Epidemic Keratoconjunctivitis

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Article initiated by:
Natario Linard Couser, MD, Vamsi Kolluru
All contributors:
Aaron Rael, BS, Yvonne Nguyen, BS, Vatinee Y. Bunya, MD, MSCE, Sarah Brown Weissbart, MD, Colleen Halfpenny, M.D., Augustine Hong, MD, S. Grace Prakalapakorn, MD, MPH, Natario Linard Couser, MD, A. Paula Grigorian, MD, Angeline Nguyen, MD, Smita Kapoor MD,DNB,MNAMS,FAICO
Assigned editor:
Angeline Nguyen, MD, Maria D. Bernal, MD
Review:
Assigned status Up to Date
 by Angeline Nguyen, MD on November 11, 2024.


Epidemic Keratoconjunctivitis
Epidemic keratoconjunctivitis.
Epidemic keratoconjunctivitis. © 2019 American Academy of Ophthalmology [1]
ICD-10
[1]30.0
ICD-9
077.1


Diagnostic Code

  • 2012 ICD-9-CM 077.1 Epidemic keratoconjunctivitis[2]
  • 2015 ICD-10-CM B30.0 Keratoconjunctivitis due to adenovirus

Background

Conjunctivitis refers to the inflammation of the conjunctiva, which is a membrane that covers the sclera and inside of the eyelids. The inflammation results in a pink or red coloration of the eye hence the disease being commonly referred to as “pink eye”. [3]

Epidemic keratoconjunctivitis (EKC) is a highly contagious form of viral conjunctivitis. [4][5] The development of corneal inflammation (keratitis), distinguishes epidemic keratoconjunctivitis from other forms of conjunctivitis and usually arises after the fourth day after the initial onset of symptoms. [3]

EKC is caused by a group of viruses known as adenoviruses that in addition to infections of the ocular surface, are responsible for causing infectious diseases of the gastrointestinal tract and respiratory system illnesses such as the common cold virus, for example. [6][7][8] The adenovirus serotypes 8, 4, 19 (now 64 by whole genome sequencing), and 37 are often associated with EKC. [7][8] Serotypes 53 and 54 have been identified as the causative agent in a few recent outbreaks of EKC.   Some data suggests that as metagenomics-based methods of viral detection improve, other viruses may be implicated in EKC.[9]

Signs and Symptoms

Ocular signs/symptoms

  • Conjunctival hyperemia/erythema (redness) of bulbar conjunctiva (Fig. 1-4)
  • Conjunctival hyperemia/erythema (redness) of palpebral conjunctiva (Fig. 5-7)
  • Follicular reaction (Fig. 5 and 6)
  • Chemosis (conjunctival edema) (Fig. 1-4)
  • Epithelial keratitis
  • Subepithelial infiltrates
  • Membranes or pseudomembranes
  • Dacryocystitis
  • Clear or yellow discharge from the eye(s)
  • Ocular itchiness and irritation
  • Photophobia
  • Epiphora (excessive tearing) (Fig. 1-2)
  • Foreign body sensation
  • Blurred vision/loss of visual acuity


Systemic signs/symptoms:

  • Lymphadenopathy (swollen nymph nodes, specifically the preauricular lymph nodes) (Fig. 8)
  • Fever
  • Headache
  • Fatigue


In about 70% of cases the symptoms may progress to the other eye, though the symptoms may be milder for the other eye.[5][10]

Conjunctival inflammation can progress to focal epithelial keratitis, and the resulting lesions can last for up to two weeks. After this period, subepithelial infiltrates (also known as “nummuli”), which are thought to be related to the immune response, can form beneath the lesions. These occur at approximately day 10 and can give rise to irregular astigmatism and photophobia. These symptoms and decreased visual acuity can persist for months or years.[5][11][12]

In about 25% of cases of EKC, patients can develop severe findings, including membranous or pseudomembranous conjunctivitis, causing scarring of the conjunctiva and symblepharon formation, wherein the eyelid adheres to the cornea.[5][13]

