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- Material and methods
Background: The diagnosis of immediate allergic reactions to drugs is difficult, requiring in vitro test development. Basophils are likely to be involved in these reactions, and to evaluate the sensitivity, the specificity, and the predictive values of the histamine-release test, we performed a prospective study in 68 patients tested for suspected drug allergy.
Methods: Positive diagnosis was established by history, skin tests, and, if needed, oral provocation tests. Histamine release in the presence of the drug was assessed on heparinized whole blood by enzyme immunoassay (Immunotech, France), and the cutoff value was set at 5% of total histamine content. Spontaneous and anti-IgE-induced histamine release was also studied in all subjects.
Results: All patients presented to our clinic with reactions ranging from maculopapular exanthema to anaphylactic shock. Thirty-five patients had proven drug allergy; 33 were not allergic to drugs and served as a control group together with 40 other subjects with no history of drug allergy. Net histamine release was positive in 18/35 allergics and 27/73 nonallergics, giving poor sensitivity (51.4%), specificity (63.0%), and positive predictive value (29.3%), but valuable negative predictive value (81.1%).
Conclusions: The usefulness of the in vitro histamine-release test for the diagnosis of drug allergy appears to be insufficient.
Allergic reactions to drugs are responsible for levels of morbidity, mortality, and health-care costs which are underevaluated. These reactions are highly prevalent, as shown by various studies. For example, Classen et al. ( 1), using a computerized surveillance of adverse drug reactions in the LDS Hospital of Salt Lake City, Utah, USA, found over a period of 18 months that 0.65% of over 36500 hospitalized patients experienced an allergic drug reaction. In a recent study ( 2), adverse drug reactions appeared to be the 4th most common cause of death in the USA, with over 106000 deaths in 1994; 25% of these reactions were of allergic nature. The diagnosis of these reactions is difficult, being based on history and clinical manifestations, and, if possible, on skin tests, biologic tests, and provocation tests as required.
Provocation tests have the best sensitivity and are certainly useful to validate new biologic tests. However, they can be performed only under the most rigorous surveillance conditions due to potentially life-threatening reactions. Biologic tests would be highly desirable to establish the nature of the culprit agent, especially when the patient is receiving several drugs simultaneously. However, there are few available biologic tools, and they have not been fully evaluated. They include serum drug-specific antibodies, histamine release (HR) ( 3), cysteinyl-leukotriene release ( 4), histamine and tryptase in body fluids ( 5), basophil membrane markers ( 6), and T-cell-based assays (proliferation, activation, clones) ( 7). HR from total blood in the presence of the drug may be due to both specific IgE and nonspecific mechanisms. In the case of allergy to myorelaxants, the HR correlates well with skin tests and specific IgE ( 8), but, although there have been numerous case reports in the literature showing some basophil HR, this diagnostic tool has not been fully validated for most other drugs.
To evaluate the sensitivity, the specificity, and the predictive values of the HR test, we studied 68 patients with suspected drug allergy prospectively.
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- Material and methods
Thus, in the present study, we showed that the positive value of the in vitro HR test for the diagnosis of drug-induced hypersensitivity (including anaphylaxis) is poor, confirming what was generally recognized, but not demonstrated. However, the high negative predictive value may be used to rule out allergic drug reactions, especially in some patient subgroups. When only β-lactam reactions of rapid onset (less than 72 h after drug intake) were taken into account, the specificity, the sensitivity, and the negative predictive value were improved.
Obvious explanations of low sensitivity are the possibility that the reactive compounds may not be the drug itself but one of its metabolites ( 11), and/or the injectable soluble form of the drug may not be available (ready to be tested on blood basophils) and/or the mechanism is not IgE-dependent. This may be particularly true for paracetamol, macrolides, and cephalosporins, of which the metabolites are not available for testing or even all known. Thus, among the six out of 10 patients with cases of anaphylactic shock and negative HR, four were due to paracetamol, one to cefatrizine (of which the injectable soluble form is not available), and one to amoxycillin-clavulanate (patient with a high spontaneous HR). However, for penicillins, where major and minor determinants, together with injectable forms of penicillin G, amoxycillin, and ampicillin are readily available and account for most B-cell epitopes (14 out of 20 had positive skin tests in this study), the HR test does not appear to be powerful either, giving a sensitivity of 60% and a positive predictive value of 15.0–41.6%. Moreover, for the reactions reported to be IgE-dependent (i.e., β-lactam reactions occurring within 72 h after drug intake) ( 19), where the HR test is expected to be positive, the sensitivity was only slightly better (68.7%), suggesting either a true low sensitivity of the assay or the involvement of non-IgE mechanisms. The low specificity of the HR test may be related to the fact that, as for specific serum IgE, positive results demonstrate sensitization to the drug but do not confirm that it caused the allergic reaction.
However, there may exist subgroups of drug-allergic patients for which HR may be of interest. For example, in the case of myorelaxant allergy, HR has been shown to correlate well with skin tests and specific IgE ( 8), but we did not have a sufficient number of such patients to confirm this report. Our two myorelaxant-allergic patients had positive HR although five out of eight controls also had positive results. In the paper of Mata et al. ( 8), the sensitivity and specificity of the HR test were 65% (26/40) and 100% (0/44), respectively. In the paper of Vervloet et al. ( 20), the sensitivity was lower (eight out of 25 patients), but the specificity was not studied. HR could be of interest as additive value, complementing β-lactam skin tests, for example. Thus, in our experience, 30% of true β-lactam-allergic patients have negative skin tests (6/20) (Table 3). They represent almost 10% of the 115 patients referred last year to our clinic with a history of β-lactam allergy but negative skin tests. Current protocols hold it safe to allow patients with nonimmediate history of penicillin allergy and negative penicillin skin tests to take penicillins when needed without previous provocation test ( 21). The six patients in the present study had personal histories of variable onsets, both immediate (n=1) and accelerated (n=5). In this regard, although HR could have been of interest to avoid the provocation test, only 3/6 of these patients had positive HR (Table 3). However, for firm conclusions in this regard, we would need more patients.
Allergies to medically prescribed drugs play significant roles in iatrogenic drug-related illness and are responsible for levels of morbidity, mortality ( 2), and health-care costs which are presently underevaluated. Their symptoms are wide ranging, from mild urticaria to potentially fatal anaphylactic shock. The underlying mechanisms are varied and include all four types of the immunologic reactions described by Gell and Coombs (22), leading to some difficulty in diagnosis. There are also numerous other types of nonallergic reactions which mimic symptoms of allergy, and which have polymorphic origins. Finally, there are many differential diagnoses including infectious agent-induced exanthema and food allergy, so that, in our experience, only 23% of the patients referred to our department for suspected drug-allergy are truly allergic. Therefore, it would be highly desirable to have discriminating biologic tests available; firstly, to establish or rule out drug-allergy, and, secondly, to specify the culprit drug in patients receiving several drugs simultaneously. However, the biologic diagnostic tools at our disposal are few and have not yet been fully evaluated. Moreover, a formal diagnosis of allergy is required in order to institute proper preventive measures and treatment. In this paper, we demonstrated that the HR test cannot be, at the present stage, a routine biologic test for the diagnosis of drug allergies. Moreover, the analysis of HR from total blood in the presence of a drug is not a routine biologic assay; it requires certain skills and is expensive. However, it certainly is relevant to the research to demonstrate an IgE-dependent mechanism in patients with a suggestive clinical history.