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Herpes simplex keratitis

Herpes simplex keratitis
Literature review current through: May 2024.
This topic last updated: Apr 10, 2024.

INTRODUCTION — Keratitis (corneal infection and inflammation) caused by herpes simplex virus (HSV) is a major cause of blindness worldwide, due to corneal scarring and opacity [1]. Keratitis is the most Prevalent form of ocular HSV-1 disease. Other forms include eyelid lesions (herpetic blepharitis), conjunctivitis, uveitis, retinitis, and, rarely, scleritis [2].

The diagnosis and treatment of HSV corneal infections will be discussed here. Discussion of the epidemiology and pathogenesis of HSV-1-related infections in general, as well as other clinical manifestations of HSV-1 infection, is presented separately. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

PATHOGENESIS

Herpes simplex virology — Two clinically important herpes simplex virus (HSV) types exist, HSV-1 and HSV-2. Humans are the only natural host for both types. HSV-1 accounts for most oral, labial, and ocular infections, and HSV-2 for most genital infections, although there is considerable and increasing overlap in these distributions.

Primary infection with HSV-1 occurs following inoculation of mucosal or skin surfaces by direct contact. Most HSV ocular disease is thought to represent virus reactivation following the establishment of latency. Latency develops after the virus enters sensory neurons and travels to sensory ganglia (the trigeminal ganglion for ocular disease) [3]. The virus remains in the ganglia for the lifetime of the host. It has been proposed that HSV-1 latency may also be established in the cornea, although this is controversial [4-7]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Pathogenesis of infection'.)

During latency, the virus does not replicate and does not damage neurons. Episodically, latency is interrupted, and infectious viral particles travel anterograde to neuronal endings where virus is shed. RNA molecules, known as latency-associated transcripts, become detectable in infected ganglia and play a part in viral reactivation [8].

Mechanisms of HSV corneal disease — The pathophysiology of HSV corneal disease is complex and involves components of three processes: active infection, inflammation caused by active infection, and immune reaction to past infection. Resulting structural changes in the cornea can lead to additional forms of keratitis such as peripheral ulcerative keratitis, neurotrophic keratopathy, and superinfection.

The cornea is the clear thin anterior refracting tissue of the eye (figure 1). The external, tear-covered, stratified epithelium overlies the collagenous, clear corneal stroma. The stroma comprises the bulk of the cornea. The single cell layer endothelium, in contact with the aqueous humor of the anterior chamber, maintains corneal clarity through fluid barrier and pump mechanisms.

Reactivated virus enters and replicates within cells of the basal epithelium of the cornea and spreads to adjacent cells. In primary infection, an inflammatory response triggers antigen-specific immune responses. Immunoglobulin G (IgG) and IgA antibodies and CD4 and CD8 T cells are involved in modulation of infection and latency [9-12]. Corneal stromal cells, keratocytes, may support active infection with ensuing necrotizing inflammation. Retained viral antigens may lead to subsequent immune-mediated stromal inflammation without viral replication [13,14].

EPIDEMIOLOGY AND RISK FACTORS — Herpes simplex virus 1 (HSV-1) infection is endemic in human populations. Most people have been exposed by middle age, with circulating antibodies to HSV-1 detectable in 90 percent or more of the population [1].

Primary HSV-1 infection is asymptomatic or not recognized more than 90 percent of the time [1]. Most clinical ocular infections are manifestations of virus reactivation; ocular involvement occurs in fewer than 5 percent of primary infections [15,16].

The majority of ophthalmic HSV cases are unilateral, with recurrences affecting the same eye. Bilateral disease (not necessarily concurrent) occurs in 1 to 12 percent of cases and is more common in patients with atopy or other immune abnormalities [17-19].

The incidence of ocular disease is 6.8 to 31 per 100,000 annually [20-23]. The prevalence of HSV keratitis in the United States is about 150 per 100,000, with an estimated 20,000 new cases and 48,000 episodes annually [16,24].

