1248

Effect of Testing for IgG Avidity in the Diagnosis of Toxoplasma gondii

Infection in Pregnant Women: Experience in a US Reference Laboratory
Oliver Liesenfeld,1,2,3 Jose G. Montoya,1,2 1
Department of Immunology and Infectious Diseases, Research
Sandra Kinney,1 Cynthia Press,1 Institute, Palo Alto Medical Foundation, Palo Alto, and 2Division
and Jack S. Remington1,2 of Infectious Diseases and Geographic Medicine, Department
of Medicine, Stanford University School of Medicine, Stanford,
California; 3Department of Medical Microbiology and Immunology
of Infection, Institute for Infection Medicine, Benjamin Franklin
Medical Center, Free University of Berlin, Berlin, Germany

The usefulness of testing for IgG avidity in association with Toxoplasma gondii was evaluated
in a US reference laboratory. European investigators have reported that high-avidity IgG
toxoplasma antibodies exclude acute infection in the preceding 3 months. In this US study,
125 serum samples taken from 125 pregnant women in the first trimester were chosen retro-
spectively, because either the IgM or differential agglutination (AC/HS) test in the Toxoplasma
serologic profile suggested or was equivocal for a recently acquired infection. Of 93 (74.4%)
serum samples with either positive or equivocal results in the IgM ELISA, 52 (55.9%) had
high-avidity antibodies, which suggests that the infection probably was acquired before ges-
tation. Of 87 (69.6%) serum samples with an acute or equivocal result in the AC/HS test, 35
(40.2%) had high-avidity antibodies. Forty women were given spiramycin, to prevent con-
genital transmission, and 7 (17.5%) had high-avidity antibodies. These findings highlight the
value of testing a single serum sample obtained in the first trimester of pregnancy for IgG
avidity.

