Introduction
Drug allergies and adverse drug reactions both occur with the regular use of medications at their intended dosages. While drug allergy refers to an immune-mediated hypersensitivity reaction to the medication [1], adverse drug reactions are a larger group and contain harmful and unintended side effects that occur after drug taking [1]. Approximately 15–20% of these reactions are related to immune mechanisms and are classified as drug hypersensitivity reactions (DHRs) [2]. Available data from Türkiye reveal a DHR frequency of 2% based on a screening size of 54,863 patients, with antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) being the most implicated medications [3]. However, the true prevalence of DHRs remains unclear due to limitations in diagnostic tools and the reliance on patient-reported histories.
Drug allergy represents a significant health concern, as it not only compromises quality of life but may also lead to serious complications, increased costs, and unnecessary drug avoidance (when misdiagnosed) [4]. Various risk factors for drug allergy have been reported in the literature, including both drug- and patient-related characteristics [5–9]. Drug-related factors include structural and pharmacological properties, frequency and duration of drug use, and the route of administration, with parenteral treatments posing higher risks [5–9]. Age, sex, a history of atopy, and a family history of drug allergy are among the most reported patient-related characteristics [5–10]. Moreover, genetic predispositions, such as specific HLA alleles and polymorphisms in drug-metabolizing enzymes, have emerged as important contributors to DHR in recent studies [5–9].
Understanding these risk factors is crucial for identifying individuals at risk of developing drug allergy and implementing preventive measures. However, comprehensive research in this area remains limited, particularly in Türkiye. While epidemiological studies exist, there is a lack of detailed case-control studies assessing the roles of patient- and drug-related risk factors in the development of drug allergy in the Turkish population.
Aim
Our aim was to identify risk factors associated with drug allergy and evaluate their impact on the development of DHRs. By addressing this gap, we aim to contribute to a better understanding of individual risk profiles and support the development of effective prevention strategies to reduce the burden of drug allergy.
Material and methods
Ethics and study design
This was a case-control study conducted between 15 October 2023 and 1 October 2024, at the Immunology and Allergy Diseases Department of the Samsun Training and Research Hospital, Samsun, Türkiye. The study was approved by the Noninterventional Clinical Research Ethics Committee of the Samsun University Faculty of Medicine (approval date: 11 September 2024; number 2024/16/7). Informed consent was obtained from all participants prior to data collection, in accordance with the Declaration of Helsinki.
We enrolled patients aged 18 years and older who presented to the Immunology and Allergy Diseases outpatient clinic with suspected drug allergies. Cases were defined as individuals with either a convincing clinical history of drug allergy, characterized by repeated reactions to the same drug with consistent symptomatology, or documented evidence of a drug allergy reaction in their medical records. The control group consisted of volunteers aged 18 years and older who presented to the same clinic during the study period for reasons other than suspected drug allergy and who had no history of drug allergy.
Patients were excluded from the study group if they had a suspicious history of drug allergy without documented evidence or if they lacked evaluation with alternative drug testing (if applicable to your study design). Individuals were excluded from both study and control groups were excluded if they were younger than 18 years old, pregnant, or had incomplete or missing data relevant to the study objectives.
Data collection
The data for both groups were obtained by reviewing the hospital’s computerised database records for detailed clinical evaluation reports routinely collected by our department, which included: age, sex, height, weight, body mass index (BMI), atopy history, family history of drug allergies, frequent use of antibiotics, kidney disease, liver disease, asthma, nasal polyps, and chronic urticaria. In addition to these, for the study group, the following information was also collected: the relationship between reactions and viral infections, the presence of urticaria/angioedema and anaphylaxis, type of the drug (NSAIDs, paracetamol, antibiotics, contrast substances, local anaesthetics, general anaesthetics, proton pump inhibitors, vitamin supplements, iron therapy, and other), reactions to multiple drug groups, and the route of administration (oral, intravenous, intramuscular, subcutaneous, dermal, eye). For antibiotics, we also recorded the specific antibiotic that caused the reactions, if such information was available.
Diagnostic methods
The diagnosis of drug allergy was based on a strong clinical history compatible with the suspected drug reaction, documented evidence, or electronic medical records. During patient interviews, the timing of the onset of the reaction, the type and severity of symptoms, the drugs used, the route of administration, dosage, duration, and the history of similar reactions were explored. The detailed medical history of the patients, associated diseases, and family history of drug allergies were also considered. All tests performed for the purpose of diagnosis were conducted with patient safety as a priority and in accordance with international guidelines [4, 1112–13].
Patients included in the study underwent provocation testing with alternative antibiotics or other safe drugs. During these provocation tests, skin test protocols were applied for the alternative drugs, but no diagnostic testing was performed for the initially suspected drug.
