Contact lens-related peripheral ulcer (CLPU) is a non-infectious corneal inflammation that appears as a single small infiltrate in the peripheral cornea associated with contact lens (CL) wear. Internationally, it is also called “contact lens-induced peripheral ulcer” and described as “peripheral corneal infiltrate.” 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 favorable course, there is international debate whether it should be called an infiltrate or an ulcer.
CLPU is classified as one of the corneal infiltrative events (CIE), a group of CL-related non-infectious corneal infiltrative lesions 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 the core challenge in practice.
CL wear is the greatest risk factor for microbial keratitis in the United States 1), 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-years 6). 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 risk 1).
CLPU has not been completely prevented even after the widespread use of modern silicone hydrogel lenses 7). While high oxygen permeability 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. In a multicenter cohort study by Sweeney et al., the clinical features of CIE including CLPU were described in detail, and the lesion size, location, and anterior chamber inflammation pattern of CLPU were shown as important differentiating points from microbial keratitis 5).
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 single 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; the lesion is larger, with irregular epithelial defects, anterior chamber inflammation or hypopyon, and severe pain. Delay in treatment can lead to corneal perforation and 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 intensified antibiotic therapy should be initiated 1).
The subjective symptoms of CLPU are relatively mild to moderate and have an acute onset. Typical symptoms are as follows.
If subjective symptoms are severe, or if all three signs of conjunctival hyperemia, mucopurulent discharge, and severe pain are present, microbial keratitis is possible. Do not persist with a diagnosis of CLPU; a workup assuming infection is necessary 1). In addition, 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 uniform, observed as a well-demarcated small peripheral corneal infiltrate.
Fluorescein staining shows only a thin staining of the epithelial defect at the center of the infiltrate. While the area directly over the lesion stains mildly, the entire infiltrate does not stain, which helps in macroscopic differentiation from infectious ulcers. Scarring may occur during the course, leaving punctate circular opacities (nummular scars), but because they are peripheral, the impact on visual function is usually minimal 4).
Comparison of clinical findings between CLPU and 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 the limbus)
Central to paracentral common
Lesion size
Small, 1–2 mm
Variable, progressively enlarging
Single/multiple
Single
Single (multiple possible with mixed infection)
Border
Regular to slightly irregular
Jagged and irregular
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 speed
Slow, improves within 48 hours
Worsens within hours to 48 hours
Course
Epithelial repair in 4–5 days
Delayed treatment leads to perforation
QHow long does it take from onset to recovery?
A
CLPU has a favorable course; 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 infiltrate and conjunctival congestion typically takes 1–2 weeks. A punctate corneal opacity (nummular scar) may remain after healing, but since the lesion is in the peripheral cornea, the impact on vision is usually minimal. 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 also a major risk factor for inflammatory events such as CLPU 1,7). In a case-control study by Carnt et al., overnight wear was reported as a modifiable risk factor that increases the risk of AK approximately 4-fold (OR 3.93) even in daily disposable lens users 11).
Lens case contamination and biofilm: If the case is not replaced for more than 3 months or if the inside of the case is not allowed to dry, biofilm forms, serving as a reservoir for gram-negative bacteria and Staphylococcus aureus 9).
Care solution incompatibility and omission of rubbing: When using multipurpose solution (MPS) alone and omitting the “rub and rinse” step, bacterial deposition on the lens increases significantly 4).
Lens type and usage conditions
Conventional and frequent-replacement SCLs: Two-week frequent-replacement SCLs (FRSCL) and monthly conventional SCLs 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-negligible 7). Mechanical irritation due to the stiffness of the material adds another factor.
Foreign matter under the lens: If makeup particles or dust get under the lens and the wearer sleeps with them, the foreign matter can be pressed into the cornea, causing epithelial damage and triggering an immune response.
Microbiological factors
Adhesion of Staphylococcus aureus to lenses: Staphylococcus aureus is often detected on lenses, lens cases, and the ocular surface during CLPU episodes, and the cell wall components of this bacterium are considered major antigens in the immune response 10).
Gram-negative bacterial endotoxins: Lipopolysaccharides (LPS) produced by Pseudomonas aeruginosa, Serratia, Enterobacter, etc., in lens cases can also induce inflammatory reactions.
Overgrowth of normal flora: The amount of normal flora on the eyelid margin and in tears can change with CL wear, leading to overgrowth of specific bacterial species in some cases 8).
In a prospective cohort by Stapleton et al., continuous wear (30 days) of silicone hydrogel lenses resulted in an annual incidence of CIE of approximately 20 per 100 person-years, reported to be significantly higher risk compared to daily disposable lenses 6,7). In Japan, CL wear is the most common trigger for infectious keratitis, showing a bimodal peak in the 20s and 60s, but the majority of cases in the 20s are CL-related 3). Younger CL wearers are likely to frequently encounter mild CIE such as asymptomatic infiltrates and CLPU.
