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Contact Lens-Induced Acute Red Eye (CLARE)

Key Points at a Glance

1. What is Contact Lens-Induced Acute Red Eye (CLARE)?

Contact lens-induced acute red eye (CLARE) is a non-infectious ocular inflammatory reaction with the three main features of acute onset hyperemia, corneal pain, and corneal infiltration during or immediately after contact lens wear. It is particularly common in users of silicone hydrogel lenses who practice overnight extended wear (EW).

CLARE is classified as one of the non-infectious corneal infiltrative events (CIE) associated with contact lens wear ²⁾. In addition to CLARE, CIE includes contact lens-related peripheral ulcer (CLPU), non-central infiltrative keratitis (IK), and asymptomatic infiltrates (AI), forming a continuous spectrum. The main etiology of CLARE is thought to be a type III or type IV allergic reaction (immune-mediated inflammation) to products (endotoxins, exotoxins, etc.) of bacteria (especially Gram-negative bacteria) that colonize the contact lens surface or ocular surface.

Contact lens wear is the greatest risk factor for infectious keratitis¹⁾, and the Australian cohort study by Stapleton et al. reported an annual incidence of all corneal infiltrative events in contact lens wearers of approximately 3–6 per 100 person-years⁵⁾. CLARE is a relatively common condition among these CIEs, occurring more frequently than infectious keratitis but characterized by a milder course.

CLARE usually resolves within 1–2 weeks after immediate discontinuation of contact lens wear. However, if it is misdiagnosed as infectious keratitis, the condition may worsen, so proper evaluation at the initial visit is important. The term CLARE originates from a historical name; although it is called “acute red eye,” the essential feature of this disease is that it involves not only hyperemia but also corneal infiltration.

Q What is the difference between CLARE and infectious keratitis?

CLARE is a non-infectious inflammation caused by an immune reaction to bacteria or their products, and bacteria are not detected on corneal scraping culture. Corneal infiltrates typically appear as multiple small round lesions mainly in the periphery, and anterior chamber inflammation is often mild. In contrast, infectious keratitis presents with a strong triad of hyperemia, discharge, and pain, accompanied by anterior chamber inflammation (anterior chamber cells, mutton-fat KP) and rapid progression. If differentiation is difficult, it is safer to treat as infectious keratitis (culture + topical antibiotics).

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Typical subjective symptoms of CLARE are as follows. Onset is acute, often noticed upon waking (after sleeping with contact lenses in place). The severity of symptoms varies widely, ranging from mild asymptomatic cases to moderate cases with visual impairment.

Subjective Symptom	Frequency/Characteristics
Hyperemia	Mixed type, mainly bulbar conjunctival hyperemia; may be localized around the lesion
Eye pain/foreign body sensation	Mild to moderate in most cases; severe pain suggests infection
Tearing	Mild to moderate
Eye discharge	Typically small amount and watery. Purulent discharge suggests infection
Blurred vision	Light scattering due to corneal infiltration. Usually mild
Photophobia	Mild. May be aggravated by fluorescent light or sunlight

If all three symptoms of hyperemia, eye discharge, and pain occur together, suspect infectious keratitis and promptly perform slit-lamp microscopy and corneal culture. Note that in all CIE including CLARE, contact lenses reduce corneal sensation (hypoesthesia), so some patients may not notice symptoms until the condition becomes severe ^1,2).

Clinical findings (findings confirmed by physician examination)

Characteristic findings confirmed by slit-lamp microscopy are shown below.

Finding	Characteristics
Corneal infiltration site	Multiple small round lesions in the periphery (slightly away from the limbus)
Infiltration diameter	Usually 1–2 mm or less. Relatively well-defined borders
Epithelial defect	None to minimal (fluorescein staining shows only faint staining at the center of the infiltrate)
Anterior chamber inflammation	None to very mild (no anterior chamber cells)
Conjunctival injection	Localized near the lesion or diffuse, moderate
Ocular discharge	Scant (purulent discharge suggests infection)

Fluorescein staining only reveals a small epithelial defect at the center of the infiltrate. The differences from infectious keratitis are that the entire infiltrate is not stained, there is no anterior chamber inflammation, and the borders are relatively well-defined.

