Jack Remington

Outcome of Treatment for Congenital Toxoplasmosis, 1981–2004: The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study

Background Without treatment, congenital toxoplasmosis has recurrent, recrudescent, adverse outcomes. Long-term follow-up of infants with congenital toxoplasmosis treated throughout their first year of life with pyrimethamine and sulfadiazine has not been reported. Methods Between 1981 and 2004, one hundred twenty infants (current mean age +/- standard deviation, 10.5 +/- 4.8 years) with congenital toxoplasmosis were treated with 1 of 2 doses of pyrimethamine plus sulfadiazine; therapy was initiated shortly after birth and continued for 12 months. Children who received treatment were evaluated at birth and at predetermined intervals; the focus of the evaluations was on prespecified end points: motor abnormalities, cognitive outcome, vision impairment, formation of new eye lesions, and hearing loss. Results Treatment of infants without substantial neurologic disease at birth with pyrimethamine and sulfadiazine for 1 year resulted in normal cognitive, neurologic, and auditory outcomes for all patients. Treatment of infants who had moderate or severe neurologic disease (as defined in this article in the Treatments subsection of Methods) at birth resulted in normal neurologic and/or cognitive outcomes for >72% of the patients, and none had sensorineural hearing loss. Ninety-one percent of children without substantial neurologic disease and 64% of those with moderate or severe neurologic disease at birth did not develop new eye lesions. Almost all of these outcomes are markedly better than outcomes reported for children who were untreated or treated for 1 month in earlier decades (P .05). Conclusions Although not all children did well with treatment, the favorable outcomes we noted indicate the importance of diagnosis and treatment of infants with congenital toxoplasmosis.

Randomized Phase II Trial of Atovaquone with Pyrimethamine or Sulfadiazine for Treatment of Toxoplasmic Encephalitis in Patients with Acquired Immunodeficiency Syndrome: ACTG 237/ANRS 039 Study

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

Longitudinal Study of New Eye Lesions in Children with Toxoplasmosis Who Were Not Treated During the First Year of Life

PURPOSEnTo determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year.nnnDESIGNnProspective longitudinal cohort study.nnnMETHODSnThirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii.nnnRESULTSnTwenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age.nnnCONCLUSIONSnMore than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.

Chapter 31 – Toxoplasmosis

Among the most tragic infectious diseases of humans are those that pass from the pregnant woman to her unborn child. Toxoplasma gondii is a protozoal parasite that can cause devastating disease in the fetus