![[Feedback]](/icons/banner/feedbackACT.gif)
![[For Subscribers]](/icons/banner/subscriberACT.gif)
![[Archive]](/icons/banner/archiveACT.gif)
![[Search]](/icons/banner/searchACT.gif)
![[Contents]](/icons/banner/tocACT.gif)
Previous Article | Next Article 
Clinical and Diagnostic Laboratory Immunology, July 2000, p. 703-705, Vol. 7, No. 4
1071-412X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Lack of Utility of Specific Immunoglobulin G
Antibody Avidity for Serodiagnosis of Reactivated Toxoplasmosis in
Immunocompromised Patients
Bénédicte
Mechain,1
Yves Jean-François
Garin,1
Florence
Robert-Gangneux,2
Jean
Dupouy-Camet,2 and
Francis
Derouin1,*
Laboratoire de Parasitologie-Mycologie,
Hôpital Saint-Louis, 75475 Paris Cedex
10,1 and Laboratoire de
Parasitologie-Mycologie, Hôpital Cochin, 75014 Paris,2 France
Received 30 November 1999/Returned for modification 25 January
2000/Accepted 22 March 2000
 |
ABSTRACT |
The avidities of Toxoplasma-specific immunoglobulin G
serum antibodies were measured in immunocompromised patients presenting with cerebral or extracerebral toxoplasmosis and/or serological reactivation. Since avidity remained high and stable in 39 of 40 patients with toxoplasmosis and 27 of 28 patients with serological reactivation, we conclude that this test cannot help diagnose toxoplasmosis in these patients.
| |
TEXT |
In immunocompromised patients, the
titration of anti-Toxoplasma-specific antibodies is poorly
contributive to the diagnosis of cerebral or extracerebral
toxoplasmosis, as the usual serological markers of an acute infection,
i.e., an increase in immunoglobulin G (IgG) levels and the presence of
IgM and/or IgA antibodies, are frequently lacking at the time of
diagnosis (3-5, 10). Besides, serological reactivations
often occur in these patients but are poorly correlated to the onset of
clinical symptoms (1, 3).
Since determination of the avidities of Toxoplasma-specific
IgG antibodies has proved useful in differentiating between acute and
chronic infections in immunocompetent patients (2, 6-9, 12,
13), our objective was to evaluate the validity of this test for
the diagnosis of cerebral and extracerebral toxoplasmosis in human
immunodeficiency virus (HIV)-infected patients and transplant recipients.
Patients and methods. (i) Patients.
We determined the IgG
avidities of individual and sequential serum samples from 41 HIV-infected patients, 18 allogenic bone marrow transplant (BMT)
recipients, and 5 organ transplant recipients (heart, 3; lung-liver, 1;
kidney-liver, 1) presenting with clinical toxoplasmosis or serological
reactivation (Table 1). In these patients, the diagnosis of cerebral or extracerebral toxoplasmosis was
established by the presence of clinical symptoms; by radiological signs
on brain-computed tomography or magnetic resonance imaging; by
demonstration of Toxoplasma gondii tachyzoites on
Giemsa-stained smears or by mouse inoculation or tissue culture; or by
response to specific therapy. Serological reactivation was defined as
at least a twofold increase in the IgG antibody titer in two sequential serum samples. In three HIV-infected patients and one heart transplant patient, serological reactivation preceded cerebral or disseminated toxoplasmosis.
(ii) Methods.
The determination of IgG
anti-Toxoplasma antibody titers was performed by
enzyme-linked immunosorbent assay (ELISA) (Platelia Toxo-IgG;
Bio-Rad, Marnes la Coquette, France). Results were expressed in
international units per milliliter and were considered positive for
titers of >6 IU/ml. Specific IgM antibody titers were determined by
ELISA (Platelia Toxo-IgM; Bio-Rad) and immunosorbent agglutination assay (ISAGA; Bio-Mérieux). Results were expressed as indices and
were considered positive for values of >1 with ELISA and >9+ with
ISAGA. Specific IgA antibody titers were determined by ISAGA, with a
threshold of positivity of 9+.
The determination of IgG antibody avidity was performed using the
Platelia Toxo-IgG kit (Bio-Rad) with 6 M urea as a dissociative agent
in the washing solution preceding the incubation of the conjugate
(9).
The IgG avidity index (IgG-AI) was calculated as (OD values under
dissociative conditions)/(OD value of untreated serum), where OD is
optical density. In a preliminary experiment, the ability of the IgG
avidity test to differentiate between acute and chronic infections had
been examined on 214 sera from 194 immunocompetent patients whose dates
of seroconversion were known. For an IgG-AI of <0.4 or <0.5, the
predictive value for an infection of less than 5 months was 79.4 or
74.5%, respectively. For an index of >0.4 or >0.5, the predictive
value for an infection of more than 5 months was 94.7 or 97.9%,
respectively. Thus, an IgG-AI cutoff value of 0.5 allowed us to
differentiate between most cases of acute and chronic toxoplasmosis, as
previously observed by others (6, 9, 12).
Results.
