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Copyrightq1996, American Society for Microbiology

Diagnostic Implications of Kinetics of Immunoglobulin M and

A Antibody Responses to Toxoplasma gondii

MERI GORGIEVSKI-HRISOHO, DANIEL GERMANN,ANDLUKAS MATTER*

Institute for Medical Microbiology, University of Bern, Bern, Switzerland

Received 18 December 1995/Returned for modification 30 January 1996/Accepted 8 March 1996

We evaluated immunoglobulin M (IgM) and IgA assays that could improve the predictive value for recently acquired toxoplasma infection for patients with positive screening test results. Follow-up sera were collected from 82 patients whose initial serum specimen had a reactive anti-Toxoplasma gondiiIgM result. According to the evolution of the immune response, patients were divided retrospectively into two groups: one in which a recent infection was unlikely and the other one with an evolving immune response suggestive of recent toxoplasma infection. All IgM and one of three IgA assays used in the study are suitable for screening pregnant patients, with a negative predictive value of 100%. The predictive value of positive results is much lower because of the low prevalence of acute toxoplasmosis in pregnant women and the long persistence of IgM after acute infection. In the present study, all except one IgM enzyme immunoassay remained positive well beyond 6 months after the initial sample was tested. The IgM immunofluorescence test had the shortest persistence of positivity in most cases. IgA tests were either too insensitive or remained reactive too long to be useful for screening pregnant patients. Interpreting enzyme immunoassays with modified cutoff values and the combi-nation of two tests could improve the predictive value of positive results to about 80% in terms of recent infection.

Infection with Toxoplasma gondii acquired during pregnancy can cause fetal infection (5, 28). Assessment of the time of acquisition of primary infection is important, because fetal infection occurs almost exclusively after postconceptional in-fection (8, 22). Fetal inin-fection is less frequent (9) and the sequelae of infection are less severe if the mother is treated during pregnancy (15). Because primary infection in pregnant women is not recognized clinically in about 90% of cases (30), its detection must be based on serological screening. Prenatal serological screening programs are still controversial (11, 23). Searching for seroconversions by monthly testing for immuno-globulin G (IgG) antibodies in seronegative pregnant women is cumbersome and expensive. Specific IgM antibodies suggest primary infection, but it is difficult to deduce the time of their acquisition (1, 4, 24). The presence of IgA antibodies against T.

gondii has been reported in patients with recently acquired

infection (7, 21), and it has been applied to neonatal serum for the diagnosis of fetal infection (26). Its potential use in screen-ing durscreen-ing pregnancy has been reported (18).

In Switzerland, a first serum sample is usually obtained dur-ing the first trimester of pregnancy for various screendur-ing pur-poses, which may include T. gondii IgG and IgM antibodies. A positive T. gondii IgM result is an inappropriate single param-eter of recent infection because of its persistence for many months or even years after acute infection (1), remaining de-tectable during successive pregnancies in some cases. The aim of our study was to search for different IgM tests or for com-binations of IgM and IgA tests which would reduce this prob-lem and improve the predictive value of positive tests for re-cently acquired infection. Because fetal infection is relatively rare but requires specific treatment (3, 6), with potential side effects, amniocentesis is considered if toxoplasmosis has

prob-ably been contracted during pregnancy in order to target such treatment to those fetuses which are actually infected (14). The discrimination between recent infection and residual IgM re-activities should help to limit these invasive diagnostic proce-dures to fetuses at risk of intrauterine toxoplasma infection.

We collected a panel of sera from asymptomatic pregnant women with anti-T. gondii IgM reactivities of more than 2 months’ duration without significant changes in the IgG and IgM reactivities. This panel was used to select IgM tests with improved specificities for detecting recent T. gondii infection with an evolving immune response as opposed to a prolonged persistence of residual IgM reactivity. The sensitivities of these IgM tests were checked by using a panel of sera from patients with an evolving immune response to T. gondii. In addition, anti-T. gondii IgA reactivities in these two panels were deter-mined by three different tests.

