Contact lens-related peripheral ulcer (CLPU) is a non-infectious corneal inflammation that appears as a single small infiltration in the peripheral cornea associated with contact lens wear. Internationally, it is also called “contact lens-induced peripheral ulcer,” and in Japan it is described as “peripheral corneal infiltration.” The pathological entity is localized neutrophil infiltration, positioned as an immune/inflammatory reaction without infection. The term “ulcer” derives from historical nomenclature, but since it does not necessarily involve epithelial defects and has a relatively good course, there is international debate whether it should be called infiltration or ulcer.
CLPU is classified as one of the contact lens-related non-infectious corneal infiltrative events (CIE) 4). CIE includes, in addition to CLPU, contact lens-induced acute red eye (CLARE), non-central infiltrative keratitis (IK), and asymptomatic infiltrates (AI). These form a continuous spectrum, and clinically, differentiation from microbial keratitis is a core diagnostic challenge.
CL wear is the greatest risk factor for microbial keratitis in the United States1), and epidemiological studies by Stapleton et al. report an annual incidence of corneal infiltrative events in CL wearers of approximately 3–6 per 100 person-years6). Among these, CLPU accounts for a certain proportion as a well-demarcated small infiltrate, and is characterized by a higher frequency but milder course than microbial keratitis. In the United States, an estimated 71,000 cases of microbial keratitis occur annually, with CL wearers forming a large population at risk1).
CLPU has not been completely prevented even after the widespread use of modern silicone hydrogel lenses7). While high-oxygen-permeable materials have reduced hypoxia-related complications, extended wear time, poor care, and lens case contamination persist, so CLPU should be recognized as a typical non-infectious inflammatory event encountered in CL wearers.
QWhat is the difference between CLPU and microbial keratitis?
A
CLPU is a non-infectious corneal infiltration caused by the host immune response to bacterial components adhering to contact lenses, appearing as a solitary small lesion about 1–2 mm in diameter in the peripheral cornea. It is not accompanied by anterior chamber inflammation, epithelial defects are minimal, the epithelium repairs in 4–5 days, and it resolves in 1–2 weeks. In contrast, microbial keratitis is an infection caused by pathogens invading and proliferating in the corneal stroma, with larger lesions, irregular epithelial defects, anterior chamber inflammation or hypopyon, severe pain, and delayed treatment can lead to corneal perforation or blindness. If any of the following are present—infiltration diameter >2 mm, distance from visual axis <3 mm, or worsening within 48 hours—microbial keratitis should be strongly suspected, and corneal scraping culture and fortified antibiotic therapy should be initiated1).
The subjective symptoms of CLPU are relatively mild to moderate and have an acute onset. Typical symptoms are as follows.
Foreign body sensation/discomfort: The most frequent initial symptom. Often occurs in only one eye.
Eye pain: Usually mild to moderate, but can be relatively severe when accompanied by epithelial defects or when a superior lesion causes friction with blinking.
Conjunctival injection: Characterized by localized ciliary injection near the lesion.
Tearing/blurred vision: Transient visual impairment may be noticed depending on the lesion location.
Photophobia: Mild photophobia due to irritation of the iris and ciliary body.
Asymptomatic: Some cases are discovered incidentally during routine examinations.
If subjective symptoms are severe, or if all three signs of conjunctival injection, mucopurulent discharge, and severe pain are present, microbial keratitis is possible, and further examination assuming infection is necessary without adhering to a diagnosis of CLPU1). Additionally, note that all CLs reduce corneal sensation (hypoesthesia), so some patients may not report symptoms until the condition becomes severe.
The clinical picture of CLPU is relatively homogeneous, observed as small, well-defined peripheral corneal infiltrates.
Location: Approximately 1–2 mm inside the corneal limbus in the periphery. Commonly occurs superiorly, but can also occur inferiorly, temporally, or nasally.
Shape: Oval or round, rarely irregular. The borders are relatively distinct.
Size: Typically 1–2 mm in diameter, rarely exceeding 4 mm5).
Depth: Limited to the corneal epithelium and superficial stroma (anterior third), with no deep extension.
Epithelial defect: Often mild, but may be absent. When present, the border between the lesion and the epithelial defect is regular.
Anterior chamber inflammation: Usually absent. Even if mild cells appear, it does not progress to hypopyon.
Conjunctival injection: Localized ciliary injection near the lesion. Characteristically not circumferential.