Infection with Toxoplasma gondii during pregnancy may lead
to severe sequelae in the fetus [1]. At present, definitive serologic
diagnosis of acute infection during gestation can be made only
if paired serum samples reveal a significant increase in titer—
most often of IgG antibodies [2]. Such increasing titers are not
commonly seen in US pregnant women, because no systematic
serologic screening to detect seroconversion is done. Although
successful screening programs have been used in France and
Austria for many years [3, 4], in the United States, usually only
a single serum sample is submitted for testing, frequently late
in gestation.
Because IgM antibodies may persist for months or even years
after acute infection [5, 6], their greatest value is in determining
that a pregnant woman was not infected recently. A negative
result virtually rules out recent infection, unless serum samples
are tested so late after infection that IgM antibody has dis-
appeared or so early after the acute infection that an antibody
response has not occurred or is not yet detectable [1, 2]. When
Received 28 July 2000; revised 10 January 2001; electronically published
16 March 2001.
Financial support: National Institutes of Health (grant AI-04717); Infec-
tious Disease Fellowship from the German Ministry of Research and Tech-
nology to O.L.
Reprints or correspondence: Dr. Jose G. Montoya, Research Institute,
Palo Alto Medical Foundation, Ames Bldg., 795 El Camino Real, Palo
Alto, CA 94301 (gilberto@leland.stanford.edu).
The Journal of Infectious Diseases 2001; 183:1248–53
䉷 2001 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2001/18308-0010$02.00
results are positive, a number of additional serologic tests, in-
cluding those for the detection of IgG [7, 8], IgA [9], and IgE
[10] antibodies, and a combination of these tests, the Toxo-
plasma serologic profile (TSP) [11, 12], can help discriminate
between recently acquired and distant infection. The differential
agglutination (AC/HS) test most closely approaches a single
reference standard test for the discrimination of recently ac-
quired and distant infection [8]. However, at present in the
United States, this test is done only by the Toxoplasma Serology
Laboratory, Palo Alto Medical Foundation (TSL-PAMF; Stan-
ford, CA), because the required antigen preparations are not
commercially available. In addition, as is true for IgM anti-
bodies, an acute pattern in the AC/HS test may persist for 11
year [8].
Recently, several tests for avidity of toxoplasma IgG anti-
bodies have been introduced to help discriminate between re-
cently acquired and distant infection [13–20]. The commercial
tests are available in Europe but are not licensed in the United
States. Results are based on the measurement of functional
affinity of specific IgG antibodies [21]. IgG affinity, which ini-
tially is low after primary antigenic challenge, increases during
subsequent weeks and months by antigen-driven B cell selec-
tion. Protein-denaturing reagents, including urea, are used to
dissociate the antibody-antigen complex. The avidity result is
determined by using the ratios of antibody titration curves of
urea-treated and -untreated sample.
We investigated the usefulness of testing for avidity of IgG
antibodies in a US toxoplasma serology reference laboratory
JID 2001;183 (15 April) Toxoplasma IgG Avidity
that processes serum samples primarily from pregnant women.
In most cases, the physician requests information about the
time of onset of the infection on the basis of results obtained
from a single serum sample. Our goal was to compare results
obtained in an IgG avidity test with those obtained in the IgM
ELISA and AC/HS tests.
Materials and Methods
We retrospectively studied 125 serum samples taken from 125
pregnant women in the first trimester of gestation. The serum sam-
ples were submitted to the TSL-PAMF between September 1994
and September 1999. Serum samples had been routinely tested by
the TSP, as described elsewhere [11, 12]. The TSP comprises the
Sabin-Feldman dye test (DT) [7], double-sandwich IgM ELISA
[22], IgA ELISA [9], IgE ELISA [10], IgE immunosorbent agglu-
tination assay (ISAGA) [10], and AC/HS test [8]. The Sabin-Feld-
man DT is considered to be positive at any titer. The starting
dilution was 1:16. The double-sandwich IgM ELISA method [22]
has been used by our laboratory and other reference laboratories
for 115 years. A result of ⭓2.0 was interpreted as positive, 1.7–1.9
as equivocal, and !1.7 as negative. The following titers were con-
sidered to be positive, negative, and equivocal, respectively, in the
tests: IgA ELISA, ⭓2.1 and ⭐1.4 (equivocal, 1.5–2.0); IgE ELISA,
11.8 and ⭐1.4 (equivocal, 1.5–1.8); and IgE ISAGA, ⭓4 and ⭐2
(equivocal, 3). The AC/HS test was interpreted, as described else-
where [8], by comparing titers obtained with formalin-fixed tachy-
zoites (HS antigen) with those obtained with acetone-fixed tachy-
zoites (AC antigen; figure 1). IgG antibodies formed early in
infection recognize stage-specific antigens in the AC preparation,
which are distinct from those formed later in infection [8, 23].
Current interpretation of results in the TSP at the TSL-PAMF
is as follows: serum samples obtained within the first 2 trimesters
that are positive in the DT and negative in the IgM, IgA, and IgE
ELISAs and reveal a chronic pattern in the AC/HS test are typically
found in patients infected before gestation. The combination of
high titers in the DT, positive IgM, IgA, and IgE ELISAs, and an
acute pattern in the AC/HS test is highly suggestive of a recent
infection. In contrast, the presence of a positive DT and IgM
ELISA but a negative, low-positive, or equivocal result in the IgA
and IgE ELISAs and IgE ISAGA and an equivocal pattern in the
Figure 1. Criteria for interpretation of differential agglutination
(AC [acetone-fixed tachyzoites]/HS [formalin-fixed tachyzoites]) test
results.
1249
AC/HS test is more difficult to interpret, since it suggests infection
before pregnancy but does not rule out recent infection.
We selected consecutive serum samples in which the TSP had
⭓1 test result that suggested the possibility of a recently acquired
infection. This approach enabled us to evaluate the discriminatory
power of testing for IgG avidity. To select serum samples for testing
for IgG avidity, we used the following criteria: first, positive or
equivocal results in the IgM ELISA or acute or equivocal pattern
in the AC/HS test or second, results in the TSP that were not clearly
consistent with an infection acquired in the distant or recent past.
In some cases, interpretation of the TSP did not allow for clear-
cut discrimination between recently acquired and distant infection,
even after a follow-up sample was tested in parallel with the first
serum sample.
IgG avidity was measured with the T. gondii IgG avidity EIA
(Labsystems), and results were interpreted in accordance with the
manufacturer’s instructions. In brief, serum samples were diluted
in 4-fold dilutions, according to their predetermined IgG titers.
Serum samples were diluted and incubated in duplicate for 60 min
at 37⬚C in T. gondii–coated microstrips. We incubated 1 well of
each duplicate serum sample and of the negative, low avidity, and
high avidity controls in PBS/Tween; the other well of each duplicate
was incubated with avidity buffer containing urea. After a wash,
antigen-bound IgG was bound by conjugate applied for 1 h at 37⬚C
and was revealed by substrate. Optical densities were read at 405
nm. For each control and serum sample, we obtained 2 titration
curves (1 for each sample incubated with PBS/Tween and 1 for
samples incubated with avidity buffer). The distance between
curves corresponds to the avidity percentage (e.g., the greater the
distance in millimeters, the lower the avidity percentage that in-
dicates low-avidity antibodies and vice versa). We interpreted avid-
ity results as follows: !15%, low avidity (may be seen in acute
primary infection with T. gondii); 15%–30%, borderline avidity (pri-
mary infection within the past 6 months is possible); and 130%,
high avidity (excludes primary infection within the previous 3
months). A high-avidity result in the first 12 weeks of pregnancy
essentially rules out a recently acquired infection during gestation.
A low or equivocal IgG avidity result cannot be interpreted to
mean that a person was infected recently with T. gondii, because
low-avidity antibodies may persist for 15 months. Thus, when the
Labsystems kit is used in the first trimester, only high-avidity an-
tibodies are clinically meaningful.
When available, we used follow-up serologic test results obtained
⭓3 weeks apart from the initial serum sample and from serum
samples obtained before the initial sample submitted to the TSL-
PAMF to resolve discrepant results between individual tests. All
such serum samples were run in each test in parallel.
Results
We studied serum samples taken from 125 pregnant women
during the first trimester. Results in the IgM ELISA were posi-
tive in 81 (64.8%), equivocal in 12 (1.0%), and negative in 25
(20%) cases; an IgM ELISA titer could not be determined in
7 samples because of high background activity. In 42 (51.9%)
of the 81 serum samples that were positive by IgM ELISA, the
IgG avidity result was high (table 1), which indicates that in-
1250 Liesenfeld et al. JID 2001;183 (15 April)

