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PubMed2006

Mic1-3 knockout of Toxoplasma gondii is a successful vaccine against chronic and congenital toxoplasmosis in mice.

BACKGROUND: We evaluated a new vaccine, Mic1-3KO, against both chronic and congenital toxoplasmosis in mice. Mic1-3KO is a mutant strain of Toxoplasma gondii RH that lacks the mic1 and mic3 genes. METHODS: OF1 mice were vaccinated with Mic1-3KO tachyzoites and challenged orally with T. gondii (strain 76K). Immune responses and protection against chronic infection (cyst load in brain tissue) and congenital infection (maternofetal transmission, survival, body weight, and chronic infection in pups) were evaluated. RESULTS: Mic1-3KO induced a strong humoral and cellular T helper (Th) 1 response and conferred highly significant protection against chronic infection (>96% reduction in cysts in brain tissue). Fewer infected fetuses were observed in vaccinated dams that were infected during pregnancy than in nonvaccinated infected dams (4.6% vs. 33.3%). All pups born to vaccinated infected dams survived and had the same weight as those born to nonvaccinated uninfected dams. Furthermore, they had significantly fewer cysts in brain tissue (>91%) than pups from nonvaccinated infected dams. During pregnancy, protection against congenital disease was associated with a cellular Th1 response regulated by interleukin-10. One month after delivery, vaccinated infected dams had >96% fewer cysts in their brain tissue than nonvaccinated infected dams. CONCLUSION: Mic1-3KO is an effective vaccine against chronic and congenital toxoplasmosis.

Animals↗
PubMed1976

Congenital toxoplasmosis in twins: a series of 14 pairs of twins: absence of infection in one twin in two pairs.

Fourteen pairs of twins with congenital toxoplasmosis were observed. In two pairs, one twin was infected and had symptoms of chorioretinitis or encephalomyelitis, while the other had a negative dye test upon repeated examination: this phenomenon has not previously been reported. In three of the other twelve pairs of twins, one of each pair died; two of them had evidence of toxoplasmosis; in the cotwin the diagnosis was based on serologic data. Clincial and biologic follow-up extended from 19 months to 8 years in five pairs. Marked discrepancies in the individual clinical patterns of the two children in each of six sets of twins were observed, with evidence of infection in one twin and subclinical infection in the other. These clinical findings correlated well with serologic data in the children in whom sufficient follow-up was permitted. The clinical pattern of congenital toxoplasmosis in twins is extremely similar in monochorial pregnancies, but discrepancies are almost the rule in bichorial pregnancies. The importance of placental lesions in determining the extent of fetal involvement is well illustrated by studies of toxoplasmosis in twins.

Child↗
PubMed1995

Diagnosis of congenital toxoplasmosis by immunoblotting and relationship with other methods.

Immunoblot has been evaluated as a diagnostic method for congenital toxoplasmosis. Like enzyme-linked immunofiltration assay (ELIFA), immunoblot can be used to compare antibody patterns and to determine if the antibodies are transmitted by the mother or synthesized by the fetus or infant. Among the 48 infants tested, 27 had congenital toxoplasmosis and 21 were suspected but had none. Reproducibility, sensitivity, specificity, and positive predictive values in immunoblot for immunoglobulins (Igs) G+M+A and/or G+M were 90, 92.6, 89.1, and 92.4%, respectively. G+M immunoblot and G+M ELIFA have better sensitivities than the conventional IgM immunosorbent agglutination assay, IgM enzyme-linked immunosorbent assay (ELISA), IgM immunofluorescence antibody test, in vitro culture, and mouse inoculation. The novel antibodies, i.e., those synthesized by infants against Toxoplasma gondii, were of the IgG class in most cases, although a confident diagnosis could be related to the number of observed Ig classes (G+M, G+A, and G+M+A). Immunoblot has a better resolution than ELIFA. In prenatal diagnosis, immunoblot could be complementary to in vitro culture and mouse inoculation. In the other cases, early detection by immunoblot appears to give the best results when compared with the other serological methods.

Animals↗
PubMed1999

Protective immunity in the rat model of congenital toxoplasmosis and the potential of excreted-secreted antigens as vaccine components.

