Variability of viral reactivations during recurrence of DRESS

Drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with viral reactivation of the herpesvirus group including human herpesvirus 6 (HHV6), HHV7, cytomegalovirus (CMV) and Epstein–Barr virus (EBV), probably favoured by certain drugs.1 Relapse and prolonged evolution of DRESS may be associated with viral reactivation, while the drug has been stopped. We report one patient with recurrences of DRESS induced by bortezomib, associated with variable viral reactivations. A 68-year-old man presented with stage III IgGκ myeloma. At Day 22 of treatment with bortezomib, lenalinomide, dexamethasone, sulfamethoxazole, amoxicillin and valaciclovir, the patient developed a DRESS with a RegiSCAR score of 7.2 The patient presented with fever, a maculopapular rash, facial oedema, pancreatic and hepatic involvement, hypereosinophilia (4900/mm3) and hyperlymphocytosis (6000/mm3) with hyperbasophilic lymphocytes. The skin and liver biopsies were compatible with DRESS. Cutaneous histopathology showed focal epidermal basal vacuolation and dermal superficial with lymphocytes, histiocytes, neutrophils and eosinophils. HHV6 (3,1 log maximal) and CMV (4,6 log maximal) viral reactivations (serum samples), researched by PCR, persisted at Days 6, 26, 33, 34, 48 and 70. Lenalinomide was stopped. Systemic corticosteroid treatment was first used and treatment by ganciclovir was added for 13 days. Bortezomib, unsuspected initially, was continued, and cyclophosphamide was added, under cover of prednisone 1 mg/kg/d, before gradual corticotherapy decrease for 5 months. Forty-nine days after stopping corticosteroids and 19 days after the fourth cure of bortezomib, DRESS relapses, with only HHV6 reactivation. The patch tests were positive for amoxicillin, penicillin G and cefotaxime; negative for sulfamethoxazole and lenalinomide; and not performed for bortezomib. Nine years after the first episode, while relapsing myeloma, bortezomib was reintroduced, associated with daratumumab and dexamethasone, but not sulfamethoxazole. Sixteen days after this treatment, the patient presented DRESS recurrence with febrile eruption, hypereosinophilia (maximum 1670/mm3), atypical lymphocytosis (Figure 1), pancreatic (lipase 2,18 N) and hepatic (ALAT 2,18 N) involvement with a RegiSCAR score of 7 and DiHS score of 5. Cutaneous histopathology showed lichenoid, with profuse epidermal basal vacuolation, some apoptotic keratinocytes (Figure 2) and dermal mononuclear infiltrate with a few eosinophils. At this time, the CMV PCR was positive at 2,6 log and EBV was positive at 2,4 log, but no HHV6 reactivation was evidenced. PCR was repeated several times at Days 3, 10, 50, 72. We concluded that this patient's DRESS was induced by bortezomib. Bortezomib-induced DRESS is rare, and our patient is the third case,3, 4 surprisingly diagnosed 10 years later, because of previous positive patch tests for antibiotics. Interestingly, bortezomib can promote viral reactivations such as CMV, HSV, EBV and HBV.5, 6 In the present case, the first episode was associated with HHV6 and CMV reactivation, the first relapse with HHV6 reactivation, and the second relapse with CMV and EBV reactivation. In the literature, HHV6, EBV, CMV or HHV7 reactivations are reported in 75% of DRESS, and more than two viruses are involved in 33% of cases.1 The presence of viral reactivations and a specific anti-EBV T-CD8 lymphocyte response with a cytokinic secretion, including TNFα and IFNγ, suggest a role played by these viruses in the pathogenesis of DRESS.1 The culprit drug introduction could induce reactivation and antigenic presentation of quiescent forms of EBV or other herpesviruses in cells such as B lymphocytes, which could secondarily trigger a multiorgan immune response directed against herpesviruses.1 Moreover, patch tests were positive for amoxicillin, penicillin G and cefotaxime. Their imputability cannot be excluded in the first episode: Picard et al. showed that recurrences with structurally unrelated culprit drugs are a frequent phenomenon in DRESS patients.7 In this respect during the first episode of DRESS, bortezomib may have been sensitized. The clinical and histopathological presentation was more lichenoid aspect in the second episode of DRESS. DRESS can be usually controlled by systemic steroids,2 whereas in severe DRESS, relapses after the decrease in systemic steroids may need antiviral treatment (ganciclovir).2 This second case of bortezomib-induced DRESS illustrates that recurrences of DRESS can be associated with different viral reactivations for the same culprit drug. None. Approved.