Task Force Microbiology: Reimbursement Proposal Template (version 28/01/08) Toxoplasma gondii opsporen van aviditeit van IgG antilichamen

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1 PROPOSAL: SUMMARY X NEW TEST O TEST WITHDRAWAL O CHANGE REIMBURSEMENT RULES OR PRICING Nederlandstalige omschrijving prestatie Toxoplasma gondii opsporen van aviditeit van IgG antilichamen B750 COM BC 18/2011 Diagnoseregel: enkel gedurende de eerste 4 maanden van de zwangerschap, enkel indien Toxoplasma gondii IgM en IgG positief zijn en geen historische gegevens betreffende IgG positiviteit beschikbaar zijn. Maximum 1 maal gedurende het leven van de vrouw Franstalige omschrijving prestatie Toxoplasma gondii - recherche d avidité des anticorps IgG B750 Règle diagnostique : seulement pendant les premiers 4 mois de grossesse, seulement quand Toxoplasma gondii IgM et IgG sont positifs et quand il n y a pas d information historique de positivité de IgG. Maximum 1 fois pendant la vie de la femme Test description: Toxoplasma IgG avidity assay Sample type(s): serum and plasma (EDTA, heparine, citraat) Procedure: Enzyme immunoassay Condition(s): only pregnant women less than 4 months pregnant with IgM positive and IgG positive toxoplasma serology with no history of positive IgG results Accreditation warranted: no Can be ordered by: primary care physician, specialists, no specific medical specialty (most often ordered by gynecologists) Maximum/ Replica limit: maximum once in a lifetime Pricing: If highly advanced automation used: 13 euro/avidity test (Architect (Abbott )) In Belgium many centres apply the RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13). Estimated number of tests/year: 1) Based on data of the population register of living births (in 2007: living births in Belgium (statbel.fgov.be)), data of births in the UZ Ghent (in 2008: 1274 births in the UZ Ghent = 1,06% of births in Belgium) and an average of 63 toxoplasma avidity assays/year in the UZ Ghent (period 15/12/04 till 01/10/08, women of child-bearing age and pregnancy unknown), an estimated number of 6000 tests/year in Belgium. This number will be lower if a specific RIZIV reimbursement code exists, with conditions associated in which toxoplasma avidity can be proposed (pregnant women, < 4 months pregnant, no history of positive IgG results, maximum once in a lifetime). 1

2 2) The RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13) was 86 times applied in the UZ Ghent in 2009: 87% for the reimbursement of toxoplasma avidity testing. Others were entamoeba histolytica antibodies (12%) and giardia lamblia antibodies (1%). Keeping in mind that the University Hospital is a tertiary hospital, the percent of toxoplasma avidity where this code is applied could be estimated to be higher in primary and secundary hospitals, so at least % of the numbers of this RIZIV code (4923 times in 2009 in Belgium (data RIZIV, in attachment)) will be applied for toxoplasma avidity testing. So an estimated number of maximum 5000 tests/year in Belgium. On the other hand, it is possible that there are centres that do no use the RIZIV code B250 for the reimbursement of toxoplasma avidity testing. For the calculation of budget savings an estimate of 70% use of the RIZIV code B250 for the reimbursement of toxoplasma avidity testing was applied. This number can be lower if a specific RIZIV reimbursement code exists, with conditions associated in which toxoplasma avidity can be proposed (pregnant women, < 4 months pregnant, no history of positive IgG results, maximum once in a lifetime). Estimated evolution over the next five years: 1) Based on the expectancy of birth evolution (in 2020: living births in Belgium; no further increase of number of births; no evolution of the fertility index (data Federaal planbureau)) an estimated number of 6500 tests/year as from 2020 till The evolution of toxoplasmosis prevalence and impact on avidity testing, is difficult to predict. That is why it is not taken into account. 2) No evolution for RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13) was seen from 2000 till 2009, (data RIZIV, in attachment). Estimated total budget/year: A specific RIZIV reimbursement code B750 is proposed, so a total budget/year of 5000 tests x 750 x x 0.25 = euro. Estimated cost savings/year: - If a specific RIZIV reimbursement code exists, with conditions associated in which toxoplasma avidity can be proposed (pregnant women, < 4 months pregnant, no history of positive IgG results, maximum once in a lifetime) this will lead to a reduction in number of toxoplasma IgG avidity tests. - The budget for the RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13) that is now applied by many centres for the reimbursement of toxoplasma IgG avidity will potentially decrease by approximately 70%, see higher). Based on RIZIV data, the budget for this code was euro in 2009, so a budget around 6600 euro can be saved. - The major advantage of avidity testing is that a high avidity result is conclusive for the exclusion of a recent infection and no further follow-up serology will be necessary. This will theoretically lead to a reduction of the budget for RIZIV codes ( B 250 Opsporen van IgG antilichamen tegen Toxoplasma gondiï (Maximum 1) (Cumulregel 329) Klasse 13) and ( B 300 Opsporen van specifieke IgM antilichamen tegen Toxoplasma gondiï (Maximum 1) (Cumulregel 329) Klasse 14). - Other cost savings by reducing unnecessary PCR analysis of amniotic fluid and antiparasitic therapy. Tests that become obsolete and can be withdrawn from reimbursement: no Expected impact of (new) concurrent test ordering: none Access for other disciplines: no 2

