EDITORIAL
DIAGNOSIS OF DRUG ALLERGY A PENDING PROBLEM?
The diagnosis of drug allergy is a problem that has not yet been fully resolved, constituting a handicap of allergologists that has some similarities with food allergies.
With the exception of biological products (gammaglobulins, vaccines, sera, hormones, etc.), most medications must bind to an organic protein as haptens in order to acquire antigenic capacity. On the other hand, it is the metabolites or antigenic determinants of medications that exercise their antigenic effect. The major (PPL) and minor determinants (MDM) of penicillin are known, but little is known about the metabolites of other medications. This explains in part why negative diagnostic tests (false negatives) are frequent, whether the tests are carried out in the laboratory or as skin tests. The unceasing development of new medications, not a few of which produce undesired reactions, complicates this problem.
Aside from the medications themselves, prepared drugs contain many other substances (colorings, flavorings, stabilizers, etc.) that also can produce hypersensitivity reactions and should be considered when studies are undertaken.
Moreover, physicians must keep in mind that medications can produce non-immunological reactions, that is, non-allergic reactions, such as side effects due to toxicity, idiosyncrasy, etc.
As regard the clinical aspects of allergic reactions to medications, their variability should be emphasized. The most severe reaction manifests as anaphylactic shock, although fortunately it is one of the least frequent. Other reactions occur within minutes and affect the skin and mucosas (urticaria, angioedema, rash, exanthema, etc.). The location, appearance, and intensity of these reactions vary. All of these manifestations are among the most common and correspond to the Type I anaphylactic reaction of the Gell and Coombs classification.
Less frequent are the cytotoxicity reactions (anemia, granulocytopenia, thrombocytopenia), which are expressions of Type II immune responses.
Serum sickness and vasculitis are not infrequent Type III reactions and an expression of immune-complex diseases. In these diseases, the consumption of complement is evident and diminished complement levels can be easily demonstrated in the acute phase of the process, constituting an important diagnostic aid.
Finally, topical medications are considered the prototypes of substances that are capable of generating delayed responses, or cellular immune reactions mediated by T lymphocytes. These reactions are classified as Type IV.
Other clinical manifestations (fixed pigmented erythema, nephropathy, hepatopathy, medication fever, etc.) are less common and their immunological mechanisms are difficult to determine.
Each of these reactions can be investigated using complex laboratory methods or challenge in specialized units. Over the years, the much more frequent immediate reactions have lead to the development of numerous diagnostic tests for the laboratory or in vivo. Many of them have been discarded because of their scant reliability and, sometimes, complex preparation (the Leftwich, Prausnitz-Küstner, and Kennedy tests, Matov''s controlled progressive challenge, Hoigné''s serological-nephelometric method, hemagglutinations, etc.) (1). At present, these reactions are diagnosed with skin tests, measurement of specific IgE in serum, reproduction in vitro of the immune reaction, and challenge tests.
The value of skin tests is limited, although they are very useful in some cases (2). Skin tests, particularly when carried out with antibiotics, often produce non-specific responses that can be either falsely negative or falsely positive (non-specific irritation). Only when skin tests are performed using the antigen determinants of penicillin or amoxycillin are they very valuable. Skin tests have more dubious value when carried out with other antibiotics, chemotherapeutics (cephalosporins, sulfonamides), and miscellaneous medications (local anesthetics, muscle relaxants, anticonvulsants, etc.) (3). These tests are not risk-free because they can generate anaphylactic reactions, although challenge tests are even more dangerous. However, the precise indication for the tests must be well established in every case because severe reactions are possible. However, such reactions are usually less frequent and intense if the medication is administered orally. Challenge tests may be interesting when the clinical history DOES NOT suggest an allergic reaction and this has to be demonstrated.
Among the laboratory tests for immediate type reactions, the only accredited test is the determination of specific IgE against a few medications, such as beta-lactams or insulin. The most appropriate method is radioimmunoassay (RAST or CAP-system). The possibility of false negative results and the small number of medications that can be assayed with reliable results limit the use of this diagnostic method. Biological methods (basophil degranulation and histamine release) are complicated to perform and yield dubious interpretations, so they are not used routinely (4). A more recent method, CAST-ELISA, could prove useful but little experience is available (5). Other laboratory methods, such as lymphoblastic transformation or inhibition of leukocyte migration (6), have lost credibility. Reasons for this include, among others, the fact that the type of reaction that they reproduce (immediate or delayed) is not well established and the reactions are non-specific.
The diagnosis of delayed reactions, which may occur in the course of beta-lactam treatment (7-9), requires the performance of a patch test. Diagnostic difficulties increase with cytological and immune-complex reactions (6). In the latter case it is difficult to establish the causality of a medication by laboratory tests and challenge tests are ethically unacceptable.
In view of the complexity of these diagnostic procedures and doubts about most of the results obtained, it seems clear that the problem of diagnosing allergies to medications is far from being resolved. It must be asked if this problem has a solution.
Something as simple as a good clinical history can provide very reliable diagnostic data. Clinical histories should provide a detailed description of the supposedly allergic clinical manifestations and the circumstances in which they appeared: the condition being treated with the medication, duration of medication use, earlier administration of the same medication, commercial preparation, etc. This data is important for the diagnosis, particularly in the case of anaphylactic shock or other severe reactions because any test in vivo is contraindicated since even skin tests can trigger the reaction again.
Therefore, the physician responsible for the care of the patient during the reaction and the physician who prescribed the medication can and should provide detailed information. It is illogical to request the study of a possible allergy to medications without giving a description of the clinical circumstances and the commercial preparation used. Moreover, one should insist that the study not be delayed too long after the supposedly allergic reaction has taken place because diagnostic possibilities decrease with time. A year after the reaction, the percentage of positive tests decreases considerably, although in some cases tests may remain positive for several years.
In conclusion, the physicians responsible for prescribing the medication and attending the patient during the supposed allergic reaction are in a position to provide valuable data for orienting the tests to be performed by specialists. Their collaboration can help to obtain reliable diagnoses without resorting to complex complementary tests.
F. Muñoz-López
REFERENCES
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5. Bircher AJ, Haldimann D, Weber J. CAST-ELISA testing for the diagnosis of immediate type allergic reactions to ß-lactamic antimbiotics. ACI Intern 1996;8:109-10.
6. Girad JP, Zawodnik S. Diagnostic procedures in drug allergy. En: Weck de AL, Bundgaard H. Allergic reactions to drugs. Berlin: Springer-Verlag; 1983.
7. Terrados S, Blanca M, García J, Vega J, Torres MJ, Carmona MJ, et al. Nonimmediate reactions to betalactams: prevalence and role of the different penicillins. Allergy 1995;50:563-7.
8. González FJ, Blanca M. T lymphocytes subpopulations and markers in allergies to betalactams. ACI Intern 1997;9:22-3.
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