Reactivation of human herpes viruses in various forms of cutaneous adverse drug reactions--a comparative study in Taiwan
Date Issued
2012
Date
2012
Author(s)
Chen, Yi-Chun
Abstract
Introduction:
Severe cutaneous adverse drug reactions (SCARs) are groups of drug hypersensitivity reaction with a heterogeneous clinical presentation. Although the prevalence of SCARs is low, they may result in prolonged hospitalization, significant disability and even death. SCARs include toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and generalized fixed drug eruption (GFDE). All these specific SCARs have different presentations, clinical courses and prognosis.
In the past studies, the association of human herpesvirus (HHV) reactivation with DRESS has been reported. Ｈowever, their roles in DRESS are debated and their influences are still elusive. Some authors consider that viral reactivation is a secondary event after an initial immunological reaction directed against the culprit drugs; however, others consider that DRESS is the consequence of viral reactivation from its very beginning. Besides, many types of HHV have been detected to be involved in DRESS. However, previous studies were limited by the use of serologic changes during the disease course or by using PCR method to detect the viral DNAs within PBMC. The sensitivity and specificity of these tests to confirm the roles of HHV were still under debate. Moreover, there is no previous large scale study to investigate the association of HHV reactivation and the development of other SCARs.
Materials and Methods:
From September 2010 to February 2012, we prospectively included the hospitalized patients being suspected to have cutaneous adverse drug reactions (cADR), including SCARs or generalized maculopapular eruption (MPE). We collected serial blood samples for patients upon admission and during hospitalization course, for:
1. Real time PCR to quantify the viral DNA from serum samples and PBMC.
2. Enzyme-linked immunosorbent assay (ELISA) were carried out to determine the changes of antibody titers in serum samples.
3. Various kinds of cytokine levels were also evaluated during different disease stages.
There kinds of HHV were examined, including HHV type 6 (HHV-6), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). According to the results of quantitative-PCR and antibody ELISA, individual viral reactivation rate was evaluated; beside, the correlation between dosage of administrated corticosteroid and viral reactivation is also evaluated. We observe the correlation between viral activities, clinical courses and patient prognosis.
Results:
Totally, 32 patients were included in this study, 16 male and 16 female, and the average age is 47.8-year-old. 14 patients were DRESS, 10 were SJS/TEN, 6 were MPE, and the other two were GFDE and erythema multiforme majus (EMM) respectively. EBV reactivation was detected in 19 patients, including 11 DRESS (78.6%), 3 SJS/TEN (30%), 4 MPE (66.7%) and 1 GFDE patient. Reactivations of HHV-6 and CMV were observed in 5 (35.7%) and 4 (28.6%) DRESS patients respectively. All of those four patients with CMV reactivation also had EBV reactivations and three of them had HHV-6 reactivation. Mostly, HHV-6 reactivated first, and then followed by sequential or simultaneous CMV and EBV reactivations, as well as fluctuating clinical courses.
According to the accumulative dose of systemic corticosteroid within 7 days after hospitalization, we divided all patients into two groups: average dose less or equal to 1mg prednisolone/kg/day and average dose more than 1mg prednisolone/kg/day. For the lower and higher dosage groups, EBV reactivation rate were 66.7% and 57.9%, respectively. The p-value of t-test for these two groups was 0.6 and the difference between these two groups was not significant.
For the cytokine study, interleukin-5 (IL-5) was significantly lower in SJS/TEN patients during the acute stage. Besides, for MPE patients, IL-6, IL-8, IL-17 and tumor necrosis factor-alpha (TNF-α) were significantly lower than DRESS and SJS/TEN patients. For DRESS patients, they could be devided into two groups according to whether multiple human herpesvirus actived, and in the viral reaction group, interferon gamma-induced protein 10 (IP-10, CXCL10) was significantly higher than another group.
Conclusion and discussion:
EBV reactivation, which was detected in various forms of cADRs, is not specific to DRESS, while HHV-6 and CMV reactivations seem to be more specific to DRESS. In this observational study, most of viral reactivation was not detected in the early stage of cADRs which may indicate that viral reactivation was not the initiator of these drug eruptions. For DRESS patients, reactivation of various HHV may correlate with fluctuation clinical courses, but only HHV-6 was documented to have negative impacts on patients’ prognosis. On the other hand, EBV reactivation did not associate with clinical deterioration in SJS/TEN or MPE patients. Although our study could not answer what is the direct cause of viral reactivation in SCAR patients, the dose of administrated systemic corticosteroid was not a major determinant. Different cytokine patterns during acute stages of various cADRs and following cytokine cascades may be one of mediators for vrial reactivation pathomechanisms.
Subjects
Cutnaeous adverse drug reaction
human herpesvirus
drug reaction with eosinophilia and systemic symptoms
human herpesvirus type 6
Epstein-Barr virus
cytomegalovirus
corticosteroid
SDGs
Type
thesis
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