Epidemic keratoconjunctivitis (EKC) is a highly contagious acute conjunctivitis caused by adenovirus (AdV) infection. It is commonly referred to as “pink eye.” In Japan, it is the most prevalent epidemic disease in the ophthalmology field and is also a disease of public health importance in various Asian countries1).
EKC was first reported by Fuchs in 1889 as “superficial punctate keratitis,” and the term “epidemic keratoconjunctivitis” came into use in 1938. Subsequently, in 1955, Jawetz et al. established the direct etiological relationship with adenovirus1). In Japan, it was decided at a symposium of the Japanese Ophthalmological Society in 1959 to adopt “epidemic keratoconjunctivitis” (ryukosei kakuketsumakuen) as the Japanese name for this condition1).
Initially, typical EKC was a clinical diagnosis made when the triad of acute follicular conjunctivitis, corneal subepithelial opacities, and preauricular lymphadenopathy was present, and the cause was limited to AdV serotype 8. Subsequently, EKC caused by species D AdV serotypes 19 and 37 was also reported, and in recent years, outbreaks caused by new serotypes AdV53, 54, 56, 64, and 85 have been confirmed1).
In Japan, the Infectious Disease Surveillance has been ongoing since 1981. EKC is classified as a Category V infectious disease under the Infectious Diseases Control Law, and is reported from approximately 690 ophthalmology sentinel medical institutions nationwide1). Pharyngoconjunctival fever (PCF), also an adenoviral conjunctivitis, is reported from approximately 3,100 pediatric sentinel sites nationwide1).
According to the 2025 Clinical Practice Guidelines for Viral Conjunctivitis, it is estimated that approximately 700,000 to 1.3 million people contract EKC annually in Japan1).
Due to general infection prevention measures such as hand hygiene and mask wearing associated with COVID-19 countermeasures, both EKC and PCF markedly decreased during the pandemic period from 2020 to 20221,2). In 2023, PCF recurred at approximately twice the normal scale, and EKC is also approaching pre-pandemic levels1).
A similar trend was confirmed in the Korean ophthalmology sentinel surveillance system (2013–2022), with the annual incidence of EKC peaking at 22.5 per 1,000 people in 2018 and decreasing to 4.0 in 20222). The weekly maximum incidence rate decreased from 49.7 in 2016 to 9.0 in 2022, but the seasonal pattern concentrated in August–September was maintained2).
Globally, AdV8 has been the main causative serotype of EKC, but its detection has decreased since 1997, and AdV54 became the most frequently detected serotype from 2015 to 20191,18). AdV54 is a serotype with few international reports, while AdV53, 56, and 64 continue to be detected, and a new serotype, AdV85, has also been discovered and reported since 20151,17).
By age group, children aged 0–6 years have the highest infection rate, followed by ages 7–19, then ages 20 and older. Under the School Health and Safety Act Enforcement Regulations, it is classified as a Type 3 “Other Infectious Disease”, and students must stay home until a physician determines there is no risk of infection. Although no specific duration is stipulated, approximately 2 weeks is generally considered the guideline.
QHow contagious is “pink eye”?
A
It is highly contagious. Adenovirus can remain infectious for more than 10 days even in dry environments, causing nosocomial infections through healthcare workers’ hands, tonometer tips, and contaminated eye drop bottles. Intrafamilial infection is also common, and the 2025 Guidelines for the Management of Viral Conjunctivitis lists a history of intrafamilial infection as one of the auxiliary findings for clinical diagnostic criteria. Because the disease remains contagious for approximately 2 weeks after onset — until clinical findings resolve — patients should refrain from attending school or work until eye discharge and redness have resolved.
Corneal subepithelial infiltrates in epidemic keratoconjunctivitis (before and after treatment comparison)
Karaca EE, Çelik G, İdacı Koç Ş, Evren Kemer Ö. Evaluating the Efficacy of Topical Tacrolimus Alone and in Combination with Prednisolone for Treating Subepithelial Infiltrates in Epidemic Keratoconjunctivitis. Biomedicines. 2025;13(4):895. doi:10.3390/biomedicines13040895. PMCID: PMC12024548. License: CC BY 4.0.