CLPU shares a common pathophysiology with CLARE and is positioned within the continuous spectrum of CIE ^2,4). CLARE is characterized by multiple small infiltrates, while CLPU is characterized by a single, relatively large lesion. Rather than strictly distinguishing between the two, it is important to evaluate them together as CIE and prioritize differentiation from infectious keratitis.

Q Why are symptoms of CLARE worse in the morning?

During overnight continuous wear, the eyelids are closed, leading to a marked reduction in tear exchange and an environment where bacterial products accumulate under the contact lens. Additionally, prolonged hypoxia increases the inflammatory sensitivity of the cornea, making it more susceptible to immune reactions against bacterial products (e.g., LPS). Symptoms improve upon lens removal in the morning due to removal of antigens and restoration of tear circulation.

3. Epidemiology and Risk Factors

Incidence

The annual incidence of non-infectious corneal infiltrative events (CLARE, CLPU, IK, AI) in contact lens wearers is reported to be approximately 3–6 per 100 person-years ⁵⁾. With 30-day continuous wear of silicone hydrogel lenses, the incidence of CIE reaches about 20 per 100 person-years, which is significantly higher than with daily wear ^5,6). Infectious keratitis is one of the leading causes of visual loss in contact lens wearers, estimated at approximately 71,000 cases per year in the United States ¹⁾.

Main Pathogenesis

The main pathologies involved in the development of CLARE are as follows.

Lipopolysaccharides (LPS; from Gram-negative bacteria) and peptidoglycans/lipoteichoic acids (from Staphylococcus aureus) produced by bacteria on the CL surface and in the lens case activate innate immunity via Toll-like receptors (TLR2, TLR4) on corneal epithelial cells, releasing inflammatory cytokines such as IL-1β, IL-6, IL-8, and CXCL1, which cause neutrophils from peripheral blood to migrate and infiltrate the peripheral cornea ²⁾. This forms the clinical picture of CLARE.

Non-infectious keratitis includes immune reactions involving type III or type IV allergies to microorganisms present on the eyelids or meibomian glands, and this immune mechanism also plays a central role in CLARE.

Lens Type and Risk Factors

The main risk factors are shown in the table below.

Risk Factor	Characteristics/Description
Overnight continuous wear (EW)	Highest risk. Reduced oxygen supply and accumulation of bacterial products overlap.
Silicone hydrogel EW	Immune reactions can still occur even with high Dk values ⁶⁾.
Prolonged wear of HEMA-based SCL	Hypoxia due to low Dk/t increases inflammatory susceptibility.
Improper lens case management	Biofilm formation increases bacterial load⁸⁾
Skipping rubbing cleaning	Marked increase in bacterial deposits on lens²⁾
Comorbid dry eye	Reduced tear flushing effect leads to stagnation of bacterial products

Silicone hydrogel lenses have high oxygen permeability and have reduced hypoxia-related complications, but they do not eliminate CLARE risk⁶⁾. EW with SCLs, especially silicone hydrogel lenses, is reported to be more frequent than with HCL (RGP lenses). One-day disposable (DD) lenses eliminate the need for lens care and biofilm risk, and are reported to reduce the risk of Acanthamoeba keratitis by approximately 3.84 times compared to DW reusable lenses¹⁰⁾.

4. Diagnosis and Examination Methods

Differentiation from infectious keratitis is most important

In diagnosing CLARE, differentiation from infectious keratitis is most important. If the triad of hyperemia, discharge, and pain is present, infectious keratitis should be suspected first and antimicrobial treatment should be started promptly. The points of differentiation are shown below.

