HHV-6 reactivation and poor CD4+ cell reconstitution predict pediatric acute GVHD

Analysis of a large pediatric cohort of post-hematopoietic stem cell transplant (HSCT) patients further validated the role of HHV-6 as a predictor of high-grade graft-versus-host-disease (GVHD), and found viral reactivation to be tied to the reconstitution of CD4+ cells. Over a dozen studies have now found HHV-6 to predict aGVHD, but this is the first to correlate viral reactivation with CD4+ cell immune reconstitution.

gvhdThe investigators, led by J.J. Boelens, MD, at the University Medical Centre Utrecht, found that patients with HHV-6 reactivation were significantly more likely to develop grade 2-4 aGVHD; 37% of patients with HHV-6 reactivation developed aGVHD compared to 20% of those without HHV-6 reactivation.

CD4+ reconstitution had a protective effect; 43% of patients with HHV-6 reactivation and poor CD4+ reconstitution developed aGVHD, vs 20% with immune reconstitution and no HHV-6 reactivation. Of interest, CD4+ cells were the only cell type inversely correlated with viral reactivation. No correlation was found between viral reactivation and reconstitution of CD3+, CD8+, NK or B-cells. Delayed reconstitution of CD4+ T cells was also associated with reactivation EBV and adenovirus. EBV, HHV-6, and age were all found to predict grade 3-4 GVHD.

The incidence of HHV-6 reactivation (defined as >1000 copies) was 27%, lower than what was found in previous large studies, in which HHV-6 reactivation rates ranged from 45% (Hill 2017) to 60% (Inazawa 2015). Unlike other studies (Hill 2017, Quintela 2016), no relationship was found between HHV-6 reactivation and higher mortality rates.

The laboratory of Jaap Jan Boelens, MD, PhD,
University Medical Center Utrecht

The authors presented data on viral reactivation as a function of CD4+ cell reconstitution, not the other way around. One older Karolinska Institute study, however, did analyze the effects of HHV-6 on lymphocytes and showed that persistent HHV-6 reactivation was tied to lymphocytopenia after 8 weeks (Wang 1999).

HHV-6 productively infects CD4+ cells, induces apoptosis of CD4+ cells (Yasukawa 1998), inhibits T cell proliferation (Flamand 1995), suppresses synthesis of IL-2 (Flamand 1995) and IL-12 (Smith 2003), and induces IL-1Beta, IL10, and TNF-alpha production (reviewed in Dagna 2013).

The authors suggest that monitoring of CD4+ immune recovery post-transplantation could identify patients at risk for GvHD and reduce the need for antivirals in some patients.

Another recent study from Italy also found CD3+ lymphocytes to correlate inversely with HHV-6 reactivation (Greco 2016).

Find the UMC Utrecht study here: Admiraal 2017.