Before treatment (left), multiple subepithelial infiltrates (SEIs) are scattered in the cornea; after 3 months of tacrolimus monotherapy eye drops (right), they have resolved. This corresponds to the course of corneal lesions in adenoviral keratoconjunctivitis discussed in the “2. Main Symptoms and Clinical Findings” section.
The incubation period is 7–14 days1). It typically begins in one eye and spreads to the other eye after a few days, becoming bilateral. Simultaneous bilateral onset occurs in about 10–20% of cases1).
Serofibrinous discharge (watery, appearing at first glance like “conjunctivitis with little discharge”)
Foreign body sensation
Photophobia and vision loss after the appearance of MSI
A characteristic feature is that eyelid swelling is more severe than in bacterial conjunctivitis. The discharge is serofibrinous, which helps distinguish it from bacterial conjunctivitis that presents with mucopurulent discharge1). Clinical symptoms peak around 5–8 days after onset and then subside.
Clinical Findings (Findings Confirmed by Physician Examination)
EKC is characterized by the following three major features1).
Follicular conjunctivitis: Follicles form from the lower palpebral conjunctiva to the fornix
Multiple subepithelial infiltrates (MSI) appearing around one week after onset
Swelling and tenderness of the preauricular lymph node
However, these three signs do not always appear simultaneously. In many cases, AdV conjunctivitis is suspected based on relatively severe follicular conjunctivitis, and typical findings accumulate during the course, leading to a final diagnosis of EKC1).
Marked hyperemia is observed in the palpebral and bulbar conjunctiva. Follicles on the palpebral conjunctiva are the most important finding for diagnosing follicular conjunctivitis, but when conjunctival hyperemia and edema are severe, follicular findings may be difficult to detect1). In the early stage, petechiae (small ecchymotic spots) may be seen on the upper palpebral conjunctiva, which has high diagnostic value1).
Pseudomembranous Conjunctivitis and Severe Disease
In severe cases, a pseudomembrane may form on the palpebral conjunctiva several days after onset, a condition called pseudomembranous conjunctivitis1). Once a pseudomembrane forms, the discharge takes on a mucopurulent appearance. Histologically, it consists of inflammatory products including fibrin, neutrophils, macrophages, lymphocytes, and dendritic cells1).
Conjunctivitis usually resolves in 2–3 weeks, but in cases with pseudomembrane formation, eyelid swelling, conjunctival injection, and edema may persist. After inflammation subsides, superficial scarring of the conjunctiva may remain, and in severe cases, a conjunctival prolapse may form1).
Multiple Subepithelial Infiltrates (MSI) and Staging Classification
After 4–5 days from onset, punctate epithelial keratitis that stains with fluorescein develops. It gradually progresses to punctate to small round subepithelial infiltrates, accompanied by mild intraepithelial infiltration around the lesions1). These are MSI. Without appropriate steroid treatment, MSI persists for several years or longer as small round to patchy subepithelial opacities, causing visual impairment (irregular astigmatism and photophobia)1).
The 2025 edition of the Clinical Practice Guidelines for Viral Conjunctivitis presents the following staging classification for the progression of MSI1).
MSI Stage 0–II (Acute Phase)
Stage 0 (Day 2 after onset): Epithelial microvesicles, 25–30 μm in size. Barely visible under slit-lamp microscopy.
Stage I (around days 4–5): Superficial punctate keratitis (epithelial surface). Punctate elevated lesions observed as small dark spots within the green tear film under fluorescein staining.
Stage II (days 6–9): Punctate keratitis (deep epithelial layer). Stage I lesions coalesce and changes extend to the deep epithelial layer. Stains with fluorescein resembling larger punctate superficial keratopathy.
MSI Stages III–V (Subacute to Chronic)
Stage III (day 7–week 2): Subepithelial infiltration. In addition to stage II lesions, mild subepithelial opacity appears.
Stage IV (3 weeks–several months): Small round subepithelial opacities. Not stained by fluorescein.
