Drug Hypersensitivity In Children Research Articles

Cutaneous adverse drug reactions in children with a focus on hypersensitivity to systemic drugs: A narrative review

Drug hypersensitivity in children is rare compared to adults. Children more frequently develop an infection-associated exanthema. Nevertheless, about 95% of children with drug hypersensitivity present with mucocutaneous involvement. Early recognition of typical clinical symptoms is important to reduce morbidity and mortality. We review relevant type I and type IV disorders of drug hypersensitivity in children and discuss their differential diagnoses and treatment.

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

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. 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. 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. 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.

Recent findings on drug hypersensitivity in children.

Drug hypersensitivity reactions (DHR) in children have a significant impact on clinical practice and public health. Both under-diagnosis (due to under-reporting) and over-diagnosis (due to the overuse of the term "allergy") are potential issues. The aim of this narrative review is to describe the most recent findings of DHR in children/adolescents and gaps regarding epidemiology, antibiotic allergy, antiepileptic hypersensitivity, vaccine allergy, and severe cutaneous adverse reactions (SCAR) in this age group.

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) in the pediatric population

Non-steroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) is predominantly encountered in adults and rarely documented and less well-defined clinically and epidemiologically in children. The cause remains unclear, with the main pathogenic mechanism being represented by a decrease in prostaglandin E2 production, increased production of cysteinyl-leukotrienes, and eosinophilic inflammation. N-ERD symptoms in the pediatric population are similar to those in adults: chronic eosinophilic rhinosinusitis with nasal polyps, asthma and respiratory symptoms upon aspirin/NSAID administration, but they can initially present with gastrointestinal or cutaneous symptoms or be more subtle, making early diagnosis difficult and requiring rigorous differential diagnosis. Pediatric onset of N-ERD should be considered by specialists when faced with cases of asthma associated with chronic rhinosinusitis and nasal polyps. Studies involving a larger number of patients are needed to determine the frequency of non-steroidal anti-inflammatory drug hypersensitivity in children with asthma and to establish the evolutionary and therapeutic characteristics of this patient category.

Don't we overestimate drug allergies in children?

On average about 10% of parents report hypersensitivity to at least 1 drug in their children. After diagnosis process a few of these reactions are being confirmed as drug hypersensitivity reactions. The aim of the study was to assess the real-life prevalence of drug hypersensitivity in children based on drug provocation tests. The authors included 113 children, aged 4-18 years, referred to Pediatrics and Allergy Clinic in Łódź, Poland, due to incidence of adverse reaction during treatment. Medical history regarding allergies to drugs was taken in accordance to the form developed by the United States Food and Drug Administration Adverse Event Reporting System. Skin prick tests, intradermal test and drug provocation test were performed in all patients. In all 113 patients suspected of drug allergy, after all diagnostic procedures, the authors proved IgE-mediated allergy to β-lactams, nonsteroid anti-inflammatory drugs, local anesthetics in 19 patients (16.8%). Previous history of allergy was a risk factor for drug allergy in studied patients (p = 0.001). The most frequent symptoms of allergy were urticaria and erythematous papular rash. Drug allergy is a difficult problem in the practice of a doctor and is difficult to diagnose, especially in the pediatric population. It seems that too often isolated symptoms reported during infection or disease are taken as a symptom of drug allergy, and not as a symptom resulting from the course of the disease. Int J Occup Med Environ Health. 2023;36(5):632-42.

Portuguese version of Parent-reported Drug Hypersensitivity Quality of Life Questionnaire (P-DrHy-Q): assessment of reliability and validity.