Clinical Photographs

Figure 1: Epiphora, chemosis and diffuse erythema of the bulbar conjunctiva in a patient with EKC; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 2: Epiphora, chemosis and diffuse erythema of the bulbar conjunctiva in a patient with EKC, shown under higher magnification; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 3: Erythema and chemosis of the bulbar conjunctiva in a patient with EKC, view of temporal portion of conjunctiva as patients looks nasally; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 4: Erythema and chemosis of the bulbar conjunctiva in a patient with EKC, view of nasal portion of conjunctiva as patients looks temporally; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 5: Follicular reaction of the palpebral conjunctiva in a patient with EKC, upper eyelid everted; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 6: Follicular reaction of the palpebral conjunctiva in a patient with EKC, view with upper eyelid everted; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 7: Erythema of the palpebral conjunctiva in a patient with EKC, view with lower eyelid everted; Clinical photograph captured courtesy of the UNC Ophthalmic Imaging Department.


Figure 8: Palpable preauricular lymph node (area between arrows) in a patient with EKC, view of de-identified left face; Clinical photograph captured courtesy Dr. Couser by permission from patient.

Diagnosis

Epidemic keratoconjunctivitis is usually diagnosed based on history and a physical examination, looking for the known signs and symptoms. [5][11][14] Physical examination is conducted using a slit lamp, however a penlight can suffice when a slit lamp is not available. [14] These methods can lead to an inaccurate diagnosis however; as it has been shown that the signs and symptoms of conjunctivitis tend to be nonspecific and make it difficult to pinpoint the exact cause or type of the disease. [14] The type of discharge is one of the main features used to differentiate among the types of conjunctivitis. Viral conjunctivitis tends to have a watery discharge, while bacterial conjunctivitis will tend to have discharge with pus, though as noted this is not a guarantee of the type of conjunctivitis. [14] These methods can lead to an inaccurate diagnosis, however, as it has been shown that the signs and symptoms of conjunctivitis tend to be nonspecific and make it difficult to pinpoint the exact cause or type of the disease.[14]

Of the testing methods available, the most commonly used are cell culture and immune assays. Polymerase chain reaction (PCR) is another method that has been shown to be more accurate than cell culture and immunoassay combination. These diagnostic methods are expensive, however, and not readily available in most outpatient settings. [11]

In Office Point of Care Testing

The RPS Adeno Detector (Rapid Pathogen Screening, AD1) was FDA approved in 2006 as a point-of-care antigen-based immunoassay for diagnosing adenovirus infections [15].  The AdenoPlus is the enhanced second-generation device by RPS and was FDA approved in 2012 and delivers a result in 10 minutes. The AdenoPlus uses direct sampling of tears and micro-filtration technology to improve sensitivity.  In 2013, Sambursky et al[16] published the results of a prospective, sequential, masked, multi-center clinical trial of 128 patients with clinically diagnosed adenoviral conjunctivitis to compare the sensitivity and specificity of the AdenoPlus with CC-IFA and PCR.  The study demonstrated that the AdenoPlus had a sensitivity and specificity of 90% and 96%, respectively compared to CC-IFA, and of 85% and 98%, respectively, compared to PCR. The sensitivity and specificity were 93% and 98%, respectively, compared with both CC-IFA and PCR.

In 2015, Kam et al [17] also reported a high specificity with AdenoPlus but a much lower sensitivity than had been previously published (39.5% versus PCR). The authors concluded that PCR is a more sensitive test and, therefore, the use of the AdenoPlus should be limited to diagnostically challenging cases.

Advantages of in office testing for adenovirus

Given the highly contagious nature of adenoviral conjunctivitis, a delay in diagnosis can lead to unnecessary isolation or empiric antibacterial or antiviral therapy [14]. As the AdenoPlus detects the presence of viral particles, the results may correlate with disease infectivity and, thus, allow patients a speedier return to school and work when the virus is no longer detectable. In a cost-effectiveness study, utilization of the RPS Adeno Detector was shown to save $429.4 million and avoid 1.1 million cases of inappropriate antibiotic use .[18]

