Herpes Simplex Keratitis

Key Points at a Glance

Herpes simplex virus (HSV, primarily type 1) establishes latent infection in the trigeminal ganglion and repeatedly reactivates to cause corneal inflammation.
The classification by the Ocular Herpes Infection Study Group (epithelial type, stromal type, endothelial type, secondary lesions) has been adopted in the Infectious Keratitis Clinical Practice Guidelines.
The representative form of epithelial keratitis is dendritic keratitis, characterized by branching ulcers with terminal bulbs as a specific finding.
The basic principle of treatment is acyclovir ophthalmic ointment 3% 5 times daily for the epithelial type, and combined use of steroid eye drops and antiviral agents for the stromal and endothelial types.
Steroid eye drops are contraindicated for epithelial keratitis. They promote viral replication and worsen the condition.
Approximately 1.7 million people worldwide are affected annually, making it the leading cause of corneal blindness in developed countries²⁾
The Herpetic Eye Disease Study (HEDS) demonstrated the efficacy of steroid eye drops for stromal keratitis and the usefulness of oral acyclovir for preventing recurrence^{3, 4)}

1. What Is Herpes Simplex Keratitis?

Herpes simplex keratitis is an inflammation of the cornea caused by infection with the herpes simplex virus (HSV). In most cases, the causative virus is type 1 (HSV-1), and cases caused by type 2 (HSV-2) are extremely rare. HSV is a neurotropic virus belonging to the Alphaherpesvirinae subfamily of the Herpesviridae family, which establishes latent infection in the trigeminal ganglion and persists throughout life.

Few cases develop keratitis during primary infection. Typically, HSV latent in the trigeminal ganglion is reactivated by triggers such as fever, cold, stress, or ultraviolet exposure, and reaches the cornea via the trigeminal nerve, causing various lesions. Its most important feature is that it is a recurrent disease, and careful history taking regardless of disease type is the starting point for determining diagnosis and treatment strategy.

Epidemiology

Based on population-based estimates from 2016, the overall incidence of HSV keratitis was estimated at 24.0 per 100,000 people per year, with approximately 1.7 million people affected worldwide annually²⁾. Of these, epithelial keratitis accounts for about 16.1 per 100,000 (approximately 1.2 million per year), and stromal keratitis accounts for about 4.9 per 100,000 (approximately 370,000 per year)²⁾. An estimated 230,000 people per year develop new unilateral visual impairment (visual acuity below 6/12) related to HSV keratitis²⁾.

Approximately 67% of the world’s population (4.85 billion people) have been infected with HSV-1. HSV-1 prevalence is particularly high outside the United States and Europe, and treatment access is limited, so the actual disease burden is likely underestimated²⁾. HSV keratitis is the leading cause of corneal blindness in developed countries. In particular, 24–42% of stromal keratitis cases result in corrected visual acuity below 6/12, and 1.5–3.0% progress to severe visual impairment (below 6/60)²⁾.

Japan’s own epidemiological surveys, such as the nationwide surveillance of infectious keratitis, have shown that viral keratitis occupies an important position alongside bacterial, fungal, and Acanthamoeba keratitis. HSV keratitis is positioned as a representative disease in Japan that follows a chronic and recurrent course and affects visual prognosis¹⁾. In terms of age distribution, cases are more common in middle-aged and older individuals, but initial onset is observed across a wide range from children to the elderly. Age-related decline in cell-mediated immunity is a factor that increases the incidence rate⁶⁾.

Classification by the Ocular Herpes Infection Study Group

The disease classification proposed by the Ocular Herpes Infection Study Group (Yuichi Ohashi et al., 1995) has also been adopted in the third edition of the Infectious Keratitis Clinical Practice Guidelines¹⁾. This classification is based on the localization and pathological differences of lesions and is an important framework that determines treatment strategy.

Epithelial type

Dendritic keratitis: Characteristic branching epithelial lesions with terminal bulbs

Geographic keratitis: A condition in which epithelial defects enlarge due to prolonged dendritic keratitis

Stromal type

Disciform keratitis: Circular stromal opacity and edema due to delayed-type hypersensitivity reaction

Necrotizing keratitis: Dense stromal opacity with vascular invasion, risk of perforation

Endothelial type

Corneal endotheliitis: Primarily corneal edema and keratic precipitates, with mild stromal opacity

Corneal limbitis: Accompanied by fan-shaped edema with the limbus as the base and elevated intraocular pressure

Secondary Lesions

Persistent epithelial defect: Secondary epithelial defect due to delayed wound healing

Neurotrophic corneal ulcer: Ulcer due to sensory nerve impairment and abnormal wound healing

The epithelial form is a condition caused by direct viral replication in epithelial cells, while the stromal form is primarily driven by immune and inflammatory responses to the virus. Whether the endothelial form is primarily due to direct infection or immune response has not been fully elucidated. Neurotrophic corneal ulcer is a wound-healing abnormality without viral replication and is a secondary complication rather than a direct HSV lesion. These differences in pathophysiology lead to fundamentally distinct treatment strategies.