Persons with HIV or other immune deficiencies are at increased risk for ocular HSV. In a retrospective study that compared 70 patients with HSV-associated eye disease with 280 controls, persons with HIV had an increased risk of developing ocular HSV (odds ratio [OR] 3.37, 95% CI 1.09-10.40) [25].

Recurrences after an initial ocular episode have been reported in 9.6 percent at one year, 22.9 percent at two years, 40.0 percent at five years, and 67.0 percent at 10 years [19].

Risk factors for recurrence include ultraviolet laser treatment, topical ocular medications (epinephrine, beta blockers, prostaglandins), ultraviolet light exposure, trauma, and ocular surgery [26]. A possible association of recurrences following COVID-19 vaccination has been suggested [27]. Immunosuppressive drugs, especially ophthalmic topical glucocorticoids, are also a risk factor for recurrent disease.

CLINICAL MANIFESTATIONS

Symptoms — Most patients with herpes simplex virus (HSV) keratitis present with an acute onset of symptoms including pain, visual blurring, photophobia, watery ocular discharge, and often a red eye.

Findings by disease type — HSV keratitis has been classified in four categories: epithelial keratitis, stromal keratitis, endotheliitis, and neurotrophic (post herpetic, meta-herpetic) keratopathy [28,29]. Most primary ocular infection presents as epithelial keratitis, while subsequent ocular infection can present as recurrent epithelial keratitis, stromal keratitis, or endotheliitis.

Primary ocular infection

Epithelial keratitis — Epithelial disease is the most frequent form of ocular HSV infection, especially for initial episodes. Physical examination is notable for conjunctival injection near the limbus (ciliary flush), decreased corneal sensation, and characteristic punctate or diffuse branching (dendritic) lesions of the epithelium (picture 1) [30]. Further findings depend on the subtype of epithelial disease, which is further classified into dendritic keratitis, geographic ulcerations or marginal keratitis:

Dendritic keratitis – This is the most common initial presentation and is characterized by dendritic lesions (picture 1), which are classic for herpes simplex keratitis. Ocular infection begins with granular punctate lesions that form vesicles, which rapidly coalesce into a linear branching dendritic lesion. The lesions are caused by actively replicating virus within epithelial cells. Dendrites may be single or multiple and vary from <1 mm to several millimeters long. Typically, the ends of the branches of the dendrite have bulbous thickenings. Although dendritic lesions may be somewhat visible with a hand light without staining, slit lamp magnification and staining with dyes such as fluorescein are usually necessary to define the details of the lesions [30,31].

Geographic ulcers – Geographic ulcerations occur as a worsening of dendritic lesions and are seen in up to 22 percent of cases of epithelial HSV [32]. They develop when a dendrite, which is initially elevated, ulcerates due to lysis of the central epithelial cells. These ulcerations may continue to have dendritic extensions at the edges [28,29]. Like dendrites, geographic ulcers represent destruction and desquamation of epithelial cells from active viral infection.

Marginal keratitis – Marginal keratitis, also termed limbitis, refers to active epithelial HSV lesions that occur at the limbus (the junctional zone of the cornea and sclera) (figure 2) [28]. Marginal lesions often are less dendritic in appearance than central corneal lesions and thus may not be as easily diagnosed. The proximity to blood vessels at the limbus allows white cell infiltration and neovascularization of the underlying corneal stroma [29].

Subsequent disease

Recurrent epithelial disease — The physical findings of recurrent epithelial disease are similar to those on initial presentation. (See 'Epithelial keratitis' above.)