Single lesion: Rarely multiple; most cases have a single lesion.
Fluorescein staining shows only thin staining of the epithelial defect at the center of the infiltrate. The lesion itself is not stained, which helps differentiate it from infectious ulcers. Scarring may occur during the course, leaving a punctate round opacity (nummular scar), but due to its peripheral location, visual function is usually minimally affected4).
Comparison of Clinical Findings: CLPU vs. Microbial Keratitis
In the management of CLPU, differentiation from microbial keratitis is most important. The clinical features of both are compared below.
Feature
CLPU (Sterile)
Microbial Keratitis
Location
Peripheral cornea (slightly away from limbus)
Central to paracentral, often
Lesion size
Small, 1–2 mm
Variable, progressively enlarging
Single/multiple
Single
Single (multiple possible with mixed infection)
Border
Smooth to slightly irregular
Irregular, jagged
Epithelial defect
None to mild
Clear, irregular border
Anterior chamber inflammation
None
Possible (including hypopyon)
Pain
Mild to moderate
Severe, acute
Conjunctival injection
Localized near the lesion
Circumferential and severe
Progression rate
Slow, improving within 48 hours
Worsening within hours to 48 hours
Course
Epithelial healing in 4-5 days
Perforation if treatment delayed
QHow long does it take from onset to recovery?
A
CLPU has a favorable prognosis. If contact lens use is discontinued and appropriate eye drops are administered, corneal epithelial repair is usually completed within 3–5 days. Subsequently, resolution of the infiltrative lesion and conjunctival hyperemia generally takes 1–2 weeks. Although a punctate corneal opacity (nummular scar) may remain after healing, it typically has minimal impact on vision because the lesion is located in the peripheral cornea. However, if there is no improvement after 2 weeks or if the condition worsens after starting treatment, progression to microbial keratitis or misdiagnosis should be considered, and reevaluation is necessary.
CLPU is not infectious, but multiple factors associated with contact lens wear contribute to its development. Major risk factors can be broadly categorized into two groups: “contact lens wear and care-related factors” and “microbiological factors.”
Contact Lens Wear and Care-Related Factors
Overnight wear and extended wear: Sleeping while wearing contact lenses is the greatest risk factor for microbial keratitis and is also a major risk factor for inflammatory events such as CLPU1,7).
Lens case contamination and biofilm: Failure to replace the lens case for more than 3 months or neglecting to dry the inside of the case leads to biofilm formation, which serves as a reservoir for gram-negative bacteria and Staphylococcus aureus9).
Care solution incompatibility and omission of rubbing: Using multipurpose solution (MPS) alone without rubbing significantly increases bacterial deposition on the lens4).
Lens Type and Usage Conditions
Conventional and frequent replacement soft contact lenses: Two-week frequent replacement soft contact lenses (FRSCL) and monthly conventional soft contact lenses are more prone to poor care and are frequently associated with both CLPU and CLARE.
Silicone hydrogel lenses: Although high oxygen permeability has reduced hypoxic complications, the incidence of CIE remains non-negligible7). Mechanical irritation due to the stiffness of the material adds another factor.
Foreign body under the lens: If makeup particles or dust get under the lens and the wearer sleeps with them, the foreign body can be pressed against the cornea, causing epithelial damage and triggering an immune response.
Microbiological Factors
Adherence of Staphylococcus aureus to the lens: Staphylococcus aureus is often detected on the lens, lens case, and ocular surface during CLPU episodes, and the cell wall components of this bacterium are considered major antigens for the immune response10).
Gram-negative bacterial endotoxin: Lipopolysaccharide (LPS) produced by Pseudomonas aeruginosa, Serratia, Enterobacter, and others in the lens case can also induce inflammatory reactions.
Overgrowth of normal flora: In some cases, the amount of normal flora on the eyelid margin and in tears changes with CL wear, leading to overgrowth of specific bacterial species8).
In a prospective cohort by Stapleton et al., continuous wear (30 days) of silicone hydrogel lenses reached an annual incidence of CIE of about 20 per 100 person-years, reported to be significantly higher risk compared to daily disposable types6,7). In Japan, CL wear is the most common trigger for infectious keratitis, showing a bimodal peak in the 20s and 60s, but the majority in the 20s are related to CL wear3). Young CL wearers are likely to frequently encounter mild CIE such as asymptomatic infiltrates and CLPU.
