Management of Adenoviral Keratoconjunctivitis: Challenges and Solutions

Labib, Bisant A; Minhas, Bhawanjot K; Chigbu, DeGaulle I

HAdV belongs to the genus Mastadenovirus and family Adenoviridae. It is a nonenveloped virus with a linear dsDNA genome and icosahedral capsids. HAdV consists of 7 groups classified through genomic sequence analysis. 3 Adenoviral-based ocular surface infections are attributed to several subtypes of Group B and D HAdV. Generally, these viruses bind CD46, a ubiquitously expressed transmembrane protein, to infect the host. 4,5 Exposure of the host to HAdV is made possible through the interaction between adenoviral fiber protein and primary host cellular receptors such as CD46, sialic acid, and heparin-sulfate proteoglycan, all of which promote the attachment and internalization of HAdV. 6, 7 Interactions between the penton base of the virus and vitronectin-binding integrins of the host support internalization and acidification of the endosome, triggering conformational changes to the viral capsid. This process culminates in the release of viral DNA genome into the host nucleus, where viral replication occurs. 2, [7] [8] [9] Challenges HAdV causes a lytic infection of the mucoepithelial cells of the conjunctiva and cornea as well as a latent infection of lymphoid and adenoid cells. 10 Members of Groups B and D HAdV cause both GIT and ocular infections. See Table 1 for the subtypes of Group B and D HAdV. 11, 12 HAdV type 3, 7, and 21 of Group B can cause keratoconjunctivitis, urinary tract infection, respiratory infection, and GIT infection. Group D HAdV can also cause both ocular and GIT infection. Some group B HAdV subtypes infect the respiratory tract. Group B HAdV including type 3, 7, 14, and 21 have been associated with acute respiratory distress (ARD) outbreaks. 2, 12 HAdV types that cause ARD are transmitted through aerosolized droplets. It is important to note that both respiratory droplets and the fecal-oral transmission route from individuals with acute adenoviral infection, or even post-infection adenoviral shedding, play an important role in the transmission dynamics of HAdV infections. 2, 13 Persistent HAdV secretions in the tears may also occur even years following the resolution of acute ocular infection. T cells in tonsillar and adenoid lymphoid tissue serve as reservoirs for harboring HAdV, making it possible to develop latent adenoviral infections. 3, 13, 14 Reactivation of persistent latent adenovirus in the host is likely facilitated through the blockade of types I and II interferon (IFN) response that is required to inhibit expression of the HAdV E1A gene. 3 Immunosuppressive steroid therapy can suppress the production of cytokines including TNF-alpha, type I IFN, and type II IFN, as well as depleted T cells and NK cells. 3, 15, 16 This inadvertently reduces the secretion of antiviral cytokines that play a major role in inhibiting viral replication. Inhibition of the IFN response allows for expression of the HAdV E1A gene, which results in reactivation and replication of HAdV DNA in epithelial cell associated with latently infected lymphoid tissue and consequential dissemination of HAdV. 3 Thus, immunosuppression could facilitate dissemination of adenovirus into the community since subclinical adenoviral infection of tonsillar and adenoid lymphoid tissue serve as a source of transmitting adenoviruses, particularly in immunocompromised children with no prior exposure and immunity to a particular strain of adenovirus. 17 Additionally, asymptomatic passage of adenovirus in the stool of patients with previous adenoviral GIT