Stage V (several weeks–several months): Granular, small round subepithelial opacities. Not stained by fluorescein. May cause visual impairment.
Findings from stage III and later correspond to so-called MSI1).
Clinical presentation varies depending on the causative AdV type1).
AdV8 (classic type): Has been considered the main type of EKC worldwide, but detection has decreased since 1997. Pseudomembrane formation is common.
AdV54: Initial conjunctivitis is moderate, pseudomembrane complication rate is low, but the MSI complication rate is 70–80%, and many cases leave subepithelial opacities after healing. Preauricular lymphadenopathy occurs in approximately 50%1,18)
AdV85: Severe conjunctivitis with eyelid swelling, conjunctival petechiae, and preauricular lymphadenopathy occurring at a high frequency of approximately 70%. Corneal complications such as punctate epithelial keratitis and MSI are also common1,17)
AdV4 (mild EKC): Presents with mild conjunctivitis, and the frequency of keratitis complications is low at approximately 30%1)
Infant/young child type: Because the adenoid tissue is underdeveloped, follicle formation is poor; severe hyperemia, edema, and pseudomembrane predominate. Preauricular lymphadenopathy is also less likely to occur. More than half of cases have systemic symptoms such as fever, pharyngitis, bronchitis, otitis media, diarrhea, and vomiting. Severe epithelial keratitis and corneal erosion may occur, and bacterial superinfection can lead to corneal ulcers1)
Chronic papillary conjunctivitis: A type in which foreign body sensation and discharge persist for more than one month after the onset of AdV conjunctivitis. Mild hyperemia and papillary hyperplasia are observed on the palpebral conjunctiva, sometimes presenting a velvety appearance. Caused by AdV3, 5, 7, 8, 19, and others1)
AdV urethritis-associated type: AdV types 37, 53, and 56 can also cause urethritis in men. Reports indicate that approximately half of patients with AdV urethritis develop conjunctivitis around the same time, suggesting a transmission route via sexually transmitted infections1)
QWhen do corneal subepithelial infiltrates (MSI) typically appear?
A
Superficial punctate epithelial keratitis appears on the corneal surface 4–5 days after onset, progressing to deep punctate keratitis stainable with fluorescein at 6–9 days, with subepithelial infiltrates forming after 7 days to the second week. After 3 weeks, these become small round to granular subepithelial opacities. MSI is thought to be a delayed-type hypersensitivity reaction to adenovirus antigens and responds well to steroid eye drops, but may recur if discontinued early, requiring gradual tapering or stepwise switching to a weaker steroid. Decreased visual acuity and photophobia may persist for months to years.
Adenoviridae are non-enveloped, icosahedral (70–90 nm in diameter) double-stranded DNA viruses. They are classified into seven species, A through G. Historically, they were classified into serotypes based on neutralization reactions, but types from AdV52 onward have been numbered as genotypes based on genomic sequences1). Currently, typing is performed by sequencing the variable regions of the AdV genome: penton, hexon, and fiber1).
In 2012, Zhou et al. revealed that the standard strain of AdV19 does not cause EKC, but rather a variant strain of AdV19 is responsible for EKC12). This variant is a chimera with the penton region from AdV22 and the fiber region from AdV37, and was reclassified as AdV641,12).
Since 2015, an AdV newly identified from EKC patients in Japan has been reported as AdV8517). AdV85 is classified as a recombinant novel human mastadenovirus D, and has also been detected in EKC cases outside Japan1,17).
The most important route of transmission is contact transmission via hands1). Adenoviruses are highly resilient and can spread through various routes.
Healthcare workers’ hands: A major cause of nosocomial infection through examinations and procedures
Tonometer tips: High infection risk due to direct contact with the eyeball
Contaminated eye drop bottles: Since eye drops for procedures are used on multiple patients, improper use can become a source of infection
Environmental surfaces: Doorknobs, counters, chairs, etc. Adenovirus suspensions can remain infectious for more than 10 days even under natural drying conditions
Household transmission is also common, and the 2025 Japanese Guideline for the Diagnosis and Treatment of Viral Conjunctivitis includes a history of household transmission as a supportive finding for clinical diagnostic criteria1).
