Drug-Related Hypersensitivity Reactions Leading to Emergency Department: Original Data and Systematic Review

The aim of the present study is to describe pharmacological characteristics of drug-related allergies and anaphylaxis leading to the emergency department (ED). An 8-year post hoc analysis on the MEREAFaPS Study database was performed (2012–2019). Subjects who experienced drug-related hypersensitivity leading to an ED visit were selected. Logistic regression analyses were used to estimate the reporting odds ratios (RORs) of drug-related allergies and anaphylaxis adjusting for sex, age classes, and ethnicity. In addition, a systematic review of observational studies evaluating drug-related hypersensitivity reactions leading to ED visits in outpatients was performed. Out of 94,073 ED visits, 14.4% cases were drug-related allergies and 0.6% were anaphylaxis. Females accounted for 56%. Multivariate logistic regression showed a higher risk of drug-related allergy among males and all age classes < 65 years, while a higher risk of anaphylaxis was observed for females (ROR 1.20 [1.01–1.42]) and adults (ROR 2.63 [2.21–3.14]). The systematic review included 37 studies. ED visits related to allergy and anaphylaxis ranged from 0.004% to 88%, and drug-related allergies and anaphylaxis ranged from 0.007% to 88%. Both in our analysis and in primary studies, antibacterials, analgesics, and radiocontrast agents were identified as the most common triggers of hypersensitivity.


Introduction
Drug-related hypersensitivity reactions are a group of adverse drug events (ADEs) that are generally unexpected (Type B reactions-Bizarre) [1] and characterized by symptoms or signs initiated by exposure to a drug at dosages that are usually tolerated [2]. Following the definition proposed by the "International Consensus on Drug Allergy", hypersensitivity ADEs, which occur in the first few hours after drug administration, are usually characterized by urticaria, angioedema, rhino-conjunctivitis, bronchospasm, and, in the most serious cases, also anaphylaxis [3]. Anaphylaxis is defined as a clinically relevant, generalized, or systemic hypersensitivity ADE that can be life-threatening or fatal [3].
Although the diagnosis of the causative agent can be very difficult, pharmacological treatments are among the leading causes of allergy and anaphylaxis-related deaths in adult individuals and hypersensitivity ADEs remain a serious public health concern both in outpatient and inpatient settings worldwide, due to their high morbidity, mortality, and socioeconomic burden [4].
From an epidemiological point of view, drug-related allergies and anaphylaxis are most frequently triggered by analgesics, antibiotics, biologics, chemotherapeutics, contrast media, nonsteroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors, again with age and geographical variations worldwide [4]. Among drug-related anaphylaxis, new triggers have been identified. These include biologics containing α-gal (i.e., cetuximab), small molecules, or novel chemotherapeutics like olaparib [5]. Disinfectants such as chlorhexidine [6], or drug ingredients such as polyethyleneglycol [7], or recently methylcellulose [8], have also been identified as novel substances inducing anaphylaxis. The global incidence of anaphylaxis was estimated to be between 50 and 112 events per 100,000 person per year, with an estimated lifetime prevalence of 0.3-5.1%, depending on the definitions used, study methodology applied, and geographical areas investigated [4,9]. Despite an increasing trend for emergency department (ED) visit and/or hospitalization due to anaphylaxis, its mortality was estimated at 0.05-0.51 per million people/year [4,10].
Taking into consideration the last update of the World Allergy Organization Anaphylaxis Guidance [4], major limitations of epidemiological studies regarding drug-related allergies and anaphylaxis reside in the lack of risk factors/triggers characterization and lack of information on large prospective population-based studies. Moreover, most studies do not differentiate between drug-related hypersensitivity ADEs and other kinds of ADEs, and the diagnosis of hypersensitivity ADEs is mostly based on a suspected clinical history or self-reporting [11].
In this context, pharmacovigilance studies, performed with an "active" approach by trained healthcare professionals, can provide detailed information about hypersensitivity ADEs and their diagnosis, especially when these studies are performed in a hospital setting (i.e., ED) [12][13][14][15][16]. This way, "active" pharmacovigilance studies may represent one of the best epidemiological strategies to fill the above-mentioned major limitations.
