Abstract
Introduction
Ocular infection with herpes simplex virus (HSV) is usually acquired early in life, with 50% of people from higher and 80% from lower socioeconomic groups in the USA having antibodies by the age of 30 years. Attacks usually resolve spontaneously within 1−2 weeks, but 50% of people will experience a recurrence within 10 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with epithelial keratitis? What are the effects of treatments in people with stomal keratitis? What are the effects of interventions to prevent recurrence of ocular herpes simplex? What are the effects of interventions to prevent recurrence of ocular herpes simplex in people with corneal grafts? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found seven systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding oral aciclovir to topical corticosteroids plus topical antiviral treatment; adding topical corticosteroids to topical antiviral treatment; antiviral agents (topical); debridement; interferons (topical); and oral aciclovir.
Key Points
Ocular infection with HSV can cause inflammation of the eyelids, conjunctivae, iris, retina, and cornea.
Infection is common and usually acquired early in life, with 50% of people from higher and 80% from lower socioeconomic groups in the USA having antibodies by the age of 30 years.
HSV epithelial keratitis tends to resolve spontaneously within 1–2 weeks, while stromal keratitis is more likely to result in corneal scarring and loss of vision. Stromal keratitis or iritis occurs in about 25% of people after epithelial keratitis.
Recurrence of ocular herpes (epithelial or stromal) for people with one episode is 10% at 1 year, 23% at 2 years, and 50% at 10 years.
Topical antiviral agents and topical interferons increase healing of epithelial keratitis compared with placebo.
Physicochemical debridement or interferon may speed up healing if added to antiviral agents, but we don't know whether debridement is effective when used alone.
When added to topical antiviral agents, topical corticosteroids reduce progression and shorten the duration of stromal keratitis compared with placebo.
Adding oral aciclovir to topical corticosteroids plus topical antiviral treatment may not increase healing compared with topical treatment alone.
Long-term oral aciclovir treatment in people with previous ocular epithelial or stromal keratitis reduces recurrence after 1 year compared with placebo.
Short-term prophylaxis (for 3 weeks) with oral aciclovir does not seem to reduce the risk of recurrence.
We don't know whether oral aciclovir reduces recurrence of ocular herpes simplex infection after corneal grafts.
About this condition
Definition
Ocular herpes simplex is usually caused by herpes simplex virus type 1 (HSV-1) but also occasionally by the type 2 virus (HSV-2). Ocular manifestations of HSV are varied and include blepharitis (inflammation of the eyelids), canalicular obstruction, conjunctivitis, corneal complications, iritis, and retinitis. Corneal complications are of two main types: epithelial keratitis is inflammation of the cells that form the surface layer of the cornea, and stromal keratitis is inflammation of the middle layer (stroma) of the cornea. HSV infections are classified as neonatal, primary (HSV in a person with no previous viral exposure), and recurrent (previous viral exposure with humoral and cellular immunity present).
Incidence/ Prevalence
Infections with HSV are usually acquired in early life. A US study found antibodies against HSV-1 in about 50% of people with high socioeconomic status and 80% of people with low socioeconomic status by age 30 years. It quoted a report which suggested overcrowding as a causal factor. However, only about 20–25% of people with HSV antibodies had any history of clinical manifestations of ocular or cutaneous herpetic disease. Ocular HSV is the most common cause of corneal blindness in high-income countries, and is the most common cause of unilateral corneal blindness worldwide. A 33-year study of the population of Rochester, Minnesota found that the annual incidence of new cases of ocular herpes simplex was 8.4/100,000 (95% CI 6.9/100,000 to 9.9/100,000), and the annual incidence of all episodes (new and recurrent) was 20.7/100,000 (95% CI 18.3/100,000 to 23.1/100,000). The prevalence of ocular herpes was 149/100,000 population (95% CI 115/100,000 to 183/100,000). Twelve per cent of people had bilateral disease.
Aetiology/ Risk factors
Epithelial keratitis results from productive, lytic viral infection of the corneal epithelial cells. Stromal keratitis and iritis are thought to result from a combination of viral infection and compromised immune mechanisms. Observational evidence (346 people with ocular HSV in the placebo arm of an RCT) showed that a previous history of stromal keratitis was a significant risk factor for the recurrence of stromal keratitis (proportion of people with recurrence: 6/174 [4%] without previous stromal keratitis v 53/172 [32%] with previous stromal keratitis; RR 10.0, 95% CI 4.3 to 23.0; P less than 0.001).Age, sex, ethnicity, and previous history of non-ocular HSV disease were not associated with an increased risk of recurrence.