Differentiation item	CLARE (non-infectious)	Infectious keratitis
Infiltrate morphology	Small round, multiple, well-defined margins	Solitary, irregular margins, tendency to enlarge
Epithelial defect	None to mild	Usually present, tending to enlarge
Anterior chamber inflammation	None to very mild	Present (anterior chamber cells, flare)
Eye discharge	Scant	Purulent to mucoid
Pain intensity	Mild to moderate	Severe, acute onset
Course	Tendency to spontaneous resolution	Worsening, tendency to enlarge
Culture	Negative	Positive (organism identification)

Examination Procedure

History: Obtain detailed information on CL type, wearing schedule (including continuous wear), care methods, onset time, and symptom progression.
Slit-lamp examination: Evaluate injection pattern, location, morphology, number, size, border regularity of infiltrates, and presence of anterior chamber inflammation.
Fluorescein staining: Assess the relationship between epithelial defect pattern and infiltrate location.
Corneal culture and Gram stain: Always perform if infectious keratitis cannot be ruled out³⁾.
Intraocular pressure measurement: Necessary for evaluation before and after starting steroid eye drops.

Red Flags for Microbial Keratitis

If any of the following are present, the condition should be managed as infectious keratitis¹⁾.

Infiltrate diameter >2 mm
Central infiltrate within 3 mm of the visual axis
Clear anterior chamber inflammation (anterior chamber cells/flare)
Purulent discharge
Worsening within 48-72 hours

5. Standard Treatment

Immediate Response

Immediate response when CLARE is diagnosed or suspected is as follows:

Immediate discontinuation of CL: The basis of treatment. Do not resume wearing until hyperemia, infiltration subsides, and epithelial repair is confirmed.
Submission of culture tests (if infection cannot be ruled out): Perform Gram stain and culture of corneal scrapings ³⁾.
Initiation of broad-spectrum antibiotic eye drops: If infection cannot be reliably excluded, start 0.5% levofloxacin or 0.5% moxifloxacin eye drops 4-6 times daily.

Treatment After Confirming Non-Infectious

After infectious keratitis has been sufficiently ruled out, treatment for CLARE begins in earnest.

With appropriate treatment (CL discontinuation + steroid eye drops), healing usually occurs within 1-2 weeks. Since misdiagnosis with infectious keratitis can lead to severe complications, close follow-up is necessary.

Mild (Typical CLARE)

Symptoms: Hyperemia and eye pain only. No discharge. Multiple small infiltrates.

Management: CL discontinuation + 0.1% fluorometholone eye drops 4 times daily (after infection is ruled out).

Outcome: Complete healing usually within 1–2 weeks.

Moderate (triad present)

Symptoms: Triad of hyperemia, discharge, and pain. Infection suspected.

Management: Treat as infectious keratitis. Perform culture and frequent instillation of fluoroquinolone eye drops (e.g., 0.5% moxifloxacin).

Outcome: Consider adding steroid eye drops after confirming negative culture.

Severe (suspected infectious keratitis)

Symptoms: Rapid progression, anterior chamber inflammation, large infiltrate, severe pain.

Management: Consider hospitalization. Perform corneal culture, Gram stain, and administer vancomycin (25–50 mg/mL) plus fortified tobramycin (14 mg/mL) eye drops every hour ¹⁾.

Outcome: Adjust antibiotics based on culture results.

Details of Pharmacotherapy

0.1% Fluorometholone (Flumetholon) eye drops: Use 4 times daily for 1–2 weeks after excluding infection. Reduces inflammation and scarring. Long-term use carries risk of steroid-induced glaucoma, so intraocular pressure monitoring is needed. In severe cases, consider upgrading to 0.1% Rinderon eye drops.

Fluoroquinolone eye drops (when infection suspected): 0.5% levofloxacin (Cravit), 0.5% moxifloxacin (Vigamox), or 1.5% levofloxacin (Cravit 1.5%) 4–6 times daily. Use empirically until infection is ruled out.