Table 1. Comparison of results of IgM samples were available for 2 patients but did not reveal sig-
ELISA and IgG avidity test in 118 serum sam-
nificant increases in antibody titers.
ples taken from pregnant women during the
first trimester. For patients with a positive IgM test, the AC/HS test was
IgM ELISA result
the sole test that was most helpful in distinguishing recently
acquired from more distant infection. Of the 125 women who
Avidity Positive Equivocal Negative
result (n p 81) (n p 12) (n p 25) were in their first trimester of pregnancy, 33 (26.4%) had an
Low 16 (19.8) 0 4 (16.0) acute AC/HS test result, 53 (42.4%) had an equivocal result,
Borderline 23 (28.3) 2 (16.7) 7 (28.0) and 39 (31.2%) had a nonacute result. Of the 33 women with
High 42 (51.9) 10 (83.3) 14 (56.0)
an acute result in the AC/HS test, 17 (51.5%) had low avidity,
NOTE. Data are no. (%) of serum samples. Be- 12 (36.4%) had equivocal avidity, and 4 (12.1%) had high-avid-
cause of high background in IgM ELISA, 7 serum
samples were not included in the comparison. ity test results (table 3). In all, 87 (69.6%) of the 125 women
had either an acute or equivocal result in the AC/HS test (often
fection in those women occurred before gestation. In 16 (19.8%) interpreted as being suggestive of a recently acquired infection);
of the 81 serum samples, IgG avidity was low. In addition, 93 IgG avidity results in these were low in 21 (24.1%), equivocal
(74.4%) of 125 serum samples had positive or equivocal results in 31 (35.6%), and high in 35 (40.2%; table 3). Of the 39 women
in the IgM ELISA (often interpreted as being suggestive of a who had a nonacute AC/HS test result, 94.9% had a high-
recently acquired infection); IgG avidity results were high in 52 avidity test result; 2 (5.1%) were equivocal by avidity test, and
(55.9%), equivocal in 25 (26.9%), and low in 16 (17.2%). In 25 none had a low-avidity test result.
serum samples that were negative in the IgM ELISA, 4 (16.0%) In 85 (68.0%) of the 125 cases, the overall interpretation of
had low avidity, 14 (56.0%) had high avidity, and 7 (28.0%)
the TSP by TSL-PAMF physicians (without inclusion of the
had equivocal avidity test results (table 1). Figure 2 compares
avidity test) was consistent with an infection acquired before
results in the IgM ELISA with those in the IgG avidity test.
conception. For 40 (32.0%) of the 125 women, interpretation
Mean titers of T. gondii–specific IgM antibodies were 4.1 in
of results in the TSP did not allow us to rule out infection
serum samples with low-avidity antibodies, 3.2 in serum sam-
ples with borderline avidity, and 2.6 in serum samples with high- acquired during pregnancy or near conception. In these women,
avidity antibodies. spiramycin was recommended in an attempt to prevent trans-
Each of the 4 serum samples that were negative in the IgM mission of the parasite from mother to fetus. Testing of IgG
ELISA and that had low IgG avidity titers had IgG titers of avidity in serum samples from these 40 women revealed high
⭓512 (table 2); 3 had an acute pattern in the AC/HS test, and avidity in 7 (17.5%), borderline avidity in 17 (42.5%), and low
each was negative by IgA ELISA (table 2). Follow-up serum avidity in 16 (40.0%).

