Corticosteroids for ocular toxoplasmosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this systematic review is to assess effects of adjunct use of corticosteroids for ocular toxoplasmosis.
Background
Description of the condition
Toxoplasmosis is a parasitic infection common worldwide caused by toxoplasma gondii. Ocular manifestations of infestation are seen in both forms of the disease, congenital and acquired. These include focal inflammation and necrosis of the retina and choroid (retinochoroiditis), scarring and atrophy of retina/choroid, focal inflammation within or around the optic nerve head (papillitis) (Folk 1984), or the anterior portion of the uvea (anterior uveitis). Secondary complications of ocular toxoplasmosis include glaucoma, cataract, posterior synechiae, and as a late complication, aberrant blood vessel formation within the choroid (choroidal neovascularization) and consequent deterioration of vision (Fine 1981). Inflammation surrounding larger retinal blood vessel branches can result in their occlusion. Transmission of this parasite is through ingestion of food contaminated with cat feces. Diagnosis is made through clinical features and detection of antibodies specific to the parasite.
Cats are the primary host for infection with toxoplasma. The parasite is transmitted to humans through ingestion of food contaminated with cat feces or by eating uncooked or under‐cooked meat from other animals infested with cysts from contamination with cat feces. The organism enters the blood stream passing through the intestinal wall and establishes itself as cysts in various organs. A congenital form of this infestation occurs in humans, in which transmission is transplacental. Diagnosis is through clinical features and detection of antibodies specific to the parasite.
Infestation with toxoplasma is prevalent worldwide (Klaren 2002). It is estimated that in the US alone, about 20% to 70% of adults have antibodies (seropositive) specific to the parasite (Anderson 1979). In addition, the incidence of reactivated toxoplasma retinochoroiditis across the world is estimated as 0.8 per 100,000/year with incidence as high as 29.3 per 100,000/year in West Africa (Gilbert 1999).
Description of the intervention/How the intervention might work
Combination anti‐parasitic therapy with pyrimethamine, sulfadiazine and/or clindamycin or azithromycin is considered standard practice in treatment of ocular toxoplasmosis. A different Cochrane systematic review (Gilbert 2002) found inadequate evidence supporting routine use of anti‐parasitic therapy for ocular toxoplasmosis. Adjunct corticosteroids are sometimes used.
Corticosteroids are postulated for use in this condition to suppress the accompanying inflammation and consequently minimize damage to ocular tissues. However, the timing of initiation and appropriate dose of corticosteroids is uncertain since they can also suppress the immune response to the parasite increasing the risk of severe disease.
Individual physicians may elect to start systemic corticosteroid therapy at the same time as anti‐parasitic therapy, five to seven days after anti‐parasitic therapy or other chosen period since initial presentation of disease. However, some physicians feel that it is inappropriate to employ steroid therapy at any time during the course of treatment for ocular toxoplasmosis. The value of adding steroids to the overall outcome parameters (e.g. time to resolution of symptoms, improvement in visual acuity, growth of lesions) is not well known, and hence the uncertainty of the necessity, or lack of it, in adding steroids to the therapeutic regimen.
The change in visual acuity may be affected by the location of lesion and/or the amount of inflammation associated with toxoplasma infection. The acute visual acuity may be poor because of the significant amount of inflammation without the lesion affecting the central macula. The use of steroids may exert an effect in change in visual acuity because of its ability to suppress inflammation.
The permanent impairment in visual acuity is most often due to the location and size of the lesion, expecially in the case where the lesion affects the foveal and perifoveal center. Often, once the ocular toxoplasmosis is controlled, inflammation has to resolve. At that time, if the lesion does not affect the central foveal region, then final visual acuity may return to baseline level.
Why it is important to do this review
A survey conducted among 1000 US‐based ophthalmologists found wide variations in practice with respect to the use of corticosteroids in addition to anti‐parasitic therapy to treat ocular toxoplasmosis (Lum 2005). A systematic review on the effects of corticosteroids for ocular toxoplasmosis will enable adoption of evidence‐based practices.
Objectives
The objective of this systematic review is to assess effects of adjunct use of corticosteroids for ocular toxoplasmosis.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized and quasi‐randomized controlled trials.
Types of participants
We will include clinical trials that have patients of any age who are not immunocompromised and are diagnosed with ocular toxoplasmosis. Selected trials may include patients presenting with either retinochoroiditis secondary to toxoplasmosis (primary or reactivation) or patients with acute manifestations of toxoplasmosis.
Types of interventions
Corticosteroids administered systemically as adjuvant therapy to anti‐parasitic therapy for ocular toxoplasmosis. We will include trials comparing use of corticosteroids versus no corticosteroids, different timing of initiation of corticosteroids ‐ early versus late, or different doses of corticosteroids in combination with anti‐parasitic therapy mentioned above.