0.1% or 0.3% sodium hyaluronate eye drops (Hyalein): 4–6 times daily. Promotes epithelial repair and stabilizes tear film.

NSAID eye drops: If infection cannot be fully excluded, NSAID eye drops such as 0.1% bromfenac sodium hydrate (Bronuck) may be used as a conservative alternative to steroids.

Management of Patients Wearing Therapeutic Contact Lenses (BCL)

Patients wearing therapeutic contact lenses (BCL) for recurrent corneal erosion or bullous keratopathy may develop CLARE-like sterile infiltrates. When using BCL, high-water-content, high-Dk thin lenses are considered safe, and prophylactic broad-spectrum antibiotics are recommended to prevent secondary infection ¹¹⁾. BCL is a temporary measure for pain relief and does not provide a long-term solution for corneal edema ¹¹⁾.

Return to CL Use and Prevention of Recurrence

After CLARE has completely resolved (infiltration subsided, epithelium repaired, hyperemia resolved, asymptomatic), consider resuming lens wear after identifying and correcting the cause of recurrence (poor care, overnight wear, lens case contamination). Switching to daily disposable lenses or changing from extended wear to daily wear schedule is effective in preventing recurrence. It often takes at least 2–3 weeks from confirmed healing to resuming lens wear.

The TFOS International Workshop on Contact Lens Discomfort defines contact lens discomfort as “a condition characterized by adverse sensations related to lens wear, which may be persistent or intermittent” ¹³⁾, and recurrent CLARE can lead to chronic discomfort. For recurrent CLARE, based on TFOS DEWS III, it is recommended to evaluate dry eye background factors (evaporative type, reduced tear film stability) and strengthen MGD treatment and tear film protection ¹⁵⁾.

Q Is long-term use of steroid eye drops dangerous?

Long-term use of steroid eye drops carries risks of steroid-induced glaucoma (elevated intraocular pressure) and reactivation of corneal herpes. Since CLARE usually heals within 1–2 weeks, steroid eye drops should be used only for a short period, and regular intraocular pressure monitoring is recommended. Avoid steroid use when infection cannot be ruled out, as it may prolong the infection.

6. Pathophysiology and Detailed Mechanisms

Immune-Mediated Non-Infectious Inflammation

CLARE is an immune-mediated inflammatory reaction without true infection. Endotoxins (lipopolysaccharides; LPS) derived from Gram-negative bacteria (especially Pseudomonas aeruginosa) colonizing the CL surface and ocular surface are considered the main antigens, leading to inflammation through the following mechanisms.

LPS activates innate immunity via TLR4 on corneal epithelial cells, releasing inflammatory cytokines and chemokines such as IL-1β, IL-6, IL-8, and CXCL1 ²⁾. This induces neutrophil migration and infiltration from limbal vessels, forming infiltrative lesions in the peripheral corneal stroma. Peptidoglycan and lipoteichoic acid from Staphylococcus aureus also activate immune responses via TLR2 ⁹⁾.

Non-infectious keratitis includes immune reactions involving type III or type IV allergies to microorganisms present on the eyelids or meibomian glands. Similar mechanisms play an important role in CLARE.

Why Overnight Continuous Wear Is an Aggravating Factor

During overnight EW, the following factors combine to increase CLARE risk.

Hypoxia: Low Dk/t causes corneal epithelial metabolic disturbance and HIF pathway activation → increased VEGF and MMP production → increased inflammatory sensitivity.
Markedly reduced tear exchange: During eyelid closure, tear circulation is extremely reduced, and bacterial products accumulate under the CL.
Biofilm formation: During continuous wear, bacterial biofilm matures on the CL surface and in the lens case, increasing the antigen load⁸⁾.

Involvement of Inadequate Care and Lens Case Contamination

Biofilm in the lens case is highly resistant to disinfectants, and 30–80% of lens cases in use show bacterial contamination⁸⁾. The bacterial load in the biofilm sustains bacterial adhesion to the CL surface, posing a chronic risk for CLARE and CLPU.