2. Main Symptoms and Clinical Findings

Dendritic ulcer of herpes simplex keratitis (fluorescein staining)

Imrankabirhossain, Wikimedia Commons, CC BY-SA 4.0

Fluorescein staining reveals the branching pattern of a dendritic corneal ulcer in fluorescent green under cobalt blue light. This corresponds to an epithelial-type lesion with terminal bulbs, as discussed in section “2. Main Symptoms and Clinical Findings.”

Subjective Symptoms

The subjective symptoms of herpes simplex keratitis vary greatly depending on the disease type.

Epithelial type: Foreign body sensation, conjunctival hyperemia, photophobia, and tearing are the main symptoms. Blurred vision occurs when the lesion involves the pupillary area. Patients rarely report severe pain; if severe pain is present, consider recurrent corneal erosion or Acanthamoeba keratitis instead.
Stromal type: Decreased vision and blurred vision are the most common complaints. Hyperemia is also frequently reported. Foreign body sensation and tearing occur when accompanied by epithelial lesions.
Endothelial type: Blurred vision due to corneal edema is the main symptom. Eye pain and headache may occur due to elevated intraocular pressure.
HSV anterior uveitis: Presents with unilateral hyperemia, eye pain, and blurred vision.

Clinical Findings (Epithelial Type)

Dendritic keratitis, the representative lesion of epithelial herpes keratitis, has four characteristic features that are key to diagnosis¹⁾.

Branching: Dichotomous branching morphology
Moderate width: Important for differentiation from pseudodendritic lesions such as those seen in herpes zoster keratitis.
Terminal bulb: The ends are swollen rather than tapered. This finding is absent in pseudodendritic lesions of herpes zoster keratitis (VZV).
Intraepithelial infiltration: The epithelium at the margin elevates, giving the lesion a clearly demarcated appearance

On fluorescein staining, the ulcer base stains positive, and the swollen marginal epithelium stains with rose bengal. When dendritic keratitis persists, the epithelial defect enlarges and takes the form of geographic keratitis. This tends to progress in immunocompromised patients and those using steroids; the marginal findings are preserved, and the presence of dendritic tails (suggesting a dendrite-like pattern) serves as a diagnostic clue.

Herpes simplex keratitis is typically unilateral, but the frequency of bilateral cases is reported to be 1.3–12% in the literature⁶⁾. Atopic predisposition, rheumatoid arthritis (40% bilateral frequency), immunosuppression, and pediatric cases (26%) are associated with a higher risk of bilaterality⁶⁾.

Clinical Findings (Stromal Type: Disciform Keratitis)

Disciform keratitis, the classic form of stromal herpes simplex keratitis, is characterized by the following findings¹⁾.

Well-defined circular, faint superficial stromal opacity with stromal and epithelial edema
Opacity more pronounced in the periphery than the center, often forming an immune ring
Keratic precipitates (KP) at the center of the lesion
Descemet’s membrane folds
Ciliary injection
May be accompanied by anterior chamber inflammation

As recurrences repeat, the opacity becomes irregular in shape and extends to deeper layers. In addition to opacity, a wide variety of lesion morphologies can appear, making diagnosis based on slit-lamp findings alone difficult in many cases.

Clinical Findings (Stromal Type: Necrotizing Keratitis)

Necrotizing keratitis is a condition in which HSV proliferates within the corneal stroma or an excessive immune response to antigens occurs¹⁾. It tends to occur with repeated recurrences, particularly in eyes with pre-existing vascular invasion, scar formation, or fatty degeneration within the stroma. It presents with dense, irregular stromal opacity accompanied by vascular invasion, and in cases with epithelial defects, stromal thinning may progress to perforation. In recent years, severe cases have become rare due to early and appropriate treatment.

Clinical Findings (Endotheliitis)

Corneal endotheliitis is diagnosed clinically when corneal epithelial and stromal edema with KP corresponding to the lesion are present, but corneal stromal opacity and anterior chamber cells are minimal¹⁾. The typical form of HSV-induced endotheliitis is the paracentral edema type, in which corneal edema occurs in a fan shape with the limbus as its base, and KP is observed at its center. It may be accompanied by elevated intraocular pressure due to trabeculitis and limbitis.

