Point-Counterpoint: In-Office 5% Povidone-Iodine Versus Supportive Therapy for Adenoviral Conjunctivitis

INTRODUCTION

Adenoviral conjunctivitis is a highly contagious disease that may cause significant ocular discomfort as well as time away from work for patients.¹ In severe cases, sight-threatening and chronic complications may occur, including corneal subepithelial infiltrates, scarring, symblepharon, irregular astigmatism, lacrimal stenosis, decreased visual acuity, and photophobia.^2–4 Management of adenoviral conjunctivitis can be a challenge as currently there are no US Food and Drug Administration–approved treatments for adenovirus conjunctivitis¹ and there is no consensus on an evidence-based treatment protocol.⁵ Evidence-based protocols remain elusive for many reasons. Challenges surrounding study sample sizes, trial designs, and the lack of early, real-time, accurate adenoviral conjunctivitis diagnosis continue to limit available evidence for clinical practice.^1,2

The American Optometric Association⁶ and American Academy of Ophthalmology⁴ practice guidelines recommend supportive treatments, including artificial tears, antihistamines, oral analgesics, and cool compresses, as they can provide some symptom relief without adverse effects.⁵ Nonetheless, these treatments do not treat the underlying infection or reduce viral loads.⁷ Therefore, it is important to educate patients on ways to reduce the spread of the infection. Practice guidelines emphasize counseling on frequent hand washing, using a separate towel and pillow, and making every attempt to minimize close contact with others during the contagious timeframe, which is considered to be “10 to 14 days from the onset of symptoms from the last affected eye.”⁴ However, data in the literature are limited to support this quarantine based on signs and symptoms. A study by Harthan et al of 12 patients with adenoviral conjunctivitis treated with artificial tears evaluated the natural history of the disease.⁷ This study found that 33% of participants had detectable levels of the virus present at day 14, but no participants had detectable levels of the virus by day 21. It also found that signs and symptoms can persist even after viral titers are no longer detectable, making it even more challenging for clinicians to determine when to allow patients to return to work or school.⁷ Instead, because a negative point-of-care immunoassay test result (eg, QuickVue Adenovirus Conjunctivitis Test; QuidelOrtho Corporation) has excellent negative predictive power,⁸ using a negative result on point-of-care in-office immunoassay testing as an alternative over signs and symptoms may be a better indicator to determine when patients can return to work or school.⁷

Off-label use of topical ophthalmic povidone-iodine for adenoviral conjunctivitis has been recommended for nearly 25 years by various optometric and ophthalmologic editorials and reviews,^9,10 although few clinical trials have evaluated the efficacy of povidone-iodine alone for adenoviral conjunctivitis.¹ The Reducing Adenoviral Patient Infected Days study is a National Eye Institute–funded pilot trial designed to explore the feasibility of a larger, more definitive clinical trial on the safety and efficacy of off-label povidone-iodine use for adenoviral conjunctivitis.^1,11 This pilot trial assessed the safety and efficacy of a single administration of 5% povidone-iodine compared with artificial tears in the treatment of adult patients with adenoviral conjunctivitis.^1,10 The results revealed that a single, in-office administration of 5% povidone-iodine may accelerate reduction in viral load and improvement of clinical signs and symptoms; however, as a pilot study, it is not powered to be a definitive study of efficacy.¹ The Reducing Adenoviral Patient Infected Days study group continues to publish data on disease natural history and trial-design recommendations to expand our understanding of adenoviral conjunctivitis and guide future studies.^7,12,13

Some larger clinical trials have evaluated various percentages (0.4% to 2%) of topical povidone-iodine in combination with 0.1% dexamethasone and suggest this combination can be a safe and effective off-label treatment for adenoviral conjunctivitis.^14–16 However, a 2022 Cochrane review by Liu et al⁴ found insufficient evidence to determine whether any off-label treatments, including topical povidone-iodine with or without steroids, are more effective than no treatment or artificial tears. Studies indicating potential benefit of povidone-iodine combined with steroids were not controlled,¹⁷ were not followed for the entire viral course,¹⁴ or had a control group that was not standardized among study participants.¹⁸ Other challenges with the povidone-iodine/dexamethasone combination treatment identified by these trials included discomfort upon instillation of povidone-iodine and a dosing schedule of 4 times per day, both of which may reduce treatment adherence.^15,16

