Corticosteroides como tratamiento adyuvante para la toxoplasmosis ocular
Resumen
Antecedentes
La infección ocular por Toxoplasma gondii, un parásito, puede dar lugar a inflamación en la retina, la coroides y la úvea y en consecuencia provocar complicaciones como glaucoma, cataratas y sinequia posterior.
Objetivos
El objetivo de esta revisión sistemática fue evaluar los efectos del uso complementario de corticosteroides con el tratamiento antiparasitario versus el tratamiento antiparasitario solo para la toxoplasmosis ocular.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL (que contiene el Registro Cochrane del Grupo Cochrane de Trastornos de los Ojos y la Visión [Cochrane Eyes and Vision Group] [2016; número 11]), MEDLINE Ovid, Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, MEDLINE Ovid Daily (enero de 1946 a diciembre de 2016), Embase (enero de 1980 a diciembre de 2016), Latin American and Caribbean Literature on Health Sciences (LILACS (enero de 1982 a diciembre de 2016)), el registro ISRCTN (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), y la International Clinical Trials Registry Platform de la Organización Mundial de la Salud (OMS) (ICTRP; www.who.int/ictrp/search/en). En las búsquedas electrónicas de ensayos, no se aplicaron restricciones de fecha o idioma. Se buscó por última vez en las bases de datos electrónicas el 7 de diciembre de 2016.
Criterios de selección
Se planificó incluir ensayos controlados aleatorizados o cuasialeatorizados. Los ensayos elegibles deberían haber incluido a participantes de cualquier edad inmunocompetentes y con diagnóstico de toxoplasmosis ocular activa. Los ensayos incluidos deberían haber comparado el tratamiento antiparasitario más corticosteroides versus tratamiento antiparasitario solo, o diferentes dosis o momentos de inicio de los corticosteroides.
Obtención y análisis de los datos
Dos autores, de forma independiente, realizaron la selección de los títulos y resúmenes obtenidos mediante las búsquedas electrónicas. Se recuperaron los informes de texto completo de los estudios categorizados como “no se está seguro” o “incluir” después que se examinaron los resúmenes. Dos autores, de forma independiente, revisaron cada informe completo para determinar su elegibilidad. Los desacuerdos se resolvieron mediante discusión.
Resultados principales
No se identificaron ensayos finalizados o en curso que fueran elegible para esta revisión Cochrane.
Conclusiones de los autores
Aunque los estudios de investigación identificaron una variación amplia en las prácticas con respecto al uso de corticosteroides, la revisión sistemática no identificó evidencia de ensayos controlados aleatorizados sobre la función de los corticosteroides en el tratamiento de la toxoplasmosis ocular. En este contexto, hay varias preguntas que siguen sin respuesta en ensayos aleatorizados bien realizados, entre ellas si el uso de corticosteroides como agente coadyuvante es más eficaz que el uso del tratamiento antiparasitario solo; en caso afirmativo, cuándo se deben iniciar los corticosteroides en el régimen de tratamiento (ciclo de tratamiento temprano versus tardío), y cuál sería la mejor dosis y duración del uso de los esteroides.
PICO
Resumen en términos sencillos
Corticosteroides para la infección por toxoplasma en el ojo
¿Cuál fue el objetivo de esta revisión?
El objetivo de esta revisión Cochrane fue averiguar si el uso de fármacos (corticosteroides) para reducir el edema (inflamación) junto con el tratamiento estándar de la toxoplasmosis en el ojo produjo un alivio más rápido de los síntomas y una mejor visión, en comparación con el tratamiento estándar solo. Los investigadores de Cochrane buscaron todos los estudios relevantes para responder a esta pregunta y no encontraron estudios.
Mensajes clave
Actualmente no hay evidencia a favor o en contra del uso de corticosteroides, además del tratamiento estándar, para acelerar la recuperación y prevenir la pérdida de la visión en los pacientes con toxoplasmosis en el ojo.
¿Qué se estudió en esta revisión?
La toxoplasmosis es una infección causada por un parásito llamado Toxoplasma gondii. Los pacientes pueden contraer toxoplasmosis por comer carne que no ha sido cocinada adecuadamente o por comer alimentos o beber agua contaminada con heces, en particular, heces de gato. La toxoplasmosis puede afectar a diferentes partes del cuerpo, incluyendo el ojo. No todos los pacientes infectados por el toxoplasma presentarán síntomas en el ojo. Sin embargo, algunos pacientes se pueden ver afectados gravemente y pueden tener una pérdida grave de la visión.