The keratouveitis type is a severe form that combines stromal keratitis, endotheliitis, and iritis, presenting with marked conjunctival injection, corneal edema, Descemet’s membrane folds, KP, and anterior chamber cells; in severe cases, hypopyon may develop.

Corneal Hypesthesia

In patients with recurrent episodes, corneal hypoesthesia becomes prominent and serves as an important supportive finding for diagnosis regardless of disease type. Stromal and endothelial types are more difficult to diagnose virologically than the epithelial type, making corneal sensitivity testing more important. Using a Cochet-Bonnet aesthesiometer, the sensory threshold can be evaluated in stages by adjusting the length of the nylon filament, and it is also useful for confirming left-right differences. When there is a history of unilateral recurrent redness and obvious hypoesthesia is found on the affected side, this strongly suggests corneal herpes regardless of the disease type. However, some cases in the early recurrence of the epithelial type do not show clear hypoesthesia, so this disease cannot be ruled out by a negative sensitivity test alone.

Q How common is bilateral herpes keratitis?

According to the literature, the incidence of bilateral HSV keratitis ranges from 1.3% to 12%⁶⁾. In a 30-year retrospective study, 4% of all patients had bilateral involvement at initial onset, and an additional 1% became bilateral upon recurrence⁶⁾. A large-scale Korean study reported 12%, and an Indian study reported up to 25% bilateral frequency⁶⁾. The rate is particularly high in patients with rheumatoid arthritis (40%) and in children (26%), and caution is needed because atopic predisposition and immunosuppressive states also increase the risk of bilaterality⁶⁾.

3. Causes and Risk Factors

Etiology

Herpes simplex keratitis is caused by HSV, a double-stranded DNA virus. HSV-1 primarily infects the orofacial region, and HSV-2 primarily infects the genital region, but both can cause ocular infection. The majority of corneal herpes cases are caused by HSV-1.

Primary infection often occurs asymptomatically in childhood. The virus travels through sensory nerve axons to the trigeminal ganglion, where it establishes lifelong latent infection. The latent virus reactivates in response to certain triggers, travels via the trigeminal nerve to the cornea, and causes recurrent inflammation.

Triggers of Reactivation

Systemic factors: Fever, common cold, stress, menstruation, fatigue, immunosuppression
Local factors: UV exposure, trauma, manipulation of the trigeminal nerve
Infections: COVID-19 infection. Reports indicate that the incidence of HSV keratitis increased 2.0–2.5 times during the first wave of the pandemic⁶⁾
Vaccination: Reactivation after COVID-19 vaccination has been reported
Ophthalmic surgery: LASIK, PRK, corneal collagen cross-linking (CXL), cataract surgery, intravitreal injection⁶⁾
Medications: Prostaglandin analogue antiglaucoma eye drops such as latanoprost, travoprost, and bimatoprost⁶⁾. It is presumed that the release of endogenous prostaglandins acts as inflammatory mediators that trigger HSV reactivation.
Rapid steroid tapering: Rapid tapering of systemic steroids triggers reactivation⁶⁾

Risk Factors for Bilateral Herpes Simplex Keratitis

The risk of bilateral involvement is high in the following conditions⁶⁾.

Immunosuppression: HIV/AIDS, malignancy, post-organ transplantation, long-term immunosuppressant use
Autoimmune diseases: Rheumatoid arthritis (40% bilateral frequency), pemphigus
Atopic predisposition: Atopic dermatitis, ocular rosacea
Childhood: 26%, higher rate than in adults
Aging: The incidence of new-onset cases increases with declining cell-mediated immunity

Risk of HSV Keratitis After Corneal Transplantation

HSV keratitis after corneal transplantation has been reported with an incidence of 9.73% in a Chinese retrospective study (411 cases)⁷⁾. Sixty-five percent of cases occurred within 1 to 3 months postoperatively, and postoperative steroid use is thought to promote viral reactivation⁷⁾. The distribution of post-transplant HSV keratitis by clinical type was: epithelial 27.5%, necrotizing stromal 20%, mixed 42.5%, and endothelial 10%⁷⁾. Corneal transplantation in eyes with a history of HSV keratitis carries a significantly higher risk of rejection and graft failure compared to transplantation for keratoconus or Fuchs endothelial corneal dystrophy⁷⁾.

4. Diagnosis and Examination Methods

Japanese Diagnostic Criteria (Ocular Herpes Infection Study Group)

The Infectious Keratitis Clinical Practice Guideline, 3rd Edition¹⁾ presents the following based on the diagnostic criteria of the Ocular Herpes Infection Study Group.