The aim of the present study was to describe pharmacological characteristics of drugrelated allergies and anaphylaxis leading to ED in Italy, estimating their risk considering subjects' demographic and clinical characteristics and the most frequently reported suspected drug classes. Furthermore, to complete the evidence obtained with our post hoc analysis, a systematic review of observational studies on drug-related hypersensitivity ADEs leading to ED visit and/or hospitalization was performed.

Post Hoc Analysis
This is an 8-year post hoc analysis performed on the MEREAFaPS Study database [15]. A retrospective observational study was conducted by reviewing all drug-related allergies and anaphylaxis observed in the database between 1 January 2012 and 30 November 2019. Following the Italian Pharmacovigilance legislation, the MEREAFaPS Study, which was conducted in Italy since 2006 and ended in November 2020, collected all ADEs through an ad hoc ADE report form in more than 90 EDs belonging to general hospitals distributed in the national territory in five Italian Regions: Lombardy and Piedmont (north), Tuscany and Emilia-Romagna (centre), and Campania (south). As already stated, the EDs involved in the MEREAFaPS Study allowed good and widespread coverage of the ED Italian population.
For the present analysis, all ADE report forms of drug-related allergy and anaphylaxis were identified with a definite list of MedDRA terms (Supplementary Table S1). Subjects who experienced one or more hypersensitivity reactions (allergies and/or anaphylaxis) leading to ED visit were selected, retrieving the following data: demographic informa-tion (age, gender, ethnic group); suspected drugs; description of the ADE according to diagnosis and symptoms, codified as detailed by MedDRA dictionary and organized by System Organ Class (SOC) [17]. If present in the MEREAFaPS Study database, the ADE's outcome "hospitalization", ADE's management (i.e., adrenaline use), and the triage colour codes were also recorded. In Italy, the triage codes are divided into four categories and are identified with colours, as follows [18]: (1) "red code" (very critical, life threat, top priority, immediate treatment access); (2) "yellow code" (on average critical, presence of evolutionary risk, possibly life-threatening); (3) "green code" (not very critical, absence of evolutionary risks, deferred services); (4) "white code" (non-critical, non-urgent patients). Anatomical Therapeutic Chemical (ATC) classification system was used to classify suspected drugs [12]. For the pharmacologic subgroup of antibiotics, the 3rd level of ATC class was considered, whereas the 5th level of ATC class was considered for NSAIDs, radiology contrast agents, analgesics, and antineoplastic agents.
Data were summarized using descriptive statistics. Categorical data were reported as frequencies and percentages, while continuous data were reported as median values with the related interquartile ranges (IQRs). Age classes were defined as follows: newborns (from 0 to 1 years); children (from 2 to 11 years); adolescents (from 12 to 17 years); adults (from 18 to 65 years); and elderly (older than 65 years). For each drug class, univariate logistic regression was used to calculate the reporting odds ratios (RORs) of drug-related allergy and anaphylaxis with 95% confidence intervals (CIs) compared to subjects who experienced non-allergy ADEs. Multivariate logistic regression was performed and adjusted for sex, age classes, and ethnicity. All results were statistically significant at p < 0.05. Data management and statistical analysis were carried out using STATA 16.1.
The coordinating centre of Lombardy Region (Vimercate, Italy) approved the MEREAFaPS Study in 2006, and the local institutional ethics committee (ASST Monza Ethic Committee) approved the MEREAFaPS Study (Notification number 3724-6 May 2021) according to the legal requirements concerning observational studies [12][13][14][15][16]. Due to the retrospective nature of the present analysis and data anonymization, patient's consent to participate was not required.

Systematic Review
This is a systematic review conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [19]. A literature search was performed in PubMed and Embase (last search performed on 25 March 2022). The PubMed search strategy was adapted to the syntax and subject headings of Embase. Records were retrieved on the same day from all sources and the search strategy was updated toward the end of the review, after being validated to ensure it retrieved a high proportion of eligible studies.
We considered for inclusion observational studies, either prospective or retrospective performed in EDs and specifically concerning outpatients, published in English. Randomized clinical trials, reviews and meta-analyses, letters to the editor, case reports, case series, and expert opinions were excluded. We included only articles focusing on drug-related hypersensitivity, anaphylactic reactions, and allergies in outpatients. Moreover, we excluded articles focusing on specific syndromes, such as Steven Johnson and toxic epidermal necrolysis. Two review authors (NL and SP) have independently screened the extracted records and identified the studies for inclusion by screening titles and abstracts yielded by search, eliminating those deemed irrelevant. Full-text articles were retrieved for all references that at least one of two review authors identified for potential inclusion. We selected studies for inclusion based on review of full-text articles. Any discrepancy between the findings of two review authors was resolved through discussion with a third expert (GC).