3 Year report (with positive result percentage) warranted: no Excel template: Yes, in attachment (Excel Budget Toxoplasma IgG aviditeit) CLINICAL/DIAGNOSTIC SCENARIO Short description: Why is this test proposed for reimbursement? Toxoplasmosis is a mostly asymptomatic infection in pregnant women, but can give serious complications to the affected fetus. The frequency of maternal seroconversion in Belgium is 6-8/1000 and the incidence of congenital toxoplasmosis 20/10000 in Belgium (Foulon et al. 2000). The transmission rate to the fetus increases with pregnancy duration (14% first trimester versus > 60% in third trimester) but the fetal damage decreases with pregnancy duration. Ten up to fifteen percent of the congenital infected children have symptoms at birth: severe neurological and ocular damage. Eighty-five up to ninety percent of the children are asymptomatic at birth but the majority will develop sequellae later in live: 44% permanent visus loss after 18 years of follow-up. Serology is necessary for the diagnosis of an acute toxoplasma infection in pregnant women. KCE recommends screening for immunity in pregnant women once in pregnancy, before or in the beginning of the pregnancy. A women who is not immune can take certain preventive measurements to avoid toxoplasma infection. An important problem in serology of toxoplasma is the fact that a positive IgM can be false positive and can be detected for a long period following the acute infection (low specificity and low positive predictive value for diagnosing acute infection) (Liesenfeld et al., 1997; Wilson et al., 1997; Kodym et al., 2006). The FDA published the following public health advisory in july 1997: Limitations of Toxoplasma IgM Commercial Test Kits: Result from any one Toxoplasma IgM commercial test kit should not be used as the sole determinant of recent Toxoplasma infection when screening a pregnant patient. Because these tests can have false-positive results, reliance on a single test result could lead to misdiagnosis, resulting in unnecessary treatment of the patient and/or termination of the pregnancy. This indicates the need for further testing when pregnant women have positive IgM and IgG toxoplasma results and no history of positive IgG results. Timing the onset of infection prior to the pregnancy is crucial, because post-conceptional acquisition represents a risk for the fetus. If an acute toxoplasma infection during pregnancy is suspected, a treatment with spiramycin is started and changed to pyrimthamine/sulfadiazine if fetal infection is diagnosed by PCR analysis of amniotic fluid. Whereas there are some recent important works that could not reveal the benefits of early treatment on the reduction in the risks of congenital toxoplasmosis (Gilbert et al., 2003; The SYROCOT Study Group, 2007), the majority of studies show the decrease in the percentage of sequelae after prenatal and postnatal treatments (Thiébaut et al, 2006; Foulon et al., 1999; Logar et al., 2002; Berrébi et al., 2010; Cortina-Borja et al., 2010). Few studies have monitored the adverse reaction to treatment and chemoprophylaxis in a systematic way: transient reversible neutropenia has been described (Petersen, 2007). Toxoplasma IgG avidity testing enables the clinician to exclude an infection more than 4 months ago, if avidity is high. Thus, a high-avidity test result in the first trimester decreases the need for follow-up serum samples and thereby reduces costs, rules out the need for PCR analysis of amniotic fluid and the need for treatment of the mother with spiramycin, removes the anxiety associated with further testing, and lessens the likelihood of misdiagnosis. 3