Definitive diagnosis: Isolation and culture of HSV from the lesion
Confirmed diagnosis: Dendritic or geographic lesions with terminal bulbs, or demonstration of viral antigens by fluorescent antibody technique
Auxiliary diagnosis: Decreased corneal sensation, definite history of epithelial herpes keratitis, or demonstration of viral DNA by PCR

However, since virus isolation and culture are rarely performed in everyday clinical practice, diagnosis is actually made by combining slit-lamp findings, auxiliary diagnostic criteria, and virological testing.

Slit-Lamp Microscopy Examination

In typical cases, diagnosis is possible based on slit lamp findings alone. In the epithelial form, a dendritic ulcer with terminal bulbs is observed; in the stromal form, discoid superficial opacity and an immune ring are seen; and in endothelitis, sectoral corneal edema and keratic precipitates are characteristic findings. Fluorescein staining and rose bengal staining under a Wood filter are used in combination.

Corneal sensitivity test

Corneal sensitivity testing is a valuable supplementary examination for diagnosing herpes keratitis. The Cochet-Bonnet aesthesiometer is recommended because it is simple to use and allows stepwise evaluation of the degree of decreased corneal sensation¹⁾. In cases with repeated recurrences, marked hypoesthesia is observed; however, this test is not specific and is not necessarily useful in first-episode or mild cases.

Virological examination

The third edition of the Clinical Practice Guidelines for Infectious Keratitis conditionally recommends the following tests¹⁾.

Immunochromatography (ICG): Checkmate® Herpes Eye (Wakamoto Pharmaceutical) is available under insurance coverage. Results are obtained within 15 minutes, and while specificity is high, sensitivity is approximately 60%. A negative result does not rule out HSV infection.
PCR method: In qualitative PCR using tears or aqueous humor, the DNA detection rate is high in epithelial herpes keratitis but lower in stromal disease. Aqueous humor PCR is essential for diagnosing endothelitis and HSV anterior uveitis. HSV exhibits spontaneous shedding from the trigeminal nerve, so a positive result alone is not diagnostic.
Virus isolation: Considered confirmatory for diagnosis, but requires culture facilities and time; rarely performed in clinical practice.
Serum antibody titers: Since most adults have a history of HSV infection, a positive result has limited diagnostic value. Negative results are useful for exclusion.

Differential Diagnosis

It is important to differentiate from pseudodendritic keratitis and other conditions with similar presentations.

Differential Diagnosis	Key Differentiating Features
Herpes zoster keratitis (VZV)	Pseudodendritic lesions: no terminal bulbs, weak fluorescein staining, Hutchinson sign, accompanied by skin rash
Acanthamoeba keratitis	Severe pain, radial keratoneuritis, contact lens wear history
Recurrent corneal erosion	Acute onset upon waking, severe pain, history of trauma
Toxic keratopathy (medication-induced)	History of eye drop use, diffuse punctate keratopathy
CMV corneal endotheliitis	Coin-shaped lesions, linear KP, unresponsive to acyclovir
Corneal graft rejection	KP localized to the graft posterior surface, Khodadoust line, excellent response to steroids

Differentiating between endotheliitis and graft rejection after corneal transplantation is particularly important. In post-transplant HSV endotheliitis, KP are distributed beyond the donor–recipient junction and do not improve with steroids alone, requiring the addition of antiviral therapy ⁷⁾. In contrast, in endothelial rejection, KP are mainly localized to the posterior graft surface, with a Khodadoust line progressing from the periphery toward the center ⁷⁾.

Q How useful is corneal sensitivity testing for diagnosis?

Corneal sensitivity testing is a valuable adjunctive test for diagnosing herpes keratitis¹⁾. Particularly in cases with recurrent episodes, a marked decrease in corneal sensitivity is observed. The Cochet-Bonnet esthesiometer is useful as it is simple and allows for severity grading. However, it is not a specific test and cannot establish a definitive diagnosis on its own. Because virus isolation and PCR have lower sensitivity in stromal and endothelial types than in the epithelial type, obtaining a medical history (history of recurrences) and confirming decreased corneal sensitivity are more important for diagnosis.

5. Standard Treatment

Treatment of herpes simplex keratitis differs fundamentally depending on the disease type. The epithelial type is caused by direct viral proliferation, so antiviral agents are the mainstay and steroid eye drops are contraindicated. The stromal and endothelial types are primarily driven by immune reactions, so the principle is to combine antiviral agents with steroid eye drops.