Prognosis
HSV epithelial keratitis tends to resolve spontaneously within 1–2 weeks, while stromal keratitis is more likely to result in corneal scarring and loss of vision. In a trial of 271 people treated with topical trifluorothymidine and randomly assigned to receive either oral aciclovir or placebo, the epithelial lesion had resolved completely or was at least less than 1 mm after 1 week of treatment with placebo in 89% of people, and after 2 weeks in 99% of people. Stromal keratitis or iritis occurs in about 25% of people after epithelial keratitis. The effects of HSV stromal keratitis include scarring, tissue destruction, neovascularisation, glaucoma, and persistent epithelial defects. The rate of recurrence of ocular herpes (epithelial or stromal) for people with one episode is 10% at 1 year, 23% at 2 years, and 50% at 10 years. The risk of recurrent ocular HSV infection (epithelial or stromal) also increases with the number of previous episodes reported (2 or 3 previous episodes: RR 1.41, 95% CI 0.82 to 2.42; 4 or more previous episodes: RR 2.09, 95% CI 1.24 to 3.50). Of penetrating corneal grafts performed in Australia over a 22-year period, 4% were in people with visual disability, with active corneal disease, or with actual or impending perforation after stromal ocular herpes simplex. Of the penetrating corneal grafts reported by The Australian Corneal Graft Registry that failed, the ocular herpes simplex was a cause for failure in 4% of cases.
Aims of intervention
To reduce the morbidity of HSV keratitis and iritis; to reduce the risk of recurrent disease; and to improve corneal graft survival after penetrating keratoplasty, with minimal adverse effects of treatment.
Outcomes
Healing time; severity and duration of symptoms; severity of complications; rates of recurrence; corneal graft survival, adverse effects of treatment.
Methods
BMJ Clinical Evidence search and appraisal July 2007. The following databases were used to identify studies for this review: Medline 1966 to July 2007, Embase 1980 to July 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We did not exclude studies described as “blinded”, “open”, “open label”, or not blinded. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table 1.
GRADE evaluation of interventions for ocular herpes simplex
| Important outcomes | Healing rates, recurrence rates, treatment failure, graft failure. | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in people with epithelial keratitis? | |||||||||
| At least 11 (at least 435) | Healing rates | Topical antiviral agents v placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for unclear measurement of outcomes |
| At least 16 (at least 856) | Healing rates | Topical antiviral agents v each other | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for unclear measurement of outcomes |
| At least 2 (at least 105) | Healing rates | Physicochemical debridement v placebo or no treatment | 4 | –1 | 0 | –2 | 0 | Very low | Quality point deducted for sparse data. Directness points deducted for variety of treatments used limiting applicability of summary results, and unclear measurement of outcomes |
| At least 7 (at least 269) | Healing rates | Physicochemical debridement plus antiviral agents (primarily topical) v physicochemical debridement alone | 4 | 0 | 0 | –2 | +1 | Moderate | Directness points deducted for variety of treatments used limiting applicability of summary results, and unclear measurement of outcomes. Effect-size point added for OR greater than 2 |
| At least 7 (at least 305) | Healing rates | Physicochemical debridement plus topical antiviral agents v topical antiviral agents alone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for variety of treatments used limiting applicability of summary results, and unclear measurement of outcomes |
| 1 (25) | Healing rates | Physical debridement plus topical aciclovir v physical debridement plus topical idoxuridine | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for unclear measurement of outcome |
| At least 3 (at least 178) | Healing rates | Topical interferons v placebo | 4 | 0 | 0 | –2 | +1 | Moderate | Directness points deducted for two interventions included in comparison, and unclear measurement of outcome. Effect-size point added for OR greater than 2 |
| At least 3 (at least 85) | Healing rates | Topical interferons v topical antiviral agents | 4 | –1 | 0 | -1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for unclear measurement of outcome |
| At least 8 (at least 401) | Healing rates | Topical interferons plus topical antiviral agents v topical antiviral agents alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for unclear measurement of outcome |
| What are the effects of treatments in people with stromal keratitis? | |||||||||
| 1 (106) | Healing rates | Adding topical corticosteroids to topical antiviral agents v adding placebo to topical antiviral agents | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and unclear follow-up |
| 1 (104) | Treatment failure | Adding oral aciclovir to topical corticosteroids plus topical antiviral agents v adding placebo to topical corticosteroids plus topical antiviral agents | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for composite outcome |
| What are the effects of interventions to prevent recurrence of epithelial or stromal ocular herpes simplex? | |||||||||
| 2 (779) | Recurrence rates | Long-term (1 year) oral aciclovir v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and sub-group analysis. Directness point deduction for inclusion of co-intervention (topical aciclovir) |
| 1 (287) | Recurrence rates | Short-term (3 weeks) oral aciclovir v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| What are the effects of interventions to prevent recurrence of ocular herpes simplex in people with corneal grafts? | |||||||||
| 1 (22 people, 23 eyes) | Recurrence rates | Oral aciclovir v placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and lack of blindingl. Directness point deducted for difference in mean follow-up length of groups |
| 1 (22 people, 23 eyes) | Graft failure | Oral aciclovir v placebo | 4 | –2 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data and lack of blinding |
Type of evidence: 4 = RCT; 2 = Observationa. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- Keratoplasty
A procedure in which diseased corneal tissue is removed and replaced by donor corneal material.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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