AdV conjunctivitis has strong transmissibility and can cause nosocomial outbreaks, necessitating prompt and accurate diagnosis1). It is important for reception staff, orthoptists, and nurses to ask patients about conjunctival hyperemia and discomfort, and to promptly use rapid diagnostic kits for patients suspected of infection1). When two or more inpatients develop conjunctivitis on the same ward, it should be considered a nosocomial outbreak, and measures such as restricting new admissions and closing the ward for at least one week should be taken1).
The 2025 Japanese Guideline for the Diagnosis and Treatment of Viral Conjunctivitis establishes the following diagnostic criteria for AdV conjunctivitis1).
Category
Item
A. Microbiological Testing
A-1. AdV antigen positive by rapid AdV antigen detection kit A-2. AdV gene detection by PCR
Presence of fever, sore throat, or bronchitis (any one)
E. Household Transmission
Present
Definite diagnosis: meets any one criterion in A and shows B-1
Clinical diagnosis: meets both B-1 and B-2, plus at least one positive finding among B-3, B-4, C, D, and E
For facilities where microbiological testing is not available or for cases where EKC is strongly suspected despite negative microbiological test results, a clinical diagnostic criteria combining conjunctival petechiae, conjunctival pseudomembrane, and household transmission—clinical findings that strongly correlate with virological testing—has been established as a supplementary approach1).
The rapid AdV antigen detection kit using immunochromatography (IC) is called an antigen detection kit and is the only test method capable of rapidly and simply identifying AdV antigens1). It is an essential test indispensable for diagnosing AdV conjunctivitis in clinical settings and should be kept readily available in ophthalmology outpatient clinics.
Test method
Sensitivity
Specificity
Reading time
Features
Immunochromatography (conjunctival swab)
Approximately 70–80%
Almost 100%
5–15 minutes
Positive confirms diagnosis. Requires conjunctival scraping with a swab.
Immunochromatography (tear fluid collection)
Approximately 70–80%
Almost 100%
5–15 minutes
Filter paper 5×5 mm applied to the lower eyelid, minimally invasive, useful in children3)
For conjunctival scraping specimens, topical anesthetic eye drops are administered, followed by firm scraping of the palpebral conjunctiva several times with a swab. Insufficient specimen volume can reduce detection sensitivity, so thorough scraping is necessary1). The collected swab is stirred in an extraction tube and pressed firmly against the inner wall to release the virus into the extraction solution1).
Tear collection is a method introduced after 2018, in which the attached filter paper is placed against the lower eyelid to collect tears containing conjunctival exudate1,3). Since it does not require scraping the conjunctiva, it is minimally invasive and useful for pediatric cases. As of April 2024, three antigen detection kits support tear collection: QuickChaser® Adeno Eye, QuickChaser® Auto Adeno Eye, and Fuji Dri-Chem IMMUNO AG Cartridge Adeno OPH1).
The specificity is nearly 100%, so a positive result confirms AdV infection. However, the detection sensitivity is approximately 70–80%, so a negative result cannot completely rule out AdV infection1).
Even when samples are collected by an ophthalmologist experienced in managing infectious conjunctivitis, AdV-DNA was detected by PCR in only about half of the cases1). Moreover, since the detection sensitivity of immunochromatography is approximately 80%, not all PCR-positive samples test positive by IC method. In clinical practice, antigen detection kits are positive in only about 10–20% of cases, with most results being negative1). However, a positive result confirms AdV infection, so performing the test has significant clinical value.
PCR is a genetic testing method that amplifies target DNA regions millions of times using sequence-specific primers and DNA polymerase, enabling identification of AdV with higher sensitivity than antigen detection kits1). It is not covered by insurance and must be outsourced to testing laboratories or referred to specialized institutions such as local public health institutes.
Serotypes can be identified from the base sequence of the hexon region, and the type is determined by the sequences of the penton, hexon, and fiber regions1). In clinical practice, infection control strategies do not differ significantly based on the serotype; however, since the severity of conjunctivitis and the frequency of corneal complications vary by serotype, knowing the serotype is useful for guiding treatment and follow-up1).