Los pacientes con infección por toxoplasma suelen tomar fármacos antiparasitarios o antibióticos que matan el parásito. También pueden utilizar corticosteroides para reducir el edema en el ojo (inflamación). El uso de corticosteroides puede dar lugar a un alivio más rápido de los síntomas y a una mejor visión.
¿Cuáles son los principales resultados de la revisión?
Los investigadores de Cochrane buscaron en múltiples bases de datos electrónicas estudios sobre el agregado de corticosteroides al tratamiento estándar de la toxoplasmosis en el ojo. No se encontraron estudios relevantes
Los pacientes afectados por el toxoplasma, y los médicos y personal de enfermería que los tratan, necesitan evidencia para saber si es útil tomar corticosteroides para la toxoplasmosis en el ojo. Necesitan más información sobre cuánto tomar, durante cuánto tiempo y cuándo empezar a tomarlos junto con el tratamiento estándar. Los estudios futuros deben reunir información sobre resultados pertinentes para los pacientes afectados por la afección, como el tiempo que se tarda en recuperarse de los signos y síntomas de la pérdida de la visión.
¿Cuán actualizada está esta revisión?
Los investigadores Cochrane buscaron estudios publicados hasta el 7 de diciembre de 2016.
Authors' conclusions
Background
Description of the condition
Toxoplasmosis is an infection caused by the Toxoplasma gondii parasite. It affects people of various age groups and is prevalent worldwide (Klaren 2002). It is estimated that in the United States alone, 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 to be 0.8 per 100,000/year, with the incidence as high as 29.3 per 100,000/year in West Africa (Gilbert 1999).
Cats are the primary hosts for toxoplasma. The parasite is transmitted to humans through ingestion of contaminated food, water, or uncooked or under‐cooked meat. Passing through the intestinal wall, the organism enters the blood stream and establishes itself as cysts in various organs. Transplacental transmission from mother to child results in a congenital form of this infestation.
Ocular manifestations are seen in both congenital and acquired toxoplasmosis. These include focal inflammation and necrosis of the retina and choroid (retinochoroiditis), scarring and atrophy of the retina or choroid, and focal inflammation within or around the optic nerve head (papillitis) or the anterior portion of the uvea (anterior uveitis; Folk 1984). 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 (Dodds 2008; Fine 1981). Inflammation surrounding larger retinal blood vessel branches can result in their occlusion. Congenital ocular toxoplasmosis usually occurs bilaterally, whereas acquired toxoplasmosis usually occurs unilaterally. Diagnosis is made through clinical features and detection of antibodies specific to the parasite. Significantly elevated serum antibody levels are both sensitive and specific for diagnosing toxoplasmosis (Papadia 2011).
Description of the intervention
Combination anti‐parasitic therapy with pyrimethamine, sulfadiazine, and clindamycin or azithromycin is considered standard practice in the treatment of ocular toxoplasmosis. Anti‐parasitic therapy is only good at stopping the multiplication of the parasite and does not eliminate it from the human body. A Cochrane review found that the use of antibiotics may reduce the risk of recurrent toxoplasma retinochoroiditis, but that there was inadequate evidence supporting routine use of anti‐parasitic therapy compared with no treatment in terms of better vision‐related outcomes (Pradhan 2016).
Practices related to initiating corticosteroid therapy for patients with ocular toxoplasmosis vary from not using corticosteroids at all, to starting them within three days or a week after anti‐parasitic therapy. The additional value to overall outcomes (for example, time‐to‐resolution of symptoms, improvement in visual acuity, growth of lesions) is not known. Consequently, there is uncertainty regarding the addition of steroids to the therapeutic regimen.
How the intervention might work
Previous case studies indicated that administering corticosteroids alone could result in fulminant toxoplasmosis (Rush 2012; Sabates 1981). Adjunctive corticosteroids have been used in the management of ocular toxoplasmosis. The use of corticosteroids in this condition is believed to suppress the accompanying inflammation, and consequently, to minimize damage to ocular tissues. However, the timing of initiation and the appropriate dose of corticosteroids are important, since they can suppress the immune response to the parasite and increase the risk for severe disease.
