EPIDEMIC KERATOCONJUNCTIVITIS (EKC)
 – A SERIOUS DISEASE WITHOUT EFFECTIVE TREATMENT


Sometimes the term "pinkeye" is used which is a broader term for conjunctivitis caused by both bacteria and virus. Viral conjunctivitis is the more common cause and mostly caused by adenovirus. For bacterial conjunctivitis there are medicinal products available but there are no treatment for viral conjunctivitis. Epidemic keratoconjunctivitis (EKC) is a serious and contagious eye infection (conjunctiva and cornea) caused by adenoviruses type: 8, 19, 37. More than 50 serotypes of adenovirus have been isolated, and at least 19 documented serotypes cause eye infection. The most commonly associated serotypes that cause EKC include adenovirus 8, 19, and 37, and less frequently and in less severe forms, serotypes 2-5, 7, 9, 10, 11, 14, 16, 21, and 29. Because of low levels of natural immunity against adenovirus in the general population, e.g. adenovirus type 8 antibodies are found in <5% of the general population in the US, every individual is considered susceptible to infection.

EKC is characterized by conjunctivitis: acute onset of watering redness, foreign body sensation and severe pain. Symptoms include inflammation in the conjunctiva (conjunctivitis) and in the cornea (keratitis), severe pain, edema, diminished eyesight, tearing, sensitivity to light, feeling or sensation that a foreign body is present in the eye, and the development of pseudo membranes. During the acute phase, which persists for approximately two-three weeks, viruses are present and replicating. In the typical case, first one eye is infected, after which the infection spreads to the other eye within two to three days. Both eyes are affected in 60% of cases. The infection in the first eye is typically the more serious. In approximately 20 - 50% of patients, corneal opacities are developed that result in deteriorating vision that remains for weeks and months, and in rare cases even years. Since the disease is often epidemic in nature, it is called epidemic keratoconjunctivitis (EKC). Adenovirus conjunctivitis is a reportable infection in Germany and is classified as a Category IV infectious disease by Japan`s National Epidemiological Surveillance of Infectious Diseases (NESID) with mandated collection, analysis and publication of reports on occurrences.

Either as a result of their symptoms, or on the recommendation of a physician in light of the highly contagious nature of the disease, patients are unable to attend work or school. Approximately 45% of people in a patient’s close surroundings, e.g., family members, will become infected. The recurrence rate is 25% within five years after a first infection, and 50% after a second.

Adenovirus is spread mainly via respiratory droplets or by direct contact with the eyes by fingers or other objects. The incubation period is 2-14 days, and a person may remain infectious for 10-14 days after symptoms develop. EKC is transferred between individuals via physical contact, e.g. from eye to hand, from hand to a doorknob, from a doorknob to another person’s hand, and then to an uninfected eye. Viruses causing EKC can survive, e.g. on doorknobs, towels, etc., for months. Adequate infection control measures must be followed in order to prevent and reduce epidemic outbreaks.
 





Fig. 1. EKC infected eyes

Current clinical practice and recommendations
Currently, no clinically applicable specific antiviral therapy is available either to shorten the course of the infection, to improve the distressful clinical symptoms, to stop viral replication, or to prevent the development of corneal opacities.

Treatment of the acute phase of the infection with topical steroids has been widely used. However, recent findings conclude that steroids may prolong the persistence of infection in the cornea, and frequent use may lead to long-lasting dry eye symptoms. The use of steroids should therefore be avoided in both the acute and the chronic phases of the disease.

Large unmet medical need

Both bacterial and viral pathogens cause acute infectious diseases of the ocular surface with similar clinical presentations. A recent evidence-based review concluded that signs and symptoms of acute bacterial and acute viral conjunctivitis are essentially identical. External ocular infections caused by adenoviruses are among the most common eye infections seen worldwide and conjunctivitis represents a large proportion of visits to ophthalmologists. A recent report states that ocular adenoviral infection represents a significant public health problem in the US and worldwide. Although exact numbers are difficult to determine, estimates suggest the number of cases of ocular adenoviral infections may be as high as 15-20 million per year in the United States. Due to the nature of the disease, the exact number of incidences of EKC is not known and it is assumed that the majority of cases are not recorded. EKC is particularly problematic in Japan where there are more than one million cases of EKC each year, as reported in several sources.

•    Ophtalmology Management, Sept 2010
•    Aoki & Tagawa. Int. Ophthalmol. Clin. 2002. 42:49-54.
•    Kinchington et al. J. Antimicrobiol. Chemother. 2005. 55:424-429.
•    Uchio et al. Br. J. Ophthalmol. 2000. 84: 968-972.

IASR - Infectious Agents Surveillance in Japan, has reported Epidemic Keratoconjunctivitis per sentinel clinics weekly since 1998 and there is steady prevalence with a peak third quarter every year.