4 Other individual tests (IgM/ IgA/ IgE/ IgG differential agglutination AC/HS)) are not suitable as alternative for toxoplasma avidity testing for the timing of toxoplasma infection during pregnancy as shown by Roberts et al A rather slow maturation of avidity is possible in certain cases, especially in pregnant women. That is why the low avidity result will not be conclusive regarding timing of toxoplasma infection. Next to the in-house developed assays, commercially available avidity assays are widely used. Some commonly used commercial IgG avidity assays are Vidas (BioMérieux ), Liaison (DiaSorin ) and Architect (Abbott ) (Petersen et al., 2005; Sickinger et al., 2008), Platelia (Bio-Rad ), Labsystems, Euroimmun and Mikrogen recomline. APPRAISAL 1) Analytical performance characteristics (analytical validation report) 1.1 Preanalytical considerations (patient variables, sample stability) Biological variation (sampling time (f.i. drug monitoring): no Interferences (medication, diet,...) Patient variables (age, risk factors, gender,...) Different factors could interfere with maturation of avidity, such as variations between individuals and the assay system used. There is an individual variation in IgG maturation. Pregnant women or immunocompromised patients have a more slow maturation. There can also be an influence on maturation by antitoxoplasma agents, but this influence is still controversial. The following studies of Sensini et al., 1996; Cozon et al., 1998; Pelloux et al., 1998; Petersen et al., 2007 presume there may be an effect of therapy, while others, Jenum et al., 1997; Flori et al., 2004, presume there is not. (Flori et al., 2004 ; Lefevre-Pettazzoni et al., 2006, Buffolano et al., 2004). Sample stability (preservation, transportation, storage,...) Samples can be stored at 2 to 8 C for up to 5 days. Longer storage requires freezing at -20 C. Avoid successive freezing and thawing. Sample type (serum, swab, urine,...) Serum or plasma (EDTA, heparin, citrate) can be used for testing. Sample volume Minimum 300 µl of test specimen is required. Prevalence (estimation of amount of positive test percentage) The analytic finding of high IgG avidity will refer to the absence of the acute infection and will be considered for the discussion of this item as positive test result. In the period of 15/12/2004 till 01/10/2008 in the UZ Ghent, 246 toxo IgG avidity tests were performed in 4

5 women of the child-bearing age (15-45 years). 67.9% of them had high IgG avidity and so recent infection < 4 months with toxoplasma could be ruled out. These results are comparable with results found in the literature (Liesenfeld et al., 2001: 55.9 % high avidity in first trimester of pregnancy; Montoya et al., 2002: 74.8% high avidity in first 16 weeks of pregancy; Flori et al., 2004: 67 % high avidity in first trimester of pregnancy). Target population Pregnant women less than four months pregnant with IgM positive and IgG positive toxoplasma serology on first sample in pregnancy with no history of positive IgG results. 1.2 Analytical considerations (reproducibility, accuracy, correlation, linearity, reference range) *shown for Vidas (BioMérieux ) and Architect (Abbott ) (Im)Precision: see below Accuracy (bias): N/A Correlation with current method/ standard: N/A Reproducibility (within run, between run): Inter-assay and intra-assay variability for Vidas (BioMérieux ) (see instruction leaflet) Intra-assay reproducibility: The high avidity control C1 and three samples were tested 30 times in a same run. Serum 1 Serum 2 Serum 3 Control C1 Mean index Standard deviation CV(%) Inter-assay, intra-instrument reproducibility : Three samples were tested singly and the high avidity control C1 in duplicate, in two different runs on the same instrument for 8 weeks. Serum 1 Serum 2 Serum 3 Control C1 Mean index Standard deviation CV(%) Inter-assay reproducibility (between systems): Three samples were tested singly and the high avidity control C1 in duplicate, on the same day on 8 different instruments. Serum 1 Serum 2 Serum 3 Control C1 Mean index Standard deviation CV(%)

6 Imprecision for Architect (Abbott ) (see instruction leaflet, Sickinger et al., 2008) Reference range The cutoff is assay dependent. Vidas (BioMérieux ) (see instruction leaflet) Low avidity: < 20% Borderline avidity: 20-30% High avidity: 30% 6

