AdVs represent the etiological agent of 15–70% of eye infections. In subcontinental countries, SEIs may be ascertained in about half of AKC cases. These focal lesions could represent a cellular immune reaction against viral antigens deposited within the corneal stroma under the Bowman membrane, resulting in uncomfortable clinical symptoms and reduced patients’ daily activity. From a histopathological point of view SEIs are related to disruption of collagen fibers in the Bowman layer along with infiltration of lymphocytes, histiocytes, and fibroblasts; these are usually bilateral and often asymmetric and have the potential to cause significant ocular morbidity, vision impairment, photophobia, glare, halos, and foreign body sensation and can persist for months or years once the initial infection [14].
A lot of treatment options have been tried for AKC including palliative therapy, such as cool compresses, lubricant eye drops, and topical steroids. In current opinion steroids, by suppressing corneo-conjunctival inflammation, provide symptomatic relief, but they do not prove capable to shorten the course of the disease. On the other hand, the employment of long-run topical steroids may be also related to side effects such as cataract and glaucoma, not to mention the fact that the topical administration of corticosteroids may also cause prolonged viral seeding [6].
Since at the current state of the art there is no approved and efficient treatment for AKC, we investigated the role of a broad-spectrum antiseptic agent like PVP-I on the course of this kind of infection. A study that used the AdV type 5/New Zealand rabbit ocular model showed that corticosteroids alone can increase viral replication and therefore the length of infectious agent shedding [5].
AdV in fact is able to persist in the host thanks to the employment of immunoevasive strategies, such as inhibiting antiviral response mediated by IFNs, preventing cytolysis of AdV-infected cells by TNFα, promoting intracellular survival by blocking apoptosis of infected cells and evading CTL-mediated cytolysis of infected cells by preventing the display of viral peptide complexed to major histocompatibility complex (MHC) class I molecules on the surface of virally infected cells [7, 15]. Few studies have reported that AdVs retain the power, through the application of multiple pathways, to inhibit the NK response in the early and acute stages of the conjunctivitis: all those features do allow the virus to stay active on the conjunctival surface and provide rise to persistent infection [8, 16].
A decrease in viral titers, virus spread, shortening of the clinical course, and preservation of visual function during AKC has been obtained using Povidone-iodine 0.4% alone or in combination with dexamethasone 0.1% [17, 18]. There is currently an ongoing phase III clinical trial examining the use of a higher concentration povidone-iodine 0.6% alone and in combination with dexamethasone 0.1% versus placebo (NCT02998541) [19].
Yates et al. evaluated the in vitro antiviral activity of the several P–I concentrations previously used in clinical studies against different HAdV types frequently associated with eye infections [20].
Povidone (polyvinylpyrrolidone, PVP) is a synthetic polymer which acts as a carrier limiting the amount of free iodine present in solution. A peculiar aspect of PVP-I iodophors is that the concentration of free iodine increases with dilution of the complexed PVP-I due to a weakening of iodine linkage with PVP [21, 22]. This feature explains why a 0.6% PVP-I solution is more rapidly bactericidal than a 5% one [23].
No specific antiviral therapy approved by the Food and Drug Administration is accessible to shorten the course of the infection or stop the viral replication. Several virustatic agents such as cidofovir and ganciclovir are suggested in the first week, though there is a lack in definite dose and comparative studies [24].
Cidofovir was reported to have a therapeutic effect in the treatment of AKC in 1% dosage. It was reported to reduce the rate of severe corneal opacities, but therapeutic dosage resulted in high toxicity on the conjunctiva and eyelids with the development of pseudomembranes and lacrimal duct stenosis [25]. Since AdV are species-specific, in vivo models for disseminated AdV infections require the use of a non-human AdV. Moreover, the outcome of antiviral therapy requires early intervention during the viral replicative phase, whereas medical consultation for severe keratoconjunctivitis usually takes place later, once pathology is mainly inflammatory [26].
The results of this study indicate that an ophthalmic solution of PVP-I 0.6% is safe and well-tolerated for the treatment of acute adenoviral conjunctivitis. Outcomes for PVP-I 0.6% showed statistical superiority compared with artificial tears for clinical resolution of the infection probably thanks to a better adenoviral eradication. PVP-I, in facts, is highly effective at producing in vitro virucidal reductions of common ocular AdV types, [17] killing the extracellular adenoviral particles [27].
Moreover, in our study the use of PVP-I 0.6% decreased the incidence of SEI development probably thanks to the reduction of viral titers and consequently the immunological stimulus.
Low concentrations of PVP-I release a higher concentration of free Iodine, which is the only responsible for the antiseptic action. On the basis of previous in vivo and in vitro studies, the chosen dosage for PVP-I 0.6% was one drop four times a day [5, 24].
Adenoviral conjunctivitis usually lasts from 2 to 3 weeks. In our study, the number of patients with complete haze resolution and subjective mild discomfort was significantly higher in the PVP-I group than in the hyaluronate-based tear substitutes group as early as the day 15 visit.
These results suggest that PVP-I may be effective at quicker resolving the viral infection and improving clinical signs, which may improve the quality of life and minimize the spread of infection. A quick recovery from conjunctivitis is also expected to translate into a positive socioeconomic impact because patients are able to return to school or work sooner.
There were no adverse effects during the study. Moreover, the drop tolerability of PVP-I 0.6% was acceptable, with a reduction also of the total discomfort score at the 15 and 21-day visit in the A group patients. This is noteworthy as a result since instillation’s comfort is a component of ocular tolerability, and ocular discomfort will affect patient preference and treatment compliance.
The diagnosis between the various forms of conjunctivitis (bacterial, viral, allergic, and even early stage of acanthamoeba keratitis) can be difficult since different forms of the condition gift analog symptoms. Misdiagnosis of bacterial conjunctivitis might occur in up half of cases, which often ends in inappropriate antibiotic treatment. PVP-I has broad-spectrum antimicrobial action that includes bacteria, viruses, and fungi [28, 29]; that’s why another advantage of its use could moreover extend to the mitigation of the negative effects of misdiagnosis and consequent reduction of the costs and risks associated with unnecessary antibiotic prescriptions [30].
Although the small size of our sample did not allow us to appreciate statistically significant differences in the visual outcome achieved between the two groups, the trend would seem to be a faster functional recovery in group A patients probably due to the lower number of SEIs. This undoubtedly represents an interesting aspect that could be evaluated in further studies.
In conclusion, according to our results, using PVP-I 0.6% in the first few days of clinically significant AKC might help to reduce the risk of SEI as a complication. Diluted povidone-iodine ought to be started as soon as possible when we suspect AKC: in fact, it decreases the incidence of SEI, presumably by decreasing the virus load. We tend to believe that it might be a useful, cheap, safe and easy to access aid in the management of AKC in common clinical practice.
