashes being more accurately identified than others. This finding might be attributed to the characteristics of this type of rash: in fact, the term “maculopapular” itself recalls a reaction with the presence of spots and helps the visual recognition. In addition, its distinctive morphology characterized by more prominent and apparently more severe lesions seems to have facilitated the process of identification. On the other hand, the frequent confusion between urticaria and micropapular rashes may reflect their similar appearance and less distinctive features. However, the exclusive use of dorsal rash images may have introduced a visual bias, potentially impacting participants’ ability to identify urticarial lesions regardless of their medical history accurately. Individuals with higher educational attainment, a personal or familial history of urticaria or previous exposure to HSRs exhibited significantly greater performance in the identification of the pictures. These variables emerged as statistically significant predictors in the logistic regression analysis, indicating that both cognitive competence and past exposure contribute to improved diagnostic reliability. These findings have practical implications for clinicians, as they highlight how caregivers’ limited ability to describe hypersensitivity reactions can complicate the clinical evaluation process. This observation is supported by previous research, including studies by Mill et al. and Ibáñez et al. , which demonstrated that most caregiver-reported histories frequently diverge from the actual timing and clinical characteristics of confirmed immediate-type HSRs. 27,28 Despite expectations, no significant difference was observed in recognition performance between healthcare professionals and non-healthcare participants. While it is plausible that formal training might confer an advantage in the recognition accuracy, the results obtained did not support this hypothesis. Several methodological and contextual factors may have influenced this outcome: primarily, the heterogeneity of professional figures within the healthcare subgroup, including non-clinical personnel with disparate levels of medical expertise, introduced considerable variability in the results. Moreover, the relatively small sample size of healthcare workers enrolled (n = 24, 5.93%) may have reduced the strength of the statistical analysis, making it more difficult to detect significant differences. Additional factors such as age, level of education and previous experience with skin diseases may have influenced the results, making it difficult to isolate the impact of a specific training. Therefore, these findings suggest that professional membership alone does not improve the ability to recognize skin rashes. However, other factors not analyzed, such as medical specialization, clinical experience and continuing training, may be more relevant in determining diagnostic skills. Our findings emphasize the need to move beyond a purely descriptive approach to HSR history-taking, in order to improve the diagnostic accuracy and safety of allergy assessments in children. Misattribution of viral rashes or other benign conditions to drug allergy can result in inappropriate labelling of children as ”allergic”. This can lead to the unnecessary avoidance of first-line therapies, increased use of broad-spectrum antibiotics and antimicrobial resistance. 29 It is interesting to note that a more accurate parental description of the type of reaction are associated with a significantly shorter duration of the allergy workup, better targeted tests performed by physicians and an earlier definite diagnosis. 