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- Material and methods
Background: Allergic reactions to β-lactams are the most frequent cause of adverse drug reactions mediated by specific immunologic mechanisms. They can be explored by in vivo and/or in vitro tests. The measurement of serum-specific immunoglobulin E (IgE) presents several advantages: safety, simplicity, and availability to nonallergologist physicians.
Objectives: To establish the diagnostic value of specific IgE determination in the diagnosis procedure of immediate β-lactam allergy.
Methods: The in vitro determination of β-lactam-specific IgE antibodies was compared in three well-defined groups of patients (n = 45): one with negative skin tests and a positive drug provocation test, another with positive skin tests, and a third control exposed population with good tolerance. Two techniques were used: the CAP-FEIA system (Phadia®) commercially available and a homemade radioallergosorbent test (RAST).
Results: The specificity of CAP-FEIA ranged from 83.3% to 100% and sensitivity from 0% to 25% depending on initial clinical manifestations. The specificity of RAST was between 66.7% and 83.3% and sensitivity 42.9% and 75%. In the subgroup of patients with an anaphylactic shock and negative skin tests, the sensitivity and specificity of RAST were 75%. Positive and negative predictive values were 45.5% and 77.1% with CAP-FEIA and 38.5% and 81.5% with RAST, respectively.
Conclusion: These results indicate that, although the specificity of β-lactam-specific IgE measurement is good, sensitivity is low. Immunoglobulin E measurement should be limited to patients with a clinical history of anaphylactic shock and negative skin tests in order to avoid a drug provocation test. More sensitive assays should be developed.
Allergic reactions to β-lactams are the most common cause of adverse drug reactions mediated by specific immunologic mechanisms. They could be life-threatening and require the identification of the molecule in question. Several clinical entities have been described and those occurring immediately after drug exposure are immunoglobulin E (IgE)-mediated and explored by skin testing and by the in vitro measurement of serum-specific IgE. The sensitivity of these tests is not 100% and even for patients with a clear positive history, a drug provocation test may be required in order to confirm the diagnosis (1).
The advantages of the in vitro determination of specific IgE antibodies when compared with in vivo testing are that the former poses no direct risk to the patient and does not require personnel with expertise. Even though in vitro tests are recommended in immediate hypersensitivity reactions (2), their exact place in the diagnostic procedure is not clear and certain authors do not use this method in daily practice (3). In one study, in terms of sensitivity, 11 of 26 patients (42%) with negative skin tests and a positive drug provocation challenge (or repeated clinical history) had specific IgE to benzylpenicilloyl or amoxicilloyl (4). The specificity of the test was 95–100%. Therefore, IgE measurements can avoid a potentially harmful drug provocation test.
This study included patients who were already diagnosed as well as negative controls. They were all classified into three groups: one with negative skin tests and a positive drug provocation test, another with positive skin tests, and a third control exposed population with good tolerance. The aim was to establish the relevance of both commercially available and homemade-specific IgE antibody measurements, by determining the respective sensitivities, specificities and, when possible, positive (PPV) and negative predictive values (NPV).
β-Lactam allergic cases with a positive history, negative skin tests and a positive drug provocation test were compared with two groups: one composed of patients with a positive history and positive skin tests (allergic controls) and another with negative skin tests and good tolerance after β-lactam administration (nonallergic exposed controls). These groups were chosen in order to address two different questions: Could β-lactam-specific IgE measurement avoid a potentially harmful drug provocation test for patients with negative skin tests? Could IgE measurement avoid the β-lactam skin tests performed by allergologists?
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- Material and methods
Several in vitro methods (5–8) are reported to be useful in the diagnosis of patients with suspected immediate allergic reactions to β-lactams, but not all have been standardized or evaluated. For safety reasons, IgE measurements are of particular interest.
In a first approach, usually undertaken by general practitioners who do not have access to drug skin tests, one is interested in the determination of the sensitivity and specificity of the IgE immunoassays in the whole population. Our results demonstrate that specificity is good for both assays and better for CAP-FEIA (85.7–100% depending on initial clinical presentations) when compared with homemade RAST (71.4–75.0%). These results have to be confronted with the data available in the literature. However, to our knowledge, no study has ever shown (as we have) the diagnostic accuracy of the specific IgE CAP-FEIA in immediate allergy to β-lactams. In a study performed by Blanca et al. (5), where data concerned only amoxicillin and penicillin G, sensitivity was the same (42%) and specificity better (97%) using RAST technology in a similar patient population. There was no information on predictive values.