Data were independently extracted from each article by two authors (SP and GC) using a data collection form. Extracted data included the name of the study authors, year of publication, the country in which participants were recruited, the period of observation, and study design. For each included study, researchers retrieved information regarding: (a) the type of health facility (i.e., community hospitals, tertiary centres, university hospitals); (b) patients' selection criteria, age, and sex (percentage of females); (c) number of patients analysed in the study, the percentage of ED visits for allergy or anaphylaxis and the number of those related to drugs; (d) number of hospitalization events for drug-related allergy or anaphylaxis; (e) percentage of each causative drug class (if available). Authors of primary studies were contacted to retrieve missing data and/or for additional information. Studies with missing data for two or more of the abovementioned criteria were excluded.
Two review authors (NL and SP) independently assessed the included studies for bias, following the Joanna Briggs Institute Critical Appraisal Checklist for analytical crosssectional study (last amended in 2017) [20]. For each domain in the tool, a judgment as to the possible risk of bias was made from the information reported in the body of papers. The judgements were made independently by two review authors (NL and SP); disagreements were resolved first by discussion and then by consulting a third author (GC). A graphic representation of potential bias was created using the software RevMan 5.4.1 (https://training.cochrane.org/, accessed on 25 March 2022).

Post Hoc Analysis
During the study period (2012-2019), out of 94,073 ED visits, 13,532 (14.4%) cases were drug-related allergies, while 548 (0.6%) were anaphylactic events. Females accounted for 56.16%. The mean age was 46 and 55 years for patients who experienced allergies and anaphylaxis, respectively. Overall, 2105 (15.6% out of 13,532) subjects who experienced a drug-related allergy and 371 (67.7% out of 548) subjects who experienced anaphylaxis were hospitalized ( Table 1).
As for drug-related allergies, the majority of subjects were female (59.2%), with a mean age of 46.3 ± 22.9 years, and Caucasian (81.72%). The most frequently reported triage colour codes were "green" (46.1%) and "yellow" (17.6% Considering anaphylaxis, the majority of subjects were female (52.4%), with a mean age of 55.7 ± 17.7 years, and Caucasian (82.3%). The most frequently reported triage colour codes were "yellow" (33.4%) and "red" (23.5% The majority of cases of anaphylaxis were treated with hydration, parenteral steroids, and antihistamines (data not shown). Overall, 58.94% of anaphylaxis (323 out of 548 cases) also reported adrenaline use during ED management ( Table 2).
Suspected drug classes and active principles associated with anaphylaxis are reported in Table 3 [8.33-15.92]) were significantly associated with a higher risk of anaphylaxis. Among antibacterials, the risk of anaphylaxis was significantly higher for pen, mainly represented by amoxicillin/clavulanate, and cephalosporins, particularly ceftriaxone. Among NSAIDs, the risk of anaphylaxis was significantly higher for dexibuprofen, followed by flurbiprofen, diclofenac, and ketorolac, while among radiology contrast agents, the risk of anaphylaxis was significantly higher for ioprimide, followed by ibitridol, iopamidol, and iomeprol. All other most frequently reported active principles involved in cases of anaphylaxis are depicted in Supplementary Table S2.   CI: confidence interval; NSAID: non-steroidal anti-inflammatory drug; ROR: reporting odds ratio. * Alone or in combinations. The total number of suspected drugs involved in anaphylaxis and non-allergy events is bigger than the number of cases because more than one suspected drug can be reported in a pharmacovigilance report form. Logistic regression analyses were used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of drug-related allergies and anaphylaxis adjusting for sex, age classes, and ethnicity.
For all suspected drug classes, the most frequently reported drug-related hypersensitivity reactions affected the skin and subcutaneous tissue (data not shown). In particular, we observed several cases of urticaria, localized or general pruritus, erythema, and rash. These dermatological manifestations showed a different degree of seriousness among patients. Considering the most severe cases, these were represented by systemic reactions, including respiratory distress and anaphylactic shock.