7 If the avidity is high, an infection in the past 4 months can be excluded. If the avidity is low, a recent infection is possible. Architect (Abbott ) (see instruction leaflet) Low avidity: < 50% Borderline avidity: 50-60% High avidity: 60% If the avidity is high, an infection in the past 4 months can be excluded. If the avidity is low, a recent infection is possible. A rather slow maturation of avidity is possible in certain cases, especially in pregnant women. The average time to reach a cutoff of 30% is 14.2 ± 4.8 months in pregnant women (Flori et al. 2004). More then 50% of pregnant women have low or borderline avidity 6 months after acute toxoplasmosis (Petersen et al., 2007). Analytical range/linearity: N/A Turnaround time (TAT) (POCT feasible, necessary,...) Vidas (BioMérieux ): Technician time averages about 1.5 hour per assay (MLT time 30 minutes and instrument time 1 hour). Architect (Abbott ): The Architect avidity test is fully automated and could be performed on daily basis. 1.3 Quality issues CTL (clinical tolerance limits): N/A Procedures available: see instruction leaflet Follow-up internal quality control: Controls are included in the test kit. Does external quality control exist? (WIV, commercial,...): yes: Wetenschappelijk instituut Volksgezondheid (WIV) and Agence française de sécurité des produits de santé (Afssaps) for toxoplasma serology. 2) Diagnostic performance 2.1 Sensitivity, specificity What was used as gold standard Documented seroconversion during pregnancy as a proof of acute toxoplasmosis. Why is expected the test under investigation performing better than the existing gold standard (if there is one) The major problem is the fact that in actual routine the majority of recent toxoplasmosis infections will not be presented as seroconversion, but as the positivity of specific Toxoplasma IgM on the first sample during pregnancy. The actual way of diagnosis of recent toxoplasmosis is to offer the follow-up serology that would not necessary bring resolution to the serodiagnosis of recent toxoplasmosis. Keeping in mind that the majority of acute 7

8 infections are a/subsymptomatic, the serology is an essential tool for the diagnosis of acute toxoplasmosis in pregnancy. Health impact of false-positives and false-negatives For the avidity testing we can not talk about false-positive or false-negative results: the IgG avidity will be high in past infection, for the majority of commercial tests > 4 months prior to testing; the low avidity result will not be conclusive regarding timing of toxoplasma infection. Based on the study of UZ Ghent regarding the proportion of IgM-positive women with pregnancy duration < 4 months, it could be shown that 41% of them had high IgG avidity. These data are indicative but are difficult to extrapolate on the whole population as cultural and hygienic reasons are important players in the grade of seropositivity of women at childbearing age. Economic impact of false-positives and false-negatives Economic impact will be difficult to calculate. It is important to note that the availability of toxoplasma IgG avidity reimbursement will potentially reduce follow-up serology. Proportion of tests than cannot be interpreted, (are inhibited) and their impact on health and cost: The potential interpretation problems will be situated if result of avidity testing is borderline. Logically, the borderline results will follow the diagnostic strategy of low avidity result. The borderline zone in avidity testing is dependent on the commercial test or validated in-house assay. Vidas (BioMérieux ) (Fricker-Hidalgo et al., Diagn Microbiol Infect Dis 2006) Method: The sera (n=553) were collected from 516 pregnant women at different intervals after infection. The date of infection was determined between the dates of 2 samples, the first negative one and the second positive one, or before the first sample (positive IgM and negative or weakly positive IgG followed by a 2-fold or greater increase), according to the kinetics of antibody production. For dating an infection by means of a documented seroconversion or a two-folded increase in IgG antibodies with a positive IgM, paired samples are necessary. With the avidity assay, one can exclude a recent infection on one serum sample without the need for further follow-up if avidity is high. Results: Infection < 4m Infection > 4m Total Low avidity Borderline avidity High avidity Total Sensitivity (low/borderline avidity when infection less than 4 months ago): 99.6% Specificity (high avidity when infection more than 4 months ago): 22.7% 8

9 Positive predictive value (infection less than 4 months ago when avidity is low/borderline): 54.6% Negative predictive value (infection more than 4 months ago when avidity is high): 98.4% Architect (Abbott ) (see instruction leaflet, Sickinger et al., 2008) Method: A total of 125 samples drawn from patients withing four months since seroconversion, have been evaluated. In addition, 89 samples drawn later than four months since seroconversion have been evaluated. The distribution of all samples is given in the following table: Results: Infection < 4m Infection > 4m Total Low avidity Borderline avidity High avidity Total Sensitivity (low/borderline avidity when infection less than 4 months ago): 100% Specificity (high avidity when infection more than 4 months ago): 31.5% Positive predictive value (infection less than 4 months ago when avidity is low/borderline): 67.2% Negative predictive value (infection more than 4 months ago when avidity is high): 100% 2.2 Likelihood ratio s (LR): N/A 2.3 NND (number needed to diagnose): N/A 2.4 Other ROC-curves (other methods) Are other results needed to interpret this lab test? The result of a toxoplasma IgG avidity assay should always be interpreted together with toxoplasma IgM and IgG results on the same sample. The test may only be performed when both IgM and IgG titers are positive. 3) Clinical impact 3.1 Diagnostic Can other (non)-laboratory examinations be avoided by this test? A high-avidity test result in the first trimester decreases the need for follow-up serum samples and rules out the need for PCR analysis on amniotic fluid. Does the test supply additional or more accurate information, not provided by other (non)-laboratory examinations? An important problem in serology of toxoplasma is the fact that a positive IgM can be false positive and can be detected for a long period following the acute infection (low specificity and low positive predictive value for diagnosing acute infection). 9