MATERIALS AND METHODS

Patients and sera.Sera were obtained between 1988 and 1993 either from pregnant women for prenatal screening or from patients with suspected acute toxoplasmosis. Sera with a reactive anti-T. gondii IgM result in a primary test were included. From these patients sequential serum specimens were collected several weeks or months after the initial one was collected. Samples were frozen within 8 h of receipt at the laboratory and were kept at2208C for up to 5 years until additional tests were performed. In our experience, freezing has no influ-ence on the results on retesting. Between 2 and 10 serum specimens from 82 selected subjects which were reactive in the primary anti-T. gondii IgM assay were available for further anti-T. gondii IgG, IgM, and IgA testing. These addi-tional tests were run simultaneously with all sera from one patient. Differences of.50% in the IgG or IgM concentrations between sequential samples were considered to indicate an evolving immune response. A stable IgG concentration in paired serum samples taken 3 weeks apart and run in parallel indicates an infection acquired at least 2 months before the first specimen was obtained (29). On the basis of the results of the follow-up tests, we divided the patients retro-spectively into two main groups.

Group I comprised 40 patients (age range, 19 to 40 years; median age, 28.5 years) in whom recent infection was unlikely because anti-T. gondii IgG and IgM concentrations remained unchanged (see above) in consecutive serum samples (2 to 10 samples per patient) collected within 59 to 657 days (median, 135 days) or because IgM antibodies persisted for.1 year, irrespective of the IgG result (one patient).

Group II consisted of 106 serum samples from 42 patients (age range, 1 to 58 * Corresponding author. Mailing address: Institute for Medical

Mi-crobiology, University of Bern, Friedbu¨hlstrasse 51, CH-3010 Bern, Switzerland. Phone: 41 31 632 32 14. Fax: 41 31 382 00 63. Electronic mail address: matter@imm.unibe.ch.

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years; median age, 26 years) with an evolving humoral immune response to T. gondii. Two to four serum samples from each patient collected within 9 to 322 days (median, 78 days) were analyzed. This group was divided into four sub-groups: subgroup A, seroconversion of anti-T. gondii IgG within a median of 32 days (8 patients and 22 samples), with the last IgG- and IgM-negative serum samples prior to seroconversion being referred to as preconversion samples; subgroup B, the anti-T. gondii IgG concentration rose by.50% within a median of 43 days (18 patients and 41 samples); subgroup C, stable anti-T. gondii IgG concentrations, with IgM concentrations decreasing by.50% within a median of 55 days (5 patients and 13 samples); and subgroup D, anti-T. gondii IgG con-centration decreasing by.50% within a median of 140 days (11 patients and 33 samples).

Methods.Anti-T. gondii IgG was quantitated by an automated enzyme immu-noassay (EIA) with fluorescence detection (VIDAS Toxo IgG; bioMe´rieux, Marcy-l’Etoile, France). The results were expressed in international units per milliliter. Paired sera were run simultaneously, and if necessary they were predi-luted. Intra- and interassay variabilities were 4 to 8% and 4 to 9%, respectively. Anti-T. gondii IgM was measured bym-capture enzyme-linked immunosorbent assay (ELISA). The details of these assays are given in Table 1. The primary test used was Toxo-M-EIA (M-ABB; Abbott Laboratories, Chicago, Ill.) between 1988 and March 1991, and thereafter, ETI-TOXOK-M reverse (M-SOR; Sorin Biomedica, Saluggia, Italy) was used. The IgM immunofluorescence test (M-IF) was performed with slides and reagents from bioMe´rieux. The slides were read with a Zeiss Axiophot microscope with an XBO 75 lamp, and Plan-Neofluar320 or340 objectives. Patients’ sera were tested in doubling dilutions from 1:100 to 1:3,200. Anti-T. gondii IgA was determined by thea-capture technique. The details of the tests are given in Table 1. All assays were performed and the results were interpreted as recommended by the manufacturers. The M-IF was consid-ered positive at a dilution of$1:100.

For quantitative comparisons, the results were expressed as standardized index (SI) values, as follows: optical density of the sample/mean optical density of the equivocal range for EIAs and doubling dilution steps of M-IF (1:10051; 1:3,200 56).

Box plot analysis was performed by using the StatView program, version 4.02.