Stromal keratitis — Stromal disease may result from an inflammatory reaction (immune keratitis), or, less commonly, an active viral infection (necrotizing or interstitial keratitis) [13]. Stromal involvement is rarely an initial ocular finding, accounting for fewer than 2 percent of initial presentations but for 20 to 60 percent of recurrent corneal disease [19,29,33]. Active stromal lesions do not usually occur at the same time as epithelial disease. Stromal disease carries a worse prognosis than epithelial keratitis. Typical physical findings depend on the type of stromal keratitis:

Immune keratitis – This accounts for 90 percent of recurrent stromal keratitis [33] and is thought to represent a delayed hypersensitivity reaction to viral antigens in the cornea [34]. Some physical examination findings include:

A "ghost-like" superficial stromal opacity beneath the site of a previous dendrite. These dendrite-shaped superficial lesions are clinically insignificant but may be helpful in making the diagnosis of past HSV infection. This is usually a subtle finding only detectable on slit lamp examination.

Localized or diffuse inflammation of the stroma, usually without epithelial disease. The stromal inflammatory deposits, which may look gray or white and form any shape, are thought to represent complexes of viral antigen with antibodies and complement. These may take the form of a ring infiltrate [34].

Stromal neovascularization may occur. Blood vessels may grow into the normally avascular corneal stroma, especially when the disease is longstanding. These vessels may regress with treatment of the keratitis. Persistent vessels often leak lipids, which opacify the cornea; this is known as lipid keratopathy [35]. Corneal stromal scarring almost always results and may decrease vision significantly depending on location and severity, making prompt treatment of active inflammation mandatory.

Stromal thinning, fibrosis and vascularization beneath the epithelium (pannus), and lipid deposits from stromal vessels are also common.

Necrotizing keratitis – The typical physical examination finding is the presence of cellular infiltrates within the stroma at one or more sites (picture 2). These infiltrates may be true abscesses and are often associated with overlying stromal ulceration. Typically, there are white cell deposits on the corneal endothelium, keratic precipitates, and an inflammatory reaction in the anterior chamber. Hypopyon or hyphema may result.

Corneal perforation may occur, particularly following glucocorticoid treatment without adequate concurrent antiviral treatment (picture 3) [8]. The severe corneal destruction and occasionally rapid progression may make necrotizing herpes simplex keratitis difficult to distinguish from bacterial or fungal infection.

Endotheliitis (disciform keratitis) — Endothelial disease is uncommon but often leads to corneal stromal edema which forms a circular (“disciform”) pattern with underlying endothelial keratic precipitates. Rarely, a line of keratic precipitates moves slowly across the endothelium in a pattern known as linear endotheliitis, which may be confused with cytomegalovirus keratitis [36].

Findings are thought to be manifestations of an immune reaction rather than infection of the endothelial cells [37]. Endotheliitis is not temporally associated with either active epithelial infection or white blood cell infiltrative stromal disease, and triggers are unknown.

DIAGNOSIS — Herpes simplex keratitis is suspected in any patient who presents with acute onset of eye pain, visual blurring, photophobia, and watery ocular discharge. Patients often have a red eye, but this is not a universal finding. Presentation is usually unilateral. The diagnosis is often made on the basis of the clinical history and examination findings without laboratory testing.

The most common presentation is that of epithelial keratitis, which has pathognomonic dendritic lesions and may also present with geographic ulcers. The presentation of stromal disease is more varied and the diagnosis requires an ophthalmologic examination with a slit lamp. (See 'Findings by disease type' above.)

Certain historical features make the diagnosis more likely, including prior unilateral keratitis in the same eye, HIV infection, a history of ultraviolet laser treatment or ultraviolet light exposure, use of topical ocular medications (epinephrine, beta blockers, prostaglandins), or immunosuppression. (See 'Epidemiology and risk factors' above.)

Physical findings differ based on the disease type (epithelial keratitis, stromal disease, endotheliitis, neurotrophic keratopathy). Slit lamp examination is usually needed to confirm the presence of typical or suspicious lesions.