Discussion
The current study summarizes the up-to-date evidence on drug-related allergies and anaphylaxis causing ED visit and hospitalization. Antibacterials for systemic use, NSAIDs, and radiology contrast agents were the most reported drug classes associated with drugrelated hypersensitivity reactions.
Although our post hoc analysis showed that female was the sex most represented in allergy events, women seem to be associated with a lower risk of drug-related allergy but a higher risk of anaphylaxis, even if at the limit of statistical significance. Considering drug-related allergy, this evidence is comparable with real-world data coming from observational studies, in which a higher risk of ADEs was usually observed in women [58,59]. Nevertheless, there are no conclusive data that drug-related allergies are more common in females than in males [60]. In general, discrepancy exists regarding the sex difference in allergy caused by different triggers, including pharmacological treatments, with females reporting significantly more allergic reactions in questionnaire studies [61]. Moreover, we also observed that women experienced anaphylaxis more frequently than men. This evidence is comparable with hospital-based studies that suggested a female predominance regarding drug-induced anaphylaxis or a history of immediate penicillin allergy [62,63]. Furthermore, some studies reported that females are twice as likely to have drug-induced anaphylaxis than males [64]. However, the reasons for this sex discrepancy are still incompletely understood [65].
Considering patients' age, we observed that most drug-related allergies occurred in adults (age 18-65 years). This result can be compared with the evidence published in the literature where it is reported that drug-related allergies typically occur in young and middle-aged adults [66]. In fact, with regards to children, it is well known that they are less likely to be exposed repeatedly to medications, especially due to the absence or lower incidence of comorbidities [59,66]. In our sample, drug-related anaphylaxis was also reported more frequently by adults (age 18-65 years), an age group known to be associated with these serious events, which occur mainly in subjects with a mean age of around 58-60 years [67,68]. Of note, the mean age of patients experiencing an allergy or anaphylaxis in our sample was even lower. Although age is consistently associated with severity of anaphylaxis in many studies [64,69], we did not observe a higher risk of drugrelated allergy and anaphylaxis in elderly (>65 years). This may be due to the presence of a relatively low number of elderly subjects who experienced an allergy or anaphylaxis as the cause of ED visits and hospitalization in our sample. Moreover, we hypothesize that the elderly included in our analysis may be represented by subjects mainly exposed to long-term pharmacological treatments (i.e., chronic treatment), which can be considered to be less associated with hypersensitivity reactions.
In Italy, triage assessment is made on a colour code basis, with highest priority given to a red code, followed by yellow, green, and white [70]. Although triage is a very useful tool for prioritizing patients upon their arrival to the ED, limited data relating to the triage assessment colour code for drug-related hypersensitivity reactions are available [71]. Nevertheless, our analysis found that more serious events, in particular anaphylaxis, were correctly coded and were mainly associated with "red" and "yellow" triage codes.
With respect to drug classes most frequently associated with anaphylaxis, striking geographical differences exist and are likely caused by local prescription patterns and are influenced by other less characterized factors, such as genetic differences [64]. Despite this, as highlighted by the results of our systematic review, the findings of the active pharmacovigilance study MEREAFaPS were in line with those of studies already published in literature on this topic. Both in our post hoc analysis and in the studies included in the systematic review, most cases of anaphylaxis were caused by the administration of antibacterials for systemic use, NSAIDs, and radiology contrast agents. In general, the best strategy for drug-related hypersensitivity management is avoidance or discontinuation of the suspected medication. Alternative medications with unrelated chemical structures should be substituted, always considering the presence of drugs cross-reactivity [72]. Antibacteri-als for systemic use, in particular penicillins, are the most common triggers observed in drug-related allergy, affecting approximately 10% of patients [73]. Another group of antibiotics frequently associated with hypersensitivity are cephalosporins, which are generally causative of maculopapular rashes and drug fever, while urticaria and anaphylaxis are uncommon [74]. Analgesics, in particular NSAIDs, can cause hypersensitivity reactions, including exacerbations of underlying respiratory diseases, urticaria, angioedema, and anaphylaxis [72]. Finally, radiology contrast agents are associated with both allergic and pseudoallergic reactions. The incidence of these reactions, including anaphylaxis, appears to be lower with non-ionic versus ionic agents. Drug-related hypersensitivity reactions to radiology contrast agents can be prevented through pre-treatment regimens with corticosteroids and H1-antihistamines [72]. Intramuscular epinephrine (adrenaline) represents the first-line treatment for anaphylaxis. However, even if its use remains suboptimal [4], in our population epinephrine was used in a relatively high percentage of cases of anaphylaxis. After anaphylaxis occurrence, patients should be referred to a specialist to assess the potential cause and to be educated on prevention of recurrences and self-management. The limited availability of epinephrine auto-injectors remains a major problem worldwide, especially in low-and middle-income countries [75].

