Carbamazepine-induced DRESS and HHV6 primary infection: The importance of skin tests


Address correspondence to Dr. Karim Aouam, Laboratoire de Pharmacologie, Faculté de Médecine de Monastir, Rue Avicenne, 5019 Monastir, Tunisia. E-mail:


A 34-year-old male with a 20-year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, carbamazepine (CBZ) was added. Thirty-four days later, the patient developed hyperthermia, (39.5°C), cervical lymphadenopathy and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of 16.1 × 103/μl (17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). HHV6 serological tests performed on day 21, detected anti HHV6 IgM, suggesting a HHV6 primary infection. Hence, CBZ was discontinued. One month later, the skin eruption, fever, lymph node swelling, liver dysfunction, and eosinophilia were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48-h reading. This report suggests the usefulness of skin tests in diagnosing CBZ-induced-DRESS, as well as s possible association between DRESS and HHV6 primary infection.

The anticonvulsant hypersensitivity syndrome, also known as drug rash eosinophilia and systemic symptoms (DRESS), is a rare but severe form of adverse cutaneous reaction. Several aromatic anticonvulsant drugs, such as carbamazepine (CBZ), phenytoin, or phenobarbital have been frequently associated with the onset of DRESS syndrome (Shear & Spielberg, 1988). As its main clinical manifestations (rash, fever, lymphadenopathy, hepatitis, and hematological abnormalities) are similar to those shown by other diseases, such as lymphoma and mononucleosis infection, DRESS may be difficult to diagnose. However, the diagnosis is usually established by evaluating the time between drug-intake and the onset of the cutaneous eruption and the resolution of the symptoms after the drug withdrawal (Ogihara et al., 2004). Skin tests may be of great value in investigating adverse cutaneous drug reactions and their usefulness depends on the tested drug and the clinical manifestations of the eruption (Barbaud et al., 2001). However, little data about the predictive value of skin tests in CBZ-induced DRESS are now available. It has recently been reported that DRESS is associated with some viral infections particularly those caused by Human Herpes virus (HHV) 6 and 7. The viral infection seems to be potentially associated with DRESS (Oskay et al., 2006).

Hence, we report a case of CBZ-induced DRESS associated with primary HHV6 infection suggesting the usefulness of skin tests in diagnosing this drug-induced side effect.

Case Report

A 34-year-old male with a 20-year history of epilepsy was treated with valproic acid (500 mg 3 times daily) and phenobarbital (200 mg once daily). As he had frequent convulsive fits, CBZ was added. Thirty-four days later, the patient developed hyperthermia and cervical lymphadenopathy. Initially, he was diagnosed with lymphadenitis and, thus, a therapy of amoxicillin-clavulanic acid (1 g twice daily) and acetaminophen (500 mg 3 times daily), was started. Two days later, a generalized cutaneous eruption (exfoliated and confluent maculae and papulae (Fig. 1) associated with facial angioedema) was also observed. Laboratory findings showed an abnormal white cell count (16.1 × 103/μl, 17% eosinophils), a liver dysfunction with an aspartate aminotransferase level of 50 IU/L (normal 7–38 IU/L) and an alanine aminotransferase level of 116 IU/L (normal 4–40 IU/L), a lactate deshydrogenase level of 3197(normal 190–430 IU/L). The platelet count, INR, the serum levels of immunoglobulins, and the renal function were conversely normal and no atypical lymphocytes were found. The serologic tests for viral infection including cytomegalovirus, Epstein-Barr virus, hepatitis B and C and human immunodeficiency virus were all negative. CBZ, amoxicillin-clavulanic, and acetaminophen were then discontinued and cetirizine (10 mg once daily) was administered. HHV6 serological tests performed on day 21 after the symptoms' onset, with an immunofluorescent antibody assay (Biotrin, Lyon, France), conversely detected anti-HHV6 IgM. About 1 month later, the skin eruption, fever, lymphadenopathy, liver dysfunction, and eosinophilia progressively disappeared. As for his epilepsy, the patient was treated with phenobarbital and valproic acid. Six weeks after complete recovery, prick and patch skin tests to CBZ were performed. CBZ was tested at concentrations of 5% in petrolatum (Romano et al., 2004). The prick test (Stallerpoint, Stallergenes, France) was performed on the volar forearm skin with a 2-day closed patch testing on the back of the patient using Finn Chambers (Finn Chamber, Epitest Ltd Oy, Tuusula, Finland). Histamine and codeine sulfate were used as a positive control for the prick test. Two healthy controls underwent prick and patch tests to CBZ according to the same procedure applied on the patient. Twenty minutes after performing these tests, we only noticed a positive reaction to histamine and codeine sulfate (prick tests to CBZ in the patient and the controls were all negative). Both prick and patch tests were strongly positive at 48-h reading (Figs. 2 and 3, respectively) and no systemic reactions were noticed after these tests. They were negative in healthy controls. Reactions due to skin tests progressively regressed with a complete resolution 1 week later.

Figure 1.

Generalized exfoliated maculae and papulae with confluence.

Figure 2.

Positive prick test at 48-h reading (C, codeine phosphate; H, histamine. Used as positive controls).