Statistical analysis
Statistics were conducted with an alpha error (significance threshold) of p < 0.05. The IBM SPSS software was used for data collection, transfer and analyses (Version 25.0; Armonk, NY, USA). Numerical variable distributions were examined to assess (non)parametricity in histogram and Q-Q plot outputs. Descriptive values were presented based on parametricity – normal distribution with mean ± standard deviation, non-normal with median (25th–75th percentiles). Numerical frequency and group-relative percentages were described for categorical variables. Normally distributed variables were analysed with the Student’s t test. Non-normally distributed variables were analysed with the Mann-Whitney U test. Categorical variables were analysed by employing appropriate χ2 tests or the Fisher’s exact test when necessary.
Results
The study group comprised 136 patients, while the control group included 87 volunteers. The median age of the study group was 44 (33–54) years, while the control group had a median age of 40 (25–52) years (p = 0.010). Females represented 74.26% (n = 101) of the study group and 63.22% (n = 55) of the control group (p = 0.079). The study group had a significantly lower height than the control group (p = 0.019), and, in relation, they also had a significantly higher BMI (p = 0.043). The control group had higher frequencies of atopy history (p = 0.008), kidney disease (p = 0.030), asthma (p = 0.001), and chronic urticaria (p = 0.019) relative to patients with drug allergies (Table 1).
Table 1
Summary of variables with regard to groups
| Parameter | Patients (n = 136) | Controls (n = 87) | P-value |
|---|---|---|---|
| Age [years] | 44 (33–54) | 40 (25–52) | 0.010‡ |
| Sex | |||
| Male | 35 (25.74%) | 32 (36.78%) | 0.079§ |
| Female | 101 (74.26%) | 55 (63.22%) | |
| Height [cm] | 163.93 ±7.50 | 166.48 ±8.40 | 0.019† |
| Weight [kg] | 75.87 ±16.37 | 73.48 ±14.89 | 0.272† |
| Body mass index [kg/m2] | 28.19 ±5.62 | 26.61 ±5.72 | 0.043† |
| Atopy history | 28 (20.59%) | 32 (36.78%) | 0.008§ |
| Family history | 22 (16.18%) | 13 (14.94%) | 0.953§ |
| Frequent use of antibiotics | 0 (0.00%) | 0 (0.00%) | – |
| Kidney disease | 2 (1.47%) | 7 (8.05%) | 0.030# |
| Liver disease | 2 (1.47%) | 4 (4.60%) | 0.212# |
| Asthma | 18 (13.24%) | 27 (31.03%) | 0.001§ |
| Nasal polyp | 11 (8.09%) | 10 (11.49%) | 0.539§ |
| Chronic urticaria | 19 (13.97%) | 24 (27.59%) | 0.019§ |
Descriptive statistics are presented using mean ± standard deviation for normally distributed continuous variables, median (25th–75th percentile) for non-normally distributed continuous variables and frequency (percentage) for categorical variables. (a) Patients may have more than one of the following.
In the study group, 93 (69.40%) patients had suffered from urticaria/angioedema and 41 (30.60%) patients from anaphylaxis. Of note, 6 (4.41%) patients were found to have a reaction-viral infection relationship. The most common drug group causing drug allergies was the NSAID group in 84 (61.76%) patients which was followed by antibiotics in 57 (41.91%) patients. The most common route of drug administration leading to drug allergies was oral (120 patients (88.24%)), followed by intravenous (11 (8.09%) patients). Penicillin derivatives were identified as the cause of most reactions in our study group (28 (20.59%) patients), followed by cephalosporins (16 (11.76%) patients) (Table 2).
