Patients with iciHHV-6 have higher inflammatory cytokines and develop acute graft vs host disease a week earlier

Joshua Hill, MD and colleagues from the Fred Hutchinson Cancer Research Center in Seattle found inherited chromosomally-integrated HHV-6 (iciHHV-6) to be associated with increased levels of inflammatory cytokines and an earlier onset of acute graft-versus-host disease (aGVDH) in transplant patients.

The study evaluated the cases of 64 patients who had undergone hematopoietic cell transplantation (HCT), in which either the donor, recipient, or both were positive for iciHHV-6. 64 matched control patients, with no iciHHV-6 from any source were also enrolled.

The study found that cytokine levels of C-reactive protein (CRP) and tumor necrosis factor receptor 1 (TNFRp55) were higher in iciHHV-6pos HCT recipients. A higher proportion of iciHHV-6pos samples had CRP levels above normal limits compared to the iciHHV-6neg samples, and the difference was most pronounced on day 21 post-HCT in cases of aGVDH grades 2-4, which is the mean time of HHV-6B reactivation after allogeneic HCT as observed in several previous studies.

The iciHHV-6pos group also had an earlier onset of aGVHD grades 2-4 by a median of 1 week. The incidence of aGVHD was not significantly higher in the iciHHV-6pos group in this study; however a previous larger study by the same group showed that HCT involving iciHHV-6 (as donors or recipients) had a higher incidence of aGVDH than controls Hill (2017).

CRP has been established as a prognostic marker for aGVDH; elevated CRP has been associated with increased rates of transplant complications and mortality (Shots 2002). TNFRp55 has been consistently shown to be predictive of aGVHD in HCT (August 2010, Nelson 2014) and is associated with kidney function decline, cardiovascular events, and mortality risk in persons with coronary artery disease  (Carlsson 2017, Park 2017, Ikonomidis 2012).

CRP and TNFRp55 levels in ciHHV-6 positive cases (grey) vs iciHHV-6 negative cases (white) differed at 21 days. Source: Biology of Blood and Marrow Transplantation

Of interest, the proinflammatory cytokines were not elevated in healthy iciHHV-6 donors or iciHHV-6 healthy controls. However, a large scale study of individuals with iciHHV-6 in Canada did find iciHHV-6 to be a predisposing risk factor for angina pectoris (Gravel 2015).

The authors conclude that their findings support additional study into the pathologic mechanisms of iciHHV-6 in the development of aGVHD, as well as the study of a potential role for antiviral prophylaxis in cases involving iciHHV-6 donors or recipients

Read the full text: Weschke 2019