Figure 2. Correlation of IgM titers with avidity test results in 118 serum samples taken from 188 pregnant women during the first trimester.
Two data points are superimposed, because results in 2 serum samples were identical (borderline avidity and negative IgM test results).
JID 2001;183 (15 April) Toxoplasma IgG Avidity 1251

Table 2. Serological test results in serum samples obtained from pregnant women during
their first trimester who had negative results in the IgM ELISA and low IgG avidity.
Gestation, IgE IgE
a
Specimen weeks Avidity, % IgG IgM IgA ELISA ISAGA AC/HS (int)
b
61642 10 6.3 2048 0.7 0.3 0 0 11600/13200 (A)
c
61681 6 7.1 4096 1.2 0.7 0.5 3 400/200 (A)
b
63081 8 1.6 2048 0.5 1.0 0.5 0 800/400 (A)
74108 12 7.1 512 1.2 1.0 0.8 0 100/400 (E)

NOTE. A, acute pattern; AC/HS, differential agglutination test; E, equivocal pattern; int, interpretation;
ISAGA, immunosorbent agglutination assay. For further explanation of the AC/HS test, see figure 1.
a
Reciprocal of serum dilution.
b
No significant increase in antibody titers was observed in follow-up serum samples obtained ⭓4 weeks
apart.
c
Serum sample obtained 8 weeks earlier revealed a negative result in the IgM ELISA and an equivocal
pattern in the AC/HS test.