Background. Drug hypersensitivity in children impacts the quality of life of the patients and their caregivers. The parent-reported drug hypersensitivity quality of life questionnaire (P-DrHy-Q), the first disease-specific quality-of-life questionnaire for caregivers who have children with drug hypersensitivity, was recently developed. The aim of this study was to assess the validity and reliability of the portuguese version of the P-DrHy-Q. Methods. A translation of the Parent-reported Drug Hypersensitivity Quality of Life Questionnaire (P-DrHy-Q) to the Portuguese population was performed, assessing its applicability in 74 caregivers from two allergy departments. The analyses included internal consistency (Cronbach's alpha) and test-retest reliability: 14 caregivers completed the P-DrHy-Q without any intervention one week after answering the first questionnaire. Results. The 12-item scale assessed the mental health and social activity. The internal consistency of the scale was good (Cronbach's alpha = 0.884) and the test-retest associations were excelent (Intra-class correlation coefficient = 0.985; p less than 0.001). The mean value of the questionnaire was (37.01 SD; 18.57) with Mental Health being more affected than Social Activity. Employed caregivers had a significant higher score (p less than 0.001). No other factor was statistically significant. Conclusions. The Portuguese version of the P-DrHy-Q is valid for evaluating quality of life impairment in Portuguese caregivers of children with drug hypersensitivity. Its application might be relevant for future research and provide clinicians and researchers with a tool to define which psychosocial support is required to provide more comprehensive care in drug hypersensitivity.

Diagnosing Single and Multiple Drug Hypersensitivity in Children: A Tertiary Care Center Retrospective Study.

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reactions with heterogeneous pathophysiological mechanisms and a broad spectrum of clinical manifestations. Since over-diagnosing is common in children, a complete allergy work-up is needed. A cross-sectional study was conducted at a tertiary care institution, covering the five-year period. Five hundred and four patients of both sexes, mean age 7.5 and with a medical history suggestive of DHR were evaluated. ENDA/EAACI guidelines were used for a diagnostic algorithm. Single drug hypersensitivity was registered in 375 patients and multiple drug hypersensitivity in 129. The main culprits in medical history were antibiotics (83%), non-steroidal anti-inflammatory drugs (NSAIDs) (8.4%) and analgoantipyretics (3.8%). Skin involvement was registered in 96.2%. DHRs were confirmed in 4.4% patients-six patients had positive skin tests and 13 had a positive drug provocation test. In the proven DHRs group, the main agents were antibiotics (72.7%), followed by NSAIDs (8.3%), and of all the skin manifestations, urticaria was most common (78.2%), followed by exanthema (10.5%) and angioedema (5.3%). Considering the above, anticipating DHRs and a proper referral of children to an allergologist is a key step in the assessment of drug hypersensitivity. A complete allergy work-up prevents unnecessary drug exclusion and allows most children to safely continue the use of first-line medications when needed.

The controversy of drug hypersensitivity in patients with cystic fibrosis and review of the literature.

Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there are conflicting data about true prevalence of drug hypersensitivity in children with CF. The suspicious drug hypersensitivity reactions (DHRs) of children with CF were enquired by the European Network for Drug Allergy (ENDA) questionnaire, and skin tests and/or drug provocation tests were performed according to the established guidelines. Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4years [4.8-12.4years]) with cystic fibrosis were included in the study, among which 22 patients with 24suspected DHRs were evaluated. Most of the suspected DHRs were of non-immediate (n=16, 66.6%) type, and the offending drugs were amoxicillin-clavulanic acid (n=7), macrolides (n=4), trimethoprim-sulfamethoxazole (TMP/SMX) (n=2), piperacillin-tazobactam (n=1), pancrelipase (n=1), and ursodeoxycholic acid (n=1). Eight (33.3%) of the DHRs were classified as immediate (ceftriaxone [n=2], ceftazidime [n=2], meropenem [n=1], AmBisome [n=2], and vancomycin [n=1]). The main clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%), and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed, and none of the skin tests revealed a positive result; however, 2 DPTs with TMP/SMX were positive. Actual drug hypersensitivity was demonstrated in 2 of 219 patients (0.9%) with non-beta-lactam antibiotics. These results conflict with previous researches that showed higher drug hypersensitivity rates but are consistent with some recent studies. Allergological diagnostic workup is mandatory in patients with cystic fibrosis in case of a suspicious DHR.

Exanthematous reactions to drugs in children.