10 This indicates the need for further testing when pregnant women have positive IgM and IgG toxoplasma titers and no history of positive IgG results. Timing the onset of infection prior to the pregnancy is crucial, because post-conceptional acquisition represents a risk for the fetus. Toxoplasma IgG avidity testing enables the clinician to exclude an infection more than 4 months ago, if avidity is high. Other individual tests (IgM/ IgA/ IgE/ IgG differential agglutination AC/HS)) are not suitable as alternative for toxoplasma avidity testing for the timing of toxoplasma infection during pregnancy as shown by Roberts et al Treatment Does the test allow (faster) starting of adequate therapy (or can useless therapy be avoided)? yes Is there a better guidance of therapy by this test? yes Can toxicity be avoided? yes Does conditional reimbursement of medication exist, based on test results? (e.g. HSV and acyclovir)? no If an acute toxoplasma infection is suspected based on serological findings, a treatment with spiramycin is started. Depending on PCR results of amniotic fluid, the treatment can be stopped if PCR is negative or switched tot pyrimthamine/sulfadiazine if PCR is positive. Sometimes an abortion will be performed. A high-avidity test result in the first trimester decreases the need for treatment of the mother with spiramycin. The majority of studies investigating the link between early prenatal and postnatal treatment, show the posttreatment decrease in the percentage of sequelae: - Foulon et al : no effect of the administration of antibiotics on fetal transmission but there are fewer severe sequelae in infected fetus the sooner therapy is started. - A large European observational study found that prenatal treatment within 4 weeks of seroconversion reduced the risk of intracranial lesions compared with no treatment, but there was no significant effect when treatment was initiated after 4 weeks (review Petersen 2007, original Logar et al., 2002). There was no consistent relationship between the type or timing of treatment and the risk of ocular lesions (review Petersen 2007, original Gras et al. 2005). - A meta-analysis on an individual patient basis included 22 European cohorts. In 1438 treated mothers identified by prenatal screening, weak evidence was found for an increased risk of mother-to-child transmission the later prenatal treatment was started after seroconversion. (review Petersen 2007, original Thiébaut et al., 2006). - Berrébi et al demonstrated based on the data of long-term outcome of children with congenital toxoplasmosis after 20 years of prospective study ( ) that the visual impairement was infrequently severe and general outcome appeared consistently good after treatment. - Cortina-Borja et al found based on observational study in 14 European centres and after 4 years follow-up that the prenatal treatment reduced the risk of serious neurological sequelae in infected fetuses. However, there are some recent important works that could not reveal the benefits of early treatment on the reduction in the risks of congenital toxoplasmosis (Gilbert et al., 2003; The SYROCOT Study Group, 2007): - Gilbert et al : A large European prospective multicentre study including 1260 infected pregnant women and their newborns found no evidence that early treatment with either spiramycin or a sulphonamide combined with pyrimethamine had any effect on maternal-fetal transmission. The authors hypothesized that the window of opportunity for treatment is very 10

11 small, probably less than 2 weeks after infection, which means that current monthly or 3- monthly screening algorithms will not diagnose the majority of new infections in time to allow treatment to prevent tranmission to the fetus (review Petersen 2007, original Gilbert et al., 2003). - The SYROCOT trial 2007: weak evidence for an association between early treatment (within 3 weeks of seroconversion) and reduced mother-to-child transmission and no evidence that prenatal treatment significantly reduced the risk of clinical manifestations. Randomised controlled trials are strongly needed to assess treatment efficacy. New drugs such as atovaquone should be compared to pyrimethamine and sulphadiazine (Petersen 2007). 3.3 Health outcome Can illness, complications, morbidity, mortality be prevented? A high-avidity test result in the first trimester decreases the need for follow-up serum samples and thereby reduces costs, rules out the need for PCR analysis of amniotic fluid and the need for treatment of the mother with spiramycin, removes the anxiety associated with further testing and lessens the likelihood of misdiagnosis. Moreover a second trimester amniocentesis carries a post procedural loss rate of 0.5%. Confirmatory serological testing with counseling decreases the rate of unnecessary abortions by approximately 50% among women with positive toxoplasma IgM test results in reference centres (Liesenfeld et al. 2001). 3.4 Other: Are there epidemiological interests to perform this test? Outbreak monitoring? no Is the test still in research faze? No, more than 10 years experience 4) Organizational impact (no data available) 4.1 Impact in the hospital Length of stay, 4.2 Impact outside the hospital Patient transportation (POCT, ) 5) Cost impact: in and outside the laboratory 5.1 (Activity-Based) Cost/test (reagents, personnel, overhead (housing, QC, )) R&D cost if applicable (in-house testing) How many reagent kits have been sold? See also Excel template Personnel cost: The hands-on time will be dependent on the degree of automation of the used assay and the number of batched tests. An average hands-on time of 20 minutes per test can be estimated, which correspond to an average personnel cost of 12 euro per test. If the sytem with highly advanced automation is used (Architect, Abbott ) the average hands-on-time of 5 minutes per test can be estimated corresponding to an average personnel cost of 3 euro per test. 11

