EUROTOXO European TOXO PREVENTION Project Prevention of Congenital Toxoplasmosis: A European initiative on the state-of-science
Systematic review of published studies evaluating postnatal treatment effect (Panel 2: treatment issues) Rodolphe Thiébaut, Hélène Bricout, Sabrina Di Costanzo, Evelyne Mouillet, and EUROTOXO panel 2 experts Full report Version August 25th, 2005
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Suggested Citation: Thiébaut R, Bricout H, Di Costanzo S, Mouillet E, Eurotoxo panel 2 experts. Systematic review of published studies evaluating postnatal treatment effect [Unpublished report]. Bordeaux (France): The Eurotoxo Group; 2005.
Correspondence regarding this report: Dr Rodolphe THIEBAUT INSERM Unité 593 & E0338 Université Victor Segalen Bordeaux 2 146 rue Léo Saignat Case 11 33076 BORDEAUX Cedex France Tel.: +33 5 57 57 45 21 Fax. : +33 5 57 57 11 72 Mel :
[email protected]
The Eurotoxo project is financed by the European Commission (Contract No. QLG4-CT-2002-30262).
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TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................... 3 INTRODUCTION ............................................................................................................... 4 BACKGROUND .................................................................................................................... 4 OBJECTIVES ........................................................................................................................ 4 METHODS........................................................................................................................... 5 SELECTION CRITERIA .......................................................................................................... 5 Study design................................................................................................................... 5 Study population criteria ............................................................................................... 5 Type of intervention considered .................................................................................... 5 OUTCOMES OF INTEREST..................................................................................................... 5 BIBLIOGRAPHIC SEARCH .................................................................................................... 6 DATA EXTRACTION ............................................................................................................. 6 DATA SYNTHESIS ................................................................................................................ 6 RESULTS ............................................................................................................................. 7 RESULTS OF THE LITERATURE SEARCH ............................................................................... 7 CHARACTERISTICS OF SELECTED PAPERS .......................................................................... 10 TREATMENT EFFECT ACCORDING TO THE PUBLISHED STUDIES.......................................... 11 STUDY QUALITY ASSESSMENT .......................................................................................... 13 DESCRIPTION OF SPECIFIC STUDIES ................................................................................... 13 Studies with highest quality score ............................................................................... 13 Other studies................................................................................................................ 14 DISCUSSION..................................................................................................................... 17 FINDINGS .......................................................................................................................... 17 Information lacking ..................................................................................................... 17 Information available but with limits .......................................................................... 17 Available evidence....................................................................................................... 17 RECOMMENDATIONS ........................................................................................................ 17 CONCLUSION .................................................................................................................. 18 REFERENCES .................................................................................................................. 19 APPENDICES.................................................................................................................... 25 APPENDIX 1. STUDY SELECTION FORM.............................................................................. 25 APPENDIX 2. DATA EXTRACTION FORM ............................................................................ 26 APPENDIX 3. STUDY QUALITY ASSESSMENT FORM ............................................................ 29
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INTRODUCTION
Background The EUROTOXO project is a European consensus initiative to define the implications of current scientific knowledge for a research agenda and policy decisions on how best to prevent congenital toxoplasmosis and its consequences. One part of this project concerns the effect of post-natal treatment on the disease and its consequences. Diagnosing and treating asymptomatic children after their birth stay upon the assumption that treatment is beneficial on either acute symptoms or in preventing later reactivation. The reported incidence of clinical signs was about 80% in 1980’s (Wilson 1980, Koppe 1986) from studies including few children (N=24 and N=12, respectively), most often not treated. Recent evaluation of clinical signs incidence in treated children is approximately 20% up to 6 years of age (Guerina 1994, Lebech 1999, Binquet 2003, Pediatrics 2004). However, no conclusion can be drawn from such historical comparison because those studies might differ by several characteristics and in particular the selection criteria are different (systematic screening with recent biological tools vs. referred cases). Therefore, we performed a systematic review of studies comparing different postnatal treatment strategies including or not an untreated group.