7. Prognosis, Complications, and Patient Guidance

Prognosis and Healing Course

The prognosis of CLARE is generally good. With discontinuation of CL wear and appropriate topical treatment (antibiotics ± steroids), corneal epithelial repair is usually complete within 3–5 days, and resolution of infiltrates and conjunctival hyperemia takes 1–2 weeks⁴⁾. Punctate corneal opacities (nummular scars) may remain after healing, but since the lesions are peripheral, visual function is usually minimally affected.

In cases of recurrent CLARE, there is a risk of progressive corneal hypoesthesia over the long term. Reduced corneal sensation leads to decreased reflex tear secretion, contributing to chronic dry eye. In CL wearers with recurrent CLARE, it is important to concurrently perform dry eye evaluation and treatment based on dry eye clinical guidelines.

Management of Recurrent CLARE

If CLARE recurs two or more times, perform the following systematic evaluation.

Evaluation Item	Content
Reassessment of wearing habits	Check for overnight wear or extended wear
Review of care methods	Check for omission of rubbing cleaning or case contamination
Dry eye evaluation	BUT, Schirmer test, fluorescein staining
MGD evaluation	Meibomian gland evaluation with slit-lamp microscopy
Reconsideration of CL type	Actively propose DD lenses or SCL material change

For recurrent CLARE, MGD treatment (warm compresses, eyelid hygiene), introduction of dry eye eye drops, and switching from continuous wear to daily wear are effective in preventing recurrence.

Differential diagnosis checklist for CLARE

Diseases that should be differentiated from CLARE are listed below.

Differential diagnosis	Key points for differentiation	Urgency
Infectious keratitis	Triad (redness, discharge, pain), anterior chamber inflammation, progressive	Emergency
Acanthamoeba keratitis	Severe pain, worse at night, radial keratoneuritis	Emergency
Herpes keratitis	Dendritic or geographic ulcer, decreased corneal sensation	Urgent
CLPU	Single, small, peripheral infiltrate, mild	Can wait
Asymptomatic infiltrate (AI)	Asymptomatic, incidental finding	Can wait
Superior limbic keratoconjunctivitis (SLK)	Superior conjunctival staining	Can wait

However, if there is no improvement after 2 weeks, or if it worsens after starting treatment, the possibility of microbial keratitis should be reassessed, and corneal culture, Gram stain, and sensitivity testing should be performed ³⁾.

Recurrence risk and long-term management

CLARE is a disease that tends to recur. The main causes of recurrence include the following:

Inadequate improvement of wearing habits (continued overnight wear, extended wear)
Improper lens case management (insufficient regular replacement, inadequate drying)
Skipping rubbing cleaning
Poor CL fitting (tight fit)
Untreated dry eye

When resuming the same CL after initial healing, identify and correct the cause before restarting use. Changing the wearing schedule to DW, switching to DD lenses, or changing to high oxygen permeability SiHy is effective in preventing recurrence.

Daily care guidance for patients

8. Latest Research and Future Prospects

TFOS CLEAR Findings (2021)

The TFOS CLEAR (Contact Lens Evidence-Based Academic Reports) published in 2021 systematized the classification, epidemiology, risk factors, and preventive measures for CIE, and has become an international standard reference for inflammatory complications including CLARE ²⁾. TFOS CLEAR emphasizes that CIE remains a major safety issue in CL wear and highlights the importance of risk stratification based on lens material, wearing schedule, and care product combinations.

Safety of Silicone Hydrogel Lenses and Overnight Continuous Wear

The widespread use of silicone hydrogel lenses has significantly reduced hypoxia-related corneal complications. However, multiple prospective cohort studies have shown that while SiHy EW reduces CLARE risk compared to HEMA-based SCL EW, the risk difference remains significant compared to daily wear ^6,7).