Although the two IgE assays were not (significantly) concordant, the homemade RAST did not bring any additional benefit in terms of predictive values. However, its significantly higher sensitivity is an interesting element (with a higher NPV), certainly due to the increased number of β-lactams available and particularly to the number of cephalosporins (three penicillins and eight cephalosporins, when compared with three and one for the CAP-FEIA).
It should be noted that the β-lactams incriminated in our study are not all available in the Phadia CAP-FEIA (19 of 45 cases and especially 19 cephalosporins). Results were best for aminopenicillin allergic patients. Nonpenicillin β-lactams are given particular attention in our study, especially in skin test-negative patients (11 of 15). The exploration of cephalosporin allergies is not standardized as well (as much or as thoroughly) as penicillins. Even if most immediate reactions to cephalosporins appear to be IgE-mediated, the cephalosporin allergenic determinants have not been properly identified, and cross-reactivity between penicillins and cephalosporins, as well as among cephalosporins, is low if they do not share the same side chain (9). Some experts have mentioned that skin testing with antigenic determinants of penicillin G, amoxicillin, and ampicillin is no longer sufficient for evaluating patients for β-lactam-induced allergy. The use of an extended panel of cephalosporin is necessary. Techniques of specific IgE detection-like sepharose-radioimmunoassay seem efficient (10), but the commercially available biologic assay CAP-FEIA lacks all but cefaclor IgE assays. The identification of β-lactam-specific IgE in patients’ sera requires the development of a large panel of molecules (in order to increase sensitivity), epitopes, and β-lactam carriers.
We could consider the PPV and NPVs depending on the relative frequencies of demonstrated drug allergy in our Drug Allergy and Hypersensitivity Database (Table 2). For serious clinical situations, PPVs displayed by the Phadia CAP-FEIA are 100%. For anaphylactic manifestations with or without anaphylactic shock, the estimated PPV and NPVs are high. Although this is a small case series, it suggests that IgE measurement could therefore have a place in the diagnosis procedure of anaphylaxis patients seen by nonallergologist physicians. Skin tests do, however, have a higher sensitivity and specificity. Immunoglobulin E assays might therefore be indicated in situations with no access to β-lactam skin testing when using nonsoluble cephalosporins and in high-risk patients.
In a second situation corresponding to allergologists who can carry out drug skin tests, one is interested in the determination of the sensitivity and specificity of IgE assays in the population with a suspicion of β-lactam allergy and negative skin tests. Does the practice of IgE assays make it possible to avoid an oral provocation test? Our results demonstrate that although specificity is good (93.3%), sensitivity is low (6.7%) for the CAP-FEIA. Sensitivity is improved by the homemade RAST (46.7%) but specificity is deteriorated (73.3%). In a published population of patients with negative skin tests, only 40 of 89 patients (44.9%) with negative β-lactam RAST had a negative provocation test (11).
It was impossible to estimate PPV and NPVs because of the lack of information on the prevalence of the positive diagnosis of β-lactam allergy in the negative skin test population. Only 15 patients with sera were identified in our database. So this situation seems to be rare and skin testing powerful in the diagnosis strategy of β-lactam allergy. The low sensitivity of the assays could be explained by a decrease over time of specific IgE levels, as it has been demonstrated for β-lactam immediate positive skin tests (2). However, when we withdrew the eight cases and five controls assessed more than 1 year after the allergy episode, sensitivity and specificity for the whole group did not significantly improve.
Moreover, immediate clinical manifestations because of β-lactams with positive oral challenge do not necessarily indicate an IgE-induced manifestation, even if it happened <6 h after drug intake. Other immunologic models proposed recent theories about non-IgE drug hypersensitivity (12). This could partly explain the lack of sensitivity of IgE assays in the population with negative skin tests especially with cephalosporin derivatives. For cephalosporins, the most reasonable explanation for the lack of sensitivity is the inadequate understanding and knowledge of the IgE determinants with this group.
However, this technique has a sensitivity of 75% in the population of patients having a history of anaphylactic shock. This population corresponds clinically to the patients who present a vital risk if the drug is re-administered. Thus, if these results are duplicated, a positive measurement of β-lactam-specific IgE in patients having had an anaphylactic shock but negative skin tests could be regarded as sufficient to avoid a life-threatening oral provocation test.
These results indicate that, although the specificity of β-lactam-specific IgE measurement is good, sensitivity is low. The place for IgE measurement should be limited to situations of severe manifestation in order to avoid drug provocations. Sensitive assays, in particular for cephalosporin allergies, should be developed. Increasing the number of β-lactam derivatives available in vitro is as important as for the in vivo diagnosis (13). A prospective multicenter study with systematic IgE measurement in situations of negative skin tests could provide us with more information about the performance of these assays.