Abstract
Objective
Medication-induced anaphylaxis is a potentially fatal event. Little is known at present about the patterns of medication-induced anaphylaxis in Asian countries. The current study aims to examine the pattern of documented incidences of drug-associated anaphylaxis in Taiwan over a 9-year period.
Methods
Cases of medication-associated anaphylaxis documented in the Taiwan National Health Insurance claims database during a span of 9 years (from January, 1997 to December, 2005) encompassing approximately 23 million person-years were reviewed. The database quantifies the drugs dispensed, clinical diagnoses, and patient demographics.
Results
Overall, 92 reports of medication-associated anaphylaxis in 92 patients were identified with potential causative agents documented. In this group, nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics were the main classes of medications most frequently implicated as the causative agent(s) in 89% of the cases. NSAIDs alone were implicated in 28% of cases, whereas antibiotics alone were implicated in another 28% of these cases. The use of multiple medications including either antibiotics or analgesics was documented in an additional one-third of the cases. A number of different NSAIDs including aspirin, diclofenac, ketoprofen, ketorolac, and meperidine were documented as the causative agents. Among the reported cases of antibiotics-induced anaphylaxis, cefazolin was the most frequently reported causative agent with 11 cases, followed by amoxicillin with four cases.
Conclusion
Antibiotics and NSAIDs were the two main classes of medications most frequently implicated in the reports of anaphylaxis in the Taiwanese population. Although this may be related to the frequent use of these medications in the Taiwanese population, the observation here does advocate for reduced combination of NSAIDs and antibiotics, and more careful patient monitoring when the
Keywords
anaphylaxis; antibacterial agents; anti-inflammatory agents; drug-related side effects and adverse reactions; epidemiology; non-steroidal;
1. Introduction
Anaphylaxis is a serious and occasionally fatal adverse event. The American College of Allergy, Asthma and Immunology describes anaphylaxis as an acute systemic reaction caused by immunoglobulin E (IgE)-mediated immunological release of mediators from mast cells and basophils to allergenic triggers, such as food, insect venoms, latex, and medication.1 Etiologically, anaphylaxis can be divided into anaphylaxis and anaphylactoid reaction, the later also known as pseudoanaphylaxis. The difference between the two is that anaphylactic reaction is an IgE-mediated reaction whereas anaphylactoid reaction is not. The severity, onset, and appearance of both reactions shows significant overlap clinically. Thus, according to the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group, the IgE- and non-IgE-mediated reactions are considered under a single term, anaphylaxis; this combined definition is used in the current study.
In a review by the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group, an estimated 1.2% to 15% of the total United States population is believed to be at risk of anaphylactic reaction.2 Most studies speculate that the prevalence of anaphylaxis is underestimated from underreporting.3,4 In addition, some studies examined a relatively small number of participants that are not representative of the general population.5 The most common causes of anaphylaxis are food, drug, and idiopathic reactions.6–10 The most common medication causes of anaphylaxis found by earlier studies include antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly when the drugs are administered parenterally.4 However, there appear to be several differences in the profiles of causative drugs for anaphylaxis across different populations.2,11–13
The aim of this study is to examine patterns of drug association in documented cases of anaphylaxis in the Taiwanese population when the drugs are administered parenterally.
3. Results
Between January 1997 and December 2005, a total of 402 individuals with anaphylaxis reaction were identified. Of this total, 14 individuals were excluded because of repeated diagnosis of anaphylaxis, 42 were excluded because of nonmedication-related anaphylaxis, and 254 were excluded because no potential causative agents for anaphylaxis were identified. A total of 92 individuals who experienced medication-induced anaphylaxis in which one or several likely causative agents were identified were included in the current study. Treatment for the anaphylaxis reaction in these individuals consisted of a combination of adrenaline, corticosteroids, and antihistamines. Based on the findings of our searches and reviews, we estimated the incidence of medication-induced anaphylaxis to be about 10.2 per 1 million person-years, affecting about 235 Taiwanese patients each year. The demographics of 92 study participants are summarized in Table 1. The mean age of this cohort is 50.37 years (range, 0 to 95 years). Most patients were in their fifth decade of life. Only six patients were younger than 10 years of age. There is a slight male predominance in the study cohort, with 55.4% being male and 44.6% being female.