Change in visual acuity (VA) may be affected by the location of the lesion or the degree of inflammation associated with toxoplasma infection, or both. Initially, VA may be poor due to associated inflammation of the vitreous, even when the lesion does not affect the macula. The use of steroids may have an effect on the change in VA due to their ability to suppress inflammation, resulting in clearance of the ocular media.
Permanent impairment of VA is most often due to the location and size of the lesion, especially in cases where the lesion affects the foveal or perifoveal region. Generally, once the ocular infestation is controlled, the associated inflammatory reaction also resolves. At this point, VA may return to the baseline level, as long as the lesion does not affect the central foveal region.
Why it is important to do this review
A survey conducted among 1000 US‐based ophthalmologists found wide variations in the practice of adjunctive use of corticosteroids with 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 was to assess the effects of adjunctive use of corticosteroids to anti‐parasitic therapy versus anti‐parasitic therapy alone for ocular toxoplasmosis.
Methods
Criteria for considering studies for this review
Types of studies
We had planned to include randomized and quasi‐randomized controlled trials.
Types of participants
We had planned to include trials that enrolled patients with the following characteristics:
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participants of any age who were immunocompetent and were diagnosed with ocular toxoplasmosis;
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participants who presented with acute manifestations of ocular toxoplasmosis or retinochoroiditis secondary to toxoplasmosis (primary or reactivation).
Types of interventions
We had planned to include trials that assessed corticosteroids as adjunctive therapy to anti‐parasitic therapy for ocular toxoplasmosis: trials that compared the use of corticosteroids versus no corticosteroids, different timing of initiation of corticosteroids (early versus late in the treatment process), or different doses of corticosteroids in combination with anti‐parasitic therapy.
Types of outcome measures
Primary outcomes
The primary outcomes for this review were:
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time‐to‐resolution of symptoms (i.e. redness, light sensitivity, blurry vision, aching, elevated intraocular pressure (IOP) secondary to ocular inflammation); and
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time‐to‐recovery of visual impairment
Secondary outcomes
The secondary outcomes were as follows.
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Change in VA at one month and at three months (whenever available) after start of treatment with corticosteroids. We had planned to include trials that evaluated VA using any measure, and examined the outcome at different follow‐up times (e.g. one year, two years).
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Amount of cells or flare in the anterior chamber and vitreous. Inflammation in the anterior chamber may have been measured using slit‐lamp biomicroscopy, and quantified using various scales, including those postulated by Bloch‐Michel 1987 and Hogan 1959. Posterior chamber inflammation may have been quantified using scales postulated by Nussenblatt 1985, or others.
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Visual acuity worse than 20/200 at one month and at three months after the initiation of treatment.
Adverse outcomes
We had planned to summarize any adverse effects of treatment with corticosteroids that were reported in the included trials.
Search methods for identification of studies
Electronic searches
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register (2016; Issue 12 in The Cochrane Library)), MEDLINE Ovid, MEDLINE Ovid Epub Ahead of Print, MEDLINE Ovid In‐Process & Other Non‐Indexed Citations, MEDLINE(R) Ovid Daily (January 1946 to December 2012), Embase (January 1980 to December 2016), Latin American and Caribbean Literature on Health Sciences (LILACS; January 1982 to December 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 7 December 2016.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), Embase (Appendix 3), LILACS (Appendix 4), ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6), and the ICTRP (Appendix 7).
Searching other resources
We had planned to search reference lists of included trials and to search the Web of Science to identify other studies that may have cited any of the included trials.
Data collection and analysis
Selection of studies
Two review authors independently assessed titles and abstracts of records identified by the electronic searches. Each abstract was classified as: (1) definitely relevant, (2) possibly relevant, or (3) definitely not relevant. We obtained and evaluated full‐text reports of the records corresponding to abstracts classified as (1) or (2). Two authors independently reviewed the full‐text reports and classified each study as: (A) include, (B) awaiting assessment, or (C) exclude. Disagreements were resolved through discussion at each stage. Studies identified as (A) would have been included and further assessed for risk of bias. We had planned to contact the authors of studies classified as (B) for clarification, and reassess these studies as further information became available; however, all studies could be classified without contacting authors. Studies identified by both authors as (C) were excluded and are listed in the 'Characteristics of excluded studies' table, along with reasons for exclusion.
Data extraction and management
The following methods will apply to future updates of the review when we find studies eligible for inclusion.