Types of outcome measures
Primary outcomes
The primary outcome for this review will be time to recovery from symptoms and signs of visual impairment and ocular discomfort.
Secondary outcomes
The secondary outcomes will be:
1. Change in visual acuity at one month and at three months (whenever available) after start of treatment with corticosteroids. We will include trials evaluating visual acuity using any measure. We will also examine the outcome at different follow‐up times (eg.,one year, two years).
2. Amount of cells/flare in the anterior chamber and vitreous. Inflammation in the anterior chamber may be measured using slit‐lamp biomicroscopy and quantified using various scales including those postulated by Bloch‐Michel 1987; Hogan 1959. Posterior chamber inflammation may be quantified using scales postulated by Nussenblatt 1985, or others.
3. Visual acuity worse than 20/200 at one month and at three months after the initiation of systemic corticosteroids.
Adverse outcomes
We will summarize any adverse effects of treatment with corticosteroids that are reported in the included trials.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) in The Cochrane Library, MEDLINE, EMBASE, Latin American and Caribbean Literature on Health Sciences (LILACS) and the UK Clinical Trials Gateway (UKCTG). There will be no date or language restrictions in the electronic search for trials.
See: Appendices for details of search strategies for CENTRAL, MEDLINE, EMBASE, LILACS and UKCTG.
Searching other resources
We will search reference lists of included trials, run searches in Web of Science to identify other studies that may have cited any of the included trials.
Data collection and analysis
Selection of studies
Both review authors will independently assess titles and abstracts of reports identified by the electronic and manual searches. Each abstract will be classified as (1) definitely include, (2) unsure or (3) definitely exclude. We will obtain and evaluate full‐text copies of articles corresponding to abstracts classified as (1) or (2). After assessing the full‐text we will classify the studies as (A) include, (B) awaiting assessment or (C) exclude. Disagreements will be resolved through discussion. Studies identified as (A) will be included and assessed further for methodological quality. We will contact the authors of studies classified as (B) for clarification and reassess these studies as further information becomes available. Studies identified by both authors as (C) will be excluded and listed in the review along with reasons for exclusion.
Data extraction and management
Two review authors will independently extract data from included trials using data forms developed for this purpose. Disagreements will be resolved through discussion.
Assessment of risk of bias in included studies
Two authors will independently evaluate included trials for methodological quality following guidelines provided in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008a). We will evaluate risk of bias in the included trials by assessing the following parameters: sequence generation, allocation concealment, masking of patients, personnel and outcome assessors, incomplete outcome data and selective outcome reporting. Each parameter will be judged as Yes, No or Unclear.
Measures of treatment effect
We will report summary relative risks for dichotomous data (visual acuity worse than 20/200), and weighted mean differences for continuous data (e.g.: change in visual acuity, number of cells in anterior chamber). We will report a summary hazard ratio for time to event outcomes (time to recovery). Data on such outcomes will be extracted either as log hazard ratios and their standard errors or as observed and expected values and variance using methods described in Parmar 1998, as applicable. We will analyze using the generic inverse variance method for data extracted as log hazard ratios.
Unit of analysis issues
We will refer to guidelines in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008b) for unit of analysis issues as well as for analysis of cross‐over trials. In addition, we will request statistical input from the Cochrane Eyes and Vision Group Editorial Base for analysis of trials involving cross‐over trials or cluster randomized trials.
Dealing with missing data
We will contact the investigators of included trials for any missing data. If the investigators do not respond within four weeks, we will extract available data from the published report. We will refer to guidelines in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (Higgins 2008b) for handling missing data.
Assessment of heterogeneity
We will examine the forest plot for evidence of variable treatment effects in the included trials. We will assess the primary outcome (time to recovery) and the change in visual acuity at one month and at three months by means of a forest plot. We will use the chi‐square test and report an I‐square statistic to assess heterogeneity. We will examine the tau‐square value in a random‐effects model to estimate the between‐study variability in the effect estimates.
Assessment of reporting biases
We will examine a funnel plot to identify evidence of publication bias. If there is a discrepancy in the outcomes mentioned in the protocol and published reports for included trials, we will contact the investigators for additional information.
Data synthesis
If we detect no statistical/methodological heterogeneity, we will use a fixed‐effect model to conduct a meta‐analysis. We will use a random‐effects model to incorporate any statistical heterogeneity (I‐square <= 50%). For substantial statistical heterogeneity (I‐square value > 50%), we will not conduct a meta‐analysis and report a narrative summary.
Subgroup analysis and investigation of heterogeneity
If data are available, we will conduct subgroup analyses based on baseline lesion size.
Sensitivity analysis
We will conduct sensitivity analyses, if there are an adequate number of trials, to determine the impact of exclusion of studies of lower methodological quality, including quasi‐randomized trials, and exclusion of industry‐funded studies and unpublished studies. We will conduct sensitivity analyses to examine the impact of any assumptions made regarding missing data and/or unit of analysis issues.