In addition, the ability to confirm adenoviral infection might allow for the study and use of novel therapies for adenoviral infections such as ganciclovir, povidone iodine, N-chlorotaurine, and cyclosporine A.[19] [20] [21] [22]

Treatment

  • Epidemic keratoconjunctivitis resolves on its own, and there is currently no effective treatment. [10][11][14] Management is centered on symptom reduction through use of cold compresses, artificial tears, and topical cycloplegic medications to alleviate significant complaints of photophobia. [5] [23][11][14]
  • Topical corticosteroids are often prescribed in severe cases and while they do assist in reducing inflammatory symptoms, they do not significantly reduce recovery time. [11]Some studies have in fact shown that the use of corticosteroids may increase the duration of disease by inhibiting removal of the adenovirus by the immune system and improving the replication of the virus. [10][11] Guidelines currently recommend for steroids to only be used in patients who have bacterial co-infection or in high-risk individuals. [24]
  • In limited studies, antiviral ganciclovir gel has been shown to shorten the duration of epidemic keratoconjunctivitis and reduce development of subepithelial infiltrates. However, other antivirals have not shown effectiveness, and more studies are needed to evaluate its treatment efficacy in EKC.[25]
  • Povidone-iodine is a disinfectant and antiseptic agent that has been shown in some studies to decrease the duration of acute epidemic keratoconjunctivitis. It has also been shown to lower the risk of subepithelial infiltrate development when used alone or in combination with a topical steroid. However, no interventions have shown superiority in resolution of subepithelial infiltrates once they have developed. Optimal concentrations of povidone-iodine have not been investigated, and further studies are warranted. [26] [27]
  • Patients should be followed closely for the formation of conjunctival membranes. If present, the membranes should be removed, and the patient should be given topical corticosteroids to minimize scar and symblepharon formation.[9]

Pathogenesis

Adenovirus D (AdV) is a lytic, nonenveloped double-stranded DNA virus with a genome encoding more than 40 structural and nonstructural proteins. Classification of AdV’s into its serotype groups (A-G) is based on hemagglutination properties, tissue tropism, serology, DNA homology, and host-receptor usage. The presence of AdV on the ocular surface causes secretion of IL-8 from ocular surface epithelial cells and eventually leads to internalization and replication of the virus.[28]

Epidemiology/Prevention

Epidemic keratoconjunctivitis is a highly contagious disease and given that no effective treatment yet exists, prevention is the best method to tackle the disease. The virus can be spread by contact with infected surfaces or objects, and the virus can remain infectious on porous surfaces for 10 days and nonporous surfaces for over one month.[9]

A patient can spread the disease by touching or rubbing their eyes and then touching another object. Objects that come into contact with the eyes, such as cosmetics, should not be shared or allowed into contact with others. [11] According to an analysis done at the Illinois Eye and Ear Infirmary in Chicago, the risk of infection from household contacts is estimated at 10-20%.[29]

It can also spread via respiratory or infected bodily secretions by entering the body through the nose, throat or conjunctiva.[30] The incubation period is about a week before the symptoms manifest.[31] A person can be contagious for two weeks or more after first showing symptoms and this should be taken into consideration when deciding whether to return to work or school. [11] A person is especially contagious if there is discharge present and should not return to work until ocular discharge has ceased.

The physician's office or hospital setting is often the point of origin for many EKC outbreaks and prevention measures should be exercised thoroughly in these locations. These include steps such as using disposable instruments and tools, employing gloves, and using disposable covers for instruments that cannot be disposed of routinely. [11] Guidelines on how to clean instruments (such as tonometers) do vary. Studies have shown differing effectiveness in cleaning agents such as hydrogen peroxide and isopropyl alcohol in their ability to eliminate adenovirus. It has been suggested that the instrument manufacturer’s cleaning protocols should be followed given the lack of universal guidelines. [11] A recent study from Hashizume et. al found that treatment with 1% potassium peroxymonosulfate led to significant reduction in all tested Human adenovirus D types and is a promising disinfectant for EKC.[32]

It has been postulated that in addition to causing acute outbreaks, EKC can also be endemic, in some instances arising from reservoirs found within individual communities. This would make the adjective “epidemic” not always true.[9]

