Transmission of Chromosomally Integrated HHV6 by Allogeneic Peripheral Blood Stem Cell Transplantation Associated with the Development of a Fatal Macrophage Activation (Haemophagocytic) Syndrome.
Authors: Crowther Mark , Molyneaux Pamela , Carman William F. , Ward Kate N. , Culligan Dominic J. 
Published: October 2019

Abstract
It is estimated that at least 1% of the UK population have chromosomal integration of HHV6 leading to persistently high levels of detectable viral DNA (Clark DA et al, JID2006: 193, p912–916). As far as we are aware transmission of integrated HHV6 by allogeneic stem cell transplantation has been described in the literature on only one previous occasion and this was not associated with disease (Clark DA et al, JID2006:193, p912–916). Indeed it remains controversial as to whether HHV6 ever causes disease in the post transplant setting. A 35-yr-old male with a past history of treated Hodgkins lymphoma (HL) developed stage 4 diffuse large B-NHL (DLBL). He achieved a CR with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) + rituximab × 8 cycles but subsequently relapsed. Following salvage chemotherapy with IVE (ifosfamide, etoposide, epirubicin) + rituximab × 3 cycles he underwent a fully HLA matched sibling allogeneic peripheral blood stem cell transplant in second CR of the DLBL using BEAM (carmustine, etoposide, cytarabine, melphalan) + alemtuzumab conditioning. On day +32 he presented with fever, pneumonitis and pancytopenia. Bone marrow examination revealed haemophagocytosis of red cells and platelets. He had a mild coagulopathy and grossly elevated ferritin (63,303 ug/l). A diagnosis of macrophage activation syndrome (MAS) probably secondary to infection was made. Cultures of blood, urine and broncho-alveolar lavage (BAL) were negative apart from HHV6 levels of 62,000 DNA copies/ml in serum. There was no clinical or radiological evidence of relapse of HL or DLBL and no evidence of CMV reactivation. He deteriorated despite intensive care unit support and treatment with broad spectrum antibiotics, aciclovir, cidofovir, caspofungin and cyclosporin-A. He showed slight improvement with high dose steroids but died on day +78. Further investigations revealed the patient was negative for serum HHV6 immediately prior to transplantation whilst his donor had very high levels of serum HHV6 (750,000 DNA copies/ml) suggestive of chromosomal integration (Ward KN et al, J Clin Microbiology2006: 44, p1571–1574). It is, therefore, highly likely that HHV6 was transmitted via the allogeneic stem cell transplant. The case raises some difficult issues in relation to the management of post transplant complications that maybe virally driven. Chromosomally integrated HHV6 is not thought to cause active infection and it has been suggested, therefore, that post-transplant patients demonstrating high levels of HHV6 should be investigated for chromosomal integration in the donor and if present not subsequently treated with potentially toxic anti-viral drugs. However, HHV6 has been associated with MAS in the non transplant setting. In our case HHV6 was the only identifiable infectious agent during this severe illness. Given the association of HHV6 with MAS and the uncertain pathogenecity of integrated HHV6 in the context of post transplant immune dysregulation, this scenario makes diagnosis and treatment challenging.