Laboratory testing (ie, viral culture or herpes simplex virus [HSV] polymerase chain reaction [PCR]) may be indicated in severe cases where the clinical findings are atypical but suspicion of herpes simplex keratitis is high. The use of real-time PCR is increasingly available and has high sensitivity [38]. However, even in such cases a therapeutic trial of antiviral therapy is usually initiated. (See 'Management' below.)

When diagnostic testing is performed, ocular samples are taken by scrapings of epithelial lesions. Three types of tests are available: viral culture, detection of viral antigen, and detection of viral DNA (preferred). Details of these tests are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Tests to confirm the diagnosis'.)

Serologic testing is generally not helpful because of the high prevalence of prior HSV exposure in the population.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for dendritic lesions includes ophthalmic herpes zoster. “Pseudodendrites” can also be seen with epithelial toxicity from medications or healing of corneal abrasions. The differential diagnosis, in the absence of obvious dendritic lesions, is that of the red eye. In recent decades Acanthamoeba keratitis has frequently been initially misdiagnosed as HSV keratitis. (See "The red eye: Evaluation and management".)

MANAGEMENT

Ophthalmology referral — The diagnosis of epithelial herpes simplex virus (HSV) keratitis with characteristic dendritic lesions can often be made by the primary care provider on initial evaluation. Primary care providers can also initiate treatment for epithelial keratitis, but they should refer the patient to an ophthalmologist within a few days for follow-up. If the initial diagnosis is in question, or if stromal disease is suspected, a prompt ophthalmologic referral is recommended.

Avoid topical glucocorticoid monotherapy — Primary care providers should avoid prescribing topical glucocorticoid therapy for epithelial keratitis because applying topical glucocorticoid drops to the infected eye (without use of concomitant antiviral medication) might lead to involvement of deeper stromal structures with threat to vision. This has been documented in case reports [39,40]. The use of topical glucocorticoid therapy should be reserved for the ophthalmologist, in combination with antivirals for treatment of stromal keratitis, after appropriate evaluation [41].

Medical treatment — The goals of treatment of HSV ocular disease are to shorten the disease course and to prevent recurrences that can lead to corneal scarring and visual impairment.

Epithelial keratitis — Topical antiviral therapy and oral antivirals are both effective for treatment of dendritic and geographic herpes simplex keratitis [42-45]. The choice between oral and topical treatment can be made based on patient preference. Oral treatments are often preferred because of their convenience and potential to avoid corneal epithelial toxicity [44]. In either case, a usual course of treatment is two weeks. Glucocorticoids are not recommended in epithelial disease.

For some patients, a gentle "wiping" debridement of the corneal epithelium may be used as an adjunct to antivirals [42,46].

Specific agents available for treatment include:

Oral agents – Oral acyclovir (400 mg five times daily), or valacyclovir (500 mg three times daily) are both effective. Valacyclovir has the advantage of less frequent dosing but may be more expensive than acyclovir. Famciclovir (250 to 500 mg three times daily) may be used for allergic patients or resistant disease. Valganciclovir, foscarnet, and cidofovir are very rarely used because of their toxicity. Treatments can be stopped one week after healing of the lesions.

Topical agents – Acyclovir 3% ophthalmic ointment is the preferred topical treatment. It is used five times daily and continued for three days after clearing of corneal lesions.

If acyclovir is not available, topical ganciclovir 0.15% gel is our preferred alternative topical agent. It is given as one application five times daily until epithelial healing occurs and then three times daily for one week. Ganciclovir gel appears to have less corneal toxicity than trifluridine and may be better tolerated for long-term use [47,48].

Trifluridine 1% is given as one drop every two hours (eight or nine doses daily). Full dosing for two weeks may be necessary to prevent early reactivation, but drops are often tapered after the first week if there is a rapid response. Treatment is limited by epithelial toxicity, especially when used for longer than three weeks.