Giemsa staining of conjunctival smear specimens from patients with clinically suspected AdV conjunctivitis shows predominance of mononuclear cells (lymphocytes), which suggests viral infection and serves as a supportive diagnostic method indicating viral conjunctivitis including AdV1).
Differential diagnosis from infectious diseases presenting with acute follicular conjunctivitis is necessary. The Viral Conjunctivitis Clinical Practice Guidelines 2025 edition includes a flowchart for the differential diagnosis of conjunctivitis, guiding diagnosis based on the presence or absence of follicles and papillae on the palpebral conjunctiva, the nature of eye discharge, accompanying corneal and eyelid findings, and the presence or absence of systemic symptoms1).
Distinguishing from HSV conjunctivitis is particularly difficult. HSV conjunctivitis is often unilateral and resolves in a relatively short period of about 7 days, but it rarely presents typical findings such as dendritic keratitis. A certain number of cases negative on the AdV rapid antigen detection kit are thought to include HSV conjunctivitis1). Since eyelid and skin lesions may coexist, attention should also be paid to skin findings.
EKC is classified as a Category V infectious disease under the Infectious Diseases Control Law, and designated ophthalmic sentinel medical institutions report cases on a weekly basis. Under the School Health and Safety Act Enforcement Regulations, it is classified as Type 3 (Other Infectious Diseases), and students must refrain from attending school until a physician determines there is no risk of infection. Although there are no clear provisions on the duration, approximately 2 weeks is generally considered appropriate based on the clinical course.
QIf the rapid test is negative, can it be said that it is not epidemic keratoconjunctivitis?
A
It cannot be said that a negative result completely rules out AdV infection. According to the 2025 Guidelines for the Management of Viral Conjunctivitis, the sensitivity of rapid antigen detection kits is approximately 70–80%. Even when specimens are collected by ophthalmologists experienced in treating infectious conjunctivitis, AdV-DNA is detectable by PCR in only about half of cases, and not all PCR-positive specimens yield positive immunochromatography (IC) results. When EKC is strongly suspected based on clinical findings and course despite negative results, diagnosis is made by combining clinical criteria such as conjunctival petechiae, pseudomembrane, and household transmission.
Currently, there is no specific antiviral agent against adenovirus, and a definitive cure for EKC is not available1). Treatment targets are anti-inflammation in the acute phase and management of MSI. The 2025 Guidelines for the Management of Viral Conjunctivitis provides a “weak recommendation” for the use of steroid eye drops, iodine preparations, and immunosuppressive eye drops in CQ1–CQ31).
Overview of the Treatment Flow (2025 Guidelines, Figure 32)
Antibacterial eye drops are not effective against viral conjunctivitis and should be used only in the early stage when severe corneal epithelial damage is present1). In severe EKC such as serotype D, bacterial superinfection is observed at a certain frequency, so antibacterial eye drops may be necessary.
Given the rapid increase in quinolone-resistant Corynebacterium in Japan, cefmenoxime eye drops are the preferred first-line treatment1). Aminoglycoside eye drops tend to cause corneal epithelial damage and should be avoided1). Any antibacterial agent should be used for a short duration with appropriate use in mind.
Steroid eye drops are not necessarily required for mild cases, but they are useful when pseudomembrane formation, filamentous keratitis, or corneal epithelial defects occur with severe inflammation, or for early symptom relief1).
However, in addition to the side effects of glaucoma and cataracts caused by topical steroid administration, delayed viral clearance has been reported1). Therefore, during the acute phase when viral replication is active, topical steroids should preferably be used in combination with iodine preparations1).
Topical steroids for MSI are effective against cellular infiltration caused by a delayed-type hypersensitivity reaction to AdV antigens. As a representative prescription example, using a strong steroid such as 0.1% betamethasone sodium phosphate (Sanbetazon®) can alleviate or resolve even fairly severe opacities. If eye drops are discontinued too early, opacities may worsen again, so strategies such as gradually reducing the instillation frequency or sequentially switching to a weaker steroid are necessary. Intraocular pressure monitoring is essential with long-term use.
