Diagnosis of Drug Allergy

Author: V. Dimov, M.D., Assistant Professor, Allergist/Immunologist, University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist, Fort Lauderdale, FL

Acute drug allergy within 2 hours of a dose of a single drug is relatively easy to diagnose. Unfortunately, most clinical presentations of drug allergy are much more complex.

The average hospitalized patient receives more than 8 drugs simultaneously. Outpatient medical management of chronic conditions often requires polypharmacy.

History is of paramount importance.

Skin prick testing is only standardized for PCN. Only 10 to 20% of patients who report a penicillin allergy have a positive reaction on skin tests.

Patch test is used for contact dermatitis which is a type IV allergic reaction (T-cell mediated).

Serum tryptase is a market of mast cell degranulation and may be helpful in diagnosis of ADR due to allergy.

Step-by-step approach to evaluation of drug allergy when receiving multiple medications

1. History

Drug reaction history
Atopic history
List of concomitant medications, with starts, stops, and dose changes
Previous exposures to same or cross-reacting drugs

2. Narrow drug candidate list by focusing on:

- temporal association between drug starts and stops and onset
- intensification and waning

3. Rank drug candidates by allergenic potential

4. Stop all drug candidates with good temporal relationship and known allergic potential. Observe consequences.

5. Consider skin testing if suspected drug is clinically imperative, to assess IgE response. Disregard negative results within 14 days of anaphylaxis (false negative), and for all haptenic drugs without validated negative predictive value.

6. Re-administer incriminated drugs as clinically indicated. Use gradual dose escalation (if skin test negative) or desensitization protocol (if reaction IgE dependent or skin test positive).

Mnemonic

HASTA la vista (Spanish, "See you later")

History
Assemble a list of drugs and rank them
Stop all drug candidates
Test
Administer - dose escalation or desensitization

Drug skin testing with invalidated reagents is not helpful if negative.

Reintroduction of a drug by serial dose escalations may be useful in idiosyncratic drug reactions of limited severity.

Re-challenge is strongly contraindicated in severe exfoliative dermatitis syndromes, and even with milder dermatoses that include mucosal membrane lesions.

History

History alone is often not sufficient for establishing drug sensitivity.

Fewer than 20% of patients with a history of drug allergy are really allergic to the offending drug. Diagnosis of sensitivity based on history alone is not sufficient.

Drug provocation tests are the gold standard for diagnosis of drug allergy.

Skin testing

Testing for drug-specific antibodies or lymphocytes is informative in theory, but no so much in practice.

Prick and intradermal skin testing for drug-specific IgE antibody have been usefully applied to β-lactam antibiotics and other drugs. Rate of false-negative tests is only well established for penicillins.

Penicillin minor determinants remain an ‘orphan drug’ in the USA and currently are accessible only under investigational protocols.

Allergic reactions observed in retreatment of history-positive, skin-test-negative patients have all been mild and self-limited; no life-threatening false-negative reactions have been reported.

More than 80% of history-positive patients will have negative penicillin skin tests.

Concentrations of 2–3 mg/mL of a cephalosporin are usually non-irritating, but each cephalosporin requires concurrent evaluation for its irritation potential in non-allergic subjects.

A positive cephalosporin skin test implies drug-specific IgE antibodies but a negative test does not exclude immediate hypersensitivity. Commercial cephalosporin skin test reagents are not available in the USA.

Specific IgE

In vitro test results have been compared with skin tests only in penicillin allergy.

Diagnostic sensitivity for penicilloyl-IgE is 65–85% compared with penicilloyl-polylysine skin tests and 32–50% compared with a combination of skin testing and provocational challenge.

Minor determinant penicillin IgE antibodies are not reliably detected by RAST.

Intradermal skin testing remains the diagnostic procedure of choice for IgE-dependent penicillin allergy.

RAST of IgE antibodies to quinolone antibiotics and other drugs have been reported but their validity is still not known.

Flow cytometry

Assessment of drug-induced basophil activation by surface markers (CD63).

Basophil activation test can be useful for in vitro diagnosis of NSAIDs hypersensitivity: specificity is 100%, sensitivity is 42.85%.

Similar to unvalidated skin tests, a clearly positive result is of greater clinical value than a negative result.

Detectable serum mast cell β tryptase (greather than 1 ng/mL) or plasma histamine (greater than 10 nmol/L) taken within 4 hours of a suspected allergic reaction suggest mast cell and basophil activation.

Immunoassays for IgG, IgM, or IgA responses to drug allergens have not been useful.

IgG to the penicilloyl determinant occur in 50% of patients receiving PCN but this is not associated with drug allergy.

Lymphocyte proliferation

Lymphocyte activation tests using drugs as stimulants are often positive in drug-allergic subjects, but this indistinguishable from nonallergic patients.

Lymphocyte transformation test was positive in 78% of patients classified as highly likely to be drug allergic. Specificity was 85%; however, false-positive results were observed, especially with NSAIDs.

References

Drug Allergy. Middleton's Allergy: Principles and Practice, Mosby; 7 edition (November 19, 2008).
Clinical review: ABC of allergies. Adverse reactions to drugs. BMJ 1998;316:1511-1514.
Number of patients with drug allergy before and after allergologic study (figure) http://goo.gl/vva0Y and JACI, 2012. 
Severe Cutaneous Adverse Reactions to Drugs. Current Opinion in Allergy and Clinical Immunology. Faith L. Chia; Khai Pang Leong. Published on Medscape, 08/2007.

Basophil activation test for evaluation of IgE-mediated hypersensitivity reactions to quinolones http://goo.gl/LFEf

Multiple choice questions

Chapter 57: Drug Allergy. Allergy and Immunology Review Corner: Chapter 57 of Pediatric Allergy: Principles & Practices, edited by Donald Y.M. Leung, et al.

Published: 07/11/2007
Updated: 02/01/2012