Subepithelial infiltrates (SEIs) are small, hazy deposits that form just beneath the outermost layer of the cornea, most often as an immune reaction following a viral eye infection. They look like scattered white or gray dots under a slit lamp and can blur vision, increase light sensitivity, and persist for months or even years after the original infection has cleared. Although adenoviral keratoconjunctivitis is by far the most common trigger, SEIs can also arise from other viral infections, contact lens wear, and certain inflammatory conditions, and the treatment approach varies considerably depending on the underlying cause.
Why Adenovirus Is the Leading Cause
Epidemic keratoconjunctivitis (EKC), caused by adenoviruses, is the infection most strongly associated with subepithelial infiltrates. The classic culprit is adenovirus serotype 8, but research in London documented that serotypes 3, 4, 5, and 7 also produce these corneal deposits.1PubMed. Clinical and epidemiological features of adenovirus keratoconjunctivitis in London In practice, any adenovirus strain that infects the eye’s surface can set the stage. The infiltrates do not appear during the acute pink-eye phase. Instead, they show up about two to three weeks later, once the active infection is winding down, which is a clue that the immune system itself is driving the problem rather than the virus directly damaging tissue.
A 2025 study using electron microscopy provided the first direct look at what these deposits actually are at the cellular level. Researchers examined a corneal button removed from a patient with persistent SEIs and found giant stromal cells with myofibroblast-like features sitting right beneath Bowman’s layer. These abnormal cells showed signs of internal stress and self-digestion (autophagy), while the deeper corneal tissue contained perfectly normal cells.2Acta Histochemica. New insights into persistent corneal subepithelial infiltrates following epidemic keratoconjunctivitis: The first case report with ultrastructural and immunohistochemical investigations In other words, SEIs appear to be localized pockets of activated, stressed cells rather than lingering viral particles. That finding helps explain why antiviral medications alone don’t clear them.
The Immune Mechanism Behind the Deposits
Research into the molecular pathway has zeroed in on a protein called HMGB1. Normally, HMGB1 sits inside cell nuclei, but when corneal epithelial cells are infected by a highly virulent adenovirus strain like HAdV-D37, the protein migrates out of the nucleus, into the cytoplasm, and eventually gets released outside the cell entirely within about 24 hours.3PLOS Pathogens. Virus and cell specific HMGB1 secretion and subepithelial infiltrate formation in adenovirus keratitis Once free, HMGB1 activates receptors on corneal stromal cells (the fibroblasts that give the cornea its structure), switching on inflammatory signaling pathways. This cascade recruits immune cells and triggers the fibroblast-to-myofibroblast transformation described in the electron microscopy study. The result is the visible hazy spots beneath the corneal surface.
This mechanism matters for treatment because it means SEIs are not a simple infection. They are an immune aftereffect. Killing the virus doesn’t undo the inflammatory chain reaction that has already been set in motion, which is why patients often feel blindsided when their eye infection “comes back” weeks after the initial redness and discharge have resolved.
Other Causes Beyond Adenovirus
While adenoviral EKC dominates the conversation around SEIs, several other conditions produce similar subepithelial deposits.
Herpes simplex virus (HSV) keratitis is one. In a study using anterior segment imaging, about 60% of eyes with HSV keratitis had subepithelial infiltrates. In roughly half of those cases, the overlying epithelium was intact, while in others there were visible epithelial swelling and defects.4PubMed. Appearance of herpes simplex keratitis on anterior segment optical coherence tomography HSV-related infiltrates can look very similar to adenoviral ones on a slit lamp, which makes a careful clinical history important for distinguishing the two.