RESULTS

The qualitative results of the anti-T. gondii IgM and IgA responses measured with the first serum samples from group I are given in Table 2.

The performances of the anti-T. gondii IgM and IgA tests in detecting patients with toxoplasmosis in the four subgroups of patients in group II are given in Table 3. All IgM EIAs had sensitivities of 100% for subgroups A to C; the M-SOR result was equivocal for one patient in subgroup D. M-IF detected all patients with toxoplasmosis in subgroups A and B. Of the IgA tests, only Platelia Toxo IgA (A-PAS; Sanofi Diagnostics

Pas-teur, Marnes-la-Coquette, France) detected all cases of toxo-plasmosis among patients in group II.

[image:2.612.56.556.83.295.2]

For further comparative analysis, the results of all eight tests were converted to SI values. Figure 1 provides the values obtained with the first serum samples from patients in groups I and II. In our study we found eight patients who were sero-converting. Data for the anti-T. gondii IgG- and IgM-negative preconversion sera obtained between 9 and 154 days before IgG seroconversion were excluded from the comparison. There was a reasonable degree of discrimination (about 90%) between the first samples from patients in groups I and II, with SI values of 2.0 for M-ABB, CAPTIA Toxo-M EIA (M-MER; Mercia Diagnostics Ltd., Surrey, England), M-SOR, and A-PAS and at a titer of 1:100 (SI 5 1.0) for M-IF. M-VID discriminated 95% of the first samples, with an SI value of 4.0. The kinetics of the IgM and IgA responses in patients in group II (without preconversion sera) are provided in Fig. 2. A continuous decrease in the SI values was evident for all but one test (M-MER). M-IF showed the most rapid decline in reac-tivity. It became negative within 3 to 6 months for seven of nine patients. This may explain the negative results obtained for TABLE 1. Technical details for the seven commercial EIAs used in the study

Test (abbreviation) Manufacturer Capture antibody T. gondii antigen Labelled antibody; detection system

Toxo-M-EIA (M-ABB)

Abbott Laboratories Goat anti-humanmchain Native antigen purified from whole tachyzoites, preserving the integrity of surface antigen determinants

HRPa

-conjugated rabbit anti-T. gondii IgG; colorimetric

CAPTIA Toxo-M EIA (M-MER)

Mercia Diagnostics Ltd. Rabbit anti-humanmchain No details available Biotinylated monoclonal antibody, HRP-conjugated streptavidin; colorimetric

ETI-TOXOK-M reverse (M-SOR)

Sorin Biomedica Rabbit anti-humanmchain Sonicated trophozoites extracted from RH strain-infected cell culture

HRP-conjugated anti-p30 mono-clonal antibody; colorimetric

VIDAS Toxo IgM (M-VID)

bioMe´rieux Affinity-purified goat anti-human mchain

Ascites from mice infected with the RH strain, prepared by sonication, centrifugation, and filtration of the supernatant, rich in p30

Alkaline phosphatase conjugated anti-p30 monoclonal antibody; fluorometric

Platelia Toxo IgA (A-PAS)

Sanofi Diagnostics Pasteur

Goat anti-humanachain Membrane extract of HEp-2 cells infected with the RH strain

HRP-conjugated anti-p30 mono-clonal antibody; colorimetric ETI-TOXOK-A

reverse (A-SOR)

Sorin Biomedica Monoclonal IgG antibody to human IgA

As for M-SOR HRP-conjugated anti-p30 mono-clonal antibody; colorimetric Toxo IgA ELISA

(A-EUR)

Eurogenetics S.A., Tessenderlo, Belgium

Affinity-purified monoclonal anti-humanachain antibody

Ascites from mice infected with the RH strain, biotinylated

HRP-conjugated streptavidin; col-orimetric

a

HRP, horseradish peroxidase.

TABLE 2. Comparison of qualitative results for anti-T. gondii IgM and IgA obtained with the first serum samples from patients

with IgM persisting for$2 months without an evolving immune response (group I)

Test No. of patients tested Positive results Equivocal results Negative results

No. % No. % No. %

M-ABB 31 21 68 10 32 0a

M-MER 30 24 80 6 20 0

M-SOR 40 19 47 9 23 12 30

M-VID 40 30 75 3 7 7 18

M-IF 39 5 13 34 87

A-PAS 40 18 45 3 7 19 48

A-SOR 40 0 22 55 18 45

A-EUR 40 0 1 2 39 98

a

Only sera reactive by M-ABB were selected.

