www.thelancet.com/infection Published online August 5, 2016 http://dx.doi.org/10.1016/S1473-3099(16)30051-2 1 Grand Round Marseillevirus in lymphoma: a giant in the lymph node Sarah Aherfi, Philippe Colson, Gilles Audoly, Claude Nappez, Luc Xerri, Audrey Valensi, Matthieu Million, Hubert Lepidi, Regis Costello, Didier Raoult The family Marseilleviridae is a new clade of giant viruses whose original member, marseillevirus, was described in 2009. These viruses were isolated using Acanthamoeba spp primarily from the environment. Subsequently, a close relative of marseillevirus was isolated from the faeces of a healthy young man, and others were detected in blood samples of blood donors and recipients and in a child with lymph node adenitis. In this Grand Round we describe the detection of marseillevirus by PCR, fluorescence in-situ hybridisation, direct immunofluorescence, and immunohistochemistry in the lymph node of a 30-year-old woman diagnosed with Hodgkin’s lymphoma, together with IgG antibodies to marseillevirus. A link with viruses and bacteria has been reported for many lymphomas. We review the literature describing these associations, the criteria used to consider a causal association, and the underlying mechanisms of lymphomagenesis. Our observations suggest that consideration should be given to marseillevirus infections as an additional viral cause or consequence of Hodgkin’s lymphoma, and that this hypothesis should be tested further. Introduction Giant viruses emerged during the 21st century following the serendipitous discovery of mimivirus through the implementation of isolation strategies by co-culture on amoebas, since these viruses replicate within amoebas, and inoculation on amoebal cultures was thereafter used for their study. 1,2 Giant viruses are visible at the virion stage under an optical microscope and contain many genes and proteins, in similar numbers to those observed in small bacteria. Studies done since 2003 by use of culture isolation and metagenomics have identified that giant viruses that infect amoebas are common in water and soils worldwide, which suggests human beings are likely to be exposed. 2,3 The presence and potential pathogenic role of these giant viruses in human beings is still poorly understood. Mimiviruses have been increasingly associated with pneumonia since their discovery in 2003, and two isolates were obtained from pneumonia patients. 4–8 Furthermore, Acanthocystis turfacea chlorella virus 1, of the family Phycodnaviridae, which is linked to Mimiviridae within the proposed order Megavirales, has been found in the pharynx of people with cognitive disorders. 9 The family Marseilleviridae is another clade of giant viruses that infect amoebas, the first member of which, marseillevirus, was described in 2009. 10,11 Marseilleviruses have icosahedral capsids with a diameter of around 250 nm and have a genome length of 346–386 kilobase pairs that encode 444–496 putative proteins. 12 Marseilleviruses had previously been isolated primarily from the environment. 10 However, since 2012, they have also been found in human patients (table 1). Thus, senegalvirus was serendipitously isolated from the stools of a healthy young Senegalese man. 13 Subsequently, giant blood marseillevirus DNA was found in the metagenome generated from the blood of a blood donor in Marseille, France, which was confirmed by assembling approximately 10–13 kilobase pair large contigs, virus detection with fluorescence in situ hybridisation (FISH), immunofluorescence, and serology. 14 Additionally, marseillevirus DNA and antibodies have been detected in blood donors and recipients in France and marseillevirus antibodies have been detected in healthy young people in Switzerland. 14–16 Moreover, during implementation of marseillevirus serological testing, we identified a strong reactivity to marseillevirus in an 11-month-old boy with lymphadenitis, which was confirmed by FISH and immunohistochemistry analysis of the lymph node, and PCR of blood serum. 17 Further attempts to assess the connection between marseilleviruses and lymphadenitis in our laboratory led to the discovery of an unexpected case, which we describe here, of detection of marseillevirus in the lymph node of a patient with Hodgkin’s lymphoma. Case presentation A 30-year-old woman living in Marseille was admitted to our hospital in May, 2014, for a dry cough and with a 1-year history of lymphadenopathies. She received glucocorticoids intermittently for asthma. Clinical examination revealed bilateral axillar and left subclavicular lymphadenitis. PET and CT scanning revealed several hypermetabolic lymphadenopathies (cervical, supraclavicular, axillar, mediastinal, latero-aortic, coeliac, and in the internal mammary chain [standardised uptake value: 11·5]), at least two splenic nodules, and a diffuse bone marrow homogeneous hypermetabolism (figure 1). Laboratory parameters revealed T cell (T) and natural killer cell (NK) lymphopenia (0·9 G/L), a slightly raised polynuclear cell count (12 G/L), and a high alkaline phosphatase concentration (129 IU/L). Serum protein electrophoresis showed no evidence of a monoclonal gammapathy. Serological tests were negative for hepatitis B virus, hepatitis C virus, HIV, and cytomegalovirus, and indicated previous infection and immunity against Epstein-Barr virus. Pathological examination of a left axillar lymph node biopsy sample showed evidence of many Reed-Sternberg and Hodgkin cells surrounded by an inflammatory granuloma composed of lymphoid elements, macrophages, and eosinophils. Immunophenotyping showed that the lymphoma cells strongly expressed CD30 but not the CD15, CD45, CD20, CD3, or ALK1 proteins. These results were Lancet Infect Dis 2016 Published Online August 5, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)30051-2 Research Unit on Emerging Infectious and Tropical Diseases (URMITE), CNRS UMR 7278, IRD 198, Inserm U1095 (S Aherfi PharmD, Prof P Colson PharmD, G Audoly PhD, C Nappez PhD, A Valensi MRes, M Million MD, Prof H Lepidi MD, Prof D Raoult MD), Département de Bio-Pathologie, Oncologie moléculaire, Hématologie et Immunologie des tumeurs (Prof L Xerri MD), and Technological Advances for Genomics and Clinics (TAGC), Inserm UMR 1090 (Prof R Costello MD), Aix-Marseille Université, Marseille, France; Méditerranée Infection Foundation (IHU), Assistance Publique-Hôpitaux de Marseille, Marseille, France (S Aherfi, Prof P Colson, M Million, Prof H Lepidi, Prof D Raoult); and Institut Paoli-Calmettes, Marseille, France (Prof L Xerri) Correspondence to: Prof Didier Raoult, Unité des Rickettsies, Faculté de Médecine, Aix-Marseille Université, 13385 Marseille CEDEX 05, France didier.raoult@gmail.com