QAre daily disposables safe?
A
Daily disposable soft contact lenses do not require a lens case, significantly reducing the risk of infection and inflammation from biofilm or contaminated solution. The frequency of CLPU due to protein deposits or care solution incompatibility is reported to be lower than with frequent replacement or conventional types7,8). However, if usage rules such as sleeping with lenses, extended wear, or excessively long wear are violated, CLPU or microbial keratitis can still occur even with daily disposables, so adherence to wearing time and immediate discontinuation when abnormalities occur are fundamental.
The diagnosis of CLPU is based on clinical findings. No special tests are required, but systematic evaluation to reliably rule out microbial keratitis is essential.
Slit-lamp examination is central to diagnosis. For observing keratitis, a five-step evaluation of the lesion is useful.
Diffuse illumination: Assess the extent of overall corneal opacity
Retroillumination: Observe the depth of cellular infiltration in the infiltrative lesion and anterior chamber inflammation (especially keratic precipitates)
Wide slit beam: Observe the entire corneal surface
Narrow slit beam: Confirm lesion depth and anterior chamber inflammation
Fluorescein staining: Evaluate epithelial damage and tear film status
In CLPU, a single small infiltrate is seen in the peripheral cornea, and no inflammatory cells are present in the anterior chamber. In HCL wearers, observing lens surface deposits and wettability before fluorescein staining may provide diagnostic clues.
Fluorescein staining is essential for determining the pattern of epithelial defects. In CLPU, only a localized epithelial defect over the infiltrate may stain, or there may be no staining at all. The following are assessed based on the staining site and morphology:
Presence of punctate staining directly over the lesion
Presence of widespread epithelial damage around the lesion (if extensive, suspect microbial keratitis)
Coexistence of other CL-related epithelial disorders such as 3&9 o’clock staining, smile mark SPK, or SEAL
If any of the following is present, it should be treated as microbial keratitis rather than CLPU1).
Infiltrate larger than 2 mm in diameter
Location within 3 mm of the visual axis
Worsening clinical course 48 hours after starting treatment
Anterior chamber inflammation or hypopyon
Severe pain and diffuse conjunctival injection
Infiltrate with irregular epithelial defect
If these warning signs are present, or if there is no improvement within 48–72 hours after diagnosing CLPU, Gram stain, culture, and sensitivity testing of corneal scrapings should be performed, and treatment should be escalated to fortified antibiotics. The third edition of the Japanese guidelines for infectious keratitis strongly recommends specimen collection and culture testing before antibiotic administration when CL-related keratitis is suspected to be severe or refractory3).
Understanding non-infectious corneal lesions similar to CLPU is helpful for differentiation.
Marginal keratitis (catarrhal corneal infiltrate): Type III/IV allergic reaction to Staphylococcus aureus at the eyelid margin. Elongated infiltrate parallel to the limbus with a clear zone.
Corneal phlyctenule: Nodular lesion with vascular invasion, a delayed-type hypersensitivity reaction to tuberculosis or sebaceous gland inflammation.
Superior epithelial arcuate lesion (SEAL): Arc-shaped epithelial damage due to mechanical irritation from the upper edge of a soft contact lens. Infiltration is mild; diagnosis is made by fluorescein staining pattern.
Treatment of CLPU is based on four pillars: ① immediate discontinuation of CL wear, ② broad-spectrum antibiotic eye drops, ③ low-dose steroid use after ruling out infection, and ④ promotion of epithelial healing. Many cases heal within about one week with eye drop therapy, and the mainstay of treatment is pharmacotherapy.
Four Pillars of Treatment
Immediate discontinuation of CL: This is the most fundamental principle of treatment. Do not resume wear until infiltration subsides, conjunctival hyperemia resolves, and epithelial healing is confirmed.
Broad-spectrum antibiotic eye drops: Until differentiation from infection is complete, broad-spectrum antibiotic eye drops are administered first. Use fluoroquinolones (e.g., 0.5% levofloxacin, 0.5% moxifloxacin, 1.5% levofloxacin high-concentration formulation) 4 to 6 times daily.
Low-dose steroid eye drops: Once the possibility of infection is ruled out, add 0.1% fluorometholone eye drops 4 times daily. This suppresses inflammation, leading to faster symptom improvement and potentially reducing scar formation.