In severe inflammatory cases where eye drop instillation is difficult in children aged 3 years or younger, oral steroids may also be considered1,9).
Iodine preparations exert a bactericidal effect by allowing free iodine to oxidatively denature surface proteins of microorganisms1). Povidone-iodine (PVP-I) has been shown in in vitro studies to be effective against many AdV types within 1 to 5 minutes, with efficacy confirmed against AdV-1, -2, -3, -4, -5, -6, -7, -8, -11, -37, -53, -54, -56, -64, -81, and -851).
However, PVP-I is generally not recommended for use on the ocular mucosa, and in Japan, a diluted solution of iodine-polyvinyl alcohol (PVA-I) with a similar inactivation effect is used instead1).
PA iodine ophthalmic and eye wash solution: Used after diluting 4- to 8-fold with physiological saline. Its safety and efficacy on the ocular surface are approved for indications of corneal herpes and eye wash sterilization.
Saniodo® ophthalmic solution: An OTC drug launched in 2022. Not covered by insurance, fully borne by the patient, limited to use within 3 days after opening, with irritation.
In a study of patients at 1 week after onset of EKC, combination therapy with 6-fold diluted PVA-I and 0.1% fluorometholone ophthalmic solution (Flumetholon® 0.1%) was shown to be more effective in suppressing the development of MSI compared to combination therapy with levofloxacin hydrate and 0.1% fluorometholone ophthalmic solution6). There are also reports that a single administration at the initial visit was effective in suppressing early symptoms5).
Cyclosporine and tacrolimus are used as non-steroidal immunosuppressive agents. Both inhibit calcineurin and suppress the production of IL-2, which is necessary for T-cell proliferation1).
Cyclosporine ophthalmic solution 0.05% / 0.5% / 1% / 2%: Reports indicate efficacy in preventing and improving the acute onset of MSI and in treating chronic persistence1,7). Compared to steroids, it has the advantage of fewer relapses after discontinuation1). In animal models, it is known to suppress MSI while increasing viral titers1)
Tacrolimus ophthalmic suspension 0.03%: For cases of persistent MSI in the chronic phase, it reduces the size and number of MSI and leads to improved visual prognosis1,8). It is also effective against steroid-resistant MSI and may allow steroid tapering. Adverse effects occur in 17.8% of cases (primarily burning sensation, redness, and foreign body sensation), and the fact that it does not cause elevated intraocular pressure is a major advantage1)
These should be considered for use in cases of steroid-resistant MSI or MSI that recurs during steroid tapering, as well as in cases where intraocular pressure elevation has occurred from steroid eye drops1).
Histological studies have shown that pseudomembranes are inflammatory products containing fibrin, neutrophils, macrophages, lymphocytes, and dendritic cells. They must be removed early to prevent adhesion and scarring due to conjunctival fibrosis and keratinization1). When performing removal, take sufficient care regarding infection control and avoid forcibly peeling the membrane.
Instruct patients to discontinue contact lens use to prevent worsening of keratoconjunctival damage due to AdV conjunctivitis and transmission of the virus. Considering the duration of viral shedding, discontinuation should be maintained for approximately 2 weeks after onset, i.e., until clinical findings have resolved1). Thereafter, the decision is made based on the presence or absence of persistent MSI.
Hospital Infection Control (2025 Guidelines, Chapter VI)
Since transmission via the hands is the primary route of infection, hand washing and wearing gloves are important1).
Healthcare workers’ hands: After physically removing viruses under running water, apply disinfectant ethanol or alcohol-based hand rub to the hands and let dry. Use disposable gloves for patients with suspected viral infection.
Ophthalmic examination instruments (slit lamp microscope, indirect ophthalmoscope, non-contact lens, trial frame, trial lens): Wipe with 80% alcohol after use.
Instruments that come into direct contact with the eyeball (contact lens, eyelid speculum, tonometer tip): After thorough rinsing, immerse in 80% alcohol for 5 minutes.