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three patients in subgroups C and D, who had subacute phases of infection. However, at low titers (1:100) M-IF discriminated poorly between early phases of the infection (subgroups A and B) and residual IgM reactivity (group I) (Table 4). M-SOR was the only IgM EIA with negative results after a 6-month obser-vation interval for four of eight patients (Fig. 2 and 3A).

On the basis of these results, we modified the cutoff values for M-SOR and A-PAS to an SI of$2.0 and that for M-VID to an SI of$4.0 to obtain a better discriminatory power be-tween the first serum samples from patients in groups I and II. All samples from patients in group II showed a decline below the modified cutoff values of M-SOR (SI,2.0) and M-VID (SI,4.0) within 6 months (Fig. 3A and B). M-VID gave SI values of ,4.0 for three initial serum samples belonging to patients in subgroup D (decreasing IgG concentration). The SI values of M-VID fell from a median of 6.5 to less than 3.0 for all samples after 6 months (Fig. 2 and 3B). In contrast to IgM tests, A-PAS continued to have an SI value greater than 2.0 for 46 of 54 (85%) follow-up serum samples for 6 months (Fig. 3C)

and 3 of 6 serum samples after 6 months. The SI values for all follow-up sera from patients in group I were,2.0.

[image:3.612.59.556.92.216.2]

Table 4 shows the sensitivity, specificity, and predictive val-ues of the IgM and IgA EIAs used as secondary tests with modified cutoff values for samples that were initially reactive (SI$0.9) by M-VID. With the first available serum samples the predictive value of each one of the IgM tests with results below the modified cutoff value for excluding an infection with an evolving immune response (group II) was very high (99%). The predictive value of tests with results above the modified cutoff value could be improved from 45 to 67% to about 80% by using a combination of two tests; thus, four of five patients whose sera had SI values above the modified cutoff values by both tests exhibited an evolving immune response. A combi-nation of three tests with SI values above the modified cutoff

FIG. 1. Comparison of the SI values obtained by different anti-T. gondii IgM and IgA tests with the first serum samples from patients in group I (h) and II (o), without preconversion samples. The box plots show the median and 50% of the values within the boxes, and 90% of the values within the bars.

[image:3.612.318.556.436.680.2]

FIG. 2. Box plots of SI values obtained by different anti-T. gondii IgM and IgA tests with all serum samples from patients in group II except preconversion samples, according to time intervals from the first samples.h, initial samples;^, sample obtained in less than 3 months;o, samples obtained between 3 and 6 months;1, samples obtained after greater than 6 months.

TABLE 3. Qualitative results of anti-T. gondii IgM and IgA tests for the first samples tested from patients in the different subgroups with an evolving immune response against T. gondii (group II)

Test

Seroconversion Increasing IgG Decreasing IgM Decreasing IgG

No. of patients

tested

Positive No. of patients

tested

Positive No. of patients

tested

Positive No. of patients

tested

Positive

No. % No. % No. % No. %

M-ABB 6 6 100 16 16 100 4 4 100 10 10 100

M-MER 3 3 100 10 10 100 4 4 100 8 8 100

M-SOR 8 8 100 18 18 100 5 5 100 11 10a 91

M-VID 8 8 100 18 18 100 5 5 100 11 11 100

M-IF 7 7 100 17 17 100 5 4 80 11 9 82

A-PAS 7 7 100 17 17 100 5 5 100 10 10 100

A-SORb 8 6 75 18 14 78 5 3 60 11 6 55

A-EURc 8 6 75 18 11 61 5 3 60 11 8 73

a

One patient with equivocal result.

b

Twelve patients with equivocal results.

c

Four patients with equivocal results and 10 patients with negative results.

