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Background: Unevaluated drug reactions that lead to the prescription of expensive alternative medication is the reason why the European Academy of Allergy and Clinical Immunology guidelines recommend verification. We evaluated whether a structured test procedure in patients with drug reactions is worth the potential risk.
Methods: We retrospectively analysed the charts of a cohort of 291 (220 females/71 males) consecutive patients from January 2003 to June 2004, who presented at the department's allergy outpatient clinic with histories of drug reactions. Twenty-three patients reported more than one independent episode resulting in 325 cases. All patients underwent the following procedure: (1) detailed history; (2) skin test and/or β-lactam-specific IgE and; (3) if inconclusive, each patient was offered provocation testing – if needed with alternative medication.
Results: We evaluated reactions to 130 antibiotics, 90 to nonsteroidal anti-inflammatory drugs, 36 to local anaesthetics and 69 to other drugs. An association between drug intake and reaction was confirmed in 100 and excluded in 157 cases. Fourteen of 104 drug provocation tests (DPT), among these four reactions to placebo, yielded positive results but were managed without difficulty. In 68 cases, the procedure remained inconclusive. Additionally, we recommended 197 safe alternative regimens to 85 patients. Overall, our test procedure resulted in clear-cut recommendations to 82.1% (239/291) of the patients.
Conclusions: A standardized work-up including DPTs in patients with drug reactions leads to clear-cut advice concerning future tolerability or avoidance of certain drugs including recommendations for alternative medication in the vast majority of patients at the cost of only a low risk of mild side effects.
According to a World Health Organisation (WHO) definition, adverse drug reactions are defined as ‘a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function’ (1). Adverse drug reactions can be classified into six categories (1): only two classes concern prompt side effects of drug therapy: common predictable reactions occurring in any individual (type A, ‘augmented reaction’), and the uncommon, unpredictable and in susceptible individuals only occurring type B reactions (‘bizarre’). Other classes attribute long-term side effects, e.g. teratogenic or carcinogenic (type D, ‘delayed’) or the adrenal cortex-suppressing effects of corticosteroids (type C, ‘chronic’).
Type A reactions make up more than 80% of all drug reactions (2) and are usually documented in common prescription manuals. According to Hunziker et al. (2), 13% of adverse drug reactions can be classified as B-type and either be of nonimmunological (intolerance, e.g. to aspirin; idiosyncratic; pseudo-allergic by direct mast cell release, e.g. reactions to radiocontrast media) or immunological origin. According to the new World Allergy Organisation (WAO) nomenclature (3), the term ‘drug allergy’ should remain restricted to patients with a proven immunological cause. The terms ‘immediate’ and ‘delayed drug allergy’ should be used to describe the onset of symptoms and the probable responsible immunological mechanism [IgE, T-cell mediated, rarely IgG mediated (4)].
Adverse drug reactions are an important issue of public health. They rank number one among hospitalizations because of anaphylaxis (5). Gomes et al. (6) report 7.8% of an unselected Portuguese population claiming to suffer from some sort of drug allergy. In selected patient groups, such as surgical patients, this proportion can even reach up to 28.1% (7).
Unevaluated drug allergies lead to the prescription of less effective or more expensive alternative drugs, thus laying high economic burdens on public health care systems (8–10). Therefore, a clinical work-up is recommended by the guidelines of the European Academy of Allergy and Clinical Immunology (EAACI) (11) and the ‘Société Française d'Anesthésie et de Réanimation’ (12).
Currently, validated, commercial in vivo and in vitro test materials are available only for type-1 β-lactam allergies and some cephalosporins. There are recommendations for in vivo and in vitro tests for diagnosing aspirin (ASA)-hypersensitivity (13). Sensitive and specific commercial in vitro tests would be more than desirable; however, most tests available are of questionable sensitivity and reproducibility so that they are used in studies but not routine settings (e.g. CD63 activation tests, lymphocyte transformation tests, CAST-ELISA). Therefore, a thorough work-up of patients with a history of adverse drug reactions, usually includes re-administration of the suspicious drug (14). This poses risk to patients at times when they do not need the drug.