Antiviral medications likely hasten the resolution of epithelial keratitis [42]. Untreated, epithelial keratitis usually resolves in two to four weeks [19], while with antiviral treatment, healing usually occurs in one to two weeks unless infection progresses to stromal disease [49]. A 2015 systematic review of 106 trials found that any of four topical antiviral agents (trifluridine, acyclovir, ganciclovir, or brivudine) were equally effective and resulted in healing of 90 percent of eyes within two weeks [42].

Treatment with antivirals is also likely beneficial in preventing progression to stromal disease, although clinical evidence is limited.

Geographic ulcers respond more slowly to treatment and are more likely than dendrites to lead to scarring. Combining topical and oral antivirals does not improve the outcomes or prevent later iritis or stromal keratitis [50].

HSV resistance to antivirals is facilitated by chronic or recurrent treatment, and the possibility of resistance to oral antivirals should be considered in patients with recurrent HSV keratitis who do not respond to therapy [51-53].

Stromal keratitis or endotheliitis — A combination of topical glucocorticoids and antivirals is the standard of care for necrotizing and immune stromal keratitis [33]. Topical glucocorticoid therapy should never be used alone, as this can cause reactivation of epithelial disease. (See 'Avoid topical glucocorticoid monotherapy' above.)

Glucocorticoids, most commonly prednisolone acetate 1% suspension, are usually given four times daily and then tapered over several weeks depending on response. Dexamethasone 0.1% and loteprednol 0.5% are other options. Some patients require prolonged use, over months to years, to maintain disease suppression. Antiviral treatments are given in the same doses as for epithelial disease, usually for the duration of glucocorticoid therapy. Oral and topical agents are equally effective, although trifluridine is avoided due to the higher likelihood of epithelial toxicity. (See 'Epithelial keratitis' above.)

In the Herpetic Eye Disease Study, patients with stromal keratitis were randomly assigned to treatment with topical trifluridine 1% plus placebo or to trifluridine plus prednisolone acetate 1% administered every two hours in a tapering 10-week course [54]. The duration of inflammation and risk of progression were significantly reduced in patients receiving prednisolone. The rate of epithelial HSV recurrence was not increased by the topical steroids. The addition of oral acyclovir to topical glucocorticoids and topical antivirals provided no additional benefit [55].

The use of other antiinflammatory agents in stromal keratitis has not been well studied. Topical cyclosporine 0.05% showed some effectiveness in several small series [56-59]. Cyclosporine 2%, not commercially available, has similar effectiveness to topical prednisolone [60].

Endotheliitis with disciform corneal stromal edema responds well to topical glucocorticoids in conjunction with prophylactic antivirals in controlled trials [54,61]. Linear endotheliitis appears to be more responsive to oral antiviral agents than to topical glucocorticoids, but this has not been validated in controlled trials because of the infrequency of this variant [37]. Treatment is reserved for ophthalmologists.

Expected course and follow-up — Patients treated for epithelial keratitis are usually seen one week after initiation of treatment, at which time lesions are often healed. Treatment is then continued for another week, at which time patients are re-evaluated.

Patients with stromal keratitis are usually also seen one week after initiation of treatment. After that, follow-up is individualized based on severity.

Patients who have had recurrent disease are usually evaluated once a year and as needed.

Surgical treatment in select patients — Although surgical treatment is rarely warranted, corneal transplantation may be indicated when scarring due to stromal keratitis significantly limits vision. Rarely, endothelial keratitis may lead to permanent corneal edema, requiring endothelial corneal transplantation.

The success rate for corneal transplantation in patients with HSV keratitis (40 percent at five years) is lower than that in many other conditions because of a high rejection rate related to corneal vascularization and because of recurrence of HSV keratitis [62]. Deep anterior lamellar corneal transplantation has been recommended over full-thickness corneal transplantation (“penetrating keratoplasty”) [63]. We administer oral acyclovir or valacyclovir to all patients undergoing corneal transplantation for herpes simplex keratitis. This therapy is continued indefinitely [64].

Surgical treatment of the cornea may also be necessary on an urgent basis to treat corneal perforation [33].