5-1. Treatment of the Epithelial Type

The first-line treatment is acyclovir (ACV, Zovirax®) ophthalmic ointment 3% administered 5 times daily¹⁾. Compliance with the dosing frequency is important due to the short half-life, and low doses carry a risk of resistant strains. After the epithelial lesions have resolved, reduce the frequency to 3 times daily and discontinue after 1 to 2 weeks. Concomitant use of antibacterial eye drops (such as levofloxacin 0.5% 3 times daily) is recommended to prevent mixed infection.

Drug	Dosage	Characteristics
ACV ophthalmic ointment 3% (Zovirax®)	Instill 5 times daily	First-line treatment. Strict adherence to frequency is important due to short half-life
Valacyclovir tablet (Valtrex®) 500mg	2 tablets, twice daily after meals	Prodrug of ACV. Switch in case of side effects or resistant strains
Levofloxacin ophthalmic solution 0.5% (Cravit®)	Instill 3 times daily	To prevent mixed infection
Trifluridine ophthalmic solution 1% (TFT)	8 to 9 times daily	Effective against ACV-resistant strains. Used in the US (not approved in Japan)

Managing side effects: ACV ophthalmic ointment may cause superficial punctate keratopathy in the central inferior cornea or blepharoconjunctivitis (base reaction). If mild, dose reduction may allow continued use, but in severe cases, switch to oral valacyclovir 500 mg, 2 tablets twice daily after meals. If no improvement after 1 week of continuous ACV ointment, consider ACV-resistant strains or other conditions presenting with pseudodendritic keratitis.

Systemic administration: The Infectious Keratitis Clinical Practice Guidelines, 3rd edition, conditionally recommend systemic administration of antiviral drugs for epithelial keratitis (weak recommendation, evidence level C)¹⁾. Oral acyclovir 2,000 mg/day is expected to have equivalent efficacy to ACV ophthalmic ointment and may be useful in cases of ointment toxicity, resistant strains, or poor adherence. However, oral ACV for HSV keratitis is not covered by insurance in Japan¹⁾.

Steroid eye drops are contraindicated in epithelial keratitis. Steroids promote viral activation and worsen the condition.

Debridement (epithelial scraping): To reduce the viral load, scraping of dendritic lesions may be performed in combination with antiviral drugs.

5-2. Treatment of Stromal Keratitis

Since stromal keratitis is primarily driven by an immune response to the virus, the principle is suppression of the immune response with topical steroids combined with ACV ophthalmic ointment¹⁾. If treated with steroids alone without ACV ophthalmic ointment, symptoms may initially improve, but recurrence and reactivation are more likely, and there is a risk of inducing epithelial keratitis during the course¹⁾.

In the HEDS (Herpetic Eye Disease Study)-1 SKN (Stromal Keratitis Not on Steroids) trial, topical corticosteroids (prednisolone phosphate in a tapering regimen) were shown to reduce the risk of persistent or progressive inflammation by 68% and shorten healing time compared to placebo in HSV stromal keratitis³⁾. At 6 months, the treatment failure rate was significantly lower in the active drug group, and earlier visual improvement was also demonstrated³⁾. This is the key evidence supporting the use of topical steroids for stromal keratitis, and it has been adopted as the basis of stromal keratitis treatment in the Japanese Infectious Keratitis Clinical Practice Guidelines, 3rd edition¹⁾. However, since the HEDS trial design did not demonstrate an additional benefit of oral ACV, the concomitant use of systemic antiviral agents should be determined on a case-by-case basis.

Topical steroid therapy in practice:

Severe cases: Start with a strong steroid such as betamethasone sodium phosphate (Sanbetazon® 0.1%) 5 times daily
Mild cases: Start with 0.1% fluorometholone (Flumetholon®)
Monitor the condition and taper slowly over months, switching to 0.1% fluorometholone after 1–2 months, then gradually reduce the frequency and discontinue after approximately 3–4 months
Gradual tapering is essential because abrupt discontinuation can cause recurrence
Subconjunctival injections are effective but prone to recurrence and reactivation, so avoid them as much as possible

Concurrent antiviral therapy: Use ACV ophthalmic ointment 3% 5 times daily in combination¹⁾.

Oral steroids: In cases with severe inflammation such as keratouveitis or when epithelial defects are present, add oral betamethasone (Rinderon® tablets 0.5 mg, 2 tablets once daily after breakfast) in addition to eye drops.