The true exanthematous reactions to drugs in children are rare and overdiagnosed. Drugs may cause exanthema either due to inducing an immune response or because of their interaction with viruses, if drugs are taken in the course of a viral infection. Also, viral infections are very often in children and they can provoke an exanthema which is difficult to differentiate from exanthematous reactions to drugs. Consequently, the majority of children are incorrectly labeled as 'allergic'. The correct diagnosis of exanthematous drug reactions in children is still an important and hot topic. Most information about the approach and management of drug hypersensitivity in children is applied from available guidelines and consensus statement for adults. Recently, a systematic clinical approach for timely differential diagnosis and management of rashes in children who present a cutaneous exanthema while receiving a drug, is proposed. It is important to consider the detailed clinical history of appearing and developing exanthematous drug reaction, as well as physical examination which includes the description and the distribution of exanthema and at the end making the appropriate diagnosis. Thus, it could reduce overdiagnosis and promote appropriate procedures, that will prevent the overlabeling of drug hypersensitivity in children.

Drug hypersensitivity in children: a retrospective analysis of 101 pharmacovigilance reports.

Our objective was to describe and discuss management of recent cases of drug hypersensitivity in children reported in a pharmacovigilance center. Two pediatric allergy units conducted a collaborative retrospective analysis of 101 adverse drug reactions reported to a regional pharmacovigilance center between January 2016 and July 2019. Time lapse between hypersensitivity reaction onset and allergy consultation varied from 1month to 12years. Sixty-two patients (61.4%) presented with immediate reactions, 11 (10.9%) with non-immediate reactions, and 28 (27.7%) had reactions impossible to classify through medical interview. Overall, 92 children (91%) were explored for simultaneously administered drugs. All 113 prick tests were negative, and 2 were uncertain. Among 108 intradermal tests, 2 were positive to penicillin and to an iodinated contrast medium, 105 were negative, and 1 was uncertain. Overall, 129 drug provocation tests were proposed. Nine provocation tests among 80 were positive (11.25%): 6 to penicillin, 1 to sulfonamide antibiotics, and 2 to non-steroidal anti-inflammatory drugs; the remaining 71 were negative. No severe reaction was observed during these tests. Finally, drug allergy was only retained in 11 reported cases (10.9%).Conclusion: These pharmacovigilance reports show the difficulty in defining drug allergy in children only by anamnesis, and that explorations, particularly provocation tests, should take place at a reasonable time lapse after drug hypersensitivity reaction onset. What is Known: • True drug allergy is rarely observed in children. • Absence of full workup leads to falsely labeling children as "allergic." What is New: • Short time lapse between hypersensitivity onset and consultation improves classification of pediatric allergy. • Timely allergy consultations are essential, and tests are useful to confirm or exclude pediatric allergy.

Development and validation of the parent-reported Drug Hypersensitivity Quality of Life Questionnaire.

Background. Drug hypersensitivity in children impacts the quality of life of the patients and their caregivers. Measurements of the quality of life in children are different from adults, because children cannot answer the questions. This research aimed to develop and validate the Parent-reported Drug Hypersensitivity Quality of Life Questionnaire (P-DrHy-Q). Methods. The 21-item scale was initially generated by researchers. Then, 3 experts were asked for their opinion about the scale. After adjusting the contents and language, the scale was answered by 97 caregivers. A factor analysis was carried out to select the items for the final scale, and Cronbach's alpha assessed the internal consistency. Finally, we examined the test-retest reliability in another group of 10 caregivers. Results. The 21-item scale was grouped into 6 factors. However, some factors were inappropriate. Therefore, the number of factors was reduced using a statistical analysis. The final 12-item scale included two factors: mental health and social activity. The scale had good internal consistency (Cronbach's á = 0.897) and the test-retest associations were good (R = 0.9439; p minor 0.001). Conclusions. The P-DrHy-Q is the first scale for assessment to consider the interaction of biopsychosocial factors on drug allergy that includes the carer-child dyad. It shows good internal consistency and reliability. Its application might be relevant for future research, and provide clinicians and researchers with a solid tool to define which type of psychosocial support is required to provide more comprehensive care in drug hypersensitivity.

