HHV-6 increases risk of an “idiopathic” pneumonia syndrome after HCT as does murine roseolovirus in a BMT mouse model. Early HHV-6 was also found to increase non-relapse mortality

A research team formed by members of Bethany Moore’s Lung Immunology Lab and Gregory Yanik’s BMT clinical team at the University of Michigan demonstrated that murine roseolovirus (MRV) is a useful homolog for the study of HHV-6 reactivation in lung disease post-hematopoietic cell transplantation (HCT). In a large retrospective study of HCT patients, they also found early HHV-6 reactivation to increase the risk of both idiopathic pneumonia syndrome (IPS) and non-relapse mortality.

Early “first” HHV-6 infection was associated with a highly significant increase in non-relapse mortality in a retrospective study of 738 HCT patients. The association between NRM and CMV or EBV was only modestly significant.

IPS is considered a “noninfectious” pulmonary complication with diffuse lung injury and high mortality; however, previous studies have shown occult pathogens can be found in more than half of the samples from patients with IPS when sensitive PCR techniques are used (Seo 2015).

The authors studied the first viral pathogen detected within 100 days of transplantation in 738 allogeneic hematopoietic cell transplant patients at the University of Michigan Medical Center to determine if they might be associated with IPS or other outcomes. 242 or 32% of the HCT patients studied had a viral infection and overall survival was significantly lower in patients with an infection, compared to those without. The difference was due largely to increased non-relapse mortality (NRM). Multivariable analysis showed that first onset infection with HHV-6, EBV and HSV resulted in a 5.5, 9.2 and 11 fold increased risk of IPS, respectively. First infection with CMV increased the risk of bronchiolitis obliterans syndrome, by almost three-fold. Although “first” HHV-6 infection caused a highly significant increase in NRM, first infections with EBV or CMV showed only borderline significance. Both HHV-6 and CMV showed an association with subsequent grade II-IV aGVHD in multivariate analysis.

MRV proves to be a useful homolog for HHV-6B in a BMT mouse model

Following up on the work done by investigators at Washington University who characterized murine roseolovirus as a mouse homolog of HHV-6 and HHV-7 (Patel 2017), Xiaofeng Zhou, PhD, infected newborn mice with MRV and later performed a bone marrow transplant (BMT) protocol after 8-10 weeks to reactivate the virus. The mice were subsequently assessed for clinical signs of GVHD and lung pathology. Most of the pre-infected BMT mice developed active MRV infections in their lungs by 2 weeks after mismatched transplant, and histological examination 6 weeks after transplant found the MRV infected mice to show features consistent with IPS. Of interest, the mice had little or no viral DNA in their BAL fluid by 8 weeks post BMT, which, the authors point out, is consistent with an “occult” infection being missed in patients with IPS.

For more information, see the full text: Zhou 2019.

Members of Bethany Moore’s Lung Immunobiology Lab. First author Xioafeng Zhou is pictured at the far left. Others from L to R are Helen Warheit-Niemi , Giovany Martinez-Colon, Bethany Moore, Steve Gurczynksi and Elissa Hult.