Objectives To review published studies evaluating postnatal treatment effect on congenital toxoplasmosis outcomes.
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METHODS
Selection criteria Study design All concurrent comparative studies of treatment in humans were included (observational or randomised).
Study population criteria We included studies that were based on children and/or adults with toxoplasmosis. Studies based on patients with congenital or postnatally acquired toxoplasmosis were included because the timing of infection in prenatal or postnatal period can rarely be determined in ophthalmic patients and we had no a priori evidence to suggest that the effect of treatment would differ in these groups. We excluded studies in which the majority of patients were immune-compromised.
Type of intervention considered We included studies that compared any type of treatment with no treatment or placebo, and studies that compared different types of treatment. Type of intervention considered. Antitoxoplasma treatment included Spiramycin, Clarithromycin, Roxithromycin, Azithromycin, Erithromycin, Macrolides, Miocamycin, Clindamycin, Lincomycin, Ketolides, Sulfadiazine, Sulfamethoxazole, Sulfadoxine, Sulfisoxazole, Sulfamerazine, Sulfonamide, Dapsone, Leucovorin, Pyrimethamine, Trimethoprim, Trimetrexate, Methotrexate, Atovaquone, Tetracycline, Doxicycline, Minocycline, Ciprofloxacin, Nifurtimox, Cyclines, and Quinolone drugs. Treatments were considered whatever their amount and their administration method. Treatment given to alleviate symptoms of ocular toxoplasmosis was only considered if it was given in combination with anti-toxoplasma treatment and compared with an alternative treatment or no treatment.
Outcomes of interest Outcomes of interest were eye manifestations (occurrence, evolution or recurrence of retinochoroiditis lesions), neurological impairment (encephalitis, intracranial calcifications, hydrocephalus, seizures and psychomotor retardation), deafness, myocarditis, polymyositis.
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Bibliographic Search We used the following databases: OldMedline (from 1950 to 1965), Medline (from 1966 to 2004), Embase (from 1980 to 2004) and Pascal biomed (from 1984 to 2004). The research was made with the Webspirs® software. The list of selected papers was proposed to the panellists of panel 2 to check if any study they known was potentially missing. Searches used the following keywords: ((Toxoplasmosis) and (Spiramycin or Clarithromycin or Roxithromycin or Azithromycin or Erithromycin or Macrolid* or Miocamycin or Clindamycin or Lincomycin or Ketolid* or Sulfadiazine or Sulfamethoxazole or Sulfadoxine or Sulfisoxazole or Sulfamerazine or Sulfonamide or Dapsone or Leucovorin or Pyrimethamine or Trimethoprim or Trimetrexate or Methotrexate or Atovaquone or Tetracycline or Doxicycline or Minocycline or Ciprofloxacin or Nifurtimox or cyclin* or quinolon*)) not (HIV infections or AIDS). There was no language restriction.
Data extraction Abstracts were scanned by two reviewers (RT and HB) and potentially eligible studies were retrieved in hard copy. Assessment of each study against the inclusion criteria and extraction of data was done independently by two of three reviewers (RT, HB, SDC) using the forms in appendix 1 and 2. In addition, two panellists contributed to the selection of studies and data extraction for papers in languages other than English or French (Uwe Gross, Francis Deroin). Quality of the studies was assessed by a quality assessment form, which was especially built for this work (Appendix 3). We recorded the following characteristics of the study quality: i) design of the study (randomization, masked evaluation), ii) selection procedures (inclusion, exclusion), conduct of the study (withdrawal, outcome measurement), analysis (adjustment for confounding factors). In addition, an overall assessment was noted 0 for unacceptable, 1 for weak but acceptable, 2 for good and 3 for very good quality. This notation was performed by the reviewer helped by the specific items checked in the quality assessment form. The final quality score was the result of a personal reviewer evaluation and not a combination of item results. For each study, the evaluation was performed by two reviewers and a third one if necessary.
