Drug Provocation Tests in Patients with a History Suggesting an Immediate Drug Hypersensitivity Reaction

The study by Messaad and colleagues (1) is the first publication clearly describing the indications, contraindications, methodology and outcomes of drug provocation tests based on recently published guidelines from the European Network for Drug Allergy of the European Academy of Allergology and Clinical Immunology (2).

Although theirs was a study evaluating immediate hypersensitivity reactions, patients with maculopapular eruptions were included. This is unusual because maculopapular eruption is often the manifestation of delayed rather than immediate hypersensitivity type reactions as T cell mediated mechanisms have been well described in its pathophysiology (3,4). One of the possible reasons why this appeared within 24 hours of the last dose may have been due to previous drug exposure and sensitization. Given the similarities in pathogenesis, a maculopapular eruption may also theoretically progress to Stevens Johnson syndrome, toxic epidermal necrolysis or drug hypersensitivity syndromes following drug provocation tests although this has never been reported.

Among patients with positive provocation tests, up to 21.4% of patients developed a reaction beyond 8 hours from the last provocation dose. Considering that the patients were observed for a maximum of 3 hours after the last dose, it would appear that up to one-fifth of patients may develop a potentially dangerous reaction after leaving the clinic. This may suggest that a longer observation period may be necessary for some patients. Any relationship between the last provocation dose achieved or the total cumulative provocation dose may also be helpful in anticipating the onset of a positive test.

Among patients with negative tests, one important cofactor that may have been missing compared to the initial reaction was concomitant infection, since at least 40% of provocation tests were for antimicrobials. If NSAID and paracetamol had initially been given for pyrexia or other symptoms associated with infection, the absence of infection during provocation tests may also have contributed to negative tests in this latter group. Alternatively, the infection may have caused the initial reaction (especially urticaria and angioedema (5), rhinoconjunctivitis, bronchospasm) in the first place rather than the drug.

It must be emphasized that the risks-benefits of drug provocation tests and the absence of other equally efficacious alternative drugs are important practical considerations in deciding whether drug provocation tests should be carried out at all. Nonetheless, this paper will be useful in helping to establish safer clinical guidelines, dose escalation protocols and monitoring measures in drug provocation testing.

References:

1. Messaad D, Sahla H, Benahmed S, Godard P, Bousquet J, Demoly P. Drug provocation tests in patients with a history suggesting an immediate drug hypersensitivity reaction. Ann Intern Med. 2004;140:1001-6.[ PMID: 15197017]

2. Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy. 2003;58:854-63.[ PMID: 12911412]

3. Friedmann PS, Lee MS, Friedmann AC, Barnetson RS. Mechanisms in cutaneous drug hypersensitivity reactions. Clin Exp Allergy. 2003; 33:861"“72. [PMID: 12859440]

4. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:683-93.[ PMID: 14568857]

5. Muller BA. Urticaria and angioedema: a practical approach. Am Fam Physician. 2004;69:1123-8. [PMID: 15023012]

Conflict of Interest:

None declared

Messaad and colleagues 1 reported a retrospective analysis of drug provocation tests in patients with suspected immediate drug hypersensitivity reaction. We still ponder the safety of such testing.

First, Messaad and co-authors observed patients for only 3 hours. This follow-up is not reassuring. Of all reactions observed, nearly a quarter began later than 8 hours. How severe were these late reactions ? What happened to patients after 3 hours, especially to those who did not return ? Messaad and co-authors did not at all mention mortality. Patients may even have died after the 3-hour observation period. Did some ?

Second, patient selection criteria deserve special emphasis. Inclusion and exclusion criteria sum up to about 40 items in the report under discussion.

Conflict of Interest:

None declared