Changes

May 2024 — minor update. The dosage regimen for aciclovir has been aligned to the manufacturer's summary of product characteristics. 

Update

Goals

To support primary healthcare professionals to:

• Recognize suspected ocular herpes simplex infection.
• Urgently refer the person to an ophthalmology specialist for confirmation of the diagnosis and appropriate treatment.
• Provide the person with information and advice about ocular herpes simplex infection.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

What is it?

• Herpes simplex virus (HSV) ocular infections can cause inflammation of the retina, iris, cornea, conjunctiva, eyelids, and surrounding skin [Barker, 2008].
  • Infection is usually caused by HSV type 1 (HSV-1), and rarely by HSV type 2 (HSV-2), typically in association with orogenital sex [College of Optometrists, 2021].
  • Infection and inflammation of different parts of the eye causes [College of Optometrists, 2021]:
    • Cornea — keratitis.
    • Iris and associated uveal tract — iritis or iridocyclitis; uveitis.
    • Retina — retinitis.
    • Conjunctiva — conjunctivitis.
    • Eyelids — blepharitis.
    • Surrounding skin — periocular dermatitis.
• Primary HSV ocular infection refers to first-time exposure to HSV in a previously HSV-seronegative person [Sawleshwarkar and Dwyer, 2015], and typically occurs in children under the age of 5 years in the case of HSV-1 [Sanders, 2014].
  • The majority of primary infections are subclinical and asymptomatic (in 94–99% of cases) [de la Parra-Colin, 2013; Sibley, 2020].
  • If symptomatic, it most commonly presents with blepharoconjunctivitis [Rowe et al, 2013; White and Chodosh, 2014; Sibley, 2020].
• Recurrent HSV ocular infection is more common clinically (representing about 95% of cases). It presents in a person with previous HSV infection which when reactivated, leads to a repeated inflammatory response [Azher, 2017].
• Lesions typically affect the cornea, causing keratitis which may affect one or more of the three corneal layers [Rowe et al, 2013; College of Optometrists, 2021]:
  • Epithelial — inflammation is restricted to the superficial layer of the cornea, which causes punctate lesions which may coalesce to form a dendritic ulcer (may be single or multiple). Epithelial keratitis is the most common ocular manifestation of HSV infection, accounting for 50–80% of cases.
  • Stromal — inflammation of the middle layer of the cornea, which may cause oedema, neovascularization, scarring, uveitis, and sometimes raised intraocular pressure. Stromal involvement may be:
    • Non-necrotizing (disciform keratitis) — epithelial oedema overlying an area of stromal thickening.
    • Necrotizing — may be associated with severe complications, such as corneal perforation.
  • Metaherpetic ulcer (trophic keratitis) — causes permanent defects in the epithelial basement membrane.

How is herpes simplex transmitted?

• Herpes simplex virus type 1 (HSV-1) is usually acquired during childhood through direct contact with active orofacial lesions or infected secretions such as saliva or tears, from a person who is actively shedding the virus [White and Chodosh, 2014; PCDS, 2021].
  • HSV-1 viral shedding occurs a mean duration of 4–60 hours from symptom onset, however, asymptomatic shedding and transmission may also occur [Stoopler, 2012; BMJ Best Practice, 2021].
• HSV persists in a latent state in sensory dorsal root ganglia proximal to the site of infection (typically the trigeminal nerve ganglion), where it can remain latent indefinitely, or reactivate in the ophthalmic branch of the trigeminal ganglion resulting in viral shedding at the corneal surface [Tsatsos, 2016; Sibley, 2020; BMJ Best Practice, 2021; College of Optometrists, 2021].
  • Factors that may lead to reactivation of latent HSV include [Tsatsos, 2016] [Poon, 2021]:
    • Corneal injury.
    • Laser photokeratectomy. 
    • Exposure to prolonged and/or bright ultraviolet light. 
    • Emotional stress.
    • Menstruation.
• Perioral HSV infection can also be a risk factor for ocular infections due to autoinoculation, with potential for HSV spread through the trigeminal ganglion [Sanders, 2014; BMJ Best Practice, 2021].
• In addition, the cornea itself can be a reservoir for HSV DNA, and the virus can persist in an infectious state within the cornea causing recurrent ocular infection, even in the absence of spread from the trigeminal ganglion [de la Parra-Colin, 2013].