Figure 3.

Positive patch test at 48-h reading.


This case report describes a patient who developed CBZ-induced DRESS. Indeed, a clear temporal relationship was observed between CBZ administration and symptoms' onset (33 days, typically 2–6 weeks) (Sullivan & Shear, 2001), the remission of symptomatological pattern after CBZ suspension, and positive results to CBZ-skin tests. Based on the Naranjo algorithm, it is probable that the systemic reaction was due to CBZ (Naranjo et al., 1981). DRESS is a nosological entity mainly characterized by a potentially life-threatening drug-induced cutaneous eruption. Since its first description with phenytoin in 1950, several drugs including other anticonvulsivant agents, sulfonamides, allopurinol have been associated with an increased risk of inducing such a syndrome (Sullivan & Shear, 2001). The clinical picture of DRESS includes fever, morbiliform eruption, lymphadenopathy, pleural effusion, cardiac and gastrointestinal disorders, liver and renal dysfunctions, hematological abnormalities such as eosinophilia and atypical lymphocytosis. It has been suggested that a defect in the epoxide hydroxylases, which induces the accumulation of toxic metabolites of CBZ, may lead to cell death or contribute to the formation of antigens triggering the immune reaction involved in DRESS (Shear & Spielberg, 1988). As the clinical picture of DRESS is similar to that of other diseases, its diagnosis may be difficult and remains mainly based on temporal considerations (i.e., the delay between drug intake and DRESS onset and the resolution after drug withdrawal) (Shear & Spielberg, 1988). The frequently used lymphocyte transformation tests are often negative in the acute stage of the disease. Interestingly, in this case the diagnosis of DRESS has been made possible by performing two different skin tests (patch and prick tests). Indeed, they were strongly positive at 48-h reading. While the patch and the intradermal tests are known to be classical devices to investigate the delayed type of drug hypersensitivity, the prick test is not a standard procedure to evaluate such reactions. It is generally performed to investigate immediate reactions. However, it is reported to be useful in diagnosing delayed drug reactions since it could mimic the allergic reaction in the tested skin (Romano et al., 2002). Moreover, little data about the predictive value of CBZ skin tests to diagnose DRESS is available in the literature. To appreciate the predictive value of patch tests, we analyzed all reported cases of CBZ-induced DRESS that had undergone patch tests according to the Pubmed database between 1993 and 2006 (Scerri et al., 1993; De Vriese et al., 1995; Okuyama et al., 1996; Galindo et al., 2002; Kim et al., 2006; Matsuda et al., 2006). Twenty-four CBZ-induced DRESS cases were reported of which 18 were positive. These data suggest a high rate of positive response to patch tests performed in CBZ-induced DRESS patients. Nevertheless, to our knowledge this is the first report suggesting the usefulness of prick test to diagnose this condition.

Moreover, it has recently been reported that DRESS is associated with HHV6 active infection. In this patient, however, only IgM antibodies against HHV6 were detected, suggesting a primary HHV6-infection. Since the first case of DRESS-associated HHV6 infection was described (Descamps et al., 1997), many articles have reported that DRESS might be associated with HHV6 reactivation (Michel et al., 2006; Schauer et al., 2006; Tamagawa-Mineoka et al., 2007). In fact, HHV6 infects approximately 90% of individuals aged around 2 years (Levy, 1997). The virus can persist in a latent form and is reactivated during immunosuppression. It seems likely that the activation of monocytes and CD4+ T lymphocytes induced by drug allergy, induces HHV6 reactivation (Hashimoto et al., 2003) and it is not completely clear whether HHV6 reactivation is a consequence of a strong immune modulation during DRESS or a cofactor which favors the manifestation of DRESS. The association between CBZ-induced DRESS and HHV6 reactivation may expose to some potential complications such as diabetes mellitus (Sekine et al., 2001). Conversely, only a few reports suggest that DRESS may be associated with HHV6 primary infection (Debarbieux et al. 2006) but not with CBZ. To our knowledge, we are the first to report a CBZ-induced DRESS associated with a HHV6 primary infection. Because the clinical manifestations of DRESS and severe HHV6 primary infection are similar, it could be argued that the clinical pictures have been induced by the virus itself. In this patient, however, this hypothesis was ruled out as he showed a strong positive response to CBZ skin tests. It can be suggested that HHV6 infection might be triggered by an eventual transient state of immunodepression caused by the CBZ hypersensitivity. HHV6 primary infection might contribute to prolong the course of the disease and increase its severity (Descamps et al., 2001).

In the light of these considerations, clinicians should be aware of the risk of DRESS in CBZ-treated patients. When unexpected clinical manifestations in CBZ-treated patients seem to suggest the occurrence of DRESS, skin tests should be performed in order to confirm the diagnosis. Moreover, the HHV6 infection status should be simultaneously investigated to establish the prognosis of DRESS.


The authors are greatly indebted to Prof. Adel Rdissi for his help in improving the language used in this article.

Conflict of interest: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All authors state that there is no conflict of interest.

Financial relationship with a biotechnology and/or pharmaceutical manufacturer: None.