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Research Letter |

Prolonged Evolution of Drug Reaction With Eosinophilia and Systemic Symptoms Clinical, Virologic, and Biological Features FREE

Florence Tetart, MD1,2; Damien Picard, MD, PhD1,2; Baptiste Janela, PhD2,3; Pascal Joly, MD, PhD1,2; Philippe Musette, MD, PhD1,2
[+] Author Affiliations
1Department of Dermatology, Rouen University Hospital, Rouen, France
2National Institute of Health and Medical Research Unit 905, Institute for Research and Innovation in Biomedicine, Rouen University Hospital, University of Normandy, Rouen, France
3Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore
JAMA Dermatol. 2014;150(2):206-207. doi:10.1001/jamadermatol.2013.6698.
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Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe drug-induced reaction characterized by systemic involvement and an unusually long latency of onset after exposure to medication. Because this syndrome is not easily identified, it remains underdiagnosed. Its physiopathological characteristics are still incompletely understood, involving reactivation of dormant herpesviruses triggered by the culprit drug.1 Moreover, herpesvirus reactivations might even have an impact on the severity and duration of DRESS.2 Usually, DRESS resolves within 1 month; however, some patients have prolonged evolution, sometimes associated with flare-ups. In addition, some patients with DRESS can develop persistent renal insufficiency or autoimmune symptoms following acute hypersensitivity events.3 Factors associated with prolonged evolution have not been identified to date. Our study aimed to assess clinical and biological features associated with prolonged evolution in a prospective cohort of 40 patients with DRESS.

Patients with DRESS were included according to the criteria described in our previous investigation.1 The study was approved by our local ethics committee (ClinicalTrials.gov, NCT 00213447). Written consent was obtained from patients. On the basis of a study in which median duration of disease was estimated at 30 days,2 prolonged evolution was defined by the persistence, at least up to day 90, of at least 1 clinical and/or 1 laboratory abnormality. Viral DNA from Epstein-Barr virus (EBV), cytomegalovirus, and human herpesvirus (HHV) types 6 and 7 was quantified by means of real-time polymerase chain reaction (RT-PCR) in serum and peripheral blood mononuclear cells of patients. Statistical analysis used nonparametric tests, the Wilcoxon test, and the Fisher exact test.

Of the 40 patients included, 32 were assessable at day 90. Seven of these 32 patients (5 female, 2 male; median age, 25 years) had prolonged evolution. Four of these 7 patients still had cutaneous lesions (n = 3), hematological abnormalities (n = 3), and/or increased liver enzyme levels (n = 1) up to day 180 and day 360.

Viral reactivations were found in 3 of 7 patients between day 0 and day 30, involving EBV and HHV-6 in 2 cases and EBV and HHV-7 in 1 case, but no late viral reactivation was found. The proportion of patients of non-European ethnicity was higher in prolonged DRESS (5 of 7 [71%] vs 2 of 25 [8%]; P = .002). Liver enzyme level increase and lymphocyte count were higher at baseline in prolonged DRESS (Table). Likewise, mononucleosis-like atypical lymphocytosis was found in 4 cases of prolonged DRESS (57%), compared with 5 cases in “usual” DRESS (20%) (P = .08). Strikingly, minocycline as a culprit drug was observed in 3 of 7 cases in prolonged DRESS, whereas it was never involved in the other cases (P = .007). There was no evidence of a significant difference between the 2 groups regarding the use of corticosteroids for management of patients with DRESS. Last, no significant difference in viral reactivation frequency was found between the 2 groups.

Table Graphic Jump LocationTable.  Comparison of Biological Parameters Between Patients With and Without Prolonged Evolution