A lack of quality evidence also surrounds the off-label use of short-term topical steroids in adenoviral conjunctivitis, particularly when used in cases of mild disease and/or the absence of pseudomembranes. The American Academy of Ophthalmology’s 2023 Conjunctivitis Preferred Practice Pattern recommends use of topical steroids in severe cases of adenoviral conjunctivitis when marked chemosis or eyelid swelling, corneal epithelial sloughing, or pseudomembranes are present.⁴ This is because topical steroids decrease the inflammatory response, hasten symptom resolution, and reduce or prevent scarring in these severe cases. Corneal subepithelial infiltrates occur approximately 1 or more weeks after adenoviral conjunctivitis onset, and treatment is guided based on the severity of the disease. In cases of mild disease, observation of subepithelial infiltrates is considered sufficient according to the American Academy Ophthalmology’s 2023 Conjunctivitis Preferred Practice Guidelines.⁴ However, if blurred vision, photophobia, or decreased vision is associated with the subepithelial infiltrates, topical steroids at the minimum effective dose should be considered.⁴ We must keep in mind that steroids do not treat the underlying infection and an animal model has shown prolonged viral shedding, suggesting steroid use may prolong the infectious period.¹⁹ It is not known whether topical steroids prolong viral shedding in humans.^4,20 Taken together, we see why no established treatment model exists for adenoviral conjunctivitis and why the search continues for effective antiadenoviral treatments that reduce virus transmission and duration of infection.

This article reviews current evidence for and against the use of povidone-iodine to treat adenoviral conjunctivitis. This point-counterpoint will focus on in-office use of 5% povidone-iodine (Betadine; Alcon) because it is the only commercial option available to clinicians in the United States. The goal of this review is to help clinicians better understand the risks and benefits of each approach and guide management decisions to help clinicians offer the most appropriate treatment for each patient.

Bausch + Lomb

POINT: 5% POVIDONE-IODINE FOR TREATMENT OF ADENOVIRAL CONJUNCTIVITIS

The human adenovirus is a nonenveloped, double-stranded DNA virus known for its resistance to common disinfectants such as 70% isopropyl alcohol and hydrogen peroxide. Human adenovirus can survive on fomite surfaces for 5 to 7 weeks.²¹ The duration of human adenovirus ocular infections varies widely, typically ranging from 7 to 28 days, often resulting in 1 to 2 weeks of missed work.^15,22 Implementing proper quarantine measures to prevent transmission can lead to lost income and decreased productivity for workers and small businesses.²² Reducing the risk of viral transmission and shortening the duration of infection can therefore have a significant economic impact on patients.²³

Ophthalmic povidone-iodine has been used as an antiseptic in standard ophthalmic surgical care since the 1980s.^24,25 Povidone-iodine is a broad-spectrum antiseptic with antibacterial, antifungal, and antiviral activity.²⁶ Importantly, no known antimicrobial resistance or cross-resistance to povidone-iodine has been reported.²⁴ Povidone-iodine releases free iodine on the ocular surface, quickly penetrating microorganisms, disrupting their cell structure, and leading to their destruction. By targeting viral particles, povidone-iodine reduces the viral load on the ocular surface.^1,24 It is also plausible that povidone-iodine use in treating viral conjunctivitis may help prevent secondary bacterial infections.²⁴

Higher baseline viral titers are linked to more severe ocular signs and symptoms and are predictive of a longer duration of viral clearance.²⁷ Additionally, Lee et al found higher baseline titers are associated with poorer clinical outcomes.²⁸ The Reducing Adenoviral Patient Infected Days study¹ initially evaluated the safety and tolerability of one-time administration of 5% povidone-iodine in adenoviral conjunctivitis compared with preservative-free artificial tears in 56 adults with adenoviral conjunctivitis. The inclusion criteria included symptom onset of less than or equal to 4 days and a positive AdenoPlus point-of-care immunoassay (now known as QuickVue Adenovirus Conjunctivitis Test; QuidelOrtho Corporation).²⁹ Patients with thyroid disease, a history of an iodine allergy to study medications, pseudomembranes, subepithelial corneal infiltrates, anterior chamber inflammation, a history of ocular surgery within the past 3 months, skin vesicles, corneal dendrites, ulceration, abrasion, or a foreign body and pregnant/nursing patients were excluded.¹ Corneal fluorescein staining increased immediately after the povidone-iodine wash but returned to baseline on day 1, whereas visual acuity remained unaffected in the povidone-iodine treatment arm.¹¹ Moreover, patients reported no change in ocular discomfort immediately after administration of povidone-iodine or on day 1.¹¹ It is important to note that 0.5% proparacaine was administered before the povidone-iodine ophthalmic solution as part of the design study, which may have contributed to the lack of reported discomfort directly after instillation of povidone-iodine. The Reducing Adenoviral Patient Infected Days pilot study also found that viral load was lower on day 4 in the 5% povidone-iodine treatment group as compared with the artificial tear group.¹ Participant-reported severity of symptoms (tearing, redness, and lid swelling) and clinician-graded severity of clinical signs (mucoid discharge, bulbar redness, and bulbar edema) were also less severe on day 4 compared with the artificial tear group. By day 7, both groups had a marked reduction in viral titers and an improvement in the signs and symptoms, although no statistical difference was shown between groups.¹