Herpes simplex keratitis, even if inactive, is a relative contraindication to laser refractive surgery, although this has been done cautiously with some success [65]. The ultraviolet light used in excimer laser corneal refractive surgery has been associated with recurrent keratitis.

Suppression of recurrence — Recurrent ocular infections with HSV-1 are treated with the same topical agents used for primary infections. Recurrences can lead to corneal scarring and visual impairment in some patients. For patients with frequent or troublesome recurrences of HSV epithelial keratitis, we suggest suppressive oral antiviral therapy with either valacyclovir or acyclovir.

Chronic antiviral therapy reduces the frequency of recurrences in patients taking the drug, but it is not known whether long term sequelae are reduced. Ultimately, decisions regarding chronic prophylactic antivirals are based on individualized assessment of recurrence frequency and severity as well as patient preference [66].

Randomized trials indicate that recurrent infections can be prevented by daily oral suppressive therapy [18,67-69].

In a randomized trial, 703 patients with a history of HSV ocular disease within the preceding year were assigned to either oral acyclovir (400 mg twice daily) or placebo for 12 months [67]. Patients assigned to the acyclovir arm had lower rates of recurrence than patients in the placebo arm (19 versus 32 percent, rate ratio 0.55, 95% CI 0.41-0.75). The magnitude of benefit was greatest in those with more frequent previous recurrences [18]. This effect did not persist after the drug was stopped.

One small randomized study evaluated the efficacy of valacyclovir (one 500 mg tablet daily) compared with acyclovir (one 400 mg tablet twice daily) in 52 immunocompetent patients who had a history of recurrent ocular HSV disease within the past 12 months; both suppressive regimens were found to be similarly efficacious (23 percent of patients with recurrences in both groups) [69].

Long-term acyclovir therapy is well tolerated but has not been studied for ocular HSV. Limiting suppressive treatment to those with more frequent episodes and the threat of vision loss may be a cost-effective approach to management [66]. Suppressive acyclovir has been successful and well tolerated in children and may prevent amblyopia from vision-threatening keratitis [70]. However, there is evidence that long-term oral prophylaxis may predispose to antiviral resistance [71].

There are no vaccines approved by the US Food and Drug Administration (FDA) for HSV. Vaccines for HSV have been studied in animal models, but they may increase the severity of immune stromal disease [72,73]. They have not yet been successful in humans [74-77].

COMPLICATIONS AND RELATED CONDITIONS

Herpes simplex keratouveitis – Uveitis, inflammation of the vascularized intraocular tissues of the iris, ciliary body, and uveal tract, may occur with or without corneal involvement by herpes simplex virus (HSV) infection. Recurrent HSV should lead the differential diagnosis when iritis and keratitis occur together. Isolated herpes simplex iritis may be difficult to diagnose. One feature that distinguishes uveitis due to HSV is the tendency for involvement of the trabecular meshwork, trabeculitis, with resulting increase in intraocular pressure. Uveitis tends to recur and is often not diagnosed as herpetic unless typical corneal lesions appear. Polymerase chain reaction (PCR) of aqueous humor for HSV-1 or HSV-2 DNA can be helpful in diagnosis, although it requires an anterior chamber paracentesis to be performed by an ophthalmologist [78].

Post-infectious epithelial disease – Following resolution of active epithelial infection, the corneal epithelium may be unstable. Punctate epithelial staining with fluorescein or lissamine green dye is common. Recurrent corneal erosions and intermittent sloughing of corneal epithelium without recurrent HSV infection may occur and may be provoked by use of topical ocular medications, such as antivirals and preserved glaucoma drops.

Neurotrophic keratopathy – This term refers to a condition of persistent non-healing corneal epithelial defects associated with corneal hypoesthesia or anesthesia [49,79]. These oval defects do not represent active viral disease and are made worse by antiviral drops. These non-healing lesions can lead to stromal scarring, corneal perforation, or secondary bacterial infection. These lesions may be distinguished from recurrent epithelial infection by the typical morphology on slit lamp examination and by the lack of Rose Bengal staining at their edges.