Strongest disinfectant: 0.1% sodium hypochlorite (however, it may cause skin damage and metal corrosion, and should not be used on hands or medical instruments).
Multipurpose disinfectant (MPD): Rubista® (Virkon®) and others can be used as an alternative to 80% alcohol wiping, and are highly effective in inactivating various viruses and bacteria1).
If two or more patients in a ward are affected, it is determined to be a nosocomial infection, and measures such as restricting new admissions and closing the ward for at least one week should be taken1).
The 2025 Clinical Practice Guidelines for Viral Conjunctivitis (CQ1) give a “weak recommendation” for the use of steroid eye drops, recommending them not for all cases but for patients with severe inflammation, pseudomembrane formation, filamentary keratitis, corneal epithelial defects, or the appearance of multiple subepithelial infiltrates (MSI). Because viral clearance may be delayed with use in the acute phase, concomitant use with an iodine preparation is desirable. Stronger steroids such as 0.1% betamethasone are effective against MSI, but early discontinuation can lead to recurrence, so gradual tapering or a stepwise change to a weaker steroid is necessary, and intraocular pressure monitoring is essential with long-term use. In steroid-resistant cases or cases with elevated intraocular pressure, cyclosporine or tacrolimus eye drops (CQ3, not covered by insurance) may be considered.
6. Pathophysiology and Detailed Mechanism of Onset
Adenoviridae is a non-enveloped icosahedral (diameter 70–90 nm) double-stranded DNA virus with a molecular weight of 20–25×10⁶. Infection begins when the adenovirus fiber, which has affinity for receptors on conjunctival epithelial cells, attaches to these receptors. Receptors differ by serotype, and the difference in clinical presentation between the EKC type (with strong conjunctivitis symptoms) and the PCF type (with prominent systemic symptoms) is determined by the relationship between the receptor and the viral fiber.
Changes in Serotype Classification and Prevalent Types in Japan
In the past, AdV types were determined as serotypes by neutralization reactions using cultured viruses1). However, because the types of neutralizing antisera available were limited, it was difficult to determine all types.
Subsequently, advances in genetic testing enabled the identification of serotypes from the nucleotide sequence of the hexon region, the gene involved in neutralization. Furthermore, the structure of the AdV genome was elucidated, revealing the existence of recombinant viruses between types1). AdV1 to 51 are serotypes determined by neutralization, while AdV52 and later are numbered as genotypes based on nucleotide sequences1). Currently, types are determined by the sequences of the penton, hexon, and fiber regions.
In 2012, Zhou et al. reported that the standard strain of AdV19 does not cause EKC, and that EKC is caused by a chimeric AdV19 mutant strain with penton region type 22 and fiber region type 37, which was redefined as AdV6412).
A study of clinical findings of AdV conjunctivitis in southern Kyushu, Japan, from 2011 to 2014 reported that AdV8, 37, and 54 caused corneal complications significantly more frequently and had longer infection periods than AdV53 and 5616). This suggests that accurately identifying the type is clinically and epidemiologically meaningful.
Kaneko et al. conducted a molecular epidemiological analysis of AdV54 and demonstrated that AdV54 is evolutionarily closely related to AdV8, and that it became prevalent in Japan after 1997, replacing the declining detection of AdV818). AdV54 is rarely reported outside Japan and is a strain unique to Japan1,18).
Pathogenesis of MSI (delayed-type hypersensitivity)
MSI is thought to be a cellular infiltration caused by a delayed-type hypersensitivity reaction to AdV antigens in the superficial layer of the corneal stroma, rather than being due to viral proliferation1). This concept has been established since the classical study by Seiji Sugiura in 1959. However, the possibility of latent adenovirus infection has not been completely ruled out.
Approximately 10 days after onset, type-specific neutralizing antibody titers rise, coinciding with the resolution of clinical symptoms. Neutralizing antibodies are type-specific; for example, infection with AdV8 does not confer neutralizing antibodies against AdV3, so clinical reinfection is possible. On the other hand, cross-reactivity exists within the same species, so patients with a history of AdV37 infection are less susceptible to AdV8 as well.