For immunocompromised patients with cerebral or
extracerebral toxoplasmosis, the IgG-AI was determined on individual
serum samples taken at the onset of symptoms. For HIV-infected and BMT patients, IgG-AI values at the time of diagnosis were >0.4 in 38 of 39 patients and >0.5 in 35 of 39 patients (Fig.
1). A low IgG-AI (0.21) was observed for
one patient with ocular toxoplasmosis who presented serological signs
of recently acquired infection, i.e., the presence of IgM and IgA
antibodies and a subsequent increase in IgG antibody titers. For 22 patients, a previous serum sample was available, and the IgG-AI was
>0.4 in all cases and >0.5 in 21 of 22 cases. Overall, no correlation
was found between the IgG-AI and the IgG antibody titer, or between the
IgG-AI and the presence of IgM or IgA antibody.
View larger version (13K):
[in this window]
[in a new window]
|
FIG. 1.
IgG avidity at the onset of symptoms of cerebral,
ocular, or pulmonary/disseminated toxoplasmosis in AIDS or BMT
patients.
|
|
In all cases of serological reactivation occurring in asymptomatic
HIV-infected patients, the IgG-AI remained at high and stable levels,
while antibody titers increased, even in three patients who further
developed a cerebral toxoplasmosis. Similarly, all BMT recipients with
asymptomatic serological reactivation except one had stable IgG-AI
values, and no relation was found between the evolution of the IgG-AI
and the serological status of the bone marrow donor. The remaining
patient presented with serological reactivation 17 months after BMT,
with a decrease in the IgG-AI from 0.53 to 0.18, and then an increase
to 0.32 at the time when IgG antibody titers respectively increased
from 24 to 196, and then to 1,390 IU/ml. This low IgG-AI persisted for
several months, and no clinical symptom suggestive of toxoplasmosis was
recorded during this period. The patient and the donor were both
seropositive for T. gondii before BMT. In the five
solid-organ transplant patients with serological reactivation, the
IgG-AI remained unchanged before and after transplantation; this was true even for the patient who developed disseminated toxoplasmosis 1 month after transplantation, possibly through heart-transmitted infection (Table 2).
Discussion.
In this study, we hypothesized that the
determination of IgG-AI could be useful for diagnosing reactivated
toxoplasmosis in immunocompromised patients, based on the concept that
neoantigens emerging from cyst rupture could induce a primary-type
immune response with low-avidity IgG antibodies. Therefore, a decrease in the IgG-AI could be of diagnostic help in two situations: (i) in
patients with serological reactivation, as an early marker of infection
recrudescence, and (ii) in patients with symptomatic visceral
reactivated toxoplasmosis.
Our results show that for all patients with asymptomatic serological
reactivation, except one BMT recipient, the IgG-AI remained unchanged
and at a high level in sequential sera taken before and after antibody
increase. No difference was noted between patients whose serological
reactivation preceded the onset of clinical symptoms and those who
remained asymptomatic.
Similarly, IgG avidity determination was of no help for the diagnosis
of visceral toxoplasmosis occurring in HIV-infected or transplant
patients. In 39 of 40 (97.5%) symptomatic patients, the IgG-AI
remained high and stable in sera taken before or after the onset of
symptoms. The stability of the IgG-AI observed in our study supports
the idea that most cases of cerebral or disseminated toxoplasmosis
occurring in immunocompromised patients result from reactivation of a
latent infection (9) and indicates a secondary immune
response to recall antigens rather than a primary immune response to
neoantigens emerging from cyst rupture. In transplant patients
receiving organs from Toxoplasma-seropositive donors, there
is a well-known risk of organ transmission of Toxoplasma (11, 14). Thus, our hypothesis was that reinfection related to a donor-transmitted strain could result in a decrease in the IgG-AI.
We observed that the IgG-AI remained >0.5 in sera taken before and
after transplantation, even in a patient who rapidly developed a case
of disseminated toxoplasmosis that was likely due to recontamination by
the heart transplant. Therefore, the IgG-AI determination could not
distinguish a reactivation from an organ-transmitted toxoplasmosis.
From these results, we conclude that the determination of IgG avidity
is of no help in the diagnosis of cerebral or extracerebral toxoplasmosis occurring in immunocompromised patients or for the interpretation of serological reactivations that are frequently observed in these patients.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratoire de
Parasitologie-Mycologie, Hôpital Saint-Louis, 1, avenue Claude
Vellefaux, 75475 Paris Cedex 10, France. Phone: 33 1 42 49 95 01. Fax:
33 1 42 49 48 03. E-mail: paracord{at}wanadoo.fr.
| |
REFERENCES |
| 1.
|
Bélanger, F.,
F. Derouin,
L. Grangeot-Keros,
L. Meyer, and the HEMOCO-SEROCO Study Group.
1999.
Incidence and risk factors of toxoplasmosis in a cohort of HIV-infected patients: 1988-1995.
Clin. Infect. Dis.
28:575-581[Medline].
|
| 2.
|
Cozon, G. J. N.,
J. Ferrandiz,
H. Nebhi,
M. Wallon, and F. Peyron.
1998.