Data synthesis Because of the heterogeneity in the study design, population, intervention, and outcomes evaluated, no meta-analysis was done. However, when possible, a relative risk and its confidence interval were calculated.
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RESULTS
Results of the literature search Searches identified 2321 abstracts from which 59 potentially eligible studies were retrieved (Figure 1). One further study that was suggested by a panelist was also retrieved but was eventually excluded (after contacting the first author Dr C. Binquet) because there was no comparison group. Five of 59 papers could not be evaluated because a translation could not be done or the paper was not available.
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Figure 1. Results of the literature search.
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References found with Webspirs N = 2321
Main reasons for exclusion N = 2262 Studies involved immunosuppressed patients, animals, etc
Selected abstracts: 59 Abstracts added by the panel: 1 Articles not ordered N=1 In Chinese language
Ordered articles N = 59
Included articles N = 22 21 articles 1 abstract
Excluded articles N = 32
Articles not evaluated N=5
14 without any comparison 5 concerning patients with immunosuppressive disorder 4 concerning prenatal treatment 4 case series 2 literature review 2 concerning experimentation on animals 1 author note
2 in Portuguese 2 never received 1 in Polish
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Characteristics of selected papers Papers selected were published between 1961 and 2002. Locations of the studies were Europe (Belgium, France, Germany, Greece, Netherlands, United Kingdom), USA (Baltimore, Chicago), South America (Brazil, Venezuela) and North Africa (Tunisia). We found 7 randomised controlled trials (Abreu 1988, Acers 1964, Bosch-Driessen 2002, Colin 1989, Jeddi 1997, Perkins 1956, Silveira 2002), 11 prospective cohort studies (Chodos 1961, Couvreur 1980, Couvreur 1984, Crespo 1993, Fortier 1997, Mets 1996, Patel 1996, Rothova 1993, Timsit 1987, Villena 1998, Wallon 2001) and 4 retrospective case series (Damms 1993, Opremack 1992, Théodossiadis 1989, Wilson 1980). 13 studies involved patients (mostly adults) that presented to ophthalmologists with toxoplasma retinochoroiditis (Abreu 1988, Acers 1964, Bosch-Driessen 2002, Chodos 1961, Colin 1989, Damms 1993, Jeddi 1997, Opremack 1992, Perkins 1956, Rothova 1993, Silveira 2002, Théodossiadis 1989, Timsit 1987). Only 8 studies (Couvreur 1980, Couvreur 1984, Fortier 1997, Mets 1996, Patel 1996, Villena 1998, Wallon 2001, Wilson 1980) involved young children who were known to have congenital toxoplasmosis. 11 studies (Acers 1964, Couvreur 1980, Damms 1993, Fortier 1997, Mets 1996, Perkins 1956, Rothova 1993, Silveira 2002, Timsit 1987, Wallon 2001, Wilson 1980) (including 3 RCTs: Acers 1964, Perkins 1956, Silveira 2002) compared antitoxoplasma treatment with no treatment or placebo, 15 studies (Abreu 1988, Bosch-Driessen 2002, Chodos 1961, Colin 1989, Couvreur 1980, Couvreur 1984, Crespo 1993, Fortier 1997, Jeddi 1997, Mets 1996, Opremack 1992, Patel 1996, Rothova 1993, Timsit 1987, Villena 1998) (including 4 RCTs: Abreu 1988, Bosch-Driessen 2002, Colin 1989, Jeddi 1997) compared different types of anti-toxoplasma treatment, and one study compared laser treatment with no treatment (Théodossiadis 1989). The outcome of evolution of retinochoroidal lesions (N=13; Abreu 1988, Acers 1964, Bosch-Driessen 2002, Chodos 1961, Colin 1989, Crespo 1993, Damms 1993, Fortier 1997, Jeddi 1997, Opremack 1992, Perkins 1956, Rothova 1993, Théodossiadis 1989), of recurrence of new retinochoroidal lesions (N=14; Acers 1964, Bosch-Driessen 2002, Colin 1989, Damms 1993, Jeddi 1997, Mets 1996, Opremack 1992, Rothova 1993, Silveira 2002, Théodossiadis 1989, Timsit 1987, Villena 1998, Wallon 2001), of occurrence of retinochoroidal lesions (N=5; Couvreur 1980, Couvreur 1984, Fortier 1997, Mets 1996, Villena 1998) were reported.. Only 3 studies reported results on clinical manifestations other than eye lesions (Fortier 1997, Patel 1996, Wilson 1980). The duration of follow up ranged from one month to 15 years. Characteristics of studies are summarised in table 1.