Prescription example (severe stromal keratitis):

Sanbetazon otic/ophthalmic solution 0.1% 5 times daily instillation
Zovirax ophthalmic ointment 3% 5 times daily instillation
Gatifloxacin ophthalmic solution 0.3% 3 times daily instillation

Prescription example (with epithelial defect):

Rinderon tablets 0.5 mg, 2 tablets once daily after breakfast
Zovirax ophthalmic ointment 3% 5 times daily instillation
Levofloxacin ophthalmic solution 0.5% 3 times daily instillation

5-3. Treatment of Endothelitis

Endothelial keratitis is treated according to the same protocol as stromal keratitis¹⁾. When it coexists with stromal keratitis, the treatment follows that for stromal keratitis. There is no consensus on whether ACV administration for pure endothelial keratitis should be topical or systemic. When corneal edema becomes irreversible, corneal endothelial transplantation is indicated.

5-4. Treatment of HSV Anterior Uveitis

For HSV anterior uveitis presenting with unilateral mutton-fat KP, anterior chamber inflammation, and elevated intraocular pressure, a combination of antiviral agents, steroid eye drops, pupil management, and intraocular pressure control is used.

Oral valacyclovir or ACV ophthalmic ointment 3% five times daily (the two cannot be billed simultaneously under insurance)
Betamethasone 0.1% eye drops 4-8 times daily (adjusted according to the degree of inflammation)
Tropicamide 1-4 times daily (pupil management)
Use beta-blockers, carbonic anhydrase inhibitors, etc. for elevated intraocular pressure
Prostaglandin eye drops may induce HSV reactivation; careful follow-up is necessary when corneal epithelial keratitis is present

5-5. Treatment of Trophic Corneal Ulcer

Trophic corneal ulcer is a wound healing disorder that does not involve viral proliferation, so the treatment strategy differs significantly.

Discontinue ACV ophthalmic ointment
Administer fibronectin eye drops, pressure patching, therapeutic soft contact lens wear, and tarsorrhaphy to promote epithelial healing
Choose preservative-free eye drops
Oral steroids may be used concomitantly in cases with severe inflammation
Concomitant oral valacyclovir is used to prevent viral reactivation

5-6. Recurrence Prevention (Long-term Oral Antiviral Therapy)

The Infectious Keratitis Clinical Practice Guidelines, 3rd edition conditionally recommend systemic antiviral administration for preventing recurrence of epithelial herpes keratitis (weak recommendation, evidence C)¹⁾.

In the HEDS-APT trial, 12-month administration of ACV 400 mg twice daily reduced the risk of recurrence of epithelial and stromal HSV disease by nearly half, with 19% in the active drug group versus 32% in the placebo group⁴⁾. Longer-term administration exceeding 12 months has been shown to further prolong recurrence intervals⁴⁾. While remaining mindful of the potential emergence of ACV-resistant strains, this is an effective option for cases with frequent recurrence or high-risk cases.

5-7. Corneal Transplantation

Corneal transplantation is indicated when scarred corneal opacities that do not respond to medical therapy remain. Outcomes have significantly improved in recent years due to advances in surgical techniques and postoperative antiviral prophylaxis⁵⁾.

Penetrating Keratoplasty (PKP)

Indications: Corneal perforation or full-thickness opacity

Outcomes: Recurrence rate 44%, rejection rate 46% without antiviral prophylaxis⁵⁾. Relative risk of graft failure reduced to 0.3 with oral ACV⁵⁾

Concerns: Immunological rejection is the main cause of graft failure⁵⁾

Deep Anterior Lamellar Keratoplasty (DALK)

Indications: Stromal opacity with healthy endothelium

Outcomes: Recurrence rate 6–10%, rejection rate 0–4.5%, 5-year survival rate 96%⁵⁾. Significantly superior to PKP (5-year survival rate 78.8%)

Advantages: Preserves host endothelium, resulting in fewer immunological rejections⁵⁾

Mushroom Keratoplasty (MK)

Indications: Conversion procedure for Descemet membrane perforation during DALK

Outcomes: 10-year graft survival rate 92%, rejection rate 9.7%, recurrence rate 7.8%⁵⁾

Features: Two-piece design with 9 mm anterior + 6 mm posterior component. Minimizes endothelial replacement to reduce antigen load⁵⁾

Postoperative antiviral prophylaxis: The American Academy of Ophthalmology (AAO) Corneal Edema and Opacification Preferred Practice Pattern and the AAO HSV Keratitis Treatment Guidelines recommend continuing oral ACV 800 mg three times daily or valacyclovir 500 mg twice daily for at least one year as antiviral prophylaxis after corneal transplantation^{5, 8, 9)}. The peak period for recurrence is 1–3 months after surgery, and special caution is required during this time⁷⁾. If HSV keratitis reactivates after transplantation, systemic antiviral therapy should be actively administered, and the steroid dosage should be carefully adjusted according to epithelial status, infection severity, and rejection activity⁷⁾.