Estimation of the avidity of immunoglobulin G for routine diagnosis of chronic Toxoplasma gondii infection in pregnant women.
Eur. J. Clin. Microbiol. Infect. Dis.
17:32-36[CrossRef][Medline].
|
| 3.
|
Derouin, F.,
A. Devergie,
P. Auber,
E. Gluckman,
B. Beauvais,
Y. J. F. Garin, and M. Larivière.
1992.
Toxoplasmosis in bone marrow transplant recipients: report of seven cases and review.
Clin. Infect. Dis.
15:267-270[Medline].
|
| 4.
|
Derouin, F.,
P. Thulliez, and Y. J. F. Garin.
1991.
Intérêt et limites de la sérologie de la toxoplasmose chez les sujets VIH+.
Pathol. Biol.
39:255-259[Medline].
|
| 5.
|
Derouin, F.,
C. Leport,
S. Pueyo,
P. Morlat,
B. Letrillart,
G. Chêne,
J. L. Ecobichon,
B. Luft,
J. Aubertin,
R. Hafner,
J. L. Vildé,
R. Salamon, and ANRS 005/ACTG 154 Trial Group.
1996.
Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients.
AIDS
10:1521-1527[Medline].
|
| 6.
|
Holliman, R. E.,
R. Raymond,
N. Renton, and J. D. Johnson.
1994.
The diagnosis of toxoplasmosis using IgG avidity.
Epidemiol. Infect.
112:399-408[Medline].
|
| 7.
|
Jenum, P. A.,
B. Stray-Pedersen, and A. Gerd Gundersen.
1997.
Improved diagnosis of primary Toxoplasma gondii infection in early pregnancy by determination of antitoxoplasma immunoglobulin G avidity.
J. Clin. Microbiol.
35:1972-1977[Abstract].
|
| 8.
|
Lappalainen, M.,
P. Koskela,
M. Koskiniemi,
P. Ammala,
V. Hiilesmaa,
K. Teramo,
K. O. Raivio,
J. S. Remington, and K. Hedman.
1993.
Toxoplasmosis acquired during pregnancy: improved serodiagnosis based on avidity of IgG.
J. Infect. Dis.
167:691-697[Medline].
|
| 9.
|
Lécolier, B., and B. Pucheu.
1993.
Interêt de l'étude de l'avidité des IgG pour le diagnostic de la toxoplasmose.
Pathol. Biol.
41:155-158[Medline].
|
| 10.
|
Luft, B. J., and J. S. Remington.
1992.
Toxoplasmic encephalitis in AIDS.
Clin. Infect. Dis.
15:211-222[Medline].
|
| 11.
|
Luft, B.,
Y. Naot,
F. G. Araujo,
E. B. Stinson, and J. S. Remington.
1983.
Primary and reactivated toxoplasma infection in patients with cardiac transplant.
Ann. Intern. Med.
99:27-31.
|
| 12.
|
Robert-Gangneux, F.,
C. Vieljeuf,
C. Tourte-Schaefer, and J. Dupouy-Camet.
1998.
Apport de l'avidité des anticorps dans la datation d'une séroconversion toxoplasmique.
Ann. Biol. Clin.
56:586-589.
|
| 13.
|
Sensini, A.,
S. Pascoli,
D. Marchetti,
R. Castronari,
M. Marangi,
G. Sbaraglia,
C. Cimmino,
A. Favero,
M. Castelletto, and A. Mottola.
1996.
IgG avidity in the serodiagnosis of acute Toxoplasma gondii infection: a multicenter study.
Clin. Microbiol. Infect.
2:25-29[Medline].
|
| 14.
|
Speirs, G. E.,
M. Hakim,
R. Y. Calne, and T. G. Wreghitt.
1988.
Relative risk of donor-acquired Toxoplasma gondii in heart, liver and kidney transplant recipients.
Clin. Transplant.
2:257-260.
|
Clinical and Diagnostic Laboratory Immunology, July 2000, p. 703-705, Vol. 7, No. 4
1071-412X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Colombo, F. A., Vidal, J. E., Oliveira, A. C. P. d., Hernandez, A. V., Bonasser-Filho, F., Nogueira, R. S., Focaccia, R., Pereira-Chioccola, V. L.
(2005). Diagnosis of Cerebral Toxoplasmosis in AIDS Patients in Brazil: Importance of Molecular and Immunological Methods Using Peripheral Blood Samples. J. Clin. Microbiol.
43: 5044-5047
[Abstract]
[Full Text]
-
Giraldo, M., Portela, R. W. D., Snege, M., Leser, P. G., Camargo, M. E., Mineo, J. R., Gazzinelli, R. T.
(2002). Immunoglobulin M (IgM)-Glycoinositolphospholipid Enzyme-Linked Immunosorbent Assay: an Immunoenzymatic Assay for Discrimination between Patients with Acute Toxoplasmosis and Those with Persistent Parasite-Specific IgM Antibodies. J. Clin. Microbiol.
40: 1400-1405
[Abstract]
[Full Text]
Top
Abstract
Text
