Comment on 'Drug reaction with eosinophilia and systemic symptoms syndrome in a patient with COVID-19': involvement of herpesvirus reactivations and adverse drug reactions in diverse cutaneous manifestations and overall disease severity of COVID-19.

Dear the Editor,

We have read with great interest the publication by Herman et al., which reported occurrence of drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug‐induced hypersensitivity syndrome (DiHS), in a COVID‐19 patient: the patient developed DiHS/DRESS 17–18 days after starting azithromycin and hydroxychloroquine. The benefits shortly after starting these drugs appeared to be minor, whereas the long‐term immune dysregulation was significant. DiHS/DRESS is a life‐threatening multiorgan system reaction induced by a limited number of the causative drugs with the immunosuppressive potential and are characterized by sequential occurrence of herpesvirus reactivations. , Here, we provide a brief insight into the similarities and differences in the clinical manifestations of COVID‐19 and DiHS/DRESS. DiHS/DRESS can mimic virally related diseases including Epstein–Barr virus‐ and cytomegalovirus‐induced infectious mononucleosis, parvovirus B19 infection, dengue virus infection and Kawasaki disease. In DiHS/DRESS, even after drug withdrawal, resolution of symptoms in one organ is often followed by a stepwise development of other organ failures, such as gastroenteritis, interstitial pneumonia, limbic encephalitis and myocarditis. Such clinical variability in the presentation and course could be mediated by sequential occurrence of herpesvirus reactivations. Initial expansions of regulatory T cells (Tregs) and their subsequent exhaustion provide a mechanism for why herpesviruses can be sequentially reactivated at the acute~subacute phases (3–40 days after onset) and why the patients have severe complications/sequelae: a gradual loss of Treg function could increase the risk of developing widespread collateral tissue damage. , , In DiHS/DRESS, the pathogenic cascade triggered by drug damages many organs from the skin to the brain, as shown in COVID‐19 patients. During the disease process in COVID‐19 as well as DiHS/DRESS, a variety of clinical symptoms may develop later depending on the herpesvirus reactivated. Indeed, diverse clinical symptoms in DiHS/DRESS have been also reported as COVID‐19‐related cutaneous manifestations without confirming viral or drug aetiologies; they include erythema multiforme, varicella, herpes zoster, pityriasis rosea, Kawasaki disease and urticaria, , , in which herpesviruses, such as varicella‐zoster virus (VZV) and human herpesvirus 6 (HHV‐6), have been suggested to play a role. A recent report also describes co‐reactivation of herpes simplex virus‐1 and VZV in a critically ill COVID‐19 patient. Because HHV‐6 has been shown to be associated with chronic spontaneous urticaria, herpesvirus reactivations including HHV‐6 could be involved in diverse cutaneous manifestations previously attributed to SARS‐CoV‐2. If so, antiviral agents may ameliorate severe COVID‐19 symptoms when used as adjuncts to putative anti‐COVID‐19 agents. In addition, adverse drug reactions (ADRs) could have contributed to the diverse cutaneous manifestations. In support of this, a recent report describe 5.84‐fold higher incidence rate of severe ADRs in COVID‐19 patients; and we have recently reported a COVID‐19 patient who developed typical COVID‐19‐associated cutaneous manifestations, symmetrical drug‐related intertriginous and flexural exanthema, in which ‘multiple drug hypersensitivity’ not only to the causative drug but also to other drugs used for COVID‐19 was demonstrated by lymphocyte transformation tests. Such ‘multiple drug hypersensitivity’ was typically observed in the acute~subacute phases of DiHS/DRESS, at which time Treg function becomes impaired. Most reports, however, demonstrated cutaneous manifestations of COVID‐19 without performing screening tests for herpesvirus reactivation and ADRs. Thus, severe COVID‐19 symptoms appear to be driven by a complex interplay involving reactivations of latent herpesviruses, antiviral immune responses and dug‐driven immune responses, as demonstrated in DiHS/DRESS. Patients who experienced herpesvirus reactivations and ADRs are more likely than those without them to have a more severe disease course; the combination of these factors could result in COVID‐19‐associated multiorgan failures. Accurate assessment of the patient's viral infection status and a possibility of ADRs is highly required. The aetiology of severe COVID‐19 symptoms may be multifactorial.

Conflict of interest

The authors have no conflict of interest to declare.

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