Patients’ Claims Regarding Drug Allergies A

Introduction: According to the World Health Organization (WHO) defi nition, drug allergies are defi ned as harmful, unintended, and undesirable reactions that occur when administered at doses used to prevent, diagnose, and treat disease. Aim: The aim of study was to determine the rate of patients’ claims to be allergic to a drug. Material and Methods: This non-commercial study is a retrospective analysis of the work of one physician at the City Institute for Emergency Medical Services Belgrade for a total of 10711 patients during the period from 2014 to 2019. Medication allergy claims are entered in the appropriate fi elds in the access program. Results: Based on the study inclusion and exclusion criteria 1721 patients were eligible for analysis. 1106 patients were female and 615 were male. Most patients claimed to be allergic to penicillin preparations (56.13%), followed by trimethoprim + sulfomethoxazole 12.02%, followed by Ibuprofen 3.95%. In addition to one-drug allergy claims, 338 (19.64%) patients reported allergy to two or more drugs: two drugs 64.80%, three drugs 22.20%, four and more drugs 6.5% each. Conclusions: In our study, the majority of reported allergic reactions indicated penicillin preparations, then trimethoprim + sulfomethoxazole followed by ibuprofen.


INTRODUCTION
According to the World Health Organization, adverse drug reactions occur in 10% of the world population and in 20% of hospitalized patients. Worldwide, in 20% of cases, drugs could be the cause of death resulting from an anaphylactic reaction [1]. According to a study by Pirmohamed et al. from 2004, adverse drug reactions led to a 6% increase in morbidity, mortality, hospitalizations, 2% mortality and costing the National Health System £ 466m annually [2].
Drug allergies, as defi ned by the World Health Organization (WHO), are defi ned as adverse, unintended and undesirable reactions to drugs that occur when administered at those doses that are used to prevent, diagnose or treat the disease [1]. According to the 2003 World Organization for Allergy (WAO) defi nition, allergic reactions are defi ned as immune-mediated hypersensitivity reactions. Th e mechanism of allergic reactions may be mediated by IgE or non-IgE reactions [3]. Originally, two types of adverse drug reactions were described: type A is predictable and dose-dependent. On the other hand, type B, which is unpredictable and dose-independent, aff ects a small population of people, with individual factors of the human body playing a large role in their emergence [4,5]. Also, type C (chronic reaction), type D (delayed), type E (end-of-treatment) and most recently, type F (Unexpected failure of therapy) have been described [5,6]. Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to various drugs [7]. Adverse drug reactions are common in clinical practice, aff ecting from 15-25% of patients, serious adverse reactions occur in 7-13% of patients [8,9]. According to Warrington et al. the incidence of allergic reactions is the highest following the administration of penicillin, cephalosporin, sulfonamide, topical and general anesthetics, acetylsalicylic acid, non-steroidal anti-infl ammatory rheumatics (NSAIDs), radioactive contrasts, and therapeutic monoclonal antibodies [10]. According to a study by Hemstreet et al. Penicillin allergy is a big risk factor for developing a sulfonamide allergy. According to their results, penicillin allergy is a predictor for the subsequent development of a sulfonamide allergy, with a large number of patients reporting an allergy to several drugs, including penicillin [11].
In the work of Kusic et al. adverse reactions to penicillin preparations were reported by 86.4% of those tested for drug allergies [12]. Senst et al. have shown that adverse reactions to antibiotics occur in more than 3% of patients in hospital settings [13], leading to complications during treatment in 10-20% of cases [14,15]. Some patients report allergic reactions to many medicines, making it diffi cult for the physician to chose which medications to prescribe [16]. Multiple drug intolerance (MDI) or Multiple drug allergy syndrome (MDAS) is defi ned as intolerance to two or more structural or pharmacologically unrelated drugs taken in three diff erent circumstances [17].
According to the data of Khan et al. a combination of acetylsalicylic acid (ASA) and nonsteroidal anti-infl ammatory drugs (NSAIDs) can cause allergic and pseudo-allergic reactions, including respiratory disease exacerbation, angioedema, urticaria, and anaphylactic reactions. "Within minutes of ingestion of therapeutic doses of ASA or NSAIDs, patients with Aspirin-exacerbated respiratory disease (AERD) typically have both rhinoconjunctivitis and bronchospasm. Th e bronchospasm induced can be severe and result in respiratory failure with a need for intubation and mechanical ventilation " [18].
It is highly suspected that all side effects when using a drug are indeed allergic reactions. In a study by Natasa Kusic et al. it is said that out of the total number of patients who were clinically tested for a reported allergy to penicillin preparations in vitro, none had a positive result and only 2.5% of those tested positive in vivo [12]. Th e study by Vicentijevic states that in 23% of patients, allergies were further examined and confi rmed by analysis [19]. Notwithstanding this suspicion, the patient's statement that they are allergic to a drug entails great caution when prescribing.
City Institute for Emergency Medical Services Belgrade (Srb. Gradski zavod za hitnu medicinsku pomoć Beograd) is a primary health care institution and has an outpatient clinic that operates 24/7 without interruption, in shift s of 12 hours each.