Additional Resources

References

  1. ↑ American Academy of Ophthalmology. Epidemic keratoconjunctivitis. https://www.aao.org/image/epidemic-keratoconjunctivitis-2 Accessed June 28, 2019.
  2. ↑ American Academy of Ophthalmology. Epidemic keratoconjunctivitis. https://www.aao.org/image/epidemic-keratoconjunctivitis-2 Accessed June 28, 2019.
  3. ↑ 3.0 3.1 Boyd, Kierstan. Conjunctivitis: What is Pink Eye? eyeSmart, American Academy of Ophthalmology. February 1, 2014. http://www.aao.org/eye-health/diseases/pink-eye-conjunctivitis
  4. ↑ Adenovirus-Associated Epidemic Keratoconjunctivitis Outbreaks – Four States, 2008-2010, Weekly, August 16, 2013, 62(32);637-641, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6232a1.htm
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Bawazeer, Ahmed. Epidemic Keratoconjunctivitis. Medscape. March 20, 2013. http://emedicine.medscape.com/article/1192751-overview#a0101
  6. ↑ Adenoviruses. Centers for Disease Control and Prevention. December 27, 2011. http://www.cdc.gov/adenovirus/about/index.html
  7. ↑ 7.0 7.1 Jin X, Ishiko H, Ha NT, et al. Molecular epidemiology of adenoviral conjunctivitis in Hanoi, Vietnam. Am J Ophthalmol. 2006; 142:1064-6.
  8. ↑ 8.0 8.1 Kinchington PR, Romanowski EG, Gordon YJ. Prospects for adenoviral antivirals. J Antimicrob Chemother. 2005; 55:424-9.
  9. ↑ 9.0 9.1 9.2 9.3 Jonas, R. A., Ung, L., Rajaiya, J., & Chodosh, J. (2020). Mystery eye: Human adenovirus and the enigma of epidemic keratoconjunctivitis. Progress in Retinal and Eye Research, 76, 100826. https://doi.org/10.1016/J.PRETEYERES.2019.100826
  10. ↑ 10.0 10.1 10.2 Meyer-Rüsenberg, Birthe et al. “Epidemic Keratoconjunctivitis: The Current Situation and Recommendations for Prevention and Treatment.” Deutsches Ärzteblatt International 108.27 (2011): 475–480. PMC. Web. 22 Mar. 2015.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147286/
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 Pihos, Andria. Epidemic keratoconjunctivitis: A review of current concepts in management. Journal of Optometry: Peer-reviewed journal of the Spanish General Council of Optometry. Vol 06. Num 02. April 2013-June 2013.http://www.journalofoptometry.org/en/epidemic-keratoconjunctivitis-a-review-of/articulo/90197282/
  12. ↑ McKenzie, Mark & Whitley, Walt. A Closer Look at Corneal Inflammation. Review of Cornea & Contact Lenses. November 15, 2012. http://www.reviewofcontactlenses.com/content/d/irregular_cornea/c/37560/
  13. ↑ symblepharon. (n.d.) Mosby's Medical Dictionary, 8th edition. (2009). Retrieved February 15 2015 from http://medical-dictionary.thefreedictionary.com/symblepharon
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 Azari AA, Barney NP. Conjunctivitis: A Systematic Review of Diagnosis and Treatment. JAMA. 2013;310(16):1721-1730. doi:10.1001/jama.2013.280318. http://jama.jamanetwork.com/article.aspx?articleid=1758756
  15. ↑ Sambursky, Robert, et al. The RPS adeno detector for diagnosing adenoviral conjunctivitis. Ophthalmology 113.10 (2006): 1758-1764.
  16. ↑ Sambursky, Robert, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA ophthalmology 131.1 (2013): 24-28.
  17. ↑ Kam, KY Ronald, et al. "Sensitivity and specificity of the AdenoPlus point-of-care system in detecting adenovirus in conjunctivitis patients at an ophthalmic emergency department: a diagnostic accuracy study." British Journal of Ophthalmology (2015): bjophthalmol-2014.
  18. ↑ Udeh, Belinda L., John E. Schneider, and Robert L. Ohsfeldt. "Cost effectiveness of a point-of-care test for adenoviral conjunctivitis." The American journal of the medical sciences 336.3 (2008): 254-264.
  19. ↑ Tabbara KF, et al. Ganciclovir effects in adenoviral keratoconjunctivitis. Poster B253. Presented at ARVO; Fort Lauderdale, Florida. 2001.
  20. ↑ Isenberg SJ, Apt L, Valenton M, et al. A controlled trial of povidone-iodine to treat infectious conjunctivitis in children. Am J Ophthalmol 2002;134:681-8 