Discussion
Development of a serologic method to differentiate recent
from more distant T. gondii infection in pregnant women by
using a single serum sample has long been a goal of industry
and academic investigators. Such a method would be of par-
ticular importance in the United States, where systematic se-
rologic screening during pregnancy is not done. The lack of
availability of serial serum samples from individual pregnant
women in the United States has severely hampered research in
this direction and has markedly compromised the ability of
physicians to determine the risk for congenital infection.
These problems led our group to develop a serologic test
panel [11, 12] that assists in defining whether a positive IgM
antibody test result for a given patient reflects recently acquired
infection. Although the panel is useful, it does not provide
definitive results in all cases. Our results reveal that the IgG
avidity test is the first method that can differentiate between
recent and more distant infection in a single serum sample if
the sample is obtained in the first trimester of pregnancy. Kits
in use in Europe extend this possibility to the fourth month of
gestation [14, 18, 20]. Unfortunately, in many instances, the
first serum sample is not submitted for testing until later in the
pregnancy.
The serum samples selected for this study had equivocal or
positive results by IgM ELISA or AC/HS test. Additional se-
rum samples from some of the same patients were tested by
TSP, but the results did not allow clear-cut discrimination be-
tween recently acquired and distant infection. When IgG avidity
and IgM ELISA results were compared in serum samples ob-
tained during the first trimester of pregnancy, 51.9% of IgM
ELISA–positive serum samples (55.9% of IgM-positive and
IgM-equivocal serum samples) had high IgG avidity test results
that essentially ruled out recent infection. These results high-
light the problem in interpretation of a positive test for IgM
antibodies without confirmatory testing. In a recent study in
which we used the TSP, a positive IgM test result did not in-
dicate a recently acquired infection in 60% of pregnant women
studied [24]. Of importance, IgM antibodies may persist for
⭓1 year after acute T. gondii infection. The value of testing for
IgG avidity, as shown in the present study, confirms and extends
the results reported by Lappalainen et al. [14].
Initial findings with the IgG avidity method suggested that
low-avidity antibodies indicated recently acquired infection
[14]. Since then, studies have shown clearly that low-avidity
antibodies can persist for many months beyond the acute in-
fection and thus are not reliable for the diagnosis of recently
acquired infection [20, 25]. In contrast, the consensus appears
to be that the IgG avidity test is best used to rule out recently
acquired infection. Depending on the method used, the presence
of high-avidity IgG antibodies can be used to rule out the
occurrence of acute infection within the past 3–5 months (table
4). Thus, its value is greatest when done in the first 3–4 months
of gestation. A high-avidity result late in the second trimester
or in the third trimester cannot be interpreted to mean that the
infection was not acquired in the first 3–5 months of gestation.
Of note, 20% of serum samples with a low-avidity result in the
present study had negative results in the IgM ELISA; testing
of the initial and follow-up serum samples in the TSP did not
suggest recently acquired infection in any of these cases.
Both the AC/HS test and the IgG avidity test were valuable
in confirmatory testing of IgM-positive serum samples, and the
2 methods had excellent agreement (94.9% of serum samples with
a nonacute pattern in the AC/HS test had high-avidity antibod-
ies). Discrepant results between the AC/HS and IgG avidity tests
only occurred in serum samples with high-avidity antibodies.
The high numbers of equivocal results in the avidity and AC/
Table 3. Comparison of IgG avidity test and
differential agglutination (AC/HS) test results
in 125 serum samples taken from pregnant
women during the first trimester.
AC/HS test result
Avidity Acute Equivocal Nonacute
result (n p 33) (n p 53) (n p 39)
Low 17 (51.5) 4 (7.5) 0
Borderline 12 (36.4) 18 (34.0) 2 (5.1)
High 4 (12.1) 31 (58.5) 37 (94.9)
NOTE. Data are no. (%) of serum samples. For
further explanation of the AC/HS test, see figure 1.
1252 Liesenfeld et al. JID 2001;183 (15 April)

Table 4. Reports in the literature on toxoplasma IgG avidity tests.

Positive
Exclusion Cutoff predictive
No. and type period, for high value of high
Study [reference] Avidity test type of serum samples months avidity, % avidity, % Comment
⫹ ⫹
Lappalainen et al. [14] Noncommercial titration 226 IgG /IgM , including 5 125 100 100% Positive predictive value
13 seroconverters for low avidity antibodies
Holliman et al. [15] Noncommercial 25 Distant infected; 11 re- 3 150 96 80% Negative predictive value
cently infected for high avidity antibodies
Sensini et al. [16] Labsystems 485 Serum samples/308 pa- ND 150 ND Delayed avidity maturation in
tients, including 13 patients receiving specific
seroconverters treatment
Guttiérez et al. [17] ETI-Toxo-G ⫹ 57 Distant infection ⫹ 12 ND 150 100 No signficiant differences be-
Enzygnost seroconverters tween methods
Jenum et al. [18] Titration (Platelia IgG); 56 IgG⫹/IgM⫹ 5 120 ND Unchanged avidity maturation
107 recent infections in patients receiving specific
treatment
Ashburn et al. [19] Noncommercial titration 43, Including 1 seroconverter ND 130 ND
Pelloux et al. [20] Vidas 330 ⫹ 26 Seroconverters 4 130 ND Avidity !30%, even 9 months af-
ter infection, in patients with
immune disorders and in preg-
nant women
Cozon et al. [25] Enzygnost 493 IgG⫹/IgM⫹ 3 135 100 39.6% Negative predictive
value of low avidity antibodies

NOTE. ND, not determined.