Toxoplasma infection is a major cause of severe foetal pathology both in humans and in domestic animals, particularly sheep. We have previously reported the development of an experimental model to study congenital toxoplasmosis in the rat. Here we demonstrate that, as in humans, total protection against congenital toxoplasmosis can be achieved regardless of the strain of Toxoplasma gondii used to infect rats, or when initial and challenge infections were carried out with different strains. Chronic infection is associated with a highly specific immunity that involves both B-and T-cell responses beginning at day 10 postinfection. The antibody isotype analysis revealed that whereas immunoglobulin (Ig)G2b is the major elicited isotype, no IgG1 antibodies are detected. T cell proliferation was assayed using crude Toxoplasma extracts or excretory-secretory antigens (ESA). The analysis of T cell supernatants showed the specific secretion of both interleukin-2 and interferon-gamma by activated T cells. Immunization of rats before pregnancy with either crude Toxoplasma extracts or with ESA elicited a B cell response that included antibodies of the IgG1 isotype and conferred on the newborns high levels of protection. Preliminary experiments of immunization using two HPLC-purified ESA, GRA2 and GRA5, conferred, a significant protection although to a lesser extent. This experimental model represents an attractive model for the identification of future vaccine candidates against congenital toxoplasmosis.

Animals↗
PubMed2003

Clinical presentation and follow up of children with congenital toxoplasmosis in Brazil.

We evaluated the clinical presentation and determined the ocular and neurologic sequelae in children with congenital toxoplasmosis in Brazil, taking into consideration the shortage of national publications on this disease. Follow-up evaluations were made of 43 children with congenital toxoplasmosis referred to Santa Casa de São Paulo, during a period of at least five years. Selection of the cases was based in clinical and laboratory criteria. A clear predominance of children with subclinical presentation of the disease at birth (88%) was found. Of the 43 children, 22 (51%) developed neurological manifestations. Using skull radiography, we detected neuroradiologic alterations in seven children (16%) and with tomography in 33 children (77%). Neurological sequelae were identified in 15 children (54%) in the group with cerebral calcifications and in 7 (47%) in the group without cerebral calcifications. We observed chorioretinitis in 95% of the cases. Reactivation of cicatricial lesions and the emergence of new ocular lesions were observed in five cases. The most frequent neurological manifestation was a delay in neuropsychomotor development. Most remarkable was the finding that cerebral calcifications were not associated with a higher incidence of neurological sequelae among the children. Chorioretinitis was the main ocular sequel of the infection, found in nearly all children; it can manifest years from birth, even in children submitted to specific therapy druing the first year of life, highlighting the importance of a follow-up of these children.

Brain Diseases↗
PubMedDate not supplied

Congenital toxoplasmosis in twins: a case report.

We report a case of congenital toxoplasmosis in a twin pregnancy at 21 weeks of gestation. The complete antenatal investigation included ultrasound examination, cordocentesis and amniocentesis. The ultrasonographic evaluation showed a distinct morphological aspect confirmed by the fetal biological profile. The time lag between placental and fetal infection, or the immunological fetal responses could explain the varying stages of the fetal disease. This is another case which early demonstrates that there may exist a distinct clinical pattern in bichorial pregnancy with varying biological fetal responses. It underlines the importance of cordocentesis in the case of maternal toxoplasma seroconversion, enabling us to gather a maximum number of biological data for complete appreciation of the fetal status. The information obtained permits a precise adaptation of the medical decision.

Abortion, Induced↗
PubMedDate not supplied

[Congenital toxoplasmosis].

Judged by the cases studied at the Hospital de Pediatría, congenital toxoplasmosis may be transmitted to several descendants and the infection capacity of the mother persists for a long time. The possibility of toxoplasma infection should be investigated in cases of hydrocephalus, convulsions, microcephalia, ocular lesions or pictures of neonatal hepatitis. To explain invasion to the central nervous system by Toxoplasma gondii, a pathogenic hypothesis is offered.

Child, Preschool↗
PubMed1987

[Congenital toxoplasmosis with delayed immune response in children. Diagnostic problems].

A newborn, delivered at term, developed a rapidly increasing hydrocephalus with intracranial calcifications and seizures during the first week of life. Clinical suspicion of congenital toxoplasmosis was at first not confirmed serologically (serum titer in the immunofluorescence test [IFT] of 1:1024 and complement-fixation reaction [CFR] of 1:40 equalling those of the mother; IgM-IFT being negative and the IFT and CFR titers significantly falling within two weeks). But in the further course of the disease the diagnosis of congenital toxoplasmosis was confirmed: 1. Microscopic tachyzoits in CSF when aged six weeks; 2. positive IgM-IFT in serum and CSF from the seventh weeks onwards; 3. steep IFT titer rise in serum and CSF from the 16th week onwards. This case demonstrates that with delayed immune response in the infected child only serial serological tests will exclude or confirm the diagnosis of congenital toxoplasmosis.

Antibodies, Bacterial↗
PubMed2002

[Treatment of subclinical congenital toxoplasmosis by sulfadiazine and pyrimethamine continuously during 1 year: apropos of 46 cases].