  21. ↑ Yoon J, Jekle A, Najafi R, et al. Virucidal mechanism of action of NVC-422, a novel antimicrobial drug for the treatment of adenoviral conjunctivitis. Antiviral Res. 2011;92(3):470-478.
  22. ↑ Romanowski EG, Pless P, Yates KA, et al. Topical cyclosporine A inhibits subepithelial immune infiltrates but also promotes viral shedding in experimental adenovirus models. Cornea 2005;24:86-91
  23. ↑ Epidemic Keratoconjunctivitis. New South Wales Health. July 1, 2012. http://www.health.nsw.gov.au/Infectious/factsheets/Pages/Epidemic-Keratoconjunctivitis.aspx
  24. ↑ Imparato, R., Rosa, N., & de Bernardo, M. (2022). Antiviral Drugs in Adenovirus-Induced Keratoconjunctivitis. Microorganisms 2022, Vol. 10, Page 2014, 10(10), 2014. https://doi.org/10.3390/MICROORGANISMS10102014
  25. ↑ Liu SH, Hawkins BS, Ren M, et al. Topical Pharmacologic Interventions Versus Active Control, Placebo, or No Treatment for Epidemic Keratoconjunctivitis: Findings From a Cochrane Systematic Review. Am J Ophthalmol. 2022;240:265-275.
  26. ↑ Grzybowski A, et al. The use of povidone-iodine in ophthalmology - Review. Curr Opin Ophthalmol 2018 29 (1), 19-32 PMID 28984794
  27. ↑ Pepose JS, et al. Randomized, Controlled, Phase 2 Trial of Povidone-Iodine/Dexamethasone Ophthalmic Suspension for Treatment of Adenoviral Conjunctivitis Am J Ophthalmol 194, 7-15 2018 - Clinical Trial. PMID 29787732
  28. ↑ Chigbu, D. I., & Labib, B. A. (2018). Pathogenesis and management of adenoviral keratoconjunctivitis. Infection and Drug Resistance, 11, 981. https://doi.org/10.2147/IDR.S162669
  29. ↑ Kuo, I. C. (2019). Adenoviral Keratoconjunctivitis: Diagnosis, Management, and Prevention. Current Ophthalmology Reports, 7(2), 118–127. https://doi.org/10.1007/S40135-019-00207-Y/TABLES/1
  30. ↑ Meyer-Rüsenberg B, Loderstädt U, Richard G, Kaulfers PM, Gesser C. Epidemic keratoconjunctivitis: the current situation and recommendations for prevention and treatment. Dtsch Arztebl Int. 2011 Jul;108(27):475-80. doi: 10.3238/arztebl.2011.0475. Epub 2011 Jul 8. PMID: 21814523; PMCID: PMC3147286.
  31. ↑ Pihos AM. Epidemic keratoconjunctivitis: A review of current concepts in management. J Optom. 2013 Apr;6(2):69–74. doi: 10.1016/j.optom.2012.08.003. Epub 2012 Sep 1. PMCID: PMC3880539.
  32. ↑ Hashizume, M., Aoki, K., Ohno, S., Kitaichi, N., Yawata, N., Gonzalez, G., Nonaka, H., Sato, S., & Takaoka, A. (2019). Disinfectant potential in inactivation of epidemic keratoconjunctivitis-related adenoviruses by potassium peroxymonosulfate. Https://Doi.Org/10.1177/1120672119891408, 31(2), 379–384. https://doi.org/10.1177/1120672119891408
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