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

Djamel Messaad, MD; Hocine Sahla, MD; Said Benahmed, MD; Philippe Godard, MD, PhD; Jean Bousquet, MD, PhD; and Pascal Demoly, MD, PhD
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From Hôpital Arnaud de Villeneuve, Montpellier, France.

Acknowledgments: The authors thank Ms. Anna Bedbrook for help with the English language.

Grant Support: In part by the University Hospital of Montpellier institutional grant, Projet Hospitalier de Recherche Clinique—7679.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Pascal Demoly, MD, PhD, Exploration des Allergies, Maladies Respiratoires, INSERM U454–IFR3, Hôpital Arnaud de Villeneuve, CHU de Montpellier, 34295 Montpellier Cedex 5, France; e-mail, demoly@montp.inserm.fr.

Current Author Addresses: Drs. Messaad, Sahla, Benahmed, Godard, Bousquet, and Demoly: Exploration des Allergies, Maladies Respiratoires, INSERM U454–IFR3, Hôpital Arnaud de Villeneuve, CHU de Montpellier, 34295 Montpellier Cedex 5, France.

Author Contributions: Conception and design: P. Demoly.

Analysis and interpretation of the data: D. Messaad, P. Demoly.

Drafting of the article: D. Messaad, P. Demoly.

Critical revision of the article for important intellectual content: J. Bousquet, P. Demoly.

Final approval of the article: D. Messaad, H. Sahla, S. Benahmed, J. Bousquet, P. Demoly.

Provision of study materials or patients: H. Sahla, S. Benahmed, P. Demoly.

Obtaining of funding: P. Demoly.

Administrative, technical, or logistic support: P. Godard.

Collection and assembly of data: D. Messaad.

Ann Intern Med. 2004;140(12):1001-1006. doi:10.7326/0003-4819-140-12-200406150-00009
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The major result of this study is that confirmed drug hypersensitivity reactions occurred in less than one quarter of patients with a history suggesting possible drug allergy. A negative drug provocation test result is important to the patient with suspected drug allergy because nonhypersensitive patients do not need to avoid these drugs in the future. The clinical histories of the patients with positive drug provocation test results were more suggestive of drug hypersensitivity reactions than the clinical histories of the patients with negative drug provocation test results. Indeed, 64.7% of the former reactions occurred within the first 8 hours after the last intake of the drug (as compared with 42.7% for the latter) and 15.7% of those reactions were anaphylactic (as compared with 7.3%). However, on a single patient basis, relying on the history to prove drug hypersensitivity (or its absence) is not possible. Similarly, although the proportion of positive test results was higher for aspirin (47.2%), other NSAIDs (27.3%), and quinolones (27.3%) than for paracetamol (16.9%), macrolides (13.7%), and β-lactams (8.4%), this information is not helpful diagnostically in a particular patient. Therefore, a complete drug allergy work-up is required: a detailed clinical history and physical examination, followed by 1 or more skin tests and drug provocation tests (6). Other laboratory-based tests that could possibly replace drug provocation tests are being studied. The drug provocation test result may have been falsely negative in some patients with mild sensitivity or a long delay between drug hypersensitivity reaction and allergy evaluation (spontaneous desensitization). Because of this possibility, we enroll our patients in a follow-up program; no patient has reported an allergic reaction to a drug that we had exonerated on the basis of a negative drug provocation result. If not included in the diagnostic procedure, important cofactors, such as exercise or sunlight, may sometimes explain the negative results (6). Tolerance induction during the provocation, although never documented in the literature, may also explain a false-negative result.

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Flow chart of study patients and results of drug provocation tests.

Some patients had more than 1 suspected drug hypersensitivity reaction (1615 suspected reactions in 1128 patients). *We excluded 15 patients with noncompatible clinical symptoms and signs (detailed in the text), 92 patients with a reaction occurring more than 24 hours after the last drug administration, and 18 patients with symptoms that disappeared while the patient continued to take the suspected drug. NSAID = nonsteroidal anti-inflammatory drug.

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Diagnostic issues in drug provocation tests
Posted on June 29, 2004
Bernard Y. Thong
Tan Tock Seng Hospital, Singapore
Conflict of Interest: None Declared

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.


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

Are drug provocation tests safe ?
Posted on July 8, 2004
Christoph Pechlaner
Innsbruck University Hospital
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

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Summary for Patients

Tests To Confirm Drug Allergy in Patients with a History of Possible Immediate Allergic Reactions to Drugs

The summary below is from the full report titled “Drug Provocation Tests in Patients with a History Suggesting an Immediate Drug Hypersensitivity Reaction.” It is in the 15 June issue of Annals of Internal Medicine (volume 140, pages 1001-1006). The authors are D. Messaad, H. Sahla, S. Benahmed, P. Godard, J. Bousquet, and P. Demoly.


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