Support for epithelial healing: Use 0.1% or 0.3% sodium hyaluronate eye drops 4 to 6 times daily to promote epithelial healing and stabilize the tear film.
Treatment Duration and Follow-up
3 to 5 days after initial visit: Confirm epithelial healing. Infiltration may persist but should show a trend of reduction.
1 week after initial visit: Confirm resolution of conjunctival hyperemia and reduction of infiltration. If asymptomatic, gradually reduce antibiotic eye drops.
2 weeks after initial visit: Infiltration almost resolved. Residual punctate opacities in the peripheral area have minimal impact on visual function.
Prevention of recurrence: When resuming CL wear, identify the causative factors (poor care, case contamination, excessive wear time, overnight wear) and ensure improvement before resuming. Actively consider switching to daily disposable lenses or high-oxygen-permeable SiHy lenses.
The use of low-concentration steroids for CLPU is recommended as it is effective for rapid resolution of infiltration and reduction of scarring. However, caution is required when infection cannot be completely ruled out. The Japanese Infectious Keratitis Clinical Practice Guidelines, 3rd edition, weakly recommends against the concomitant use of steroid eye drops for bacterial keratitis, and the indiscriminate use before identification of the causative organism should be carefully considered 3). In particular, the use of steroids for Acanthamoeba, fungal, and Nocardia infections is contraindicated as it poses a clear risk of exacerbating the disease 1,3).
In clinical practice, for typical CLPU meeting the five criteria of (1) solitary, small, peripheral, (2) no or mild epithelial defect, (3) no anterior chamber inflammation, (4) mild pain, and (5) localized conjunctival injection, fluorometholone is used concomitantly. When the decision is uncertain, a conservative approach with antibiotic monotherapy plus NSAID eye drops (e.g., bromfenac) and observation is safe.
If the diagnosis of CLPU is uncertain and microbial keratitis is highly likely, follow the flow based on the AAO Bacterial Keratitis PPP 1).
No threat to vision (infiltrate ≤2 mm and non-central ulcer ≥3 mm from visual axis): Initiate empirical treatment with fluoroquinolone eye drops and evaluate for improvement after 48 hours.
Threat to vision (infiltrate >2 mm, <3 mm from visual axis, or worsening after 48 hours of treatment): Perform corneal scraping for Gram stain and culture, and start fortified antibiotics such as vancomycin 50 mg/mL plus fortified tobramycin 14 mg/mL every hour. Adjust medication based on culture results.
The combination of fortified aminoglycosides (tobramycin 14 mg/mL, gentamicin 14 mg/mL) and vancomycin (25–50 mg/mL) is a standard regimen covering both Gram-positive cocci and Gram-negative bacilli 1). If Acanthamoeba is suspected, combination therapy with polyhexamethylene biguanide, propamidine isethionate, neomycin, etc., is selected.
Relationship with therapeutic contact lenses (BCL)
Patients wearing therapeutic contact lenses (BCL) for other conditions such as recurrent corneal erosion or bullous keratopathy may develop sterile infiltrates resembling CLPU. According to the AAO Corneal Edema and Opacification PPP, high-water-content, high-Dk thin lenses are safe when using BCL, and prophylactic broad-spectrum antibiotics are recommended to prevent secondary infection 2). BCL is a temporary measure for pain relief and epithelial healing and is not a long-term solution for corneal edema2). If CLPU is suspected during BCL wear, temporarily remove the BCL to directly assess the lesion and make decisions in parallel with antibiotic treatment.
QCan I resume wearing contact lenses during treatment?
A
During treatment for CLPU, contact lens wear must be completely discontinued. The criteria for resuming wear are: ① complete resolution of corneal infiltration, ② disappearance of conjunctival injection, ③ complete repair of the epithelial surface, ④ absence of subjective symptoms, and ⑤ identification and correction of the causative factors (poor care, lens case contamination, excessive wearing time, overnight wear, etc.). In many cases, this takes 2–3 weeks or more after starting treatment. When resuming, switching to daily disposable lenses or silicone hydrogel lenses is recommended. Replace the lens case every month, and ensure thorough rubbing cleaning and drying.
6. Pathophysiology and Detailed Mechanism of Onset
The pathophysiology of CLPU is understood as the host’s innate immune response to microbial components adhering to the contact lens surface. It is characterized as a sterile inflammation due to interaction with bacterial components, not an infection.