HS tests remain a drawback of these methods. In cases with
equivocal results in either the AC/HS or avidity test (43.2%
and 26.4%, respectively), only confirmatory testing by the TSP
or testing of follow-up serum samples could help distinguish
between recently acquired and distant infection.
Interpretation of avidity test methods was based solely on
results in serum samples obtained sequentially from pregnant
women who seroconverted and not on outcome in their children.
Follow-up data in only a small number of children (n p 13) born
to mothers who had high-avidity antibodies in the first trimester
have been published elsewhere [26]. None of the 13 was infected
with T. gondii, according to long-term serologic follow-up [26].
A question for consideration is whether a high-avidity test
result in the first trimester can rule out the possibility of fetal
infection in women who acquired the infection a few months
before gestation. The likelihood of congenital transmission as
a result of an infection acquired in the weeks before or near
the time of conception is extremely low, approaching zero [27].
Congenital toxoplasmosis has been reported in only 6 children
of women whose serologic test results revealed they probably
were infected before pregnancy [1]. Each of these women was
infected 1–3 months before becoming pregnant. Avidity testing
does not overcome the limitations of serologic testing in this
regard. Thus, the dictum that no serologic test is perfect can
be extended to the avidity test. No investigators who have de-
veloped avidity tests have claimed that their methods can un-
equivocally rule out infection acquired a few weeks before the
beginning of pregnancy.
Unfortunately, commercial kits for IgG avidity are not li-
censed in the United States. This method would be well suited
to rule out recently acquired infections in IgM-positive preg-
nant women who have high-avidity antibodies in their first
months of gestation. An approach to testing for and manage-
ment of T. gondii infection in pregnant women would be to
screen for IgG and IgM antibodies in the first trimester of all
women in whom the serologic status is not known at concep-
tion. For women with negative results in both tests, information
and education would be of paramount importance to prevent
infection [1]. In serum samples positive for both IgG and IgM
antibodies, IgG avidity would be determined. A high-avidity
test result would decrease significantly the number of additional
confirmatory or follow-up serologic tests needed and the need
for spiramycin and invasive techniques, including polymerase
chain reaction (PCR) analysis of amniotic fluid.
These findings were emphasized further by our experience in
the present study: even in the setting of a reference laboratory
in which TSP is used to distinguish between recently acquired
and distant infection, high-avidity antibodies were detected in
17.5% of 40 women for whom spiramycin had been recom-
mended, because recently acquired infection could not be ruled
out in a single serum sample by the TSP. Since serum samples
were chosen retrospectively, all decisions about spiramycin
treatment were made without knowledge of avidity test results.
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 likeli-
hood of misdiagnosis [24].
Whether the avidity test can replace any of the present tests
in the TSP or should simply be added to that panel requires
further evaluation of the avidity tests being marketed. At present
no avidity test has been released by the Food and Drug Ad-
ministration for US marketing. We now routinely use the avidity
JID 2001;183 (15 April) Toxoplasma IgG Avidity
test as an additional diagnostic tool in the TSP for patients with
a positive or equivocal IgM test or acute or equivocal pattern
by AC/HS test. We conclude that IgG avidity testing of serum
samples of women in the first trimester of pregnancy is a valuable
confirmatory test for the exclusion of recently acquired T. gondii
infection, especially in US laboratories, which usually have only
a single serum sample for testing.
Acknowledgments
We greatly appreciate the help of Meg Davis and Raymund Ramirez
(Department of Immunology and Infectious Diseases, Research Insti-
tute, Palo Alto Medical Foundation, Palo Alto, CA).
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