Q Can steroid eye drops be used for epithelial herpes simplex keratitis?

Steroid eye drops are contraindicated in the epithelial type (active epithelial disease). They activate viral replication, leading to progression to geographic ulcers and worsening of the condition. On the other hand, in the stromal type (such as disciform keratitis), the primary mechanism is an immune response to the virus, so the combination of ACV eye ointment and steroid eye drops is the standard treatment^{1, 3)}. It is important to taper steroid eye drops gradually over months rather than abruptly discontinuing them¹⁾.

Q How can HSV recurrence after corneal transplantation be prevented?

In patients with a history of HSV keratitis, it is recommended to start oral antiviral agents (acyclovir 800 mg three times daily or valacyclovir 500 mg twice daily) before surgery and continue for at least one year postoperatively^{5, 8)}. The peak recurrence period is 1 to 3 months after surgery, making this period especially important⁷⁾. Regarding surgical technique, DALK preserves the host endothelium and demonstrates an excellent 5-year survival rate of 96%, compared with PKP (5-year survival rate 78.8%)⁵⁾. Mushroom keratoplasty also achieves a 10-year graft survival rate of 92%⁵⁾.

6. Pathophysiology and Detailed Pathogenesis

HSV Infection Cycle

Primary infection: Primary infection usually occurs in childhood through contact with the orofacial area, and most cases are asymptomatic. The virus enters cells via specific receptors on corneal epithelial cells (such as Nectin-1 and HVEM)⁶⁾. After infection, the virus travels through sensory nerve axons to reach the trigeminal ganglion, where it establishes lifelong latent infection.

Latent infection: HSV-1 maintains its genome within the neuronal nucleus, evading immune surveillance⁵⁾. During latency, it produces latency-associated transcripts (LAT), which maintain the integrity of the viral genome while suppressing cellular apoptosis⁶⁾. CD8-positive T cells and cytokines suppress viral gene expression, keeping the virus in a dormant state⁵⁾.

Reactivation: Various triggers cause latent virus to reactivate and reach the cornea along the trigeminal nerve. In COVID-19 patients, immunosuppression and cytokine storm syndrome occur, and exhaustion of HSV-1-specific CD8-positive T cells is thought to promote reactivation of latent virus⁶⁾.

Epithelial Pathophysiology

In epithelial herpes simplex keratitis, HSV actively replicates in corneal epithelial cells. The characteristic feature is that the virus actively replicates at the margins rather than in the epithelial defect. Dendritic lesions form along the corneal nerve pattern. With repeated recurrences, corneal sensory nerves become damaged and hypoesthesia progresses.

Stromal Immune Mechanism

HSV stromal keratitis is primarily driven by an immune response led by CD4-positive T cells. Langerhans cells (antigen-presenting cells of the cornea) that have taken up HSV antigens present them to CD4-positive T cells, and activated T cells release cytokines. This causes neutrophil infiltration into the corneal stroma, leading to tissue destruction. Mouse models have shown that removing CD4-positive T cells from the corneal stroma prevents the development of stromal keratitis, confirming that the immune response is central to the pathogenesis of the stromal form.

In addition, molecular mimicry has been demonstrated between the HSV UL6 protein and human corneal antigens, suggesting that an autoimmune mechanism may be involved in the chronicity and recurrence of stromal keratitis.

Difference between necrotizing and non-necrotizing forms: Non-necrotizing (disciform) keratitis is a pure delayed-type hypersensitivity reaction without active viral proliferation. In contrast, in necrotizing keratitis, neutrophil infiltration through new blood vessels occurs in response to antigen-antibody complexes accumulated in the stroma of corneas with repeated recurrences, leading to more severe tissue destruction.

Pathophysiology of endothelialitis

It remains unclear whether endothelialitis is primarily caused by direct viral infection of endothelial cells or by immunological attack. It is thought that both mechanisms may be involved. Endothelialitis caused by HSV often occurs during the course of stromal or epithelial types, whereas isolated endothelialitis without other forms is more frequently attributed to cytomegalovirus (CMV)¹⁾.

Pathophysiology of neurotrophic keratopathy

Neurotrophic corneal ulcer is a wound healing disorder caused by the accumulation of multiple factors during repeated recurrences. Contributing factors include stromal inflammation, corneal nerve damage, epithelial basement membrane damage, and side effects of antiviral drugs. Corneal nerve damage due to HSV infection causes a state of “neurotrophic keratopathy,” which, combined with decreased tear secretion and reduced blink reflex, delays epithelial healing. Clinically, while geographic keratitis with viral replication shows irregular epithelial defects, neurotrophic corneal ulcer is characterized by oval-shaped epithelial defects with gray-white rounded elevation of the marginal epithelium that appears slightly detached from the stroma. Viruses are not isolated, but residual DNA may be detected by highly sensitive PCR. Since viral replication is not involved, the mainstay of treatment is discontinuation of antiviral eye drops and promotion of epithelial healing.