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Treatment effect according to the published studies In the figure 2 presented below, estimations of treatment effect and 95% confidence intervals are provided with date of publication, type of population, compared treatment and evaluated outcomes. The main result is that the type of treatment evaluated, the type of outcomes evaluated and the study populations are very different according to studies avoiding any real meta-analysis and pooled estimation of any global treatment effect. Nevertheless, 16/21 (76%) of measured treatment effects (calculated most often by the meta-analysts) were not significantly different from 0 (the confidence interval included 1) and the confidence intervals were sometimes very large due to restricted sample size.
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Figure 2. Treatment effect according to the study’s year of publication reported as relative risk (RR) and 95%confidence interval. Study Perkins Acers Couvreur Timsit Timsit Colin Theodossiadis Theodossiadis Rothova Rothova Rothova Rothova Rothova Rothova Mets Jeddi Jeddi Villena Wallon Bosch-Driessen Silveira
Year Population 1956 Children+adults 1964 Adults 1980 Children 1987 Children+adults 1987 Children+adults 1989 Children+adults 1989 Adults 1989 Adults 1993 Adults 1993 Adults 1993 Adults 1993 Adults 1993 Adults 1993 Adults 1996 Children 1997 Unavailable 1997 Unavailable 1998 Children
Outcome Treatment Evolution Pyrimethamine vs no Recurrence Pyrimethamine vs no Occurrence PS+spira vs no Recurrence PS vs no Recurrence Spira vs no Recurrence Clinda vs PS Evolution Laser vs medication Recurrence Laser vs medication Evolution PS vs no Evolution Clinda+Sulfadia vs no Evolution CMX vs no Recurrence Clinda+Sulfadia vs no Recurrence CMX vs no Recurrence PS vs no Recurrence PS vs no Evolution Clinda vs PS Recurrence Clinda vs PS Recurrence 2 years PS vs 1 yr PS+spira+sulfadox vs no 2001 Children Recurrence after rebound 2002 Adults Recurrence Pyri+Azithro vs PS 2002 Children+adults Recurrence CMX vs no
RR 0,65 1 0,21 0,26 0,84 0,54 3,33 0,75 0,64 0,89 1,1 1,08 0,72 0,79 0,29 0,51 0,76 2,05 0,72 0,6 0,28
inf
0,01
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sup 0,18 0,928 0,2 0,16 0,19 0,38 2,91 0,55 0,19 0,19 0,2 0,39 0,37 0,32 0,17 0,45 0,68 1,79 0,42 0,36 0,18
0,26 12,9 2,79 0,46 0,24 1,2 23,39 2 0,27 0,24 0,25 0,61 0,75 0,54 0,4 4 7,03 14,29 1 0,91 0,5
0,1
1
10
100
Study quality assessment The quality of the evaluated studies varied from 0 (very poor) to 3 (excellent). Only 3 (15%) studies among 20 presented a quality score equal or greater to 2 (figure 6). 8 studies had a quality score of 0. This evaluation was a subjective summary provided by the reviewer. The quality assessment consisted also in the evaluation of specific topics. Among studies with poor quality scores (