Two review authors will independently extract data from the 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 risk of bias, following the guidelines provided in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will evaluate risk of bias in the included trials by assessing the following items: sequence generation; allocation concealment; masking of participants, personnel, and outcome assessors; incomplete outcome data; and selective outcome reporting. Each risk of bias domain will be judged as 'low', 'high', or 'unclear' risk of bias, using the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions.
Measures of treatment effect
We will report a summary hazard ratio for time‐to‐event outcomes (time‐to‐recovery). Data on such outcomes will be extracted as either 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 use the generic inverse variance method for data extracted as log hazard ratios. We will report summary risk ratios for dichotomous data (visual acuity worse than 20/200), and mean differences for continuous data (for example, change in visual acuity, number of cells in anterior chamber), with 95% confidence intervals.
Unit of analysis issues
We will refer to the guidelines in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions for unit of analysis issues, as well as for analysis of cross‐over trials (Higgins 2011b). In addition, we will request statistical input from the Cochrane Eyes and Vision 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. Whenever the investigators do not respond within four weeks, we will extract available data from the published report. We will refer to the guidelines in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions for handling missing data (Higgins 2011b). We will not impute data for the purposes of this review.
Assessment of heterogeneity
We will assess clinical and methodological heterogeneity across trials by comparing the study designs, participant characteristics, treatments, and outcome measures. When appropriate, we will combine data from trials in a meta‐analysis, and examine the forest plot for evidence of variable treatment effects in the included trials. We will use the Chi² test and I² statistic to assess heterogeneity. We will examine the Tau² value in a random‐effects model to estimate the between‐study variability in the effect estimates.
Assessment of reporting biases
When the number of studies permits (10 or more), we will examine a funnel plot to assess for any 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 clinical or methodological heterogeneity, we will use a fixed‐effect model to conduct a meta‐analysis when analyzing fewer than three studies, and a random‐effects model when analyzing three or more studies. For substantial statistical heterogeneity across studies (I² > 50%; significant Chi² test of heterogeneity and Tau² values), we will not conduct a meta‐analysis, but will report a narrative summary. We will conduct subgroup analyses as described below to determine sources of heterogeneity.
Subgroup analysis and investigation of heterogeneity
When sufficient data are available, we will conduct subgroup analyses based on baseline lesion size, presence or absence of vitritis, degree of vitritis, type of ocular toxoplasmosis (acquired or congenital), and history of recurrences.
Sensitivity analysis
When there are an adequate number of trials, we will conduct sensitivity analyses to determine the impact of excluding studies of lower methodological quality (including quasi‐randomized trials), and excluding industry‐funded studies and unpublished studies. We will conduct sensitivity analyses to examine the impact of any assumptions made regarding missing data or unit of analysis issues.
Summary of findings
We will use the GRADE approach to assess the certainty of the body of evidence. We will present the summary of the comparative effects between treatments for outcomes with corresponding GRADE assessments in a "Summary of findings" table, as described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011). Two review authors will independently judge the certainty of the body of evidence for each outcome according to the risk of bias in individual trials, indirectness, heterogeneity, imprecision (wide confidence intervals), and publication bias. We will assign each outcome a grade of 'very low', 'low', 'moderate', or 'high' certainty of evidence, and document reasons for downgrading. We will resolve any discrepancy by discussion.
Results
Description of studies
Results of the search
The original electronic searches yielded a total of 372 references (Jasper 2013). After removing duplicate reports, we screened 345 records and excluded 321 records after reading the abstract. We obtained full‐text reports of 21 records for further investigation. After reading the full‐text reports, we identified no studies eligible for this review.
For this review update, we identified 221 additional references from electronic searches as of 7 December 2016 (Figure 1). We excluded 219 records after screening titles and abstracts, and two after reviewing the full‐text report (Baharivand 2013; Balaskas 2012).
Study flow diagram
Included studies
We found no studies that met the inclusion criteria set for this review.
Excluded studies
We excluded 23 studies, either because of ineligible study design, or because the study did not evaluate corticosteroids as adjuvant therapy. Reasons for excluding the studies after full‐text review are listed in the 'Characteristics of excluded studies' table.
Risk of bias in included studies
We found no studies that met the inclusion criteria set for this review.
Effects of interventions
We found no studies eligible for this review.
Discussion
Summary of main results
We conducted a search of several electronic literature databases to identify randomized or quasi‐randomized trials that evaluated the role of corticosteroids in the management of ocular toxoplasmosis. Despite using a sensitive search strategy, we did not identify any such trials. Our search highlighted the lack of rigorous evidence on the adjunctive use of corticosteroids in the treatment of ocular toxoplasmosis.