Mechanism of Action of Antiviral Drugs

Acyclovir is monophosphorylated by viral thymidine kinase (TK) in infected cells, and then triphosphorylated by host cell kinases. This active form inhibits viral DNA polymerase, blocking viral DNA synthesis. Since it is not phosphorylated in normal cells, it has high selectivity for herpes viruses and few side effects. ACV-resistant strains arise mainly due to loss or mutation of TK activity that prevents ACV phosphorylation, with particularly high risk in immunocompromised patients⁶⁾.

7. Latest Research and Future Outlook

Development of Novel Antiviral Drugs

To address ACV-resistant strains, research is underway on multiple novel molecules targeting different stages of HSV-1 infection⁶⁾.

Viral attachment inhibition: Aptamers, retrocyclin 2, antibodies
Host cell entry inhibition: G1/G2 cationic peptides
DNA replication inhibition: Nucleoside analogs, CRISPR/Cas9
Protein synthesis inhibition: BX795
Viral release inhibition: OGT 2115

BX795 and OGT 2115 have shown efficacy against ACV-resistant HSV strains and are promising candidates⁶⁾. Since it is difficult for HSV-1 to simultaneously acquire resistance to three different therapeutic mechanisms, combination therapy with multiple molecules is expected as a future treatment strategy⁶⁾.

Diagnostic Biomarkers Using Tear Metabolomics

Specific metabolic changes (decreased arginine, altered sphingolipid metabolism) have been identified in the tears of patients with active epithelial HSV keratitis, suggesting their potential as novel diagnostic biomarkers through noninvasive tear sampling.

Advances in Corneal Transplantation and Combined Amniotic Membrane Transplantation

With the introduction of DALK and mushroom corneal transplantation, outcomes of corneal transplantation for HSV keratitis have dramatically improved⁵⁾. Large-diameter (9 mm) DALK significantly reduces postoperative astigmatism, with 44% achieving visual acuity of 20/20 or better⁵⁾. A protocol of high initial dosing and long-term tapering has yielded favorable 10-year outcomes even in scarred eyes with neovascularization⁵⁾.

For HSV keratitis accompanied by severe inflammatory response, large deep ulcers, and persistent epithelial defects, combined pharmacotherapy and amniotic membrane transplantation has been reported⁷⁾. Amniotic membrane tissue contributes to promoting epithelial healing, reducing inflammation, suppressing fibroblast proliferation, and inhibiting neovascularization⁷⁾.

Therapeutic Vaccines and Donor Cornea HSV Testing

Research on therapeutic vaccines aimed at preventing recurrence of HSV keratitis is ongoing, and animal studies have confirmed reduction of corneal symptoms. Routine HSV testing of donor corneas has also been proposed, with expected improvement in graft survival through detection, treatment, and prevention; however, it has not yet become widespread due to cost and legal constraints⁷⁾.

8. References

日本眼感染症学会, 感染性角膜炎診療ガイドライン改訂委員会. 感染性角膜炎診療ガイドライン（第3版）. 日眼会誌. 2023;127(10):859-870.
Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb SL, Newman LM. Incidence of herpes simplex virus keratitis and other ocular disease: global review and estimates. Ophthalmic Epidemiol. 2022;29(4):353-362.
Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1883-1896.
Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339(5):300-306.
Nardella M, Yu AC, Busin M, Rizzo R, Zauli G. Outcomes of Corneal Transplantation for Herpetic Keratitis: A Narrative Review. Viruses. 2024;16(9):1403.
Chaloulis SK, Mousteris G, Tsaousis KT. Incidence and Risk Factors of Bilateral Herpetic Keratitis: 2022 Update. Trop Med Infect Dis. 2022;7(6):92.
Wu D, Huang H, Zheng M, et al. Clinical manifestations and outcomes of herpes simplex keratitis following corneal transplantation: a retrospective study. Front Med (Lausanne). 2025;12:1654643.
American Academy of Ophthalmology. Corneal Edema and Opacification Preferred Practice Pattern. Ophthalmology. 2019;126(1):P216-P285.
White ML, Chodosh J. Herpes Simplex Virus Keratitis: A Treatment Guideline. American Academy of Ophthalmology Hoskins Center, 2014.

Related keywords