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value for at least two of the tests did not further improve the predictive value for evolving infections. The calculation of pre-dictive values was based on an estimated prevalence of 10% recent infections in patients with a reactive M-VID (SI$0.9) screening test result. This corresponds to a prevalence of 0.6% suspected primary infections (2) in the population tested in our laboratory.

DISCUSSION

It is crucial in pregnancy screening programs for congenital toxoplasmosis to ascertain whether T. gondii infection was ac-quired before or after conception, because only primary infec-tion during pregnancy carries a risk of fetal damage, and fur-ther invasive diagnostic procedures such as amniocentesis should be restricted as much as possible to those at risk. The only reliable way to achieve this is by documenting serocon-version during pregnancy. Since appropriate periconceptional serum samples are only rarely available, tests for the detection of IgM antibodies are required by many physicians to reveal active T. gondii infection when pregnant women are first seen, usually during the first trimester. Because T. gondii IgM anti-bodies commonly persist well beyond 6 months, positive test results are very poorly predictive of infections acquired within the previous 2 to 3 months (1, 4, 24).

We collected follow-up sera from 82 patients whose initial serum sample was reactive for anti-T. gondii IgM antibodies. Additional tests were then performed in order to evaluate the diagnostic values of recently developed IgM and IgA assays and to find a combination of commercially available tests to improve the estimation of the time of acquisition of T. gondii infection. According to these additional serological test results, the patients were divided retrospectively into two groups, and only their first available serum samples were used to evaluate predictive values. In the first group (group I) acute toxoplas-mosis was considered unlikely, because there was no evolution of the IgG and IgM antibody response within an observation interval of at least 2 months. However, this group may include patients with an infection of relatively short duration (3 to 6 months). Group II consisted of patients with an evolving anti-body response to T. gondii within an observation interval of 9 to 322 days. Except for some seroconverting patients, the time of infection was not precisely known. Patients in the subgroup with declining antibody concentrations are likely to have been infected for more than 2 to 3 months (29). Thus, there may be an overlap in the duration of infection in patients in the two groups.

[image:4.612.62.554.84.207.2]

All IgM tests used in the present evaluation are suitable for screening for recently acquired toxoplasmosis, because the pre-dictive values of negative results are close to 100% for popu-lations with a low prevalence of acute toxoplasma infection. Positive IgM test results, however, are more difficult to inter-pret. Because of their usual persistence for more than 6 months, they have a poor specificity for T. gondii infections acquired during the preceding 3 months, which is a relevant FIG. 3. Scattergrams of SI values of M-SOR, M-VID, and A-PAS with

[image:4.612.63.297.358.685.2]

fol-low-up sera from patients in groups I and II versus time interval after the initial samples were obtained. The solid horizontal line shows the cutoff value for positive results; the broken line indicates the modified cutoff value (see text for details);E, group I, follow-up samples;}, group II, follow-up samples.

TABLE 4. Sensitivity, specificity, and predictive values of IgM and IgA test resultsa

Criterion for recent infection

No. of samples fulfilling criterion/no.

of samples tested

Test characteristics when using modified

cutoff values for EIAs Predictive value of resultwith less than modified cutoff value (%)

Predictive value of result equal to or greater than modified cutoff value (%) Group II Group I Sensitivity

(%)

Specificity (%)

M-SOR SI$2 37/41 2/40 90 95 99 67

M-VID SI$4 39/42 2/40 93 95 99 67

M-IF positive 37/40 5/39 93 87 99 45

M-VID SI$4 and M-SOR SI$2 37/41 1/40 90 98 99 80

M-VID SI$4 and A-PAS SI$2 35/42 1/39 83 98 98 79

M-VID SI$4 and M-IF positive 35/40 1/39 88 97 99 79

M-VID SI$4, M-IF positive, and A-PAS SI$2b

40/42 3/40 95 93 99 59

a

Results for patients with toxoplasmosis and an evolving immune response determined by using modified cutoff values for different EIAs used alone or in combinations as secondary tests in samples that were reactive by M-VID. Predictive values are based on an estimated prevalence of 10% recent infections in patients with a reactive M-VID (SI$0.9) as screening test.

bAt least two of three test results above the modified cutoff values.