12 Reagents cost: Vidas (BioMérieux ) : Reagent kit = 265 euro /kit voor 30 testen --> 8,8 euro/test Architect (Abbott ): Reagent kit + calibrator/control kit = 397,78 euro + 109,41 euro = 507,19 euro voor 50 testen --> 10 euro/test As next to the widely used commercial assays from different producents, also in-house tests are still used for toxoplasma avidity testing, estimation of only commercial kits will not be accurate. 5.2 Reimbursement Can other tests be withdrawn? no 5.3 Profit elsewhere in the hospital - If a specific RIZIV reimbursement code exists, with conditions associated in which toxoplasma avidity can be proposed (pregnant women, < 4 months pregnant, no history of positive IgG results, maximum once in a lifetime) this will lead to a reduction in number of toxoplasma IgG avidity tests. - The budget for the RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13) that is now applied by many centres for the reimbursement of toxoplasma IgG avidity will potentially decrease by approximately 70%, see higher). Based on RIZIV data, the budget for this code was euro in 2009, so a budget around 6600 euro can be saved. - The major advantage of avidity testing is that a high avidity result is conclusive for the exclusion of a recent infection and no further follow-up serology will be necessary. This will theoretically lead to a reduction of the budget for RIZIV codes ( B 250 Opsporen van IgG antilichamen tegen Toxoplasma gondiï (Maximum 1) (Cumulregel 329) Klasse 13) and ( B 300 Opsporen van specifieke IgM antilichamen tegen Toxoplasma gondiï (Maximum 1) (Cumulregel 329) Klasse 14). - Other cost savings by reducing unnecessary PCR analysis of amniotic fluid and antiparasitic therapy. - Confirmatory serological testing with counseling decreases the rate of unnecessary abortions by approximately 50% among women with positive toxoplasma IgM test results in reference centres. (Liesenfeld et al. 2001) 6. Decision making 6.1 Impact on the clinical decision making process and patient management See Overexploitation/underutilization For the moment there is no limitation of the use of the existing general RIZIV code B250 Opsporen van AL tegen dierlijke parasieten (max 1) (cumulregel 329 klasse 13). 6.3 Incorporated in Clinical Practice Recommendations/Guidelines? 1 CDC guidelines (Preventing Congenital Toxoplasmosis, March 31, 2000 / 49(RR02); 57-75) mentioned on the research agenda as a priority for research the improvement of diagnostic tests to determine when a person becomes infected with Toxoplasma. 12

13 2 CLSI (formerly NCCLS) (Clinical use and interpretation of serologic tests for toxoplasma gondii; approved guideline M36-A, 2004) gives a general algorithm for serological testing, with the recommendation for IgG avidity testing when toxoplasma IgM and IgG antibodies are present. 3 Various European national guidelines for the prevention of congenital toxoplasmosis exist. Toxoplasma IgG avidity testing is incorporated in these guidelines in Austria and Italy (reviewed by the European toxo prevention project National public health policies and routine programs to prevent congenital toxoplasmosis, Europe, 2005, Full report, Version 5, December 12 th, 2005). 13

