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Cornea Open. Author manuscript; available in PMC 2023 Jun 27.
Published in final edited form as:
Cornea Open. 2023 Mar; 2(1): e0006.
Published online 2023 Mar 22. doi:10.1097/coa.0000000000000006
PMCID: PMC10299741
NIHMSID: NIHMS1864758
PMID: 37378070
Kyongjin Cho, MD and Irene C. Kuo, MD
Author information Article notes Copyright and License information PMC Disclaimer
Adenoviral conjunctivitis is the most common etiology of viral conjunctivitis1 and is highly contagious. Epidemic keratoconjunctivitis (EKC) raises the most concern because of its striking acute presentation, and because in its chronic phase, it can be associated with persistent visual disturbance from corneal subepithelial infiltrates (SEI). Despite longstanding nomenclature, HAdVs are likely endemic.2 No treatment for ocular adenoviral infections exists, and ocular sequelae can be significant, making infection control important.
Therefore, it may be surprising that after more than a half century of reports of large outbreaks, a safe and effective treatment for adenoviral conjunctivitis, let alone for EKC, still eludes us. A recent Cochrane review of the safety and efficacy of topical therapeutic agents for EKC, which included 10 studies of 892 participants, found the evidence for specified outcomes was of low to very low certainty because of imprecision and high risk of bias.3, 4 Polyvinyl pyrrolidone [also known as povidone iodine (PVP-I)] was favored over artificial tears in resolving signs and symptoms of EKC by 7 days, but the evidence was of low certainty because of inadequate sample sizes and high risk of bias. The reliability of estimates of quantitative comparisons of effects between interventions and controls was limited by clinical and methodological diversity in studies. The design and conduct of future comparative studies should incorprate greater methodologic rigor.
PVP-I or polyvinyl alcohol iodine (used in Japan instead of PVP-I), alone or with steroid, was associated with lower risks of SEI development than tears or steroid, but the evidence was of very low certainty. Estimates were consistent with no effect in facilitating SEI disappearance, and with no difference between tacrolimus or cyclosporine and steroid in preventing rebound of SEI. There was little to no examination of virus eradication or transmission to the fellow eye, respectively. A few factors account for the limited evidence and may be important considerations in planning future clinical trials of treatments for conjunctivitis caused by adenovirus.
First, adenoviral conjunctivitis (including EKC) is diagnosed clinically in most studies. Of the six trials comparing treatments for acute EKC (vs. treatments for subepithelial infiltrates), four had laboratory confirmation of adenoviral infection (immunochromatography, conjunctival smear for lymphocytic predominance, and polymerase chain reaction (PCR).5, 6 Unfortunately, none of these tests is widely available. Another test was an enzyme-linked immunosorbent assay-based rapid screening test, which offers in-office result within 10 minutes and is inexpensive. In the United States, this test has a Clinical Laboratory Improvement Amendment (CLIA) Certificate of Waiver from the Food and Drug Administration (FDA). In fact, this test (known in that period as AdenoPlus) was used to enroll patients in recent trials for treatment of adenoviral conjunctivitis7 and keratoconjunctivitis.8 However, because of widely ranging sensitivity and false negative test results in clinical studies (40% and 63%, respectively, in studies),9, 10 some authors conclude that AdenoPlus should be used selectively—when there is a diagnostic suspicion and a high pretest probability for adenoviral conjunctivitis.11 In one study in which 500 participants with EKC and a positive AdenoPlus test result were recruited from 58 centers world-wide for an FDA licensure trial of auriclosene (0.3%) solution vs. vehicle, the positive predictive value varied widely, from 56% (United States) to 98% (Sri Lanka).8 Different specimen collection techniques or varying profiles of geographically endemic adenoviral serotypes may account for the range. Another possibility is variability of clinical diagnosis of EKC across all 58 centers; the authors concede, “baseline composite clinical symptoms differed by countries of origin.” Altogether, across 58 centers, the AdenoPlus had a positive predictive value of 78% [1- (110/500)]. Moreover, although the labeling states that it should be used in adults (not children) within 7 days of developing conjunctivitis, this instruction is not heeded in all studies, including the recruits in the US in the auriclosene trial who ranged in age from 1-90 years.8
Clinical diagnosis of adenoviral conjunctivitis has limited accuracy. Of 1520 medical center employees who were clinically suspicious for adenoviral conjunctivitis, a minority (8-9%) were positive by PCR, a third of whom had EKC.12-14 Most patients with conjunctivitis, however, neither have access to PCR or nor see an ophthalmologist. Instead, conjunctivitis comprises 1-2% of all visits to primary care providers in the US15 and the UK.16 Although viral conjunctivitis tends to exhibit follicular conjunctival changes and more watery discharge than bacterial conjunctivitis, and itching is a hallmark of allergic conjunctivitis, conjunctivitis can stump even experienced ophthalmologists.1
Public health policies for conjunctivitis regarding absences from school17 or work furlough12 must be predicated on accurate diagnosis. However, without a rapid, accurate diagnostic test at the onset of symptoms, clinical trials may be limited by some factors. Viral load at baseline may vary depending on different viral types,8 inaccuracy of clinical diagnosis particularly in early stages of conjunctivitis, and unclear length of pretherapeutic window. This window (which includes the time between symptom onset and trial enrollment, sometimes based on a positive AdenoPlus test) is likely quite variable. Both this window and the viral load may affect clinical manifestation at time of trial enrollment and response to treatment. Both must be considered in the design of future trials.
