Chromosomal integration of the HHV‐6 genome in a patient with nodular sclerosis Hodgkin lymphoma

We read with interest the recent article by Siddon et al (2012), which reported the analysis of biopsies from 31 patients with nodular sclerosis Hodgkin Lymphoma (NSHL) for the presence and distribution of Human Herpesvirus Type 6 (HHV-6) by immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH). The authors found HHV-6 DNA in 86% of biopsies and HHV-6 infected Reed-Sternberg cells in 46% of biopsies, and concluded that HHV-6 may play a role in NSHL pathogenesis (Siddon et al, 2012). We report a case of a girl with NSHL and chromosomally integrated HHV-6 (ciHHV-6). When aged 17 years, she presented with fatigue, pallor, night sweats, and retrosternal discomfort. Imaging examinations (including positron emission tomography) showed enlargement and elevated metabolism of supraclavicular and mediastinal lymphnodes and a pericardial effusion. Biopsy revealed NSHL with single cells positive for Epstein-Barr virus (EBV) encoded small RNA (EBER). She was treated according to EuroNet-PHL-C1 and suffered an intrathoracal relapse 9 months after end of therapy. The relapse biopsy showed the return of EBER in single/ sporadic cells. During treatment, she underwent virological routine screening by PCR, which was repeatedly highly positive for HHV-6 (persistently > 10 copies/ml whole blood), suspicious for ciHHV-6. To substantiate the suspicion of ciHHV-6, hair follicles of the patient and her parents′ peripheral blood and hair follicles were tested for HHV-6 DNA. The father’s peripheral blood and both the girl’s and the father’s hair follicles tested positive, indicating inherited ciHHV-6. A nested PCR resulting in different sized amplicons for variant A and B revealed HHV-6 Type A (Aberle et al, 1996). FISH analysis of dividing phytohaemagglutinin-stimulated peripheral blood leucocytes (Nacheva et al, 2008) demonstrated integration of HHV-6 DNA at the telomere region of the long arm of one homologue of chromosome 7 in both the patient and her father (Fig 1). CiHHV-6 variant A as well as variant B has been found in patients with various diseases, such as meningitis, encephalitis, multiple sclerosis, convulsions, myocarditis, liver dysfunction, haemolytic and aplastic anaemia, and haematological malignancies including different types of lymphoma (Hodgkin lymphoma (HL), non-Hodgkin lymphoma and Burkitt lymphoma). Furthermore, it has been reported in healthy individuals (Clark & Ward, 2008; Morissette & Flamand, 2010; Strenger et al, 2010, 2011a). Given that the HHV-6 genome is found in every nucleated cell, persistently high copy numbers are detected in blood and tissue, which might be interpreted as persistent active HHV-6 infection (Clark & Ward, 2008; Strenger & Urban, 2010). Following stem cell transplantation from a donor with ciHHV-6, ciHHV-6 is found in the recipient in every cell derived from haematological stem cells (Clark & Ward, 2008; Strenger et al, 2011b). Despite an estimated prevalence of 0 2–5% (Clark & Ward, 2008), ciHHV-6 is rarely diagnosed, because HHV-6 PCR is only performed in individuals with diseases known to be associated with this virus. Although detection of HHV-6 specific mRNA (Clark & Ward, 2008) and antigens (Strenger et al, 2009) was reported in individuals with ciHHV-6, the pathophysiological mechanisms and immunological consequences associated with ciHHV-6 and feasibility of virostatic treatment are still under discussion (Clark & Ward, 2008). In the light of the findings of Siddon et al (2012), it might be speculated that ciHHV-6 is not only a coincidental bystander but rather played a role in the pathogenesis of HL