Strengths and Limitations
Our study has some limitations. First, the retrospective nature of the study may have led to an underestimation of allergic and anaphylactic ADEs, because ED physicians could not report the reaction or could not recognize the allergic nature of the reaction. This possibility has been evidenced by several studies, such those published by Sundquist et al. [76] and Martelli et al. [77], who evidenced a reduced capacity to recognize anaphylaxis in ED. Another cause of underestimation of anaphylaxis could be the death of serious cases before their arrival in ED. However, considering that the ADEs were collected through a national active pharmacovigilance initiative, the issue of underreporting, especially for anaphylaxis, can be considered of relatively low relevance. Moreover, we did not evaluate the effect of concomitant medications and comorbidities on hypersensitivity reactions and the seriousness of each drug-related allergy. It should be of great importance to have information on concomitant medications since they may potentiate anaphylaxis symptoms or reduce the efficacy of its treatment [78,79]. Even some comorbidities, such as respiratory and cardiovascular diseases, have been associated with poorer prognosis as they may lead to insufficient compensatory mechanisms to endure anaphylaxis complications [80]. Furthermore, we cannot exclude a partial lack of additional data mainly due to the specific condition of each ED (i.e., lack of time, general conditions of patients, and other emergencies). Our analysis is based on ADE reports that are affected by limits that include inaccurate and incomplete information on patients (i.e., sex, age, ethnicity, triage colour code), also mainly related to lack of clinical data in the ED electronic sources. Finally, we cannot have data on the recurrence of anaphylaxis, which involves 3% of patients within one year [37].
Despite these shortcomings, our study overcomes the limitations listed by the World Allergy Organization Anaphylaxis Guidance [4]. As for lack of large prospective populationbased studies, this is the first nationwide multicentre study investigating allergic ADEs as the cause of ED visits in Italy. Our analysis included five Italian Regions located in northern, central, and southern Italy, allowing us to reach an estimated coverage of over 45% of the Italian population (more than 28 million inhabitants) [15]. Few multicentre studies examined such a large population with an active pharmacovigilance approach in ED. Most studies were carried out in single hospitals, involving few EDs, and larger studies have usually been performed on administrative databases (i.e., insurance claims), using ICD-9 and ICD-10 codes [22][23][24]26,30,36,37,45]. The use of ICD codes in observational studies may have been associated with a misclassification of patients, with the possible introduction of a selection bias. Moreover, these codes cover anaphylaxis definition as reported by Regateiro et al. [64] only partially. On the contrary, the use of MedDRA standardized medical terminology in our study allowed us to reach a proper differentiation between drug-related hypersensitivity ADEs and other kinds of ADEs, with a certainty of the diagnosis. In fact, each ADE and diagnosis in pharmacovigilance report forms were identified and then coded by trained monitors, and additional information was requested to ensure the greatest correspondence between what occurred and what was entered in the database, thus minimizing the misclassification and the selection bias in this post hoc analysis. Moreover, while several studies concerning allergies and anaphylaxis did not always report risk factors and triggers [22,24,27,31,32,36,37,43,45], the use of the ATC classification system allowed us to record all active principles causative of the hypersensitivity event with certainty.

Conclusions
In conclusion, drug-related hypersensitivity reactions represent a relevant clinical issue worldwide. Despite the large number of available marketed medications, pharmacological triggers associated with hypersensitivity are mostly well-known drug classes. Both our post hoc analysis and the systematic review confirmed the association between allergy and anaphylaxis and antibiotics for systemic use, NSAIDs, and radiology contrast agents, especially in women and adults. This information should always be taken into consideration by general practitioners, patients and their caregivers, and ED healthcare professionals, to both minimize the occurrence of drug-related hypersensitivity reactions and improve their management.