How common is ocular herpes simplex?

• Ocular herpes simplex infections have an incidence of 5–15 new cases per 100,000 people per year [College of Optometrists, 2021].
  • Long-term US studies of ocular HSV-1 infections have found the mean age for the first episode to be 37 years [Liesegang, 1989].
  • The incidence of epithelial keratitis is six times higher in people who have undergone corneal transplantation (for non-herpetic corneal disease) [de la Parra-Colin, 2013].
• The overall prevalence of ocular herpes simplex in developed countries is 149 cases per 100,000 population [Sibley, 2020].
• Men and women are affected equally [Wilhelmus, 2015].
• Up to 12% of people with ocular herpes simplex have bilateral infection, most commonly in younger age groups [Tsatsos, 2016; Azher, 2017].

What are the complications of ocular herpes simplex?

• Complications of ocular herpes simplex include:
  • Corneal scarring and visual impairment — this may be progressive and irreversible after recurrent ocular herpes simplex infections, and is seen in 18–28% of cases of stromal keratitis.
    • Herpes simplex keratitis is the leading cause of corneal blindness in developed countries.
    • Ocular herpes simplex infection is the most common cause of unilateral corneal blindness worldwide.
    • Overall, 90% of affected eyes maintain a visual acuity of driving level acuity or better, and only 3% develop vision worse than 20/100 or 6/30 [Liesegang, 1991].
  • Corneal perforation — may be a complication of necrotizing stromal keratitis.
  • Secondary infection with bacteria or fungi.
  • Secondary glaucoma following stromal keratitis.
  • Systemic infection, such as aseptic meningitis, encephalitis, or hepatitis (rare; people who are immunocompromised or immunosuppressed are more at risk).

[Liesegang, 1991; Barker, 2008; Rowe et al, 2013; White and Chodosh, 2014; Sibley, 2020; College of Optometrists, 2021]

What is the prognosis of ocular herpes simplex?

• Blepharoconjunctivitis tends to resolve within 2 weeks, and epithelial keratitis tends to resolve in 1–2 weeks. Epithelial keratitis may resolve spontaneously without the need for drug treatment.
• About 25% of people with epithelial keratitis will develop stromal keratitis or iritis.
  • Stromal keratitis has a variable and unpredictable course, and is more likely to lead to complications such as corneal scarring and visual impairment.
• Recurrent ocular herpes simplex infection is common — reported rates are 20% by 2 years; 40% by 5 years; and 67% by 7 years; with the risk increasing after each subsequent episode.
  • A total of 40% of people experience 2–5 relapses in a lifetime, while 11% experience 6–15 relapses.
  • Stromal keratitis is associated with a higher risk of recurrence than epithelial keratitis — the recurrence rate of stromal keratitis is about 10% per year.
  • People with a history of immunosuppression and atopy are also more at risk of recurrent episodes.

[Liesegang, 2001; Barker, 2008; de la Parra-Colin, 2013; Rowe et al, 2013; White and Chodosh, 2014; Sibley, 2020; College of Optometrists, 2021]

When should I suspect ocular herpes simplex infection?

The diagnosis of suspected ocular herpes simplex infection in primary care is clinical based on the person's symptoms and signs. These are usually unilateral (up to 88% of cases), but may be bilateral, especially in children and people who are immunosuppressed or atopic.

• Suspect ocular herpes simplex infection if a person presents with:
  • A past history of ocular herpes simplex infection.
  • A recent history of blepharoconjunctivitis which is not resolving as expected — herpes simplex keratitis tends to occur 1–2 weeks after conjunctivitis and lid disease.
  • Typical symptoms of:
    • Malaise and fever — more common in primary herpes simplex infection.
    • Eye pain — be aware that repeated recurrences may lead to reduced or absent corneal sensation, leading to mild discomfort or no pain.
    • Eye irritation or photophobia.
    • Eye watering — suggests keratitis.
    • Blurred vision — more common with keratitis than iritis.
  • Signs of:
    • An acute red eye. For more information, see the CKS topic on Red eye.
    • Crops of vesicles and ulcers on an erythematous base, or pustules along the lid margin or periocular skin, which eventually crust over.
    • A hazy cornea (due to oedema or scarring from a previous herpes episode) or a localized 'creamy' opacity (suggests stromal keratitis).
    • A fixed irregular pupil or erythema around the whole cornea (limbal injection, suggests iritis or uveitis).
    • Reduced corneal sensitivity — suggests keratitis.
    • Reduced visual acuity.