Although the above-mentioned guidelines (11, 12) recommend testing in patients with drug reactions, there are no data about the overall effectiveness of such a procedure. In this study, we tried to assess the risk–benefit ratio of our structured approach consisting of a fixed sequence of history, (if available) measurement of specific IgE, skin test and, finally, drug provocation test (DPT). We did this by retrospectively analysing the charts of 291 consecutive patients with drug reactions, who were referred to our allergy outpatient clinic from January 2003 to June 2004.
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In this study, we assessed how often a structured approach for evaluating drug reactions (Fig. 1) leads to clear-cut answers to the patient's vital question: ‘Which are the drugs for my coming needs?’. In other words, we tried for a fine-tuning of the patient's individual pharmacotherapy. 79.1% of the cases were clearly answered. Half of the patients could reuse the drug on future occasions, one-third should avoid it (Table 1). Only the remaining sixth part remained unresolved. In addition, we recommended alternative medication to 85 patients. In our eyes, this risk–reward ratio is a favourable one.
In general, there are two main counterarguments against DPTs with suspicious drugs. First, they cause high costs of inpatient treatment for otherwise healthy individuals for safety reasons only. Although the prescription of alternative drugs in penicillin allergic patients is known for causing high costs per se (9), an evaluation of the total cost-effectiveness of testing for drug reactions remains an open issue (8). A possible cost-effectiveness of DPTs in the German healthcare system was suggested by Blaschke and Fuchs (22). Secondly, exposing otherwise healthy patients in advance of need to drugs having caused – at least by history – some kind of adverse reaction, is an ethical caveat. Usually, the gain of knowledge leading to an optimization of the patient's therapy is seen as favourable compared with the risks of a DPT (23). Even large scale DPTs with suspicious drugs in patients with a history of type-1 reaction to drugs in two recent studies from France with 1372 adults (24) and Serbia-Montenegro in 1170 children (25), reported no sequelae from provocation-testing. In our patients, DPTs were also safe. There were reactions in 20.0% (14/70) patients including the four reactions to placebo. Hence, the inclusion of placebo-challenges was essential in our patients to avoid false positive reactions especially in patients with histories of type-1 bronchial and cardio-vascular reactions, that are hard to objectify. The remaining 15.2% (10/66) responders to verum correspond well with the 17.6% reported by the above-mentioned study of Messaad et al. (24). We think that the low risk of mild reactions upon DPTs with suspicious drugs and the risk-free DPTs with alternative medication were well worth the outcome. However, the need for a DPT will always remain a careful case-by-case decision according to the caring physician's personal risk–benefit estimation.
As already highlighted by others (26, 27), many patients are falsely labelled as ‘allergic to local anaesthetics’ although allergic reactions to local anaesthetics are very rare. We confirmed only two reactions and could exclude nearly all the others (Fig. 2). Often, we even recommended the suspicious local anaesthetic as proven alternative in a therapeutic dosage for common local interventions.
In contrast to data by Blanca et al. (28), who found sIgE to amoxicilloyl in 53% and to benzylpenicilloyl in 68% in 129 patients with type-I reactions to penicillins, measuring specific IgE to β-lactams was insensitive in our patients (4/116 subjects, 3.4%). Only half of these cases (52/116, 44.8%) had a type-1 suggestive history which can partly explain this difference but, probably, Blanca et al. (28) had described a more preselected population.
Our focus in patients requiring analgesics primarily aimed at finding alternative medication. Apart from experimental systems such as an ELISA against propyphenazone (29), in vitro tests are currently not available. Skin tests with NSAIDs bear the risk of false positive reactions because of their high irritancy (30). The high didactic value of negative DPTs with alternative drugs in patients with adverse reactions to analgesics including patients with ASA-hypersensitivity was already stressed by Laking et al. (31). Because of their low risk of side effects and their good tolerability even in ASA-hypersensitivity patients (32, 33), mefenamic acid and paracetamol (acetaminophen) were the first line alternatives that we recommended to our patients (Table 2). However, these two analgesic drugs are not very potent and, therefore, diclofenac was the other most often proposed alternative. Laking et al. (31) also mentioned that these patients should stick to the recommended analgesics for a better quality of life. However, to 11 patients, we recommended rofecoxib (Vioxx®, MSD, Vienna, Austria) as alternative medication, a drug that was withdrawn later on from the market worldwide for safety concerns in patients with a high risk of cardiovascular disease (34).