In lens-wearing eyes, tear exchange is restricted, and mucin, proteins, and lipids in tears deposit on the lens surface, forming a biofilm-like membrane. This membrane facilitates colonization by commensal bacteria from the eyelid margin and tears, especially Staphylococcus aureus 10). Peptidoglycan and lipoteichoic acid, cell wall components produced by S. aureus, as well as endotoxin (lipopolysaccharide, LPS from Gram-negative bacteria), activate the innate immune system via Toll-like receptors (TLR2, TLR4) expressed on corneal epithelial cells.
Activated corneal epithelial cells release inflammatory cytokines and chemokines such as IL-1β, IL-6, IL-8, and CXCL1, leading to migration and infiltration of neutrophils from peripheral blood into the peripheral corneal stroma4). This neutrophil-predominant inflammatory reaction forms the clinical picture of “single, well-demarcated small infiltrates.” Indeed, while S. aureus is often isolated from lenses and conjunctival sacs during CLPU episodes, corneal scrapings are frequently sterile, supporting that it is an antigen response rather than an infection 10).
Synergistic Effects of Mechanical and Hypoxic Factors
CL wear imposes continuous mechanical friction and hypoxic stress on the corneal surface, altering epithelial barrier function and innate immune thresholds 4). At the site where the upper eyelid contacts the upper edge of the lens with each blink, mechanical stimulation is strong, consistent with the finding that CLPU commonly occurs in the superior peripheral cornea. With silicone hydrogel lenses, mechanical stimulation from the material’s stiffness may cause lens edge impressions and concurrent SEALs 7).
Hypoxia activates the hypoxia-inducible factor (HIF) pathway, increasing expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases, promoting neovascularization and stromal remodeling. Chronic hypoxia and repeated inflammation may contribute to long-term damage to the limbal stem cell niche and neovascular invasion.
CLPU, as part of Corneal Infiltrative Events, forms a spectrum of sterile inflammatory diseases 4,8).
CLPU: Well-defined single small infiltrate, often superior to peripheral, mild epithelial defect, with a distinct clinical picture.
CLARE (Contact Lens-induced Acute Red Eye): Acute conjunctival hyperemia and multiple non-central infiltrates after overnight wear. The endotoxin hypothesis is prominent, and association with lens case contamination has been reported.
Infiltrative Keratitis (IK): A condition with moderate symptoms and multiple non-central infiltrates, more symptomatic than CLPU but milder than CLARE.
Asymptomatic Infiltrative Keratitis (AIK): Multiple infiltrates with minimal symptoms.
These are distinguished by differences in clinical presentation and course, but the underlying pathophysiology (sterile inflammatory response to bacterial components) is common 8). The decisive difference between CLPU and microbial keratitis is that the former is a host immune response, while in the latter, pathogens proliferate in the corneal stroma. Therefore, clinical judgment requires comprehensive evaluation of whether improvement is achieved with empirical antibiotic therapy, presence of anterior chamber inflammation, progression rate of infiltration, and culture results.
The lens case plays an important role as a microbial reservoir in CLPU and CIE in general9). In a review by Wu et al., bacterial contamination was found in 30–80% of lens cases in use, with Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia reported as the most frequent contaminants9). Bacteria in biofilms are highly resistant to disinfectants, and complete eradication is difficult with MPS alone, so rubbing and cleaning, as well as regular replacement and drying of the case, are essential.
Basic and clinical research on CL-related corneal infiltrative events continues to advance. The TFOS CLEAR (Contact Lens Evidence-Based Academic Reports) published in 2021 systematized the classification, epidemiology, risk factors, and prevention of CIE, and has become an international standard reference for inflammatory complications including CLPU4). TFOS CLEAR emphasizes that CIE remains an important safety issue in contact lens wear and highlights the importance of risk stratification based on lens material, wearing schedule, and care product combinations.
Potential predictive biomarkers under investigation include inflammatory cytokine profiles (IL-6, IL-8, MMP-9) in tears, conjunctival surface microbiome analysis, and TLR expression patterns, but these are not yet at the stage of clinical application. Antimicrobial modifications of lens materials (e.g., silver ion incorporation, peptide surface modification) are also being evaluated for both long-term safety and clinical efficacy.
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Szczotka-Flynn L, Diaz M. Risk of corneal inflammatory events with silicone hydrogel and low dk hydrogel extended contact lens wear: a meta-analysis. Optom Vis Sci. 2007;84(4):247-256.
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