Contact lens wear is another route to corneal infiltrates. Continuous-wear silicone hydrogel lenses carry a notable risk: in one study, lenses recovered during an infiltrative event harbored substantial bacterial contamination about 65% of the time, compared to only about 12% during uncomplicated wear. Heavy bacterial bioburden on the lens was associated with roughly an eightfold increase in the risk of a corneal infiltrative event, and smoking roughly quadrupled the risk as well.5PubMed Central. Risk Factors for Corneal Infiltrative Events during Continuous Wear of Silicone Hydrogel Contact Lenses Contact lens-related infiltrates can be sterile (immune-mediated) or infectious, and the distinction guides whether you need antibiotics, anti-inflammatory drops, or both.6PubMed. The epidemiology of contact lens related infiltrates
Ocular rosacea, a chronic inflammatory condition of the eyelids and ocular surface, can also produce subepithelial infiltrates. Histological examination of rosacea-affected corneas has revealed large subepithelial collections of chronic inflammatory cells, and in some cases actual granuloma formation.7Ophthalmology. Ocular Rosacea: A Histologic and Immunopathologic Study In rosacea, the infiltrates tend to be part of a broader pattern of lid margin inflammation, meibomian gland dysfunction, and corneal vascularization rather than appearing in isolation.
What SEIs Feel Like and How They Affect Vision
The hallmark symptoms are blurred vision, glare, and photophobia (light sensitivity). Many people describe a foggy or hazy quality to their vision, as if looking through a dirty window. The severity depends on how many infiltrates are present, how large they are, and whether they sit near the center of the cornea (the visual axis) or off to the sides. Peripheral infiltrates can be entirely asymptomatic and discovered only during a routine exam.
A study comparing 66 eyes with post-EKC subepithelial infiltrates to 37 healthy control eyes found that the affected corneas were measurably thinner than normal ones. First-affected eyes averaged about 526 micrometers thick compared to 557 micrometers in healthy controls.8PubMed Central. Evaluation of the impact of subepithelial corneal infiltrates on corneal biomechanics after epidemic keratoconjunctivitis The thinning and altered biomechanics suggest that persistent SEIs change the structural properties of the cornea, not just its optical clarity. For patients considering refractive surgery like LASIK later on, this is worth discussing with an ophthalmologist.
Telling Sterile Infiltrates From Infectious Ones
One of the trickiest clinical decisions with corneal infiltrates is figuring out whether they are sterile (immune-driven) or infectious (bacteria or other organisms actively multiplying in the cornea). The distinction matters enormously because the treatments are opposite: sterile infiltrates respond to anti-inflammatory or immunosuppressive drops, while infectious ones need antimicrobials and can worsen dramatically if you suppress the immune response with steroids.
Several features help clinicians sort this out. Infectious infiltrates tend to be larger, sit centrally, produce mucopurulent discharge, and cause more severe pain and photophobia. They usually have a defect in the overlying epithelium. Sterile infiltrates, by contrast, more often have an intact epithelial layer over them.9PubMed. Sterile Corneal Infiltrate: A Difficult Dilemma An anterior chamber reaction (visible inflammatory cells floating in the fluid behind the cornea) or a hypopyon (a white sediment layer at the bottom of the anterior chamber) both point toward infection. When there is genuine uncertainty, clinicians often start with broad-spectrum antibiotics and wait for culture results before adding steroids.
First-Line Treatment With Steroids
Topical corticosteroid eye drops remain the standard first-line treatment for visually significant SEIs after adenoviral infection. Drops like prednisolone acetate or dexamethasone are effective at suppressing the immune activity that sustains the infiltrates, and most patients see improvement within weeks. The catch is that steroids cannot be used indefinitely. Prolonged use raises intraocular pressure (IOP), which can damage the optic nerve and lead to glaucoma. In a randomized study of post-surgical steroid use, a clinically significant IOP rise occurred in about 5% of patients, and moderate elevations appeared in about 13%.10Indian Journal of Clinical and Experimental Ophthalmology. Impact of prednisolone, dexamethasone, and fluorometholone eye drops on intraocular pressure in patients post-cataract surgery: A randomized controlled study While those numbers come from a surgical population rather than SEI patients specifically, steroid-induced IOP elevation is a well-recognized risk across all ophthalmic steroid use.