Drug Allergy in Children: What Should We Know?

The drug allergy “label” may have a lifetime of consequences for a child. Many children with alleged drug allergies are proven to be tolerant to the culprit medication when challenged. The field of drug hypersensitivity is a recently evolving field of research, but studies on its epidemiology and diagnostic tools are lacking in children. Clinical history is significant in the diagnosis and classification of drug hypersensitivity in children. Diagnostic tools have been evaluated in a limited number of children; therefore, the guidelines are mainly in line with those for adults. Here, we review the clinical characteristics, main drugs, risk factors, and diagnosis of drug hypersensitivity to aid in its accurate diagnosis in children.

Two approaches for diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity in children

BackgroundThe oral provocation test (OPT) with culprit drug is the gold standard in the diagnosis of nonsteroidal anti-inflammatory drug hypersensitivity (NSAID-H). Some authors have proposed that the total number of OPTs required to diagnose NSAID-H is much lower with acetyl salicylic acid (ASA) provocations, regardless of patients' reaction history, and less time consuming. ObjectiveThis study aims to evaluate the total number of OPTs required to confirm NSAID-H according to the drugs (ASA or culprit NSAID) used in the initial OPT. MethodsThe study included patients with a history of NSAID-H. Data on the demographic and clinical features, coexisting chronic or allergic disease, and laboratory results were collected from medical records. The drug used for the initial OPT (ASA or culprit NSAID), results of the OPT, and the total number of OPTs were reviewed. ResultsWe included 56 children with suspected hypersensitivity reaction to NSAIDs. NSAID-H was confirmed in 21 children (37.5%). We calculated that if all OPTs were performed with culprit drugs as an initial choice, the number of OPTs required for diagnosis would be 3 or more in 85.7% of positive cases. The number of episodes was an independent risk factor for NSAID-H by multiple logistic regression analysis (odds ratio, 4.3; 95% confidence interval, 1.48-12.24; P = .007). ConclusionPerforming an initial OPT with ASA regardless of patients' reaction history can result in much lower numbers of OPT to diagnose NSAID-H and can improve patient compliance.

Proven immunologically-mediated drug hypersensitivity in children with a history of multiple drug intolerances

BackgroundChildren may be referred to pediatric allergy clinics for reactions to multiple drugs. Multiple drug hypersensitivity (MDH) is defined as immunologically-mediated hypersensitivity to 2 or more chemically different drugs. ObjectiveThe aim of this study is to report the allergy workup results of children who had a history of potential hypersensitivity reactions to 2 or more unrelated drugs. MethodsThis study was conducted in the Pediatric Allergy and Immunology department of our hospital. Children who described hypersensitivity reactions to 2 or more drugs were included and were evaluated by allergy workup (skin and/or provocation tests) between January 2011 and July 2016. ResultsDuring the study period, 886 children were evaluated for a history of drug intolerance. Of these children, 73 (8.2%) had a history of drug reactions to 2 or more chemically different drugs. The median age of the children who had a history of reactions to 2 or more drugs was 7.8 (min-max: 2.5-16.4) years, and 59% (n = 43) were male. Among the suspected drugs, antibiotics (65.9%) ranked first, and nonsteroid anti-inflammatory drugs (34.1%) were the second. All 73 children were evaluated with skin or provocation tests with the suspected drugs, and MDH was confirmed in only 2 (2.7%) children. ConclusionMultiple drug hypersensitivity is uncommon in children. The incidence and prevalence of MDH may vary with the specific population studied. Evaluating children with a history of MDH, by performing drug hypersensitivity testing, will help avoid the morbidity associated with unnecessary drug avoidance.