Global Trends in CL Wearers

The number of CL wearers worldwide is estimated to reach approximately 300 million ¹⁴⁾, making the prevention of CL-related complications an important public health issue. The combined effect of digital devices and CL wear is a major risk factor for CL-related complications such as dry eye and CLARE, especially in young adults ¹²⁾.

Development of Antimicrobial CL Lenses and Coating Technologies

CLs coated with silver nanoparticles, antimicrobial peptides, and photocatalytic coatings are being researched, and are expected to reduce the incidence of CLARE and infectious keratitis by suppressing bacterial colonization. Currently, they have not yet reached practical application.

Research on Predictive Biomarkers

Analysis of inflammatory cytokine profiles (IL-6, IL-8, MMP-9) in tear fluid and conjunctival surface microbiome analysis may be applied to assess CLARE predisposition, but are currently at the research stage. In the future, tear biomarker measurements before CL wear could potentially identify high-risk individuals for CIE in advance, and are expected to be applied to personalized prevention strategies ²⁾.

Combined Risk of Digital Devices and CLARE

During screen work, the blink rate significantly decreases from about 16 times per minute to 5–7 times per minute, and incomplete blinks also increase ¹²⁾. Incomplete blinks hinder the uniform spreading of tear film and increase evaporation. When VDT work is combined with continuous CL wear, tear film instability worsens markedly, leading to stagnation of bacterial products and potentially increasing CLARE risk ¹²⁾.

9. References

American Academy of Ophthalmology. Bacterial Keratitis Preferred Practice Pattern. Ophthalmology. 2024;131(2):P265-P330.
Stapleton F, Bakkar M, Carnt N, et al. CLEAR - Contact lens complications. Cont Lens Anterior Eye. 2021;44(2):330-367.
感染性角膜炎診療ガイドライン第3版作成委員会. 感染性角膜炎診療ガイドライン（第3版）. 日本眼科学会雑誌. 2023;127(10):819-905.
Sweeney DF, Jalbert I, Covey M, et al. Clinical characterization of corneal infiltrative events observed with soft contact lens wear. Cornea. 2003;22(5):435-442.
Stapleton F, Keay L, Edwards K, et al. The incidence of contact lens-related microbial keratitis in Australia. Ophthalmology. 2008;115(10):1655-1662.
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.
Steele KR, Szczotka-Flynn L. Epidemiology of contact lens-induced infiltrates: an updated review. Clin Exp Optom. 2017;100(5):473-481.
Wu YT, Willcox M, Zhu H, Stapleton F. Contact lens hygiene compliance and lens case contamination: A review. Cont Lens Anterior Eye. 2015;38(5):307-316.
Jalbert I, Willcox MD, Sweeney DF. Isolation of Staphylococcus aureus from a contact lens at the time of a contact lens-induced peripheral ulcer. Cornea. 2000;19(1):116-120.
Carnt N, Minassian DC, Dart JKG. Acanthamoeba Keratitis Risk Factors for Daily Wear Contact Lens Users: A Case-Control Study. Ophthalmology. 2023;130:48-55.
American Academy of Ophthalmology. Corneal Edema and Opacification Preferred Practice Pattern. Ophthalmology. 2024.
Wolffsohn JS, Lingham G, Downie LE, et al. TFOS Lifestyle: Impact of the digital environment on the ocular surface. Ocul Surf. 2023;28:213-252.
Dumbleton K, Caffery B, Dogru M, et al. The TFOS International Workshop on Contact Lens Discomfort: Report of the subcommittee on epidemiology. Invest Ophthalmol Vis Sci. 2013;54:TFOS20-36.
Craig JP, Alves M, Wolffsohn JS, et al. TFOS Lifestyle Report Executive Summary: A Lifestyle Epidemic—Ocular Surface Disease. Ocul Surf. 2023;30:240-253.
Jones L, Downie LE, Korb D, et al. TFOS DEWS III: Management and Therapy. Am J Ophthalmol. 2025;279:289-386.

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