The other common problem is rebound. Many patients find their infiltrates return when steroid drops are tapered, creating a frustrating cycle of treatment, improvement, tapering, and relapse. This is where alternative therapies become important.
Cyclosporine as a Steroid-Sparing Alternative
Topical cyclosporine A at a concentration of 0.05% has emerged as a go-to option for patients whose infiltrates keep recurring when steroids are tapered, or who develop steroid-related side effects. In a study of 22 eyes treated with cyclosporine drops, about 82% showed clinical improvement, with meaningful gains in visual acuity and a significant reduction in infiltrate severity scores. Intraocular pressure actually decreased during the treatment period rather than rising.11PubMed Central. Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis A separate study confirmed that topical cyclosporine is well tolerated and effective as an alternative to steroids for post-adenoviral infiltrates.12PubMed. Cyclosporin A eye drop and subepithelial adenoviral keratoconjunctivitis infiltrates
Cyclosporine works by a different mechanism than steroids. Rather than broadly damping down inflammation, it selectively suppresses T-cell activation, which appears to be a key part of the immune response maintaining SEIs. It takes longer to kick in than steroids do, so some patients start on both and then wean off the steroid while continuing cyclosporine. The main side effect is stinging or burning on instillation, which usually improves over a few weeks.
Tacrolimus for Steroid-Resistant Cases
When both steroids and cyclosporine fall short, tacrolimus is the next option in the toolkit. Topical tacrolimus at 0.03% has shown strong results in small studies. In one series, tacrolimus brought the average infiltrate severity score down from about 2.2 to 0.25, and corrected visual acuity improved significantly with no meaningful change in intraocular pressure.9PubMed. Sterile Corneal Infiltrate: A Difficult Dilemma13Cornea. Tacrolimus for the Treatment of Subepithelial Infiltrates Resistant to Topical Steroids After Adenoviral Keratoconjunctivitis
A larger and more recent study compared tacrolimus alone to tacrolimus combined with prednisolone over 18 months. Both approaches effectively reduced infiltrates and improved visual acuity. The combination worked faster, which could matter for patients with significant visual impairment who need quicker relief. However, the combination group had a significantly higher rate of IOP elevation, reinforcing the familiar trade-off with steroids. Tacrolimus alone caused no recurrence and posed a lower IOP risk, making it a reasonable long-term maintenance option.14PubMed Central. Evaluating the Efficacy of Topical Tacrolimus Alone and in Combination with Prednisolone for Treating Subepithelial Infiltrates in Epidemic Keratoconjunctivitis
Can Early Treatment Prevent SEIs From Forming?
One of the more promising findings in recent years is that intervening early during the acute adenoviral infection may reduce the odds of developing SEIs at all. A treatment protocol tested prospectively found that early intervention cut the incidence of subepithelial infiltrates dramatically, from 57% in the control group to 10% in the treated group. At the one-month mark, no treated patients had SEIs compared to 31% of controls.15PubMed Central. A treatment protocol for minimizing duration and complications of adenoviral epidemic keratoconjunctivitis
Diluted povidone-iodine (PVP-I) applied in the first days of infection has also shown benefit. In one study, patients who received 2% povidone-iodine drops developed SEIs at a rate of about 33%, compared to about 46% in those who did not receive it.16PubMed Central. Effect of diluted povidone iodine in adenoviral keratoconjunctivitis on the rate of subepithelial corneal infiltrates The effect is modest compared to the protocol above, but povidone-iodine is cheap, widely available, and has broad antimicrobial activity. A newer combination of povidone-iodine 1% with low-dose dexamethasone 0.08% in a single prepared eye drop showed significant improvements in visual acuity, symptoms, and infiltrate scores, with reduced recurrence compared to either agent alone.17PubMed Central. The efficacy of combined povidone-iodine 1% and dexamethasone 0.08% prepared eye drops in treating post-viral corneal subepithelial infiltrates
The practical challenge is that many people with viral conjunctivitis do not seek care until the infection is already well established, and rapid adenovirus testing is not universally available. By the time the diagnosis is confirmed, the window for prevention may have narrowed. Still, the evidence argues for early, aggressive management of suspected adenoviral keratoconjunctivitis rather than a “wait and see” approach.