Although a successful treatment ideally would shorten symptom and sign duration or be associated with more participants with symptom and sign resolution, these outcomes may not be easily attainable. A standardized and validated grading system might help patient-reported outcomes. In fact, various grading scales have been used for different etiologies of conjunctivitis, including bacterial conjunctivitis (bulbar conjunctival injection, palpebral conjunctival injection, and conjunctival discharge/exudate graded on a 0-3 scale)18 and allergic conjunctivitis.19 The viral conjunctivitis grading scales used by Pepose et al. range from 0 to 3 for bulbar conjunctival redness and watery conjunctival discharge. In trials of auriclosene for viral conjunctivitis, 10 clinical signs including corneal staining, follicular response of the conjunctiva, scarring of the conjunctiva, and edema of the conjunctiva were assessed on a 0-3 scale as were symptoms including foreign body sensation and epiphora8; “resolution of viral conjunctivitis was defined as “a 0 or 1 on the follicular conjunctivitis scale with 0 or 1 on the conjunctival injection score.” Future trials would benefit from a standardized, validated grading scale. Recently, a variety of objective evaluation methods has been introduced with the development of computer algorithm technology. Park et al. announced a method for automatically classifying conjunctival hyperemia by detecting the density of conjunctival blood vessels and vascular boundaries using extraocular segment photos.20 In the future, perhaps this technology can be used for grading of conjunctivitis severity. However, it is not yet possible to measure the characteristic discharge in viral or bacterial conjunctivitis.
Goals of pharmacotherapy for either the acute or chronic phase of adenoviral conjunctivitis are to lessen symptom severity, to shorten the duration of signs and symptoms, and to decrease the chance of developing sequelae (e.g., SEI, membranes, symblepharon) associated with long-term morbidity. Successful treatment must be balanced against long-term dependence on or adverse effects from pharmacotherapy.12 To help determine best treatment(s) with high certainty evidence requires larger sample size than currently been reported (achievable if earlier diagnosis were possible) and rigorous trial design. Such design would be characterized by appropriate data reporting and analysis to reduce the risk of bias, better diagnostic capability (thus ensuring uniformity in pretherapeutic window and applicability of trial results), agreement on outcome measures that are important to patients and physicians, and standardization such as a validated scoring system for signs and symptoms of acute adenoviral conjunctivitis. Without accurate diagnostic testing, patients should be enrolled at onset of signs and symptoms to reduce variability of the pretherapeutic window. Identification of an effective treatment from well-designed trials would lead to less antibiotic use, less suffering, and lower cost to society incurred by adenoviral conjunctivitis. Until there is a safe and effective treatment for adenoviral conjunctivitis, infection control remains paramount.
Conflict of Interest and Financial Disclosures:
ICK reports partial salary support from the National Eye Institute, National Institutes of Health, for her editorial work at Cochrane review (UG1 EY020522)
Contributor Information
Kyongjin Cho, Department of Ophthalmology, The Dankook University College of Medicine, Cheonan, Korea.
Irene C. Kuo, Department of Ophthalmology, Wilmer Eye Institute, the Johns Hopkins University School of Medicine, Baltimore, Maryland.
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