30 Including non-clinical variables such as caregiver education, prior exposure to hypersensitivity events and familiarity with dermatologic conditions in diagnostic algorithms may help define risk stratification and optimize the allocation of diagnostic resources. Furthermore, structured tools such as standardized pictures should be incorporated into the diagnostic process, particularly in settings with limited access to specialized testing. Methodologically, our study may have certain limitations that must be acknowledged. Indeed, potential confounding variables such as emotional memory distortion, cultural perception of illness or media influence were not directly assessed and may have influenced participants’ responses. Although the sample size was relatively large, further research with wider samples could provide more precise information on the role of health training in skin rash recognition. References 1. Adverse drug reaction, European Medicines Agency (EMA). Available at: https://www.ema.europa.eu/en/glossary-terms/adverse-drug-reaction (Accessed: 8 April 2025). 2. Pichler WJ. Immune pathomechanism and classification of drug hypersensitivity. Allergy . 2019;74(8):1457-1471. doi:10.1111/all.13765 3. Lazarou J, Pomeranz BH, Corey PN. Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA . 1998;279(15):1200. doi:10.1001/jama.279.15.1200 4. Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. Journal of Allergy and Clinical Immunology . 2004;113(5):832-836. doi:10.1016/j.jaci.2003.12.591 5. Rajan TV. The Gell–Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol . 2003;24(7):376-379. doi:10.1016/S1471-4906(03)00142-X 6. Doña I, Torres MJ, Celik G, Phillips E, Tanno LK, Castells M. Changing patterns in the epidemiology of drug allergy. Allergy . 2024;79(3):613-628. doi:10.1111/all.15970 7. Tli H, U-p K, Hunziker T, et al. Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey. Allergy . 1997;52:388-393. 8. Ardern-Jones MR, Friedmann PS. Skin manifestations of drug allergy. Br J Clin Pharmacol . 2011;71(5):672-683. doi:10.1111/j.1365-2125.2010.03703.x 9. Saretta F, Tomei L, Mori F, Mayorga C. In vitro diagnostic testing for drug allergy in children. Pediatric Allergy and Immunology . 2023;34(4). doi:10.1111/pai.13955 10. Bousquet PJ, Gaeta F, Bousquet-Rouanet L, Lefrant JY, Demoly P, Romano A. Provocation Tests in Diagnosing Drug Hypersensitivity . Vol 14.; 2008. 11. Rerkpattanapipat T, Chiriac AM, Demoly P. Drug provocation tests in hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol . 2011;11(4):299-304. doi:10.1097/ACI.0b013e328348a4e9 12. Arıkoğlu T, Kuyucu S, Caubet J. New diagnostıc perspectives in the management of pediatrıc beta‐lactam allergy. Pediatric Allergy and Immunology . 2022;33(3). doi:10.1111/pai.13745 13. Barbaud A, Garvey LH, Torres M, et al. EAACI/ENDA position paper on drug provocation testing. Allergy . 2024;79(3):565-579. doi:10.1111/all.15996 14. Elzagallaai A, Greff M, Rieder M. Adverse Drug Reactions in Children: The Double‐Edged Sword of Therapeutics. Clin Pharmacol Ther . 2017;101(6):725-735. doi:10.1002/cpt.677 15. Blanca-Lopez N, Atanaskovic-Markovic M, Gomes ER, et al. An EAACI Task Force report on allergy to beta-lactams in children: Clinical entities and diagnostic procedures. Pediatric Allergy and Immunology . 2021;32(7):1426-1436. doi:10.1111/pai.13529 16. Cunha F, Cunha I, Gomes E. Safety of direct oral provocation test to delabel reported mild beta-lactam allergy in infants. Allergol Immunopathol (Madr) . 2023;52(2):10-15. doi:10.15586/aei.v52i2.887 17. Brüske I, Standl M, Weidinger S, et al. Epidemiology of urticaria in infants and young children in Germany - Results from the German LISAplus and GINIplus Birth Cohort Studies. Pediatric Allergy and Immunology . 2014;25(1):36-42. doi:10.1111/pai.12146 18. Sackesen C, Sekerel E, Kocabas N, Adalioglu G. The Etiology of Different Forms of Urticaria in Childhood . Vol 21.; 2004. 