How to manage adenoviral conjunctivitis

Adenoviral conjunctivitis (Ad-CS) has never been so popular a topic as it is right now. With over 26 million viewers tuning in to watch the Olympics, Americans have watched Bob Costas’s unilateral conjunctivitis worsen, then become bilateral. His ocular condition prompted many commentators to remark, “Can’t someone help him?” Members of the RAPID (Reducing Adenoviral Patient-Infected Days ) research group, along with many other optometrists, sat helplessly staring at our television screens, wishing we could send him a bottle of Betadine! So why didn’t he get that treatment? Why aren’t more patients correctly diagnosed with Ad-CS and treated with Betadine?

Epidemiology

Adenoviral conjunctivitis (Ad-CS), also known as “pink eye,” is one of the most common eye infections worldwide. Ad-CS is highly symptomatic, causing discomfort, tearing, lid swelling, photophobia, and decreased vision. Some 15%-35% of the patients develop subepithelial corneal infiltrates that can progress to permanent visual impairment. Because of the epidemic potential of some adenoviral serotypes, Ad-CS is a reportable condition in Germany and Japan.^1,2

Outbreaks of viral conjunctivitis spare no nationality, age, gender, or social class.^3-6 Patients with acute conjunctivitis typically present to a primary-care provider and are estimated to comprise as much as 2% of a general practitioner’s practice.⁷ Medical management of Ad-CS is estimated to cost $670 million annually with patients losing 5 or more days of work or school per infection.⁸

Ad-CS is more contagious than other forms of conjunctivitis (or even other viral conditions including herpes simplex virus or human immunodeficiency virus) partly due to the virus’s ability to remain infectious in the desiccated state for weeks at room temperature.⁹

Adenoviruses have no outer lipid bilayer and are highly resistant to disinfection.¹⁰ The virus is transmitted directly through droplets or smears of infected bodily fluids, primarily tears or respiratory secretions, and by fomites on towels, doorknobs, soap, counters, instruments, eye drops, and eyeglasses. The hands of nearly 50% of patients with Ad-CS presenting for care were culture positive.¹¹ The period of contagion lasts about 3 weeks.1 Incubation period for Ad-CS is about 10 days (range 7-16 days) prior to the onset of symptoms. Symptoms typically persist for 7 to 28 days.

Studies report that most eyes test negative with culture by 13 days after the onset of symptoms.^12,13 The duration and severity of symptoms and complications differ among the more than 20 adenovirus serotypes associated with conjunctivitis; however, serotypes 8, 19, 37, and 53 are known to have the greatest epidemic potential.¹⁴

Next: Diagnostic difficulty

Diagnostic difficulty
Research for effective treatment of Ad-CS has been seriously hampered by the lack of clear diagnostic indicators to differentiate Ad-CS from other causes of conjunctivitis. The proportion of infectious conjunctivitis due to viral infections has been reported anywhere from 20%-70% and that 65%-90% is thought to be due to adenoviruses. The etiology of acute conjunctivitis is often made based on clinical signs and symptoms, but the diagnostic accuracy is less than stellar, ranging from 40%-72%.

The diagnostic conundrum of Ad-CS may be resolved by the availability of the first point-of-care test, the Rapid Pathogen Screening AdenoPlus Detector, distributed by Nicox. AdenoPlus, which has FDA approval, CLIA waiver, and a CPT code, yields a bivariate “yes/no” for the presence of adenovirus antigen to a lower limit of 40-50 virions. Its sensitivity was 85% (29 of 34) and specificity was 98% (89 of 91) compared to qPCR in a sample of 128 consecutive patients with acute conjunctivitis.¹⁵

However, its accuracy has been brought into question by a study of 9 patients tested with both AdenoPlus and qPCR. AdenoPlus gave negative readings in 6 of 9 eyes with high qPCR adenovirus titers and positive readings in 3 patients with zero PCR titers.¹⁶

Treatment
Currently there are no drugs that are FDA approved for use in the management of Ad-CS. The use of topical ganciclovir (Zirgan, Bausch + Lomb) is currently being investigated, but the adenoviral structural characteristics may prove too hardy for this anti-viral agent.