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time frame frequently encountered in screening of pregnant women. In German-speaking European populations, the inci-dence of primary toxoplasmosis has recently been estimated at 6/1,000 pregnancies (2, 12, 16). Observed incidence rates have been even lower in several studies conducted in other popula-tions of the Western Hemisphere (13, 17, 27). These findings are compatible with a prevalence of recently acquired toxo-plasmosis of 0.6% or less in the test population. Under these circumstances, the predictive value of a reactive M-VID screening test result for toxoplasmosis with an evolving im-mune response is#0.7%. Thus, most positive results may lead to unnecessary interventions (20).

The specificities of IgM test procedures can be improved by supplemental testing based on techniques that differ from those of the primary assay. M-IF is suitable for this purpose because of its short persistence, but it has shortcomings that are characteristic of immunofluorescence tests: they are sub-jective, poorly standardized, and highly dependent on equip-ment and experience for proper interpretation, and the results are not easily comparable between laboratories. Alternatively, a semiquantitative interpretation of EIAs in conjunction with the knowledge of IgG antibody levels can help to distinguish recent toxoplasmosis from residual IgM reactivity. By using modified cutoff values for M-SOR or M-VID (2.0 or 4.0, re-spectively), the positive predictive value for toxoplasmosis with an evolving immune response could be improved considerably, especially when the tests were used in combination. The use of three tests did not improve the predictive values. Because the decline in the reactivity of A-PAS was slower than those of most IgM EIAs, this test may be less helpful in the context of screening pregnant women (18). Tests showing a low avidity of IgG may be useful for confirming recent infection, but a high avidity for IgG may be acquired within 2 to 3 months; these tests are not commercially available at present (18).

These data provide the basis for our current preferences in the use of serologic tests for screening pregnant women. We screen for IgG and IgM antibodies using very sensitive tests in order to include all individuals suspected of having acute tox-oplasmosis and to attain a very high negative predictive value. If the IgM screening test is reactive, we perform at least one second test with a shorter persistence yet a high sensitivity in the seroconversion phase (M-SOR or M-IF). If at least one of the tests performed has a result below the modified cutoff value, a repeat specimen obtained 2 to 3 weeks later tested simultaneously with the first serum sample may reveal an evo-lution of the IgG or IgM antibody response and may help determine the time of infection. If the SI values are$4.0 and

$2.0 for M-VID and M-SOR, respectively, or if the M-IF titer is 1:$100, a T. gondii infection is likely to have been acquired within the preceding 3 to 6 months. The combination of two tests with results above the modified cutoff values may increase the predictive value in terms of recent infection with an evolv-ing immune response to 80%. These patients should be sub-jected to further diagnostic procedures, and therapeutic deci-sions can be based on the results of those procedures. The availability of sensitive methods of detecting T. gondii in am-niotic fluid (14) without the need for fetal blood sampling helps to reduce the risk of this diagnostic intervention (20). This should allow limitation of treatment with pyrimethamine and sulfadiazine to patients with proven cases of fetal infec-tion. The benefit of this therapeutic option compared with a single-drug regimen with spiramycin for the prevention of fetal infection must justify these procedures (6). The highly effective treatment of newborns with congenital toxoplasmosis has also been documented recently (10, 19, 25). Treatment for 1 year appears to improve the prognosis for subsequent neurological

and cognitive functioning for infants with congenital toxoplas-mosis. These results support efforts to identify patients with acute gestational and congenital toxoplasmosis (25).

ACKNOWLEDGMENTS

We are grateful to M. C. Descombes for providing some of the follow-up sera. Some test kits were kindly provided by Mercia Diag-nostics, Sorin Biomedica, bioMe´rieux, Sanofi Diagnostics Pasteur, and Eurogenetics S.A.

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Figure

TABLE 2. Comparison of qualitative results for anti-T. gondii IgMand IgA obtained with the first serum samples from patientswith IgM persisting for �2 months without an
TABLE 3. Qualitative results of anti-T. gondii IgM and IgA tests for the first samples tested from patients in the different subgroupswith an evolving immune response against T
TABLE 4. Sensitivity, specificity, and predictive values of IgM and IgA test resultsa

References

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