UNLABELLED: In France, most of children suffering from congenital toxoplasmosis have an infraclinic or moderate type at birth. This study aimed at evaluating, on the mid term, tolerance and results of postnatal treatment previously given in severe toxoplasmosis. METHODS: A retrospective study considered 46 children with a mild or moderate congenital toxoplasmosis treated over 12 months with sulfadiazine-pyrimethamine and treatment was completed since three months. RESULTS: Five children suffered from a lesion of chorioretinitis during treatment and two after. After a mean follow-up of 27.1 months, ten children (21.7% 95%CI [12.1-35.9]) had at least one ocular injury. Specific IgG titers and immune load were diminished to become almost non-existent at the end of the year of treatment (respectively p < 10(-5) and p = 0.0005). No thrombocytopenia was observed. Twenty-three children (50%) had at least one episode of neutropenia < 1000/mm3, 14 had only one, nine presented two or more installment. None was followed by an infection. CONCLUSION: This therapeutic pathway is more demanding but shorter than those usually offered when associating pyrimethamine-sulfadiazine. Yet, it does give identical result on the mid term. Longer follow-up is needed to appreciate. Active molecule on cysts should be introduced.

Age Factors↗
PubMed1996

Early neonatal diagnosis of congenital toxoplasmosis: value of comparative enzyme-linked immunofiltration assay immunological profiles and anti-Toxoplasma gondii immunoglobulin M (IgM) or IgA immunocapture and implications for postnatal therapeutic strategies.

Diagnostic strategies for congenital toxoplasmosis have changed profoundly in recent years. Immunological diagnostic methods, long considered disappointing, can now be used at a very early stage. Over a 3-year period, 1,050 infants at risk of congenital toxoplasmosis (born to 1,048 mothers infected during pregnancy) were monitored for a minimum of 12 months and a maximum of 7 years. More than 6,000 serum specimens were analyzed by comparative mother-infant immunological profiles (CIPs) based on an enzyme-linked immunofiltration assay (ELIFA) and an immunocapture method for the detection of specific immunoglobulin M (IgM) and IgA. IgG antibodies were also titrated. One hundred three cases of congenital toxoplasmosis were demonstrated. The CIP-ELIFA method had a better diagnostic yield (sensitivity, 90%) than specific IgM and/or IgA detection by immunocapture assay (sensitivity, 77%). By using a combination of these tests, congenital infection was diagnosed in the first month and the first 3 months of life in 90 and 94% of infants with toxoplasmosis, respectively, with a specificity of 99.8% and a positive predictive value of 99% at 8 months of age. This dual diagnostic approach (ELIFA and IgM-IgA immunocapture) is highly efficient and has important implications for therapy. Indeed, early postnatal diagnosis based on objective evidence enables therapy with pyrimethamine-sulfadoxine to be started immediately for 24 months, while spiramycin (which used to be given preventively for 9 to 12 months to all infants at risk) can be stopped after the first 3 months of life.

Animals↗
PubMed2004

Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.

AIMS: To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS: Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS: Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION: This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.

Adolescent↗
PubMed2004

A comparative study of congenital toxoplasmosis between public and private hospitals from Uberlândia, MG, Brazil.

The main purpose of the present study was to examine if there is difference in terms of incidence rates of congenital toxoplasmosis among populations assisted in public and private hospitals from Uberlândia, state of Minas Gerais, Brazil. A total of 805 serum samples from cord blood were collected, being 500 from public hospital and 305 from private hospital, and all patients answered a questionnaire about pregnancy and newborns. An indirect enzyme linked immunosorbent assay (ELISA) was performed to detect IgG antibodies to Toxoplasma gondii and the positive samples were retested to verify the presence of specific IgM and IgA antibodies in a capture ELISA. We found significant differences among data from both hospitals with respect to maternal age, origin city, gestational age, number of visits to physicians during pregnancy, type of delivery, and birth weight. Seroprevalence of IgG antibodies against T. gondii for patients from public and private hospitals was 57.6% and 41.9% respectively, and this difference was statistically significant (P < 0.0001). In addition, the frequency of congenital toxoplasmosis measured by the presence of IgM and/or IgA antibodies toward T. gondii was exclusively located in samples from public hospital (0.8%), and no positive sample was seen in private hospital (0%). Considering that almost all babies suffering from congenital toxoplasmosis, if undiagnosed and untreated, will develop visual or neurological impairments by adulthood, the results presented herein emphasized the importance to accomplish screening programs for toxoplasmosis during pregnancy, particularly in the public hospitals, due to the expressive rate of congenital disease showed in the patients attended at these centers.

Animals↗