When Drops Are Not Enough: Surgical Options
A small percentage of patients end up with persistent, visually significant SEIs that do not respond adequately to any combination of drops. For these cases, laser-based procedures offer a more definitive solution.
Phototherapeutic keratectomy (PTK) uses an excimer laser to ablate the superficial corneal tissue where the infiltrates sit. Studies have reported improvements in photophobia, best-corrected visual acuity, and contrast sensitivity after PTK, sometimes with the addition of low-dose mitomycin C to reduce post-procedure scarring.18PubMed. Phototherapeutic keratectomy for the treatment of corneal opacities after epidemic keratoconjunctivitis
A more tailored approach is topography-guided transepithelial photorefractive keratectomy (PRK), which maps the corneal surface irregularities caused by infiltrates and directs the laser accordingly. In 18 eyes treated this way, uncorrected visual acuity improved by six or more lines on a standard eye chart in every case, and corrected visual acuity reached essentially perfect in all eyes at 12 months. The average tissue removal was about 55 micrometers deep. No infiltrate recurrence, haze, or pressure elevation was observed during follow-up.19Therapeutics and Clinical Risk Management. Topography-Guided Transepithelial Photorefractive Keratectomy for the Treatment of Persistent and Visually-Significant Adenoviral Corneal Infiltrates These results are encouraging, though the study was small. Surgical options are generally reserved for patients who have tried medical therapy for at least several months without adequate improvement.
SEIs in Children
Subepithelial infiltrates in children deserve separate mention because the presentation and risk profile can differ from adults. In blepharokeratoconjunctivitis (a combined lid and corneal surface inflammation common in pediatric populations), certain ethnic groups showed a statistically higher risk of developing subepithelial punctate keratitis as well as corneal vascularization and marginal ulceration.20British Journal of Ophthalmology. Blepharokeratoconjunctivitis in children: diagnosis and treatment Children may not articulate symptoms like glare or blurred vision clearly, so parents and clinicians need to be alert to behavioral changes like light avoidance, squinting, or rubbing. Treatment generally follows the same ladder as in adults, starting with topical steroids and moving to steroid-sparing agents, but with even more caution about IOP monitoring since children are generally more susceptible to steroid-induced pressure elevation and less likely to report early symptoms of it.
Living With Persistent Infiltrates
For many people, SEIs are a time-limited annoyance that clears within a few months with treatment. For others, they become a chronic condition requiring ongoing management. The recurrence problem is real: infiltrates frequently return when immunosuppressive drops are stopped, and some patients end up on low-dose cyclosporine or tacrolimus for years. The good news is that these steroid-sparing agents carry a much lower risk profile for long-term use than corticosteroids do.
If you wear contact lenses and develop corneal infiltrates, the most important immediate step is to stop wearing the lenses until the situation is fully evaluated. Even after the infiltrates resolve, your eye care provider may recommend switching lens types, reducing wear time, or improving your cleaning regimen. Given that bacterial contamination on lenses is strongly linked to infiltrative events, moving from extended-wear to daily-disposable lenses is a common recommendation.
Adenoviral conjunctivitis is extremely contagious, so anyone with an active infection should take standard precautions: frequent handwashing, not sharing towels or eye drops, and staying home from work or school during the acute phase. Reducing the spread of the virus in the first place remains the most effective way to prevent the downstream complication of subepithelial infiltrates. The ongoing challenge, as researchers have noted, is that no approved antiviral drug exists for ocular adenovirus, leaving clinicians to manage the immune consequences of an infection they cannot directly treat.21PubMed Central. Management of Adenoviral Keratoconjunctivitis: Challenges and Solutions