14 COMMENTS TO DO/ACTIONS ATTACHMENTS EXCEL DATA RIZIV EXCEL BUDGET TOXOPLASMA IGG AVIDITEIT RELEVANT EVIDENCE/REFERENCES (federaal planbureau, bevolking) Alvarado-Esquivel C, Sethi S, Janitschke K, Hahn H, Liesenfeld O. Comparison of two commercially available avidity tests for toxoplasma specific IgG antibodies. Arch Med Res 2002; 33: Ashburn D, Joss AWL, Pennington TH, Ho-Yen DO. Do IgA, IgE, and IgG avidity tests have any value in the diagnosis of toxoplasma infection in pregnancy? J Clin Pathol 1998; 51: Béla SR, Oliveira Silva DA, Cunha-Junior JP, et al. Use of SAG2A recombinant toxoplasma gondii surface antigen as a diagnostic marker for human acute toxoplasmosis: analysis of titers and avidity of IgG a nd IgG1 antibodies. Diagn Microbiol Infect Dis 2008; 62: Beghetto E, Buffolano W, Spadoni A, et al. Use of an immunglobulin G avidity assay based on recombinant antigens for diagnosis of primary toxoplasma gondii infection during pregnancy. J Clin Microbiol 2003; 41: Berrébi A, Assouline C, Bessières MH et al. Long-term outcome of children with congenital toxoplasmosis. Am J Obstet Gynecol. 2010;203(6): 552.e1-6. Breugelmans M, Naessens A, Foulon W. Prevention of toxoplasmosis during pregnancy an epidemiologic survey over 22 consecutive years. J Perinat Med 2004; 32: Candolfi E, Pastor R, Huber R, Filisetti D, Villard O. IgG avidity assay firms up the diagnosis of acute toxoplasmosis on the first serum sample in immunocompetent pregnant women. Diagnos Microbiol Infect Dis 2007; 58: Cortina-Borja M, Tan HK, Wallon M, et al. Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study. PLoS Med. 2010; 7(10). pii: e De Paschale M, Agrappi C, Belvisi L, et al. Revision of the positive predictive value of IgM anti-toxoplasma antibodies as an index of recent infection. New Microbiol 2008; 31: Flori P, Tardy L, Patural H, et al. Reliability of immunoglobulin G antitoxoplasma avidity test and effects of treatment on avidity indexes of infants and pregnant women. Clin Diagn Lab Immunol 2004; 11:

15 Flori P, Bellete B, Crampe C, et al. A technique for dating toxoplasmosis in pregnancy and comparison with the Vidas anti-toxoplasma IgG avidity test. Clin Microbiol Infect 2008; 14: Foulon W, et al. Treatment of toxoplasmosis during pregnancy : impact on fetal transmission and children s sequelae. Am J Obstet Gynecol 1999; 180: 410. Foulon W, Naessens A, Ho-Yen D. Prevention of congenital toxoplasmosis. J Perinat Med 2000; 28: Fricker-Hidalgo H, Saddoux C, Suchel-Jambon AS, et al. New Vidas assay for toxoplasmaspecific IgG avidity: evaluation on 603 sera. Diagn Microbiol Infect Dis 2006; 56: Golkar M, Rafati S, Abdel-Latif MS, et al. The dense granule protein GRA2, a new marker for the serodiagnosis of acute toxoplasma infection : comparison of sera collected in both France and Iran from pregnant women. Diagn Microbiol Infect Dis 2007; 58: Jenum PA, Stray-Pedersen B, Gundersen A-G. Improved diagnosis of primary toxoplasma gondii infection in early pregnancy by determination of antitoxoplasma immunoglobulin G avidity. J Clin Microbiol 1997; 35: Kaul R, Chen P, Binder SR. Detection of immunoglobulin M antibodies specific for toxoplasma gondii with increased selectivity for recently acquired infections. J Clin Microbiol 2004; 42: Kodym P, Machala L, Rohácová H, Sirocká B, Malý M. Evaluation of a commercial IgE ELISA in comparison with IgA and IgM ELISAs, IgG avidity assay and complement fixation for the diagnosis of acute toxoplasmosis. Clin Microbiol Infect 2007; 13: Leite M, Sicilliano S, Silvieri L, et al. Correlation between specific IgM levels and percentage IgG-class antibody avidity to toxoplasma gondii. Rev Inst Med Trop S Paulo 2008; 50: Lefevre-Pettazzoni M, Le Cam S, Wallon M, Peyron F. Delayed maturation of immunoglobulin G avidity : implication for the diagnosis of toxoplasmosis in pregnant women. Eur J Clin Microbiol Infect Dis 2006; 25: Liesenfeld O, Press C, Montoya JG, et al. False-positive results in immunoglobulin M (IgM) toxoplasma antibody tests and importance of confirmatory testing: the platelia toxo IgM test. J Clin Microbiol 1997; 35: Liesenfeld O, Montoya JG, Kinney S, Press C, Remington JS. Effect of testing for IgG avidity in the diagnosis of toxoplasma gondii infection in pregnant women: experience in a US reference laboratory. J Infect Dis 2001; 183: Liesenfeld O, Montoya JG, Tathineni NJ, et al. Confirmatory serologic testing for acute toxoplasmosis and rate of induced abortions among women reported to have positivie toxoplasma immunoglobulin M antibody titers. Am J Obstet Gynecol 2001; 184: Montoya JG. Laboratory diagnosis of toxoplasma gondii infection and toxoplasmosis. J Infect Dis 2002; 185 (Suppl 1): S73-S82. Montoya JG, Liesenfeld O, Kinney S, Press C, Remington JS. VIDAS test for avidity of toxoplasma-specific immunoglobulin G for confirmatory testing of pregnant women. J Clin Microbiol 2002; 40: Montoya JG, Rosso F. Diagnosis and management of toxoplasmosis. Clin Perinatol 2005; 32: Nascimento FS, Suzuki LA, Rossi CL. Assessment of the value of detecting specific IgA antibodies for the diagnosis of a recently acquired primary toxoplasma infection. Prenat Diagn 2008; 28: National public health policies and routine programs to prevent congenital toxoplasmosis, Europe, 2005, Full report, Version 5, December 12 th,