Daily disposable (DD) lenses reduce the risk of Acanthamoeba keratitis by approximately 3.84 times compared to DW reusable lenses, and switching to DD is estimated to prevent 30–62% of severe keratitis cases 11). For inflammatory events including CLPU, switching to DD lenses is a rational preventive strategy that eliminates the risk of poor care.
QAre daily disposable lenses 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 incidence of CLPU due to protein deposits or care solution incompatibility is reported to be lower than with frequent replacement or conventional lenses 7,8). The risk of Acanthamoeba keratitis is also reduced by approximately 3.84 times compared to DW reusable lenses, offering a public health preventive effect 11). However, if usage rules such as sleeping while wearing, 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 upon abnormality are essential.
The diagnosis of CLPU is based on clinical findings. No special tests are required, but systematic evaluation to reliably exclude microbial keratitis is essential.
In CLPU management, systematically obtaining the contact lens wearing status and care habits is key to differential diagnosis and risk assessment. The minimum items to confirm are as follows:
Type of CL and wearing history: soft/hard, daily disposable/biweekly frequent replacement/monthly, presence of silicone hydrogel, start date of use
Wearing time and mode: daily wearing hours, presence of overnight wear, continuous wear, or extended wear
Care habits: frequency of lens case replacement, performance of rubbing cleaning, type of care solution (MPS/hydrogen peroxide), reuse of storage solution
Onset and course of symptoms: time of onset, acute or gradual onset, worsening within 48 hours, diurnal variation of symptoms
Details of subjective symptoms: degree of pain (mild to moderate or severe), nature of discharge (mucoid/purulent), presence of photophobia or tearing
Episode just before onset: foreign body under lens, forced wearing/removal, wearing during bathing/swimming, contact with makeup
Past history: previous similar episodes, history of CL-related keratitis, comorbidities such as atopic dermatitis or dry eye
Slit lamp examination is central to diagnosis. For observing keratitis, a stepwise evaluation of the lesion in the following five stages is useful.
In CLPU, a single small infiltration in the peripheral cornea is characteristic, with no inflammatory cells in the anterior chamber. In HCL-wearing eyes, observing lens surface deposits or wettability before fluorescein staining may provide diagnostic clues.
It is essential for determining the pattern of epithelial defects. In CLPU, only localized epithelial defects at the center of the infiltrate may be stained, or there may be no staining at all. The following are evaluated based on the staining site and morphology.
If any of the following are present, the condition should be treated as microbial keratitis rather than CLPU 1).
If these warning signs are present, or if there is no improvement within 48–72 hours after diagnosing CLPU, Gram staining, culture, and sensitivity testing of corneal scrapings should be performed, and treatment should be switched 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 refractory 3). Acanthamoeba keratitis (AK) is a serious corneal infection in contact lens wearers, and the majority (over 88%) of AK patients are contact lens wearers. In differentiating from CLPU, confirm severe pain that worsens at night, the presence of radial keratoneuritis (an early sign), and poor response to treatment.
The treatment of CLPU is based on four pillars: (1) immediate discontinuation of contact lens wear, (2) broad-spectrum antibiotic eye drops, (3) low-dose steroid eye drops after ruling out infection, and (4) promotion of epithelial healing. Many cases heal within about one week with eye drop treatment, and pharmacotherapy is the mainstay of treatment.
Four pillars of treatment
Immediate discontinuation of CL: This is the most fundamental principle of treatment. Do not resume wearing 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 should be used first. Fluoroquinolones (e.g., 0.5% levofloxacin, 0.5% moxifloxacin, 1.5% levofloxacin high-concentration formulation) are used 4–6 times daily.
Low-dose steroid eye drops: Once the possibility of infection is ruled out, 0.1% fluorometholone eye drops are used 4 times daily for 2–4 weeks. This can lead to faster symptom improvement and reduced scar formation. In severe cases, consider increasing the dose or systemic administration.
Support for epithelial healing: Use 0.1% or 0.3% sodium hyaluronate eye drops 4–6 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 repair. Infiltration may persist, but evaluate for a decreasing trend.
1 week after initial visit: Confirm resolution of conjunctival injection and reduction of infiltration. If symptoms are absent, 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 contact lens use, identify the causative factors (poor care, case contamination, excessive wearing time, overnight wear) and confirm improvement before resuming. Actively consider switching to daily disposable lenses or high-oxygen-permeable silicone hydrogel lenses. Review the wearing schedule (prohibit continuous wear) and ensure thorough cleaning (rubbing and disinfection) methods.
Combination of low-concentration steroids for CLPU is recommended as it is effective for rapid resolution of infiltration and reduction of scarring. However, caution is needed when infection cannot be completely ruled out. The Japanese Infectious Keratitis Clinical Practice Guidelines, 3rd edition, weakly recommends against combining steroid eye drops for bacterial keratitis, and cautious judgment is advised before using steroids without identifying the causative organism 3). In particular, steroid use for Acanthamoeba, fungal, or Nocardia infections is contraindicated as it poses a clear risk of exacerbation 1,3).