However, it has been suggested that neutralizing antibodies may not be maintained throughout life, and the possibility of reinfection with the same type in adulthood after childhood infection cannot be ruled out.
Arıcı et al. (2022) examined 33 patients (66 eyes) with SEI (subepithelial corneal infiltrates) and reported that the central corneal thickness (CCT) of the affected eyes was 526.1±28.1 μm, significantly thinner than the control group (557.0±38.1 μm) (p=0.003)13). The best-corrected visual acuity (logMAR) in affected eyes was 0.20±0.29, significantly worse than the control group (−0.01±0.05), and a negative correlation was found between SEI density and IOPg/IOPcc (r=−0.479, p=0.006)13). It should be noted that the reduced central corneal thickness in SEI-affected eyes may lead to underestimation of intraocular pressure measurements during steroid therapy.
According to the 2025 Guidelines for the Management of Viral Conjunctivitis, the number of reported EKC cases per sentinel site during the pandemic period decreased to approximately one-third of the pre-pandemic level due to COVID-19 countermeasures, but recovered to nearly normal levels by 20231). PCF resurged to approximately twice the normal level in 2023, and attention should be paid to the possibility that EKC may also experience outbreaks exceeding pre-pandemic levels in the future1,2).
Monitoring trends in age groups that have shown high incidence rates in the past, particularly in daycare centers, kindergartens, and schools, is important2).
The development of specific antiviral drugs is ongoing. Ganciclovir gel and povidone-iodine have been reported to shorten the duration of acute EKC and reduce the risk of subepithelial infiltrates, but the optimal concentration and dosage have not been established5,10,11). A Cochrane review (Liu 2022) concluded that current evidence for topical pharmacological interventions in EKC is limited, and no agent has demonstrated clinically robust benefit compared with control groups15).
Cyclosporine and tacrolimus eye drops are considered promising for the treatment of MSI, and are weakly recommended as CQ3 in the 2025 Guidelines for the Management of Viral Conjunctivitis, particularly in steroid-resistant cases or those that flare upon steroid tapering1,7,8).
Among antiviral agents under investigation, cidofovir eye drops inhibit viral DNA polymerase intracellularly, but randomized controlled trials have not shown significant improvement in clinical course, and adverse effects such as lacrimal duct stenosis and conjunctival inflammation have been reported. Trifluridine eye drops have demonstrated in vitro reduction of viral load against AdV types 8, 19, and 13, but no shortening of treatment duration has been observed in human clinical trials. Oral famciclovir is a candidate for Phase II trials as a potent inhibitor of AdV.
Rapid diagnostic kits with low invasiveness and high sensitivity, such as immunochromatographic assays using tear fluid collection and silver amplification automated immunochromatography, have been introduced1,3,4). These are expected to reduce the burden particularly in pediatric cases and improve detection rates in cases where conventional sensitivity was low, such as in the second affected eye.
Acute dacryoadenitis secondary to EKC is an extremely rare complication in adults. Takahashi et al. (2022) reported adult acute dacryoadenitis associated with EKC, and serum testing confirmed positivity for adenovirus type 3 IgM14). The proposed mechanisms include direct invasion of the lacrimal gland or secondary spread from keratoconjunctival lesions, with only 4 to 5 adult cases reported to date14).
Since 2015, a novel virus, AdV85, has been identified in Japan, with reports including 5 cases in Fukushima Prefecture17). AdV85 is a recombinant human mastadenovirus D that presents with the typical clinical picture of EKC (severe conjunctivitis, petechial hemorrhage, preauricular lymphadenopathy, and MSI)1,17). Close attention to future epidemiological trends is necessary.
Seo Y, Kim I, Cha J, Kang S, Gwack J. Ophthalmologic Sentinel Surveillance Results, 2013-2022. Public Health Wkly Rep. 2023;16(29):992-1004.
Migita H, Ueno T, Tsukahara-Kawamura T, Saeki Y, Hanaoka N, Fujimoto T, et al. Evaluation of adenovirus amplified detection of immunochromatographic test using tears including conjunctival exudate in patients with adenoviral keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol. 2019;257(4):815-820.
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