The ideal treatment for Ad-CS would be safe, effective, low cost, and widely accessible. Ophthalmic Betadine 5% (povidone iodine, Alcon) meets these criteria. Melton and Thomas reported that since they began using the single, in-office protocol of 5% Betadine “…we have not had a patient to go on to develop the legendary subepithelial infiltrates.”¹⁷

There is preliminary evidence from in vivo animal and human studies,^18-20 but a definitive clinical trial that determines Betadine’s efficacy against Ad-CS has yet to be conducted. Anecdotally, practitioners using Betadine on a regular basis are proponents of its efficacy. Betadine’s safety profile has been demonstrated with decades of use as a topical antiseptic in neonates, children, and adults. The cost per 30 mL single-use bottle of 5% ophthalmic Betadine is approximately one quarter the cost of a 5gm tube of ganciclovir.

The urgency for a randomized clinical trial with 5% ophthalmic Betadine increases as more eyecare providers adopt off-label use of Betadine for the treatment of Ad-CS. Evidence from a well-designed randomized trial, whether the result is no effect or positive, would have high public health impact. A positive trial outcome of a single, in-office treatment of Betadine could revolutionize management of Ad-CS.

Almost all clinical studies of Betadine demonstrated quicker resolution of disease as compared to controls receiving standard care. In a series of 36 patients, Abel stated that 83% reported decreased lid swelling and decreased crusting 1 day after treatment with 10% Betadine or 2 days of 5% Betadine used 3 times daily. The vast majority of patients, 94%, reported “marked improvement” of symptoms within 24 to 48 hours of treatment.⁷

In a prospective study of 61 patients using 2% Betadine 4 times a day for 7 days, 46% recovered completely within a week, and 77% reported “absence of general ocular discomfort” within 7 days.⁶ A Web-based, uncontrolled, unmasked trial of Betadine is now underway. All of these studies are uncontrolled, unmasked, or both.

Next: Anecdotal use

Anecdotal use
Despite the lack of well-designed clinical studies, the utilization of Betadine in the management of Ad-CS is widespread among clinicians.

In 2013, optometrists and ophthalmologists at seven clinical meetings were queried using either audience response systems (clickers) or paper surveys regarding their use of Betadine. Of the 649 responses, 29.3% of practitioners utilized Betadine at least some of the time in their management regimen of Ad-CS (see Figure 1).

Of those using Betadine, approximately 23% reported using it for at least 76% of their patients presenting with Ad-CS (see Figure 2).

This indicates that those who have found Betadine to be a viable treatment option incorporate it most or all of the time. Additional questions were asked of attendees at a course presented by Drs. Melton and Thomas at the American Academy of Optometry. Attendees were asked about the utilization of AdenoPlus to aid in the diagnosis of acute conjunctivitis. Only 10% of the 340 attendees reported utilizing this point-of-care test (see Figure 3).

Those using Betadine in the management of Ad-CS were more likely to incorporate AdenoPlus (15.4% vs. 6.3% of those not using Betadine) as illustrated in figure 4.

There was some difference in the frequency of use of AdenoPlus based on how often Betadine was utilized. In those who used Betadine in at least 76% of their Ad-CS cases, the AdenoPlus was employed 33.3%, which was the highest utilization among all groups (see figure 5).

Until research provides the definitive answer if Betadine is effective or not, it seems a reasonable treatment regimen to try when these patients present within the first few days of infection onset. It is rapid, inexpensive, and has the potential to significantly lessen the duration of a patient’s infection. The decision to use Betadine can be guided by the results of AdenoPlus, which should improve the clinician’s accuracy at diagnosing Ad-CS.ODT

References:

1. Meyer-Rusenberg B, Loderstadt U, Richard G, Kaulfers PM, et al. Epidemic keratoconjunctivitis: the current situation and recommendations for prevention and treatment. Dtsch Arztebl Int. 2011 Jul;108(27):475-80.