19. Bezirganoglu H, Arik Yilmaz E, Sahiner UM, et al. The common triggers of urticaria in children admitted to the pediatric emergency room. Pediatr Dermatol . 2022;39(5):695-701. doi:10.1111/pde.15020 20. Brockow K, Ardern-Jones MR, Mockenhaupt M, et al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy: European Journal of Allergy and Clinical Immunology . 2019;74(1):14-27. doi:10.1111/all.13562 21. Mortureux P, Léauté-Labrè C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taı¨eb AT. Acute Urticaria in Infancy and Early Childhood A Prospective Study . http://archderm.jamanetwork.com/ 22. Mori F, Liccioli G, Tomei L, et al. How to manage drug-virus interplay underlying skin eruptions in children. World Allergy Organization Journal . 2024;17(3). doi:10.1016/j.waojou.2024.100877 23. Norton AE, Konvinse K, Phillips EJ, Broyles AD. Antibiotic Allergy in Pediatrics. Pediatrics . 2018;141(5). doi:10.1542/peds.2017-2497 24. Piccorossi A, Liccioli G, Barni S, et al. Epidemiology and drug allergy results in children investigated in allergy unit of a tertiary-care paediatric hospital setting. Ital J Pediatr . 2020;46(1):5. doi:10.1186/s13052-019-0753-4 25. Hjortlund J, Mortz CG, Skov PS, Bindslev-Jensen C. Diagnosis of penicillin allergy revisited: The value of case history, skin testing, specific IgE and prolonged challenge. Allergy: European Journal of Allergy and Clinical Immunology . 2013;68(8):1057-1064. doi:10.1111/all.12195 26. Burakevych N, McKinlay CJD, Alsweiler JM, Harding JE. Accuracy of caregivers’ recall of hospital admissions: implications for research. Acta Paediatr . 2015;104(11):1199-1204. doi:10.1111/apa.13208 27. Mill C, Primeau MN, Medoff E, et al. Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children. JAMA Pediatr . 2016;170(6):e160033. doi:10.1001/jamapediatrics.2016.0033 28. Ibáñez MD, Rodríguez del Río P, Lasa EM, et al. Prospective assessment of diagnostic tests for pediatric penicillin allergy. Annals of Allergy, Asthma & Immunology . 2018;121(2):235-244.e3. doi:10.1016/j.anai.2018.05.013 29. du Plessis T, Walls G, Jordan A, Holland DJ. Implementation of a pharmacist-led penicillin allergy de-labelling service in a public hospital. Journal of Antimicrobial Chemotherapy . 2019;74(5):1438-1446. doi:10.1093/jac/dky575 30. Liccioli G, Tomei L, Pessina B, et al. The importance of clinical history in the diagnosis of drug hypersensitivity in children. Pediatric Allergy and Immunology . 2024;35(3). doi:10.1111/pai.14091 Population N Previous urticaria University graduates High school diploma Junior high school diploma Caregivers Patients 7-13 years Patients 14-17 years HSR history 202 98 59 65 78 141 50 11 Controls 203 50 49 70 84 135 44 24 Total 405 148 108 135 162 276 94 35 Table 1. Demographic characteristics of participants in the case (HSR history) and control groups. HSR, Hypersensitivity Reaction. Picture Response “urticaria” Response “maculopapular rash” Response “micropapular rash” Population test results (N=405) 1. Micropapular rash 182/405 (44.94%) 79/405 (19.51%) 144/405 (35.56%) 2. Urticaria 153/405 (37.78%) 43/405 (10.62%) 209/405 (51.60%) 3. Maculopapular rash 75/405 (18.52%) 284/405 (70.12%) 46/405 (11.36%) HSR history group results (N=202) 1. Micropapular rash 79/202 (39.11%) 38/202 (18.81%) 85/202 (42.08%) 2. Urticaria 92/202 (45.54%) 19/202 (9.41%) 91/202 (45.05%) 3. Maculopapular rash 33/202 (16.34%) 146/202 (72.28%) 23/202 (11.39%) Control group results (N=203) 1. Micropapular rash 103/203 (50.74%) 41/203 (20.20%) 59/203 (29.06%) 2. Urticaria 61/203 (30.05%) 24/203 (11.82%) 118/203 (58.13%) 3. Maculopapular rash 42/203 (20.69%) 138/203 (67.98%) 23/203 (11.33%) Table 2 . Responses provided to the questionnaire by the overall population, HSR history group, and control group. HSR, Hypersensitivity Reaction. Picture Response “urticaria” Response “maculopapular rash” Response “micropapular rash” 1. Micropapular rash Non-healthcare subjects Healthcare professionals - with HSR history - without HSR history 172/381 (45.14%) 10/24 (41.67%) 6/18 (33.33%) 4/6 (66.67%) 76/381 (19.95%) 3/24 (12.50%) 3/18 (16.67%) 0/6 (0%) 133/381 (34.91%) 11/24 (45.83%) 9/18 (50%) 2/6 (33.33%) 2. Urticaria Non-healthcare subjects Healthcare professionals - with HSR history - without HSR history 142/381 (37.27%) 11/24 (45.83%) 9/18 (50%) 2/6 (33.33%) 43/381 (11.29%) 0/24 (0%) 0/18 (0%) 0/6 (0%) 196/381 (51.44%) 13/24 (54.17%) 9/18 (50%) 4/6 (66.67%) 3. Maculopapular rash Non-healthcare subjects Healthcare professionals - with HSR history - without HSR history 72/381 (18.90%) 3/24 (12.50%) 3/18 (16.67%) 0/6 (0%) 263/381 (69.03%) 21/24 (87.50%) 15/18 (83.33%) 6/6 (100%) 46/381 (12.07%) 0/24 (0%) 0/18 (0%) 0/6 (0%) Table 3. Questionnaire responses for each rash type comparing non-healthcare subjects and healthcare professionals, with stratification based on HSR history. HSR, Hypersensitivity Reaction. Population Response “urticaria” Response “micropapular rash” Total Picture 1 “micropapular rash” HSR history Control Total 79 (48.17%) 103 (63.58%) 182 (55.83%) 85 (51.83%) 59 (36.42%) 144 (44.17%) 164 162 326 Picture 2 “urticaria” HSR history Control Total 92 (50.27%) 61 (34.08%) 153 (42.27%) 91 (49.73%) 118 (65.92%) 209 (57.73%) 183 179 362 Non-clinical factors OR 95% CI (Lower-Upper bound) P College graduated 1.95 1.17-3.25 0.010* HSR history 1.67 1.02-2.73 0.042* History of urticaria 1.85 1.09-3.12 0.022* Healthcare professionals 0.97 0.39-2.38 0.949 jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Table 4 . Questionnaire responses for micropapular rash and urticaria (pictures 1 and 2) and ordinal logistic regression model on non-clinical predictors (adults only). OR, Odds Ratio; CI, Confidence Interval; HSR, Hypersensitivity Reaction. *p < 0.05. Figure legends: Graphical Abstract. Created with BioRender.com. Figure 1 . Standardized multiple-choice questionnaire, used to evaluate participants’ ability to recognize common drug-related skin rashes: micropapular rash, urticaria and maculopapular rash. The questionnaire was administered to caregivers and pediatric patients (aged 7–17 years). Information & Authors Information Version history V1 Version 1 27 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Giacomo Gagliardi 0000-0003-3839-583X [email protected] Azienda Ospedaliero Universitaria Meyer View all articles by this author Leonardo Tomei 0000-0002-7177-7939 Azienda Ospedaliero Universitaria Meyer View all articles by this author Giulia Liccioli 0000-0002-5216-0423 Azienda Ospedaliero Universitaria Meyer View all articles by this author Simona Barni 0000-0001-5598-2740 Azienda Ospedaliero Universitaria Meyer View all articles by this author Mattia Giovannini 0000-0001-9568-6882 Azienda Ospedaliero Universitaria Meyer View all articles by this author Lucrezia Sarti 0000-0001-8055-3788 Azienda Ospedaliero Universitaria Meyer View all articles by this author Benedetta Pessina Azienda Ospedaliero Universitaria Meyer View all articles by this author Erika Paladini Universita degli Studi di Siena Dipartimento di Medicina Molecolare e dello Sviluppo View all articles by this author Anna Ariano Universita degli Studi di Siena Dipartimento di Medicina Molecolare e dello Sviluppo View all articles by this author Salvatore Grosso Universita degli Studi di Siena Dipartimento di Medicina Molecolare e dello Sviluppo View all articles by this author Francesca Mori 0000-0001-7483-0128 Azienda Ospedaliero Universitaria Meyer View all articles by this author Metrics & Citations Metrics Article Usage 266 views 171 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Giacomo Gagliardi, Leonardo Tomei, Giulia Liccioli, et al. 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