Seven of 32 patients (22%) had prolonged evolution lasting more than 90 days, lasting until day 180 (n = 4) and even up to 1 year (n = 3). Comparative analysis showed a predominance of minocycline use in patients of non-European ethnicity, more frequent pustular eruption, more severe hepatic cytolysis, and higher lymphocyte count at baseline in the prolonged evolution group. Several pharmacogenetic studies have shown an association between HLA types, ethnicity, and severe drug reaction, arguing for ethnicity as an additional key factor in the occurrence of adverse drug reactions. In this respect, in a series of minocycline-induced DRESS,4 all patients were of non-European ethnic origin with Fitzpatrick skin phototypes V and VI, and minocycline was reported to be detected in the plasma and/or skin of some patients up to 17 months after minocycline withdrawal.4 Drug accumulation in the skin of predisposed patients could explain prolonged evolution of DRESS and in particular the persistence of cutaneous involvement. In a previous study, we showed that drug use was able to reactivate EBV or HHV-6 in vitro.1,5 Minocycline, although not tested, might also reactivate herpesviruses or unidentified viruses. In addition, a previous report linked HHV-6 reactivation and severity and duration of symptoms, as well as occurrence of flares.2 In the present study, no difference was found regarding the role of viral reactivation in the persistence of symptoms. However, more pronounced lymphocytosis, presence of mononucleosis, and more severe hepatic cytolysis suggest a more important viral-dependent reaction in prolonged DRESS.

Corresponding Author: Philippe Musette, MD, PhD, Clinique Dermatologique, Hôpital Charles Nicolle, 1 rue de Germont, 76031 Rouen Cedex, France (philippe.musette@chu-rouen.fr).

Published Online: December 25, 2013. doi:10.1001/jamadermatol.2013.6698.

Author Contributions: Drs Tetart and Picard served as co–first authors, each with equal contribution to the manuscript. Drs Tetart and Picard had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tetart, Picard, Janela, Musette.

Acquisition of data: Tetart, Picard, Janela, Joly.

Analysis and interpretation of data: Tetart, Picard, Janela, Musette.

Drafting of the manuscript: Tetart, Picard, Musette.

Critical revision of the manuscript for important intellectual content: Janela, Joly.

Statistical analysis: Tetart, Janela.

Administrative, technical, or material support: Picard.

Study supervision: Picard, Musette.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by a French national program of clinical research (Programme Hospitalier de Recherche Clinique).

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Nikki Sabourin-Gibbs, PhD, Rouen University Hospital, edited the manuscript. Sylvie Ranger-Rogez, PhD, Department of Virology, Limoges University Hospital, Limoges, France, provided viral RT-PCR; and Vincent Descamps, PhD, Department of Dermatology, Bichat University Hospital, Paris, France, and Michel D’Incan, PhD, Department of Dermatology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France, recruited patients with DRESS. These additional contributors were not compensated for their contribution.

Picard  D, Janela  B, Descamps  V,  et al.  Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2(46):46ra62.
PubMed   |  Link to Article
Tohyama  M, Hashimoto  K, Yasukawa  M,  et al.  Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol. 2007;157(5):934-940.
PubMed   |  Link to Article
Chen  YC, Chang  CY, Cho  YT, Chiu  HC, Chu  CY.  Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan. J Am Acad Dermatol. 2013;68(3):459-465.
PubMed   |  Link to Article
Maubec  E, Wolkenstein  P, Loriot  M-A,  et al.  Minocycline-induced DRESS: evidence for accumulation of the culprit drug. Dermatology. 2008;216(3):200-204.
PubMed   |  Link to Article
Mardivirin  L, Descamps  V, Lacroix  A, Delebassée  S, Ranger-Rogez  S.  Early effects of drugs responsible for DRESS on HHV-6 replication in vitro. J Clin Virol. 2009;46(3):300-302.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable.  Comparison of Biological Parameters Between Patients With and Without Prolonged Evolution

References

Picard  D, Janela  B, Descamps  V,  et al.  Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2(46):46ra62.
PubMed   |  Link to Article
Tohyama  M, Hashimoto  K, Yasukawa  M,  et al.  Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol. 2007;157(5):934-940.
PubMed   |  Link to Article
Chen  YC, Chang  CY, Cho  YT, Chiu  HC, Chu  CY.  Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan. J Am Acad Dermatol. 2013;68(3):459-465.
PubMed   |  Link to Article
Maubec  E, Wolkenstein  P, Loriot  M-A,  et al.  Minocycline-induced DRESS: evidence for accumulation of the culprit drug. Dermatology. 2008;216(3):200-204.
PubMed   |  Link to Article
Mardivirin  L, Descamps  V, Lacroix  A, Delebassée  S, Ranger-Rogez  S.  Early effects of drugs responsible for DRESS on HHV-6 replication in vitro. J Clin Virol. 2009;46(3):300-302.
PubMed   |  Link to Article

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