Corneal involvement is a hallmark of epidemic keratoconjunctivitis, setting it apart from other adenoviral conjunctivitis like simple follicular conjunctivitis or pharyngoconjunctival fever.³⁰ Povidone-iodine carries an inherent risk of keratitis because of its cytotoxic effects on the corneal epithelium.^24,31 However, these cytotoxic effects target virally infected or exposed epithelial cells and lower viral titers, potentially reducing the likelihood of subepithelial infiltration by dampening the immune response to the virus.⁷ Singh et al²⁶ demonstrated povidone-iodine not only reduces viral replication in ocular tissue but also decreases inflammatory gene expression in RNA ocular infections. Further studies are warranted to evaluate povidone-iodine’s effect on reducing inflammatory expression in DNA-based adenovirus. The resolutions of clinical signs and symptoms of adenoviral conjunctivitis are inappropriate indicators of viral clearance because the associated inflammatory responses result in sustained clinical findings like bulbar injection and conjunctival follicles.⁷ Reducing the inflammatory response via povidone-iodine treatment and initiation of corticosteroid therapy, either as monotherapy or in combination, may be useful to shorten the duration of the immune response.²⁰ Unexpectedly, in the Reducing Adenoviral Patient Infected Days study, the incidence of subepithelial infiltrates and pseudomembranes was higher in the 5% povidone-iodine group compared with the preservative-free artificial tear group, but the effect was not statistically significant. The number of participants who developed these sequelae was small, making interpretation difficult.¹

In summary, timely in-office treatment with a 5% povidone-iodine wash can reduce viral load, alleviate signs and symptoms more rapidly, and potentially enable patients to return to work sooner compared with palliative treatment of viral conjunctivitis. Povidone-iodine is a cost-effective, efficient, and well-tolerated virucidal agent that mitigates patient burden via ease of single dosing and shortened duration of viral infection.^1,11

COUNTERPOINT: SUPPORTIVE TREATMENT FOR ADENOVIRAL CONJUNCTIVITIS

Currently, topical povidone-iodine is US Food and Drug Administration approved for “pre-surgical prepping of the periocular region (lids, brow, and cheek) and irrigation of the ocular surface (cornea, conjunctiva, and palpebral fornices).”³² However, povidone-iodine is not US Food and Drug Administration approved for treating any type of conjunctivitis. The 2022 Cochrane review by Liu et al² found there are limited studies on the use and safety of povidone-iodine for viral conjunctivitis and there are no specifications regarding proper technique for such treatment.² Most pertinent studies have small sample sizes with a risk of bias, resulting in low-certainty evidence that is insufficient to determine whether povidone-iodine demonstrates a treatment advantage over artificial tears or topical steroids.²

The Reducing Adenoviral Patient Infected Days study, in addition to its limitations as a pilot study, was confounded by a high false-positive diagnosis rate because of the limited accuracy of point-of-care immunoassay.¹ The study authors acknowledge “these limitations directly affect the application of results to clinical practice.”¹ It is difficult to accurately diagnose adenoviral conjunctivitis from clinical signs and symptoms alone; therefore, many patients may not benefit from this treatment as they may not truly have adenovirus. Research confirms this, as diagnosing adenoviral conjunctivitis based on clinical signs and symptoms alone varies from 21% to 72% compared with laboratory confirmation.^1,33,34 Point-of-care testing such as the QuickVue Adenoviral Conjunctivitis Test (QuidelOrtho Corporation) can aid in clinical diagnosis, but it has limitations. The Reducing Adenoviral Patient Infected Days study demonstrated that the true negative rate of the point-of-care immunoassay test was high (98.5%), indicating that a negative test can be helpful clinically by ruling out adenoviral conjunctivitis, and therefore, use of povidone-iodine would not be indicated. However, for subjects testing positive for adenoviral conjunctivitis with point-of-care testing, 50% ultimately tested negative for adenovirus when quantitative polymerase chain reaction, the gold standard for confirming adenoviral conjunctivitis, was performed.^1,7,28 This false-positive diagnostic challenge affects the reliability of research trials that guide clinical management. Adenoviral conjunctivitis treatment studies that enroll subjects presumed to have adenovirus, without confirmation of adenovirus by quantitative polymerase chain reaction, may include subjects that are actually negative for adenoviral conjunctivitis. This error reduces efficacy and statistical power and may account for inconsistencies in the literature for adenoviral conjunctivitis treatment benefits.¹