Overall completeness and applicability of evidence
The current approach for treatment of ocular toxoplasmosis consists of a combination of anti‐parasitic drugs with or without the use of corticosteroids. Most published research suggests widespread use of adjunctive corticosteroids (Acers 1964; Benzina 2005; Bosch‐Driessen 2002; Djurkovic‐Djakovic 1995; Kishore 2001; Lam 1993; Mittelviefhaus 1992; Nozik 1977; Psilas 1990; Raskin 2002; Rothova 1989; Soheilian 2005; Timsit 1987). Several of these published studies examined the effectiveness of different antibiotics for ocular toxoplasmosis. Other variations in practice, such as use of antibiotics alone, have also been reported (Guldsten 1983).
Recent research suggests that there is widespread variation in clinical practice for treating ocular toxoplasmosis. In a cross‐sectional survey of uveitis specialists, 17% of 76 respondents used oral corticosteroids in the treatment of ocular toxoplasmosis in immunocompetent patients, regardless of clinical findings (Holland 2002). The other clinicians used corticosteroids for specific indications, such as severe vitreous inflammatory reaction (71%), decreased vision (59%), proximity of the lesions to the fovea or optic disc (35%), and for large lesions (5%). Prednisone was the most commonly reported corticosteroid (97%), used in varying doses and schedules (started simultaneously with the antibiotics, or started one to seven days after starting the antibiotics). The most popular regimen for the treatment of ocular toxoplasmosis, adopted by 29% of clinicians in this survey, was a combination of antibiotics (pyrimethamine and sulfadiazine) and corticosteroids (Holland 2002). As we noted earlier in this review, such variation in practice was also documented in a more recent cross‐sectional survey of 1000 ophthalmologists (Lum 2005). Oral corticosteroids were started three days after initiating anti‐parasitic therapy in randomized controlled trials that compared different antibiotics for treating ocular toxoplasmosis (Bosch‐Driessen 2002; Soheilian 2005).
There has been a long‐standing debate about the use of corticosteroids in the treatment of ocular toxoplasmosis (O'Connor 1976). Ocular damage in toxoplasma infection has been attributed to the intraocular inflammation that occurs due to tissue damage caused by the organism. Therefore, it is postulated that corticosteroids, because of their anti‐inflammatory properties, may be beneficial for patients with ocular toxoplasmosis. Animal studies have shown that corticosteroids are a useful adjunct to minimize ocular damage. There was no systemic illness or recurrence of ocular inflammation in chronically infected rabbits treated with hydrocortisone (Kaufman 1960).
Potential biases in the review process
We aimed to minimize potential biases in the review process by conducting a highly sensitive search for trials, and following rigorous methods as recommended by Cochrane.
Agreements and disagreements with other studies or reviews
Our findings were consistent with those described in a recently published technology assessment conducted by the American Academy of Ophthalmology (Kim 2012). Our review findings were based on a more comprehensive search than that conducted for the technology assessment described in Kim 2012. Both our review and Kim 2012 concluded that there was no evidence from randomized controlled trials to support or refute the effectiveness of adjunct therapy with steroids to treat ocular toxoplasmosis.
A few non‐randomized studies supported the use of corticosteroids as an adjunct to antibiotic therapy. However, we did not include such studies in this review, and have not conducted a comprehensive search and critical appraisal of evidence from non‐randomized studies. In a retrospective, non‐randomized evaluation of the effectiveness of different treatments for ocular toxoplasmosis, Damms 1993 showed that there was a significant improvement in vision when steroids were used in combination with the antibiotics, in comparison to antibiotic monotherapy. Treatment with steroids was also reported to have improved the visualization of extramacular lesions, due to the improvement in the clarity of the vitreous following steroid use. Hegab 2003 suggested that corticosteroid use should be limited to severe reactions in patients with toxoplasmosis. A major limitation of this study was the lack of data on patients who may have recovered from the infection with antibiotic treatment only, and who had not been reported. The non‐randomized studies also did not provide valid data on the effects of different durations and doses for steroid use, and on disease outcomes. Although animal studies and evidence from non‐randomized studies provided corroborative evidence, they did not provide definitive evidence of the effectiveness of adjunctive corticosteroid use for ocular toxoplasmosis.
Study flow diagram
