DRESS and HHV6 the first reports

DRESS mimics viral infection. Interestingly, all of the clinical and biological manifestations described in the DRESS are observed in some viral infection and especially HHV-6 infection. In 1993, Akashi et al. reported a severe infectious mononucleosis-like syndrome and primary HHV-6 infection in an adult (Akashi et al., 1993). A 43-year-old man was admitted with high fever, generalized exanthe-matic eruption followed by an exfoliative dermatitis, lymphadenopathy, atypical lymphocytes, hepatitis, and renal dysfunction. Lymphocyte population was mainly T-cell lymphocytes (52.6% CD8). CD19 and CD20 lymphocytes' levels were very low, 0.8 and 0.6%, respectively. The skin biopsy analysis demonstrated a diffuse infiltration with atypical lymphocytes in the dermis. HHV-6 infection was demonstrated by serial changes in titers of antibody against HHV-6 associated with an HHV-6 viremia. HHV-6 DNA was demonstrated in serum samples collected on days 10 and 13.

We had the opportunity to report the first case of DRESS associated with HHV-6 infection (Descamps et al., 1997). This DRESS was induced by phenobarbital in a 25-year-old Laotien woman. This patient fulfilled the characteristics of the DRESS (an exfoliative dermatitis with edema of the face, fever, lymphadenopathy, atypical circulating lymphocytes, eosinophilia, hepatic failure, and lymphocytic infiltrates in skin biopsy). This DRESS was complicated by a hemophagocytic syndrome. In 1997, HHV-6 has not been implicated in drug reaction. But viral infections were thought to play a role in some cutaneous drug reactions: the well-known ampicillin-induced exanthema in the Epstein-Barr virus (EBV)-mon-onucleosis syndrome illustrated this. Moreover, in this case, the association with a hemophagocytic syndrome was remarkable and questioning. Fulminant form of virus-associated hemophagocytic syndrome had been reported in Asia from where our patient originated with HHV-6 or EBV (Chen et al., 1995). Therefore, we investigated in this case concomitant viral infections and especially herpesvirus infections. An active HHV-6 infection was demonstrated on a rise in the anti-HHV-6 IgG antibodies titers in four consecutive sera. But PCR analysis for HHV-6 DNA in serum samples was negative. Other viral investigations (EBV, HIV) were negative. Two years later, two other groups reported three cases of DRESS caused by sulfasalazine (two cases) and allopurinol (one case) (Suzuki et al., 1998; Tohyama et al., 1998). Tohyama demonstrated an increase in the anti-HHV-6 IgG antibody titer with the detection of HHV-6 DNA from peripheral blood mononuclear cells (identified as HHV-6 variant B). No anti-HHV-6 IgM antibody was detected. Interestingly, it was not observed in the sera of four patients who developed cutaneous drug adverse reaction without any symptom of DRESS, an increase of anti-HHV-6 IgG antibodies. They concluded that this association was specific to the DRESS. A new step was reached by Suzuki et al. (1998) who detected in one patient with allopurinol-induced DRESS, HHV-6 genome in pathologic cutaneous lesions. After a rechallenge with allopurinol, the cutaneous eruption was reproduced. HHV-6 genome was found by PCR and in situ hybridization procedures in skin biopsies done at the initial acute phase and after a rechallenge. An increase of anti-HHV-6 IgG antibodies was also demonstrated. HHV-7 genome was also found by an in situ hybridization procedure at the acute phase of the initial eruption.

The conclusion after these initial reports was that HHV-6 reactivation was associated with DRESS and could participate in the pathogenic process. The sequence of the events (adverse drug reaction, virus reactivation, immune response, systemic symptoms) was not clear.

We prospectively evaluated the prevalence of HHV-6 infection in patients hospitalized in our dermatological department with DRESS (Descamps et al., 2001). Seven consecutive cases were included. All patients were seropositive for anti-HHV-6 IgG antibodies with a dramatic increase in two cases and detection of anti-HHV-6 IgM antibodies in four cases. In one patient studied, HHV-6 genome was detected in lesional skin by PCR procedure. We proposed that HHV-6 might play a role in the development of DRESS in susceptible patients. Many cases have been now reported (Conilleau et al., 1999; Sekine et al., 2001; Kunisaki et al., 2003; Masaki et al., 2003; Zeller et al., 2003; Descamps et al., 2003a,b; Enomoto et al., 2004; Ogihara et al., 2004; Michel et al., 2005).

One of the difficulties in addressing the question of the association of DRESS and HHV-6 infection is the reliability and relevance of virological tests for the diagnosis of HHV-6 active infection. HHV-6 is a ubiquitous "parasite" that is present in a vast majority of the human population. Primary infection occurs within the first 2 years of life and HHV-6 persists in peripheral blood mononuclear cells and many tissues (including salivary glands and brain) (Zerr et al., 2005). HHV-6 causes a chronic persistent or latent infection. It may be also difficult to draw any conclusion about a relationship between the presence of anti-HHV-6 IgG antibodies and a specific disease (Sullivan and Shear, 2001). While first reports of the association of HHV-6 infection and DRESS were based on serological tests with low value, recent reports used relevant real time quantitative PCR procedure in serum or from PBMC (Collot et al., 2002; Descamps et al., 2003b).

The diagnosis of reactivation, de novo infection or new infection may be another difficult question to answer. As the majority of adults is seropositive for HHV-6 infection, DRESS in adult seropositive patients is in its large majority clearly associated with reactivation of HHV-6. In children, it may be in some cases difficult to differentiate a primary or a reactivation. Some primary HHV-6 infections were reported in children (Mahe et al., 2004).

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