Fig 2. Epidemic Keratoconjunctivitis reported per sentinel weekly 200 – 2010, Japan
Source: IASR- Infectious Agents Surveillance Report, Japan

There is no accurate epidemiological data from other Asian countries, but outbreaks of EKC in several large Asian countries have been reported in different scientific journals. In the USA and Europe, there are several reports of sporadic outbreaks. Outbreaks seem to be more common in schools and military camps where people are typically in close proximity.

Socioeconomic aspects and transmission of the disease
EKC is a highly contagious disease which occurs worldwide sporadically and epidemically and is endemic in East Asia, including Japan, China, India, Korea and Taiwan. It has gained recognition as a major health problem in several of these countries. Work places and public institutions, such as schools and children’s day care centres, must be closed following the outbreak of an epidemic. Many work hours are lost every year as a consequence of the disease.

Although EKC normally clears up within 2-3 weeks, the costs to society both in terms of health care costs and the loss of production, because of its highly contagious nature, are very substantial. The disease also has long-term implications for eyesight and recurrence. EKC is a disease where there is a lack of effective treatment and a large unmet medical need. A pharmaceutical that could be used for the treatment of EKC and for the prevention of its spread, would be highly desirable for patients suffering from the disease, for those who come into contact with such patients, and for treating physicians.

Conjunctivitis

Acute conjunctivitis caused either by bacteria, a virus or by irritants is an extremely common condition; however, studies are rare. Several drug treatments for conjunctivitis are available depending on the cause of the infection and include anti-infectives, anti-inflammatory agents, and anti-bacterials. Epidemiology is a challenge in this area given that this is an acute disorder with a high incidence, but low prevalence, which can also resolve on its own and thus may not be recorded by a physician. O’Brien, et al. (2009), found that studies from the UK show approximately 20–70% of infectious conjunctivitis are of viral etiology. Adenovirus is the most frequent cause of viral conjunctivitis as it is highly contagious and often occurs in areas of overcrowding (Origlieri and Bielory, 2009). According to Datamonitor´s report, Stakeholder Opinions: Ophthalmology 2010, robust studies investigating the overall prevalence of viral and/or bacterial conjunctivitis are lacking.



Fig 4. Conjunctivitis disorders

The global market for ophthalmic pharmaceutical products for 2008 is estimated to exceed 80 billion SEK (12 BUSD). According to Datamonitor´s report, after glaucoma, conjunctivitis is the second biggest ophthalmic disease market with global sales of over 20 billion SEK (3 BUSD) in 2008. Conjunctivitis is a high-incidence ophthalmic disease; the condition is often seasonal, making it harder to record the prevalence of the different types of the disease. Outbreaks in hospitals and schools often occur, but the fact that symptoms can improve after a short time means the prevalence is often not tracked. Ophthalmologists interviewed by Datamonitor estimated that conjunctivitis can affect 30–40% of the population at some point during their life. The BRIC markets (Brazil, Russia, India, and China) and MENA (Middle Eastern, North African) markets experienced rapid year-on-year growth in all ophthalmology indications between 2004 and 2008, and in the conjunctivitis market in BRIC there was a CAGR of 21%.

Historically, China and India often have not been regarded as eligible pharmaceutical markets; however, their importance in the future cannot be neglected. China, for instance, will soon be the world’s fifth largest pharmaceutical market.  A large proportion of the populations will benefit from modern drugs in these markets. Today, approximately one-third of the Chinese population are covered by health insurance and in 2009, the Chinese health authorities set a goal that in 2011, 90% of the population should be covered by health insurance. There are opportunities for both patent protection and attractive pricing for selected drugs. With the assumption of even a very low penetration for the treatment of EKC in Asian markets, there is still a large sales potential in Top Asian markets. Datamonitor believes these emerging markets will offer important growth to both new and existing ophthalmic players.

The following quotes are taken from Datamonitor’s Report, 2010: Stakeholder Opinions: Ophthalmology – Conjunctivitis Section:

“I am not aware of any sources that have done prevalence studies of conjunctivitis. I do not know if there is reporting. When we have a certain number of episodes in the hospital we have an outbreak alert, but I do not know if any government has tracked that on a routine basis - I am not aware of any.”            US key opinion leader

“[Conjunctivitis prevalence]…I get the impression that there are definitely different numbers throughout the world, especially in that it is more infectious as we get elsewhere - but in the developed countries I would say that conjunctivitis prevalence is about 30–40% of the general population.”                 US key opinion leader

“Conjunctivitis is not really monitored in any way. It is a very low prevalence - high incidence type disease. It occurs then it goes away, so you do not have to do a cross sectional [study] and say what percentage of the population have it. A patient may have it [conjunctivitis] then symptoms disappear and you do not have it again - it is hard to measure that [in a study].                        US key opinion leader

Medical need for treatment for EKC
A global survey among ophthalmologists / key opinion leaders interviewed by D2L Pharma Research Solution, highlights that there is a large unmet medical need for treatment for EKC.


Fig 5. Need for treatment