Biopsies from patients with 5 types of lymphoproliferative disorders of the ocular adnexa were found to contain HHV-6 DNA in 9 of 70 (12.9%) samples. While an overall detection rate of 12.9% is significant, HHV-6 was even more prevalent among those with benign lymphoproliferative disorders; HHV-6 was found in 22.7% of those with IgG4-related ophthalmic disease and 28.6% of those with orbital reactive lymphoid hyperplasia. HSV-1, HSV-2, VZV, CMV, HHV-8, BK virus, JC virus, HTLV-1, Coxsackie virus, enterovirus, influenza, Bartonella, chlamydia, Acanthamoeba, toxocara, toxoplasma, and fungal 18S/28S were not found in any samples.
Multiplex and broad-range PCR was used for initial detection of the viral, bacterial, parasitic, and fungal agents, and upon receiving a positive result, qPCR was run to quantify the DNA in the samples. In total, 29 specimens were positive for at least one pathogen. EBV was the most frequently encountered pathogen and was found in 14 samples, but HHV-7 was present in 12 samples, and HHV-6 was found in 9. HHV-6/EBV coinfections were found in 3 cases, HHV-6/HHV-7 coinfections in 2 cases, a HHV-6/HHV-7/EBV triple infection was found in one case, and a quadruple infection of HHV-6/HHV-7/EBV/Bacteria was also found in a single case. HHV-6 is able to increase the severity of EBV infections, so identifying and treating HHV-6 is advantageous not only in inhibiting the direct effects of the virus, but also to limit its indirect, transactivating properties.
Quantification of the viral DNA revealed that HHV-6 was not only found more frequently in the two benign disorders, but it was also found at higher viral loads in these conditions compared to the malignant disorders. The two HHV-6 positive samples from conjunctival MALT lymphoma and orbital MALT lymphoma contained 1.61×102 viral copies/ul and 6.10×101 copies/ul, respectively. In contrast, IgG4-ROD samples had a mean load of 1.71×103 copies/ul, and orbital RLH samples had a mean load of 1.46×103 copies/ul. HHV-6 viral load has been shown to be higher in tissue with active infection than in tissue with latent infection (Sultanova 2016, Chapenko 2016).
While EBV is strongly linked to malignancies such as Burkitt’s lymphoma, nasopharyngeal and other head and neck carcinomas, T-cell lymphoma, and Hodgkin’s lymphoma, HHV-6 and -7 are not frequently suspected in cases of neoplasia. This study adds to a growing body of evidence that suggests a pathogenic role for these two viruses in lymphoproliferative disorders and tumorigenesis. Although the authors note that the weak controls did not allow them to determine the rate of HHV-6 positivity in normal ocular tissue, they also state that the normal conjuctival and orbital tissues tested were not positive for pathogens. In addition, another study found HHV-6 in the orbital connective tissue of 20% of patients with idiopathic orbital inflammation (IOI), but 0% of controls (Bijlsma 2013). HHV-6 was found in the lacrimal gland of controls, however, at a rate comparable to that found in the group with IOI (16% vs 20%, respectively).
HHV-6 has formerly been implicated in cases of primary ocular MALT lymphomas (Daibata 2000), as well as a host of other ocular disorders, including corneal inflammation (Okuno 2011), retinal necrosis (Papageorgiou 2014), uveitis (Maslin 2007, Nahdi 2013), retinal vein occlusion (Takizawa 2006), optic neuropathy and tonic pupil (Oberacher-Velten 2005), corneal ulcers (Boto-de-los-Bueis 2015), conjunctivitis (Boto-de-los-Bueis 2015), optic disc edema and retinal vasculitis (Ogata 2011), and optic neuritis (Moschettini 2006). Not only does the present study reinforce the link between HHV-6/7 and eye disease, but on a broader scale, it underscores their capacity to induce and/or promote tumorigenesis through chronic inflammatory stimulation or activation of oncogenes.
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Find the full paper here: Usui 2016.