How should I assess a person with suspected ocular herpes simplex infection?

In a person presenting with suspected ocular herpes simplex:

• Ask about:
  • The location of lesions.
  • The degree and duration of symptoms such as eye pain and blurred vision.
  • A history of previous episodes of ocular herpes simplex.
  • A history of contact lens use.
  • Known trigger factors for recurrent episodes, such as ultraviolet light, physical or emotional stress, fatigue, fever, menstruation, immunosuppression such as topical or systemic corticosteroids (including inappropriate or excessive use), extremes in temperature, eye trauma, or trigeminal nerve manipulation surgery.
  • Any associated complications.
  • Any underlying medical conditions that may affect the course of herpes simplex infection, such as immunosuppression or atopy.
• Examine the eyes and periocular skin for:
  • Conjunctival injection (red eye).
  • Crops of vesicles and ulcers on an erythematous base, or pustules along the lid margin or periocular skin, which may be crusting.
  • A hazy cornea (due to oedema or scarring from a previous herpes episode) or a localized 'creamy' opacity (suggests stromal keratitis).
  • A fixed irregular pupil or erythema around the whole cornea (limbal injection) suggests iritis.
  • Reduced corneal sensation, if felt necessary and appropriate — this should produce brisk blepharospasm (if reduced, suggests epithelial keratitis).
• Perform a general examination to check for:
  • Pyrexia, regional (pre-auricular) lymphadenopathy, and hepatosplenomegaly, which may indicate generalized herpes simplex infection (more common in people who are immunosuppressed or atopic).
• Stain the cornea with fluorescein:
  • A fine, linear branching lesion (dendritic ulcer) or wider linear appearance (amoeboid ulcer) may indicate significant epithelial involvement. Note: the absence of dendritic ulceration does not exclude a diagnosis of herpes simplex keratitis.
• Test visual acuity using a Snellen chart.
• Laboratory investigations are not necessary in primary care.

What else could it be?

• Other conditions that may present similarly to ocular herpes simplex include other causes of acute red eye, such as:
  • Herpes zoster ophthalmicus — vesicular rash in the distribution of the ophthalmic division of the fifth cranial nerve; rarely recurrent; typically affects older people. For more information, see the CKS topic on Shingles.
  • Orbital cellulitis — eye pain, blurred vision, double vision, limited and painful eye movements, headache, fever, and malaise. For more information, see the CKS topic on Cellulitis— acute.
  • Acute glaucoma — painful red eye, blurred vision, and headache, typically in a person older than 50 years of age. The pupil may be semi-dilated, fixed, and oval in shape. For more information, see the CKS topic on Glaucoma.
  • Iritis or uveitis (from other causes) — see the CKS topic on Uveitis.
  • Scleritis or episcleritis — inflammation of the sclera or episclera causing red eye, eye pain, visual disturbance, and photophobia.
  • Keratitis due to other infections — such as Epstein-Barr virus and adenovirus, chlamydia, and Acanthamoeba protozoan infection (which is more common in contact lens wearers).
  • Conjunctivitis — may cause bilateral red eye with purulent discharge. For more information, see the CKS topic on Conjunctivitis - infective.
  • Corneal abrasion — may be a history of eye trauma, usually presents with eye pain, watering, and a sensation of a foreign body in the eye. May have a stellate or dendritic appearance of the cornea on fluorescein staining. For more information, see the CKS topic on Corneal superficial injury.
• For more detailed information on the differential diagnosis of acute red eye, see the CKS topic on Red eye.

Scenario: Management

From age 1 month onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of herpes simplex ocular.

Search dates

September 2016 - July 2021

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp Herpes simplex ocular/diagnosis*,etiology,therapy*
• Herpesvirus 1, Human*
• Antiviral Agents / therapeutic use*
• Keratitis, Herpetic / diagnosis*
• “Eye herpes” or” Ocular herpes” or Keratitis or HSV.ti,ab

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.