The profiles of causative medications for anaphylaxis in the current study cohort are shown in Table 2. In cases where a single causative agent was identified, NSAID-type analgesics alone were implicated in 28% of cases whereas antibiotics alone were implicated in 27% of the cases. In 34% of cases, combinations of drug classes were felt to be causative of anaphylaxis; these comprised the following sub-groups: 1) analgesics and antibiotics; 2) either analgesics or antibiotics combined with another medication class; and, 3) analgesics and antibiotics combined together with medication from one or more additional classes. The overall distribution of classes of causative agents is illustrated in Figure 1. In the group with analgesics-only associated anaphylaxis, ketorolac and meperidine were each implicated in seven patients; aspirin was implicated in six patients, and diclofenac and ketoprofen were each implicated in four patients. In the group with antibiotic-only associated anaphylaxis, cephalosporins were the most frequently implicated antibiotic class (used in 19 patients), followed by penicillin and its derivatives, which were used in eight patients. The cephalosporins that were documented to cause anaphylaxis included cefazolin, cefmetazole, ceftriaxone, cefradine, ceftizoxime, and cephapirin. Penicillin and its derivatives that were implicated included penicillin, amoxicillin, and oxacillin. The drugs responsible for anaphylaxis are listed in Tables 2 and 3.
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4. Discussion
Our current study identified a total of 92 documented cases of medication-induced anaphylaxis in a retrospective review over 9 consecutive years in Taiwan. This translates to an incidence of medication-induced anaphylaxis of 10.2 per 1 million patient-years. This is about 3-fold the number reported by van der Klauw et al.11 Most previous studies consist of case reports or specific patient groups. Although NSAIDs and antibiotics were the two most frequently used causative agents we identified, a significant subset of patients developed anaphylaxis reaction while being on a combination of medications that included, in addition to NSAIDs and/or antibiotics, other classes of medications, thus raising the possibility of polypharmacy contributing to the development of anaphylaxis reaction. Although NSAIDs were frequently found to be associated with anaphylaxis, this study suggests that the frequency of drug-induced anaphylactic shock does not differ among specific NSAIDs.
Similar to our current observation, NSAIDs and antibiotics were the two most frequently implicated classes of medications in drug-induced anaphylaxis in reported series across different ethnic groups.4 In an observational study taken in the emergency department in Switzerland,16 the frequency of medication-induced anaphylaxis doubled that of food reactions. About half of the suspicious drugs were NSAIDs, followed by antibiotics. In a study on patients presenting to an emergency department in a predominantly Chinese community in Hong Kong,13 NSAIDs were found to be the most frequent causes of medication-induced anaphylaxis. In the current study, use of analgesics alone was responsible for more than a quarter of anaphylaxis, whereas the use of antibiotics alone was the second most frequent cause of medication-induced anaphylaxis. It is likely that the frequent association between NSAIDs and antibiotics with anaphylaxis reflects a combination of their frequent use clinically and perhaps an inherent propensity of these classes of chemicals to cause anaphylaxis.
Although NSAIDs and antibiotic classes of drugs have been consistently found to be the most frequently reported causative drugs for anaphylaxis across different populations, specific drugs and drug families are differentially implicated. For instance, among the anaphylaxis-causing antibiotics, penicillin was the most frequent culprit and the most well-studied cause, with a frequency of 1–5 per 10,000 patient courses of treatment.6 However, in the Korean population, Yang et al12 showed cephalosporins—rather than penicillin—to be the most frequent cause of antibiotic-induced anaphylaxis. The findings by Yang et al12 are similar to the findings of our current study, where cephalosporins were responsible for the majority of cases of antibiotic-induced anaphylaxis. Though one may raise the possibility of pharmacogenetic differences between Asian and Caucasian populations, this most likely reflects a difference in physician dispensing habits and medical practices rather than ethnicity-related genetic or other ethno-demographic factors.
Several previous studies that examined the profiles of medication-induced anaphylaxis have focused on subpopulations that may not represent the general population. It has been proposed that a better approach of estimating the risk of anaphylaxis would be to use estimates specifically calculated from epidemiologic studies measuring anaphylaxis in the general population.2 This study offers a solution to approximate the risk of anaphylaxis as it is an epidemiologic study using population-wide health coverage data collected over 9 years; thus, it gives a better overview on the estimates of anaphylaxis applicable to the general population.
Like many prior studies, our current study likely also underestimates the true incidence of anaphylaxis reaction in the general Taiwanese population as clinicians may fail to diagnose anaphylaxis in the absence of a fully developed shock. In addition, some patients and caregivers may not recognize anaphylaxis and patients may have recovered from these reactions without being properly diagnosed and treated. As the dataset used for data retrieval was extracted from a national claim-based database, it is reasonable to presume that the incidences of serious reactions are well reported. Nevertheless, we believe that the prevalence of medication-induced anaphylaxis is still underreported.
The results from our study show that drug-induced anaphylaxis is a significant health problem in Taiwan, and the risk for anaphylaxis may increase when common culprits such as NSAIDs and cephalosporin-class antibiotics are used together or in combination with other medications that have been shown to cause anaphylaxis. This underscores the importance of carefully instructing patients on the warning symptoms and signs of anaphylaxis and closely monitoring patients when a combination of these potential causative agents is administered.
Conflicts of interests
The authors declared no conflict of interests.