2. Aoki K, Tagawa Y. A twenty-one year surveillance of adenoviral conjunctivitis in Sapporo, Japan. Int Ophthalmol Clin. 2002 Winter;42(1):49-54.

3. Matsui K, Shimizu H, Yoshida A, Nagaoka E, et al. Monitoring of adenovirus from conjunctival scrapings in Japan during 2005-2006. J Med Virol. 2008 Jun;80(6):997-1003.

4. Buffington J, Chapman LE, Stobierski MG, Hierholzer JC, et al. Epidemic keratoconjunctivitis in a chronic care facility: risk factors and measures for control. J Am Geriatr Soc. 1993 Nov;41(11):1177-81.

5. Ford E, Nelson KE, Warren D. Epidemiology of epidemic keratoconjunctivitis. Epidemiol Rev. 1987;9:244-61.

6. Trinavarat A, Atchaneeyasakul LO. Treatment of epidemic keratoconjunctivitis with 2% povidone-iodine: a pilot study. J Ocul Pharmacol Ther. 2012 Feb;28(1):53-8.

7. Abel R, Abel AD. Use of povidone-iodine in the treatment of presumptive adenoviral conjunctivitis. Ann Ophthalmol Glaucom. 1998;30(6):341-3.

8. Udeh BL, Schneider JE, Ohsfeldt RL. Cost effectiveness of a point-of-care test for adenoviral conjunctivitis. Am J Med Sci. 2008 Sep;336(3):254-64.

9. Chaberny IE, Schnitzler P, Geiss HK, Wendt C. An outbreak of epidemic keratoconjunctivtis in a pediatric unit due to adenovirus type 8. Infect Control Hosp Epidemiol. 2003 Jul;24(7):514-.

10. Sauerbrei A, Wutzler P. Virucidal efficacy of povidone-iodine-containing disinfectants. Lett Appl Microbiol. 2010 Aug;51(2):158-63.

11. Azar MJ, Dhaliwal DK, Bower KS, Kowalski RP, et al. Possible consequences of shaking hands with your patients with epidemic keratoconjunctivitis. Am J Ophthalmol. 1996 Jun;121(6):711-2.

12. Warren D, Nelson KE, Farrar JA, Hurwitz E, et al. A large outbreak of epidemic keratoconjunctivitis: problems in controlling nosocomial spread. J Infect Dis. 1989 Dec;160(6):938-43.

13. Ward JB, Siojo LG, Waller SG. A prospective, masked clinical trial of trifluridine, dexamethasone, and artificial tears in the treatment of epidemic keratoconjunctivitis. Cornea. 1993 May;12(3):216-21.

14. Roba LA, Kowalski RP, Gordon AT, Romanowski EG, et al. Adenoviral ocular isolates demonstrate serotype-dependent differences in in vitro infectivity titers and clinical course. Cornea. 1995 Jul;14(4):388-93.

15. Sambursky R, Trattler W, Tauber S, Starr C, et al. Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjuncvitis. JAMA Ophthalmol. 2013 Jan;131(1):17-22.

16. Pelletier JS, Stewart K, Trattler W, Ritterband DC, et al. A combination povidone-iodine 0.4%/dexamethasone 0.1% ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Ther. 2009 Aug;26(8):776-83.

17. Melton RT, R. Antiviral Strategies. Rev Optom. 2011 http://www.revoptom.com/cmsdocuments/2011/9/sept2011_algorithms.pdf. Accessed 2/1/7/14.

18. Kawana R, Kitamura T, Nakagomi O, Matsumoto I, et al. Inactivation of human viruses by povidone-iodine in comparison with other antiseptics. Dermatology. 1997;195 Suppl 2:29-35.

19. Wutzler P, Sauerbrei A, Klocking R, Burkhardt J, et al. Virucidal and chlamydicidal activities of eye drops with povidone-iodine liposome complex. Ophthalmic Res. 2000 Mar-Jun;32(2-3):118-25.

20. Monnerat N, Bossart W, Thiel MA. Povidone-iodine for treatment of adenoviral conjunctivitis: an in vitro study. Klin Monbl Augenheilkd. 2006 May;223(5):349-52.