In clinical practice, for typical CLPU meeting the following five conditions: (1) single, small, peripheral; (2) no or mild epithelial defect; (3) no anterior chamber inflammation; (4) mild pain; (5) localized conjunctival injection, combination therapy with fluorometholone is used. When in doubt, a conservative approach with antibiotic monotherapy plus NSAID eye drops (e.g., bromfenac) and observation is safer.
If the diagnosis of CLPU is uncertain and microbial keratitis is highly suspected, follow the flow based on the AAO Bacterial Keratitis PPP 1).
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 rods 1). If Acanthamoeba is suspected, multi-drug therapy including polyhexamethylene biguanide, propamidine isethionate, and neomycin is selected.
Relationship with Therapeutic Contact Lenses (BCL)
In patients wearing therapeutic contact lenses (BCL) for other conditions such as recurrent corneal erosion or bullous keratopathy, sterile infiltrates similar to CLPU may develop. The AAO Corneal Edema and Opacification PPP recommends high-water-content, high-Dk thin lenses for safety during BCL use, and prophylactic broad-spectrum antibiotics to prevent secondary infection 2). BCL is a temporary measure for pain relief and epithelial healing, not a long-term solution for corneal edema2). If CLPU is suspected during BCL wear, temporarily remove the BCL, directly evaluate the lesion, and decide 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 epithelial healing, ④ absence of subjective symptoms, and ⑤ identification and correction of the cause (e.g., poor care, lens case contamination, excessive wearing time, overnight wear). In many cases, this takes at least 2–3 weeks 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.
The pathophysiology of CLPU is understood as a host innate immune response to microbial components adhering to the contact lens surface. It is not an infection but a sterile inflammation caused by interaction with bacterial components.
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). Cell wall components produced by S. aureus, such as peptidoglycan and lipoteichoic acid, 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 epithelium releases inflammatory cytokines and chemokines such as IL-1β, IL-6, IL-8, and CXCL1, leading to migration and infiltration of peripheral blood-derived neutrophils into the peripheral corneal stroma4). This neutrophil-predominant inflammatory reaction clinically forms “single, well-demarcated small infiltrates.” Indeed, while Staphylococcus aureus is often isolated from lenses and conjunctival sacs during CLPU onset, corneal scrapings are frequently sterile, supporting that it is an antigen response rather than an infection 10). It can be positioned as a type III or type IV immune reaction to proteins or bacteria adhering to CL, and immune cell infiltration from limbal vessels contributes to lesion formation.
Synergistic Effects of Mechanical and Hypoxic Factors
Contact lens wear imposes continuous mechanical friction and hypoxic stress on the corneal surface, altering epithelial barrier function and innate immune thresholds 4). Mechanical stimulation is strong at the site where the upper eyelid contacts the lens edge during blinking, consistent with the predilection of CLPU for the superior peripheral cornea. With silicone hydrogel lenses, mechanical irritation due to material stiffness may cause lens edge impressions or 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 invasion of new blood vessels.
CLPU, as part of Corneal Infiltrative Events, forms a spectrum of sterile inflammatory diseases 4,8).
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, whereas 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 for CLPU and CIE in general 9). In a review by Wu et al., 30–80% of used lens cases showed bacterial contamination, with the most frequent contaminants being Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia 9). Bacteria in biofilms are highly resistant to disinfectants, and complete eradication with MPS alone is difficult, making rubbing, regular case replacement, and drying essential.
Basic and clinical research on CL-related corneal infiltrative events continues to progress. 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 CLPU 4). TFOS CLEAR emphasizes that CIE remains a significant safety issue in contact lens wear and highlights the importance of risk stratification based on the combination of lens material, wearing schedule, and care products.
Potential predictive biomarkers under investigation include tear fluid inflammatory cytokine profiles (IL-6, IL-8, MMP-9), conjunctival surface microbiome analysis, and TLR expression patterns, but none are yet at the clinical application stage. Antimicrobial modifications of lens materials (e.g., silver ion incorporation, peptide surface modification) are also being evaluated for long-term safety and clinical efficacy.
Epidemiological Background and Public Health Significance of CLPU
With the increasing number of contact lens wearers, the incidence of non-infectious corneal infiltrates including CLPU is also rising. In the Australian cohort by Stapleton et al., the annual incidence of infectious keratitis was 2–4 cases per 10,000 person-years among contact lens wearers 12), and non-infectious infiltrates occur even more frequently. With approximately 300 million contact lens wearers worldwide 13), improving contact lens safety is an important public health issue.
Switching to DD lenses not only reduces the risk of AK by approximately 3.84-fold 11), but is also thought to lower the risk of inflammatory events such as CLPU in general. TFOS DEWS III clearly states that contact lens wear can trigger dry eye and ocular surface disorders 14), and active management of dry eye is important in preventing CLPU.
The TFOS Lifestyle report provides a detailed analysis of the relationship between modern lifestyle and contact lens-related complications 15), pointing out that prolonged use of digital devices, VDT work, and irregular sleep patterns significantly reduce contact lens safety. Lifestyle modifications may also be effective interventions for preventing CLPU.
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