The Frequency of Nonsteroidal Anti-Inflammatory Drug Hypersensitivity in Children with Asthma

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the second-most frequent drug type to cause hypersensitivity reactions in children. Asthma is one of the risk factors for NSAID hypersensitivity (NSAID-H) in adult patients. There are limited number of studies evaluating NSAID-H among children with asthma. Our aim was to assess the frequency of confirmed NSAID-H and evaluate the classification of NSAID-H in children with asthma. Methods: Patients followed with a diagnosis of asthma in our Pediatric Allergy Clinic were evaluated for NSAID-H. Patients were questioned whether they had used NSAIDs, and if they experienced any reaction with these drugs. A control group was also questioned for reactions to NSAID use. Results: 976 children with asthma and 2,000 healthy children as a control group were included in this study. The mean age of the patients with asthma was 10.61 ± 4.21 years and 59.5% were male. Ten (1%) had a reaction history to NSAIDs. NSAID-H was confirmed in 9 (0.9%) who were tested with the suspected drugs. Six of these were classified as “single NSAID-induced urticaria/angioedema or anaphylaxis” and 3 were classified as “NSAIDs-exacerbated respiratory disease.” In the control group, only 1 subject had a reaction history to acetylsalicylic acid and no reaction developed in the provocation test. Conclusions: In our study, NSAID-H was found more frequent in children with asthma than in the control group. Children with asthma should be evaluated for reactions to NSAIDs during hospital visits.

The historical factors associated with the true non-steroidal anti-inflammatory drug hypersensitivity in children

The historical factors associated with the true non-steroidal anti-inflammatory drug hypersensitivity in children

EPS4.9 Drug hypersensitivity in children with cystic fibrosis

EPS4.9 Drug hypersensitivity in children with cystic fibrosis

Specific Aspects of Drug Hypersensitivity in Children.

Suspicion for drug hypersensitivity (DH) is a common reason for children's referral to an allergy department, with β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) as the most frequently involved drugs. The prevalence of DH in children remains not well defined as epidemiologic studies in children are lacking, and the most of those take into account adverse drug reactions (ADR) without a systematic allergy work-up to confirm or exclude hypersensitivity. The clinical history is mandatory in order to classify the reaction as being immediate or non-immediate and then to subsequently adapt the allergy work-up. Mainly due to the lack of studies, the same guidelines used for diagnosis of drug allergy in adults are generally used in the pediatric population, and the diagnosis is based mainly on in vivo tests (i.e. skin tests and/or drug provocation test) and rarely on in vitro tests. However, specific aspects of management of DH in children have been recently highlighted.

Non-steroidal anti-inflammatory drug hypersensitivity in children

IntroductionThere are rather few publications about hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAID) in the paediatric age. In this study, we aimed to assess the frequency of confirmed NSAID hypersensitivity in children with a previous reported reaction to NSAID in order to investigate the role of the drug provocation test (DPT) in the diagnostic workup and to explore the factors associated with confirmed NSAID hypersensitivity. MethodsWe conducted a retrospective analysis of the clinical files from every patient under 18 years old who attended two Portuguese paediatric allergy outpatient clinics, from January 2009 to August 2014, due to a suspected NSAID hypersensitivity. ResultsWe included 119 patients, with a median age of nine years (P25–P75: 5–14). Ibuprofen was the commonest implicated NSAID in the patients’ reports (n=94–79%). After DPT, NSAID hypersensitivity was confirmed in nine (7.6%) patients, excluded in 93 (78.2%) and was inconclusive in 17 (14.3%). In the majority (n=95–79.8%), the reaction occurred in the first 24h after intake. Eighty-four patients (70.6%) reported only cutaneous manifestations and 18 (15.1%) had systemic symptoms. Anaphylaxis represented a relative risk to NSAID hypersensitivity confirmation. No association was found for atopy and the number of previous reactions. ConclusionIn our study, NSAID hypersensitivity was confirmed in a small proportion of the patients with a previous reported reaction. Ibuprofen was the most implicated drug with urticaria/angio-oedema as the commonest manifestation. Anaphylaxis was associated with confirmed drug hypersensitivity. The drug provocation test was essential to establish the diagnosis.

Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group.

When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti-inflammatory drug-associated angioedema and serum sickness-like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up-to-date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research.