Table 2
Summary of clinical features and associated factors in drug allergy. Patients (n = 136)
| Parameter | Results |
|---|---|
| Reaction and viral infection relationship | 6 (4.41%) |
| Urticaria/angioedema | 93 (69.40%) |
| Anaphylaxis | 41 (30.60%) |
| Reaction to multiple groups of drugs | 32 (23.53%) |
| Drug groupa | |
| NSAIDs | 84 (61.76%) |
| Paracetamol | 27 (19.85%) |
| Antibiotics | 57 (41.91%) |
| Contrast substance | 3 (2.21%) |
| Local anaesthetic | 2 (1.47%) |
| General anaesthetic | 1 (0.74%) |
| Proton pump inhibitors | 4 (2.94%) |
| Vitamin supplementary | 4 (2.94%) |
| Iron therapy | 1 (0.74%) |
| Other | 3 (2.21%) |
| Route of administrationa | |
| Oral | 120 (88.24%) |
| Intravenous | 11 (8.09%) |
| Intramuscular | 6 (4.41%) |
| Subcutaneous | 2 (1.47%) |
| Dermal | 0 (0.00%) |
| Eye | 0 (0.00%) |
| Antibioticsa | |
| Penicillin | 28 (20.59%) |
| Cephalosporins | 16 (11.76%) |
| Quinolones | 9 (6.62%) |
| Macrolides | 3 (2.21%) |
| Other | 3 (2.21%) |
Discussion
In this study, the aim was to identify risk factors for drug allergies and evaluate the clinical characteristics of drug allergies. According to the results, the average age and BMI of individuals in the study group were significantly higher compared to the control group. NSAIDs and antibiotics caused the majority of drug allergies examined, while oral drug administration was identified as the most common route. Penicillin derivatives were the most frequently implicated antibiotics in drug allergies. Anaphylaxis was present in 30.60% of drug allergy cases, while urticaria/angioedema was observed in 69.40%. Additionally, it was noteworthy that the control group had higher rates of conditions such as a history of atopy, asthma, kidney disease, and chronic urticaria, which clearly shows the unpredictable nature of drug allergies.
Sex is a determining factor in drug allergies due to sex-based variations in immune and metabolic features [6, 14], and females have well-recognised predispositions to immune-related and unrelated adverse drug reactions [15]. Age is thought to affect the frequency of drug reactions by altering both immune responses and metabolic processes [6, 16, 17]. In our study, the study group was older than the control group. Regarding sex, 74.26% of the study group consisted of women, compared to 63.22% in the control group; however, the difference was not statistically significant. Al-Ahmad et al. conducted an observational database study analysing drug allergy clinic visits in Kuwait. In this study, 1,553 patients were evaluated, and drug hypersensitivity was confirmed in 645 (41.5%) patients. The average age of the patients was 41.52 ±16.93 years, with 63.7% being women [18], indicating similarities with our results. In terms of penicillin skin tests, a notable feature is that adult females appear to have up to 10-fold higher risk for positive results compared to adult males, which shows the need for careful consideration in females [5]. In an epidemiological study by Gamboa, the female-to-male ratio of patients presenting for the first time with drug allergies was reported to be approximately 2 : 1 [14]. In a large study conducted on 25,695 electronic inpatient records in the United Kingdom, female sex was identified as a risk factor for multiple drug intolerance syndrome, while no significant relationship was found between age and multiple drug intolerance syndrome [19]. Epidemiological studies related to DHR from different regions of the world report variable results related to age, likely due to various biases such as differences in study populations and diagnostic criteria [16, 17, 20]. For instance, a study from Türkiye involving children found that drug allergies were not associated with age and sex [7], which could suggest the impact of sex hormones on drug-related adverse events [15]. Our study supports previous findings that age is a significant risk factor for drug allergies in adults, indicating that older individuals may have greater risks. The lack of a significant difference regarding sex in the present study may be associated with the sample size, as well as different environmental and genetic factors.
BMI also appears to be another important factor that influences drug metabolism and immune responses. It is suggested that a high BMI may increase the risk of drug allergies by enhancing inflammatory processes [21, 22]. In our study, the average height of the study group was significantly lower than that of the control group, while their BMI was significantly higher. In a case-control study focusing on anthropometric measurements, patients with drug allergies had significantly higher BMI, waist and hip circumference, waist-to-hip ratio, fat mass, body fat percentage, and body fat mass compared to the control group [21]. In another similar study, drug allergies were found to be associated with obesity [22]. A large study from the United States involving 2,375,424 patients found that a BMI above 30 was a risk factor for multiple drug intolerance syndrome [23]. On the other hand, a comprehensive study from the United Kingdom found no relationship between weight and multiple drug intolerance syndrome [19]. Previous studies have particularly emphasized the effects of high BMI on inflammation and immune responses, with some noting that obesity is a risk factor for multiple drug intolerance syndrome, while others have not confirmed this relationship.
Drug classes are among the most important pharmacological factors that determine the type and frequency of drug allergies. Factors affecting drug immunogenicity include the drug’s ability to act as a hapten, be a prohapten, or bind covalently to immune receptors [24]. Therefore, certain drug classes are believed to be associated with a higher frequency of drug allergies compared to others [25]. Due to these properties, and possibly the frequency of medication use in the population, specific drug classes like beta-lactams, sulfonamide antibiotics, NSAIDs, and antiepileptics, are generally associated with a higher incidence of drug hypersensitivity reactions than other drug classes [8]. While NSAIDs and antibiotics are thought to cause more hypersensitivity than other drug classes, there is a need for more studies on this topic [26, 27]. In our study, the most common cause of drug allergy was NSAIDs (61.76%), followed by antibiotics (41.91%). Within the antibiotic group, the most common reactions were related to penicillin derivatives (20.59%) and cephalosporins (11.76%). In the study by Al-Ahmad et al., anti-inflammatory drugs and analgesics were the most frequently confirmed causes of drug allergies (39.22%). Antibiotics were identified a cause in 38.1% of cases, and 73.98% of these cases were caused by beta-lactam antibiotics [18]. This relationship is replicated in children, for which antibiotics were primarily responsible for 55% of drug allergies, with 89.4% of these occurring due to beta-lactams. The most frequently implicated beta-lactam was amoxicillin-clavulanic acid, followed by third-generation cephalosporins and ampicillin-sulbactam [7]. Our study supports existing findings in the literature by identifying NSAIDs and antibiotics as the most frequently implicated drug classes in drug allergies. It is known that NSAIDs, particularly through COX-1 inhibition, trigger both immunological and non-immunological mechanisms, while antibiotics, through their hapten effect, stimulate immune responses, leading to allergic reactions [8, 24, 25].
Studies examining drug administration routes in the context of allergies indicate that oral drugs lead to milder reactions through immunomodulatory effects via gastrointestinal barriers, while intravenous, topical and intramuscular applications are linked to faster and more serious reactions [8, 28]. In the current study, the most common route of drug allergy was oral (88.24%), followed by intravenous route (8.09%). The lower incidence of intravenous administration in our study may be attributed to its less frequent use, owing to the design of our study.
Urticaria, angioedema, and anaphylaxis are the most common clinical presentations of drug allergies. In our study, urticaria/angioedema was detected in 69.40% of individuals with drug allergies, anaphylaxis in 30.60%, and in 6 (4.41%) patients, the reactions were found to be associated with viral infections. In a study conducted in Kuwait, the most frequently observed symptoms were urticaria (57.80%), angioedema (42.50%), respiratory symptoms (47.60%), and erythema (33.60%) [18]. In another study, chronic urticaria and angioedema were identified as risk factors for multiple drug allergy syndrome [29]. Our study shows that urticaria and angioedema are the most common symptoms in drug allergies, which is consistent with the literature. Although anaphylaxis occurs less frequently, it is life threatening and requires prompt intervention.
Chronic diseases and atopy can influence immune responses, potentially facilitating hypersensitivity. In our study, the rates of atopic history, kidney disease, asthma, and chronic urticaria were significantly higher in the control group compared to those with drug allergies. This might be caused by the fact that the control group was comprised of patients admitted to the Immunology and Allergy Department, as these individuals are likely to have a history of allergies or comorbidities that could bias the comparisons. Chronic kidney disease, cardiovascular diseases, and malignancies have been found to increase the risk of both cutaneous and systemic DHRs, and also increase mortality in severe reactions [9, 30]. Nonetheless, several studies claim that the risk of drug allergy does not increase in atopic patients [7, 28, 31, 32], while others confirm a relationship [8, 33, 34]. In our study, the higher rate of atopic individuals in the control group supports the argument that atopy does not increase the risk of drug allergy [35]. Some studies have associated drug allergies with viral infections [30, 36, 37], but this relationship has not been confirmed in other studies [7]. In our study, the viral infection rate in those with drug allergies was found to be only 4.41%, which is a very low but considerable frequency that warrants future research. Despite the potential bias explained above, our findings do not support the argument that chronic diseases, particularly conditions like kidney disease and asthma, contribute to the risk of drug allergies through their effects on the immune system.
One of the strengths of our study is the detailed investigation of factors associated with drug allergies, made possible by its case-control design. However, our study is retrospective. The study does not generate epidemiological data, and thus, the results should not be considered in this respect. Genetic factors that could have influenced the results were not evaluated. Due to institutional constraints, diagnostic tests for the culprit drug could not be performed in our hospital. Therefore, the diagnosis was primarily based on clinical history, documented reports, or medical records rather than confirmatory skin or challenge tests for the suspected drug. Furthermore, the variability in diagnostic methods used for confirming drug allergies made standardization of the findings difficult. These limitations highlight the need for larger-scale, prospective, and multicentre studies in the future.
Conclusions
The average age and BMI of the drug allergy group were higher than those of the control group. The most common causes of drug allergies were NSAIDs and antibiotics, with penicillin and its derivatives being the most frequently implicated antibiotic. Anaphylaxis was observed in 30.6% of the cases, and urticaria/angioedema in 69.4%. Oral drug intake was identified as the most common route for drug allergies, which was likely due to the preference of oral treatments. This study contributes to a better understanding of the factors associated with drug allergies and the common allergens involved. Future studies should validate these findings in broader and more diverse populations and develop strategies for the prevention of drug allergies.