16 Pelloux H, Brun E, Vernet G, et al. Determination of anti-toxoplasma gondii immunoglobulin G avidity : adaptation to the Vidas system (biomérieux). Diagn Microbiol Infect Dis 1998; 32: Petersen E, Borobio MV, Guy E, et al. European multicenter study of the LIAISON automated diagnostic system for determination of toxoplasma gondii specific immunoglobulin G (IgG) and IgM and the IgG avidity index. J Clin Microbiol 2005; 43: Petersen E. Toxoplasmosis. Semin Fetal Neonatal Med 2007; 12: Sensini A. Toxoplasma gondii infection in pregnancy: opportunities and pitfalls of serological diagnosis. Clin Microbiol Infect 2006; 12: Pfrepper K-I, Enders G, Gohl M, et al. Seroreactivity to and avidity for recombinant antigens in toxoplasmosis. Clin Diagn Lab Immunol 2005; 12: Prince HE, Wilson M. Simplified assay for measuring toxoplasma gondii immunoglobulin G avidity. Clin Diagn Lab Immunol 2001; 8: Roberts A, Hedman K, Luyasu V, et al. Multicenter evaluation of strategies for serodiagnosis of primary infection with toxoplasma gondii. Eur J Clin Microbiol Infect Dis 2001; 20: Roux-Buisson N, Fricker-Hidalgo H, Foussadier A, et al. Comparative analysis of the VIDAS toxo IgG IV assay in the detection of antibodies to toxoplasma gondii. Diagn Microbiol Infect Dis 2005; 53: Sickinger E, Gay-Andrieu F, Jonas G, et al. Performance characteristics of the new architect toxo IgG and toxo IgG avidity assays. Diagn Microbiol Infect Dis 2008; 62: Syrocot study group. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients data. Lancet 2007; 369: Wilson M, Remington JS, Clavet C. Evaluation of six commercial kits for detection of human immunoglobulin M antibodies to toxoplasma gondii. J Clin Microbiol 1997; 35:

17 BUDGETTAIRE WEERSLAG VOORSTEL TERUGBETALING TOXOPLASMA IgG AVIDITEIT Nomenclatuur Omschrijving Situatie 2009 Voorstel Verschil aantal B waarde totaal B kostprijs B waarde aantal totaal B Totaal B Honoraria Honoraria testen (euro) testen 100% (1) 25% (3) (2) opsporen van AL tegen dierlijke parasieten aaaaaa-bbbbbb opsporen van IgG aviditeit tegen Toxoplasma gondiï TOTAAL TOTAAL Schatting aantal testen: Er wordt geschat dat 70% van de analysen zullen wegvallen (zie tekst voorstel) LEGENDE: BUDGETTAIRE WEERSLAG VOORSTEL TERUGBETALING TOXOPLASMA IgG AVIDITEIT (1) de honoraria werden berekend met behulp van de waarde van de letter B in 2010 ( euro) (2) algemeen nomenclatuur nummer dat tot op heden vaak wordt gebruikt voor de tarifiëring van Toxoplasma IgG Aviditeit bepalingen (3) berekend volgens formule B x 0, x 0,25