RISK OF TRANSMISSION TO OTHERS — For patients with herpes simplex keratitis, the risk of transmitting herpes simplex virus (HSV) to others from the infected eye is thought to be low. However, persons with HSV keratitis are likely to also have infection elsewhere and risk of transmission from those sites should be considered. As HSV is usually transmitted by mucosal contact, transmission of the virus would not be expected from ocular secretions alone. However, individuals with herpes keratitis may harbor HSV elsewhere (eg, oral secretions) and may transmit HSV from these sites. In addition, transmission from asymptomatic donors to corneal transplant recipients has been reported [80].

SUMMARY AND RECOMMENDATIONS

Pathogenesis – Keratitis (corneal infection and inflammation) caused by herpes simplex virus (HSV) is a major cause of blindness from corneal scarring and opacity worldwide. Most ocular disease is thought to represent HSV reactivation rather than a primary ocular infection. Corneal disease results from active infection, inflammation, and immune reaction to past infection. (See 'Pathogenesis' above.)

Classification – Herpes simplex keratitis has been classified in four categories: infectious epithelial keratitis, stromal keratitis, endotheliitis, and neurotrophic keratopathy. Epithelial disease is most common, manifested as dendritic lesions or geographic ulcerations of the cornea. (See 'Findings by disease type' above.)

Diagnosis – The diagnosis of herpes simplex keratitis is largely clinical. Patients often present with an acute onset of variable symptoms including pain, visual blurring, photophobia, watery ocular discharge, and often a red eye. Physical examination is notable for conjunctivitis, decreased corneal sensation, and characteristic dendritic lesions of the cornea (picture 1). Serologic testing is not useful. (See 'Clinical manifestations' above and 'Diagnosis' above.)

Subsequent disease – Stromal keratitis accounts for 20 to 60 percent of recurrent corneal disease. Immune (non-necrotizing) keratitis usually presents as immune-mediated stromal inflammation without concurrent epithelial disease. Necrotizing stromal keratitis is due to active viral infection and may progress to corneal perforation. (See 'Subsequent disease' above.)

Management – The treatment of herpes simplex keratitis is dependent upon whether the episode of disease is caused by active viral replication (epithelial herpes simplex keratitis) or immune response to past infection (stromal keratitis or endotheliitis). Topical glucocorticoids should not be used when active HSV epithelial disease is present. (See 'Management' above.)

For patients with epithelial herpes simplex keratitis, we suggest antiviral therapy (Grade 2C). Oral and topical antivirals are equally effective, but oral agents are more convenient to use. Oral acyclovir (400 mg five times daily), or valacyclovir (500 mg three times daily) can be used. Valacyclovir has the advantage of less frequent dosing but may be more expensive than acyclovir. Treatments can be stopped one week after healing of the lesions. (See 'Epithelial keratitis' above.)

For patients with stromal keratitis, we suggest combination therapy with a topical glucocorticoid and antiviral treatment (Grade 2C). Commonly used topical glucocorticoids include prednisolone acetate 1%, dexamethasone 0.1%, and loteprednol 0.5%. (See 'Stromal keratitis or endotheliitis' above.)

Suppression of recurrence – We suggest that patients with frequent or troublesome recurrences of HSV epithelial keratitis receive ongoing suppressive oral antiviral therapy with either valacyclovir or acyclovir (Grade 2B). Valacyclovir is given 500 mg once daily and acyclovir 400 mg twice daily. (See 'Suppression of recurrence' above.)

Surgical treatment – Patients who have significant vision impairment due to corneal scarring from keratitis may require corneal transplantation. Concurrent long-term use of oral acyclovir improves corneal graft survival. (See 'Surgical treatment in select patients' above.)

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Topic 6896 Version 37.0

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