IgE antibodies in penicillin allergy

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Lars Yman, Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden
 
Clinical data on test performance
The early work of Levine (1,2) on the allergenic properties of penicillins and their metabolites, and the studies of IgE antibody measurements in the diagnosis of penicillin allergy by Kraft and coworkers, (3,4) have been followed by numerous immunological and clinical studies on penicillins and other b-lactam antibiotics. IgE antibodies against the allergens studied were measured with a range of techniques derived from the original RAST® method.
 
For common inhaled or ingested allergens like pollen, epithelia, dust components and food, the prevalence is high enough and the clinical diagnosis accurate enough to permit reliable calculations of clinical sensitivity and specificity of the test employed as support in the investigation of suspected atopic allergy. When it comes to adverse reactions to drugs, however, the prevalence is low and, the causes of the reactions extremely complex, and therefore the true clinical diagnosis is less obvious. Less than 10% of all adverse reactions to drugs are considered to have immunological (allergic) background (Fig 1) (5), and only a part of those are IgE mediated.
 
Adverse drug reactions
 

Adverse drug reactions

Drug allergy (<10 %)
IgE
Cytoxic
Immune complex
Cell mediated
Unknown		Drug intolerance (>90 %)
Pharmalogical
Idiosyncratic
Overdosage
Drug interaction
Nonspecific mediator release
Prevalence (adults, any drug) < 5 %
Death from anaphylaxis 1/10 000 reactions

Fig. 1. Adverse drug reactions.

Extensive prospective studies of the type performed for Pharmacia CAP System and ImmunoCAP consecutive cases with suspected allergy have therefore never been reported for drug allergens.
 
Sensitivity data reported in the literature are, generally speaking, based on the agreement of tes (in vivo or in vitro) with the physician´s interpretation of historical data, or agreement between skin test and IgE antibody measurement in samples collected and stored over long periods of time.
 
True specificity data are not available as very few positive test reactions, in vivo or in vitro, are confirmed or disqualified by drug challenge.
 
Considering this situation and the fact that standardized skin-testing reagents and procedures do not exist, and that challenge and even skin test is often avoided because of the inherent risks, it is not surprising that reported data on performance of in vitro tests are variable and difficult to interpret.
 
Selected examples of informative published studies:
  • In an American study, 566 history positive patients with negative skin tests received penicillin. Seven (1.2 %) had possibly IgE -mediated reactions. None of 568 history negative and skin test negative patients in the same study had any reaction. Out of 167 skin test positive individuals, only 9 received penicillin and only 2 of those reacted in a way compatible with IgE mediated penicillin allergy. The results support the statement that skin testing is sensitive, but may indicate low specificity. Only 2 out of 9 skin test positive patients reacted to the drug (6).
     
  • Doubts about the specificity of skin testing are supported by data summarized in a review by Weiss and Adkinson 1988 (7), suggesting only a 50 -70 % risk of an acute allergic reaction to the drug in patients with positive history and positive skin test. Benzylpenicilloyl-specific IgE antibodies can according to the authors be detected in 60-95 % of the patients with positive skin test to penicilloylpolylysine.
     
  • During 1983-90, 175 patients with a history of immediate type reaction to penicillin were referred to an allergy clinic by general practitioners. 132 were tested and 4 patients were found to have penicillin specific IgE antibodies. The 128 patients without detectable IgE antibodies were challenged with 250 mg phenoximethylpenicillin orally. None of them had any reaction (8).
The study gives good indication that the clinical sensitivity of IgE antibody measurement is high. No patient (0/128) was falsely classified as negative.
  • Measuring IgE antibodies against penicillin G, penicillin V, ampicillin, and amoxicillin, the specificity of Pharmacia CAP System FEIA was found to be 89 % when compared to negative skin test in 105 patients with a positive history of immediate hypersensitivity to b-lactams (9). The agreement with positive skin test in another group of 58 patients reported in the same paper was 31 %. True sensitivity to the drug was not confirmed in any of the groups. In the light of the data mentioned above, from studies where reactions to therapeutic doses of the drugs were recorded, both sensitivity and specificity are likely to be underestimated.
Concluding remarks
The diagnosis of penicillin allergy is further complicated by the diversity of   immunological responses to the b-lactam antibiotics and to products thereof (10). Data suggest that the ImmunoCAP reagents introduced so far are adequate for the measurement of specific IgE antibodies to the major allergenic determinants with high sensitivity and specificity (about 90 %). It is our strong belief that further expansion of the allergen panel with cephalosporins (11) and other drugs will stimulate further studies and contribute to the understanding of the adverse reactions to penicillins and to antibiotics in general.

References:

    1. Levine BB, Zolov DM. Prediction of penicillin allergy by immunological tests. J Allergy Clin Immunol. 1969; 43: 231-44.
    2. Levine BB, Redmond AP. Minor haptenic determinant-specific reagents of penicillin hypersensitivity in man. Int Arch Allergy Appl Immunol.1969; 35: 445-55.
    3. Kraft D, Wide L. Clinical patterns and results of radioallergosorbent test (RAST) and skin tests in penicillin allergy. British Journal of Dermatology. 1976; 94: 593-.
    4. Kraft D, Roth A, Mischer P, Pichler H, Ebner H. Specific and total serum IgE measurements in the diagnosis of penicillin allergy. A long term follow up study. Clin Allergy. 1977; 7: 21-28.
    5. Boguniewicz M. Adverse reactions to antibiotics. Is the patient really allergic? Drug Safety 1995; 13: 273-280
    6. Sogn DD et al. Results ov the National Institute of Allergy and Infectious Diseases collaborative clinical trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992; 152: 1025-1032
    7. Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clinical Allergy. 1988; 18: 515-540
    8. Surtees SJ, Stockton MG, Gietzen TW. Allergy to penicillin: fable or fact? BMJ. 1991; 302: 1051-2.
    9. Sanz ML, Garcia BE, Prieto I, Tabar A, Oehling A. Specific IgE determination in the diagnosis of b-lactam allergy. Invest Allergol Clin Immunol. 1996; 6: 89-93
    10. Blanca M. Allergic reactions to b-lactams. ACI News. 1995; 7: 88-90
    11. Romano A, Quarantino D, Papa G, Blanca M, Venuti A. Detection of IgE cephalosporin antigens: preliminary findings with experimental prototypes (Pharmacia CAP System). J Allergy Clin Immunol. 1997; 99 (No 1,part 2): 430
1997