Further clinical trials are indicated, but until additional information is available, patient selection for povidone-iodine use must take a variety of factors into consideration. Several contraindications to povidone-iodine should be considered, some absolute and some relative. According to the povidone-iodine package insert,³² the use of povidone-iodine should be avoided in those with an allergy or sensitivity to iodine, as local reaction can occur. Although an allergy to povidone-iodine appears to be relatively rare, localized reactions are more frequent and are thought to be secondary to chemical sensitivity in most cases.³⁵ Risk should also be carefully considered for those with thyroid disorders, as no studies are available to rule out the possibility of iodine absorption.³² Because povidone-iodine is classified as pregnancy category C, careful consideration should dictate whether betadine is appropriate for those who are pregnant or able to become pregnant. Absorption of povidone-iodine through intact skin is thought to be minimal; however, use should be minimized in those who are or will soon be breastfeeding as exposure can increase iodine levels in breastmilk, cause transient hypothyroidism in infants, and interfere with newborn thyroid screening tests.³⁶ The povidone-iodine package insert reports the safety of povidone-iodine has not been evaluated in pediatric populations,³² and the Reducing Adenoviral Patient Infected Days study did not include a pediatric population.¹ Furthermore, safety has not been sufficiently evaluated in pediatric populations.³² Two studies evaluating povidone-iodine for conjunctivitis in infants suggests this treatment is well tolerated; however, these studies either were nonmasked or included conjunctivitis of any etiology, thus making it difficult to ascertain treatment benefit in the use of adenoviral conjunctivitis.^37–39

The application of povidone-iodine to the ocular surface can cause prolonged ocular hyperemia and irritation, staining of the corneal epithelium, and transient changes in visual acuity.^40,41 Although some studies documented minimal ocular discomfort after povidone-iodine application, corneal staining is still seen in these cases.^1,11 Such complications are more likely if insufficient posttreatment saline rinse is performed, allowing prolonged contact of povidone-iodine with the ocular surface.

Although the package insert states “sterile saline solution in a bulb syringe should be used to flush the residual prep solution from the cornea, conjunctiva, and the palpebral fornices,”³² there is currently no standard or approved technique for using povidone-iodine in the management of viral conjunctivitis. This lack of standardized guidance may lead to instances of inadequate postapplication saline rinse and increased risk of ocular discomfort and corneal compromise. For these reasons, careful patient selection must be performed to ensure the patient can tolerate the treatment protocol, including adequate posttreatment saline rinse. This may exclude the very young and those with developmental or cognitive impairment. Before proceeding with povidone-iodine to manage viral conjunctivitis, the risk of any preexisting corneal compromise must be evaluated and considered as well.

Additional consideration should be given to the timing of symptom onset. Ocular application of povidone-iodine to treat viral conjunctivitis has been shown to improve patient symptoms only if performed early in the disease process, specifically within the first 4 days of onset.¹ Because the symptoms of conjunctivitis can begin to improve within 7 days of onset and the condition self-resolves in 2 to 3 weeks,¹ use of povidone-iodine after this timeframe may cause unnecessary discomfort and risk in some patients, particularly as 5% povidone-iodine did not reduce the incidence of subepithelial infiltrates or pseudomembranes in the Reducing Adenoviral Patient Infected Days pilot study.¹

CONCLUSION

Both povidone-iodine 5% and supportive therapies of artificial tears and cool compresses have a role in the treatment of adenoviral keratoconjunctivitis. The decision to offer 5% povidone-iodine as a treatment option depends on several patient-centric factors. Based on the Reducing Adenoviral Patient Infected Days pilot study, there is early evidence to support offering a single in-office administration of 5% povidone-iodine to adult patients who present within 4 days of symptom onset and a positive QuickVue Adenovirus Conjunctivitis Test (QuidelOrtho Corporation) to reduce viral load, alleviate signs and symptoms more rapidly, and potentially enable patients to return to work sooner compared with artificial tears alone. However, clinicians should monitor for and educate patients on the off-label use of this treatment and educate patients on the advantages and disadvantages, which include the potential for complications such as subepithelial infiltrates and pseudomembranes despite povidone-iodine treatment.^3,10

For some patients, povidone-iodine may not be a suitable treatment option and available evidence must be carefully weighed before proceeding with topical povidone-iodine for treatment of viral conjunctivitis. Such treatment may be best deferred for those with a negative QuickVue Adenovirus Conjunctivitis Test (QuidelOrtho Corporation), those of pediatric age, those unable to cooperate with a thorough posttreatment saline rinse, those who are pregnant or nursing, and those with an allergy or sensitivity to iodine. Careful consideration must be taken for those with thyroid disease and those who present later in the course of conjunctivitis.

CONFLICTS OF INTEREST AND FUNDING DISCLOSURE

Dr Klemencic was a full-time employee at Alcon in 2023. All other authors declare no conflicts of interest.