The interferon‐γ‐induced protein 10/CXCR3 axis is associated with human herpesvirus‐6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms*

Abstract

Summary Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug‐induced immune response. Previous reports have found that CXCL10, also known as interferon‐γ‐induced protein (IP)‐10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP‐10 in DRESS and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown. Objectives This comparative prospective cohort study aimed to ascertain the roles of the IP‐10/CXCR3 axis in DRESS and SJS/TEN. Methods Plasma IP‐10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP‐10, human herpesvirus (HHV)‐6 reactivation and the development of long‐term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs). Results Significantly higher plasma IP‐10 levels were observed in patients with DRESS with long‐term sequelae (effect size 0·81) and also in those with HHV‐6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP‐10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV‐6 reactivation. The percentages of CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were also higher in the PBMCs of HHV‐6‐reactivated patients with DRESS than in those of patients with SJS/TEN. Conclusions Higher plasma IP‐10 levels are associated with the development of long‐term sequelae in DRESS. Higher IP‐10/CXCR3 expression in skin and more abundant CLA+ CXCR3+ CD4+ cells and CLA+ CXCR3+ CD8+ cells were observed in patients with DRESS with HHV‐6 reactivation. The IP‐10/CXCR3 axis is associated with HHV‐6 reactivation and development of long‐term sequelae in DRESS. What is already known about this topic? Elevated levels of interferon‐γ‐induced protein‐10 (IP‐10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Patients with DRESS tend to develop long‐term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP‐10 has been associated with these autoimmune diseases in previous studies. What does this study add? The patients with DRESS with HHV‐6 reactivation exhibited higher levels of IP‐10 in the plasma and skin than the patients with DRESS without HHV‐6 reactivation and the patients with SJS/TEN. Patients with DRESS with higher plasma IP‐10 levels tended to develop sequelae during long‐term follow‐up. What is the translational message? IP‐10 is a useful biomarker to predict the development of long‐term sequelae in patients with DRESS. Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804–805.

Case of vitiligo universalis as a sequela of drug‐induced hypersensitivity syndrome

“…Similar to the previous study, elevated plasma levels of CXCL10, an IFN‐γ‐induced chemokine, in our patient may explain the mechanism of vitiligo following DIHS. Furthermore, one study reported that the higher level of CXCL10 may play a role in DIHS with long‐term sequelae, such as Hashimoto thyroiditis 16 . Based on previous studies and our case, we postulate that dysfunction of Treg cells, reactivation of virus and elevated CXCL10 level may contribute to the development of vitiligo following DIHS.…”

A case report of toxic epidermal necrolysis (TEN) in a patient with COVID-19 treated with hydroxychloroquine: are these two partners in crime?

“…In this instance, it is not to be discounted that a rare side effect, such as TEN, occurring with a not commonly associated drug, hydroxychloroquine, could have been favored by the particular immune stimulation induced by the virus SARS-CoV-2 [3]. SJS/TEN, and SCAR more generally, have been classically demonstrated to be associated with viral replication [11,[32][33][34].…”

Comment on “Viral reactivation in hospitalized DRESS patients: A retrospective study from a tertiary medical center in the United States”

“…We agree with the authors' opinion that timing is indeed an important factor that can influence rates of viral reactivation. Our previous reports 2, 3 and the studies of Japanese experts 4 all showed that reactivation of HHV-6 usually could be detected 2 to 4 weeks after the initial diagnosis. However, in addition to timing, the methods used to detect HHV-6 reactivation may also affect the results.…”

“…We have used this method in another recent study. 3 In that study, 33 patients with DRESS received whole-blood quantitative PCR to detect the presence of HHV-6 DNA. Among them, 11 patients showed positive results (33.3%).…”