AIM
Th e aim of our study was to establish incidence of patients' claims that they are allergic to some drug.

MATERIAL AND METHODS
Th is is a non-commercial cross-sectional study, as a result of the work of a medical doctor from City Institute for Emergency Medical Services Belgrade, in the period of 5 years, starting from 16 April 2014 to 14 April 2019 on 10711 patients. Information regarding medication allergy is taken as part of the medical history when a patient arrives at the outpatient ambulance. Th e patient's allergy to а drug was confi rmed by a doctor aft er an adverse event in the past, and the patient was informed that he was allergic to the drug and should no longer use it. Patient's answers are entered into the corresponding fi eld in the access program. Th e data was exported to excel where the data was searched and sorted. Th e search identifi ed patients who appeared two or more times. Th eir allegations of drug allergies were compared. Th e criteria for inclusion in the study were patients' claims that they should not take one or more drugs because of an allergic re-action. Exclusion criteria: If a patient repeatedly reported allergies to the same medication during the visits, then one entry was left and the others were deleted. Also, if patients made diff erent allegations of drug allergies at diff erent visits, then all patient records were deleted. 1721 patients remained for analysis, accounting for 16.067% of the total number of patients examined. Patients claim to be allergic to bactrim, which is synonymous with all combina-tions of sulfamethoxazole and trimethoprim, or ibuprofen preparations, or claim that they should not receive any of the penicillin preparations because their doctor explained it to them. Patients sometimes claim to be allergic to the acetylsalicylic acid preparations produced by only one manufacturer and may use parallels from other manufacturers. Descriptive statistics methods have been applied for the primary processing of statistical data, and

RESULTS
Th e study included 1721 subjects, 1106 (64.27%) female and 615 (35.73%) male, Chisquare = 160.4556331 p <0.01. At the time of data collection, the average age of our subjects was 50 ± 16.5 years, range from 17 -95. Most respondents claimed to be allergic to penicillin (all penicillin preparations) (56.13%), trimethoprim + sulfamethoxazole (Baktrim®, Galenika and other generics) was second (12.02%), followed by ibuprofen (Brufen® Farmar A.V.E. Anthoussa Plant and other generics) in the third place (3.95%) ( Table 1). In addition to allegations of allergy to one drug, 338 (19.64%) respondents claimed to be allergic to two drugs (64.80%), three drugs (22.20%), four drugs (6.50%) and more than four drugs (6.50%). Penicillin was reported in more than 65% of allegations of allergic reactions to multiple drugs (combination with two, three, four or more than four drugs). Th e most common combinations of medicines that patients claimed to be allergic to were: penicillin + other antibiotics (125, 7.26% of patients, most in combination with trimethoprim-sulfamethoxazole 49 i.e. 2.85% of patients, followed by cephalosporins 31 patients or 1,80%, and 45 patients (2.61%) reported allergy claims to other, various antibiotics, followed by a combination of penicillin and analgesics (92 patients), with penicillin and NSAIDs being the most prevalent (56 patients), penicillin + salicylates (19 patients) and penicillin + pyrazolones (17 patients). Allergy claims to analgesics from various 878 Volume 7 • Number 1 • April 2020 • HOPH pharmacological groups were reported in 19 patients, 16 patients claimed to be allergic to combinations of analgesics and antibiotics, 7 patients claimed to be allergic to the combination of penicillin and iodine as a contrast agent for diagnostics. Seven patients claimed allergies to combinations of antibiotics from diff erent pharmacological groups (Table 2).

DISCUSSION
Out of the total number of patients, 16.6%, mostly female, claimed to be allergic to some drug and should not use it. Most oft en, patients have been reported to be allergic to penicillin preparations, followed by trimethoprim-sulfamethoxazole preparations, then to ibuprofen and diclofenac and caff etin. Of the total number of patients who claimed to be allergic to a drug, one fi ft h claimed to be allergic to more than one drug. Th e allegation of allergy to two drugs was given by 64.8%, three medicines 22.2%, to four and more medicines in 13%. Th e most common are combinations of penicillin with other antibiotics: trimethoprim + sulfamethoxazole and cephalosporins.
Th e average age of our subjects at the time of taking medical history was 50 ± 16.5 years, which is less than in the Velickovic et al [12] study and Hemstreet BA [11], or more than in the Gambo study [20]. Th e study by Velickovic et al. in 2015 reported that gender representation in allergic drug reactions is approximately similar to our data [21]. Zhou et al. in their study [22] found a higher representation of female gender, slightly lower than in our study. Mertes et al also showed that allergic reactions to drugs are more common in female subjects [23].  Drug allergy reports vary across studies. In the research Vicentijevic-Radosavljevic S. 17.3%, patients claimed to be allergic to some drug, most commonly to penicillin, cephalosporins, and NSAIDs [19]. Th e study by Velickovic et al. record claims of surgical patients that they are drug-allergic in 38.5% of cases, mostly antibiotics most commonly penicillin, NSAIDs and iodine preparations [21]. According to a Zhou study published in 2016, 35.5% of patients report drug allergies. Th e most common adverse reactions were reported aft er administration of penicillin, sulfonamide attibiotics, opioids as the most common codeine, followed by NSAIDs, including ibuprofen 0.7% and macrolides [22). Hemstreet B et al. reported that almost half of the patients reported an allergic reaction to trimethoprim-sulfomethoxazole [11]. Vicentijevic-Radosavljevic S reported that 23% of drug allergy claims were confi rmed by testing [19].

The most frequent combinations of drugs
Multiple drug allergies reported by patients are relatively common. In a study by Blumenthal KG et al. multiple drug intolerance (MDI) occurs in 6.4% of patients, and the incidence and prevalence of drugs varies from study to study. Multiple Drug Intolerance Syndrome (MDIS) in 1.2% of patients. "MDIS patients have intolerance or side eff ect reactions to three or more drug classes; Multiple Drug Alergic Syndrome (MDAS) patients had reactions to two or more drug classes with a possible immunologic mechanism". Most common multiple drug intolerance are those to penicillin, opioids, sulfonamides, NSAIDs, and macrolides, sulfonamide, cephalosporins, opioids, and NSAIDs [24]. In the study by Macy YE published in 2012, multiple drug intolerance syndrome was reported in 2.1% of penicillins, sulfonamides, and macrolides, with NSAID in 12 th place [17]. Omer et al. stated that 4.9% of patients had allergic reactions to three or more drugs, and that the incidence of MDIS is similar in patients with and without penicillin intolerance. Th ere is a wide range of medicines that contain antibiotics, including cephalosporin glycopeptides, macrolides penicillin, etc. and nonantibiotics, were paracetamol, lipid regulators, ace inhibitors, antihistamines and NSAIDs, aspirin, etc [25]. Sullivan et al study, 13% of patients who were allergic to penicillin developed allergic reactions to other "non-penicillin" antibiotics, such as sulfonamides (to which trimethoprim-sulfamethoxazole belongs), tetracyclines, erythromycin, vancomycin, and aminoglycosides [26], slightly less than our data show. According to ALIMS, there is no cross-reaction between penicillin and salicylate, that is, between penicillin and pyrazolone (Novalgetol®), whereas in the study by Pinho et al one patient developed drug reaction with eosinophilia and systemic symptoms (DRESS) while administering metamizole and amoxicillin as evidenced by a positive patch test, which is similar to our study [27]. Zhou et al in their study also proved that there is a cause-and-eff ect relationship between developing allergic drug reactions. According to the Campagna MD et al study, a cross-allergic reaction between penicillin and fi rst-generation cephalosporins is 1%, while the use of third-and fourthgeneration cephalosporins carries a negligible risk of cross-allergic reaction with penicillin [18]. According to the study by Hemstreet et al penicillin intolerance is a signifi cant risk factor for developing a sulfonamide intolerance. According to their results, penicillin allergy is a predictor for the subsequent development of sulfonamide allergy, with a large number of patients reporting an allergy to several drugs, including penicillin [11]. Some of our patients claimed that they are allergic to penicillin and a contrast agent, although according to Th e Agency for Medicines and Medical Devices of Serbia (ALIMS) there were no reports that a contrast agent containing iodine (eg Optiray®) interacted with penicillin and caused adverse allergic reactions. Th e study by Velickovic et al record claims by surgical patients that they are drug-allergic, most notably antibiotics, most commonly penicillin, NSAIDs and iodine preparations [21]. Although a study by N. Kusic et al stated that none of the patients who were clinically tested for a reported allergy to penicillin preparations were positive in vitro, and only 2.5% of those tested were positive in vivo [12], Vicentijevic Radosavljevic S found that 23% of reported allergic reactions were confi rmed by testing [19].
A limitation of our study is that no allergy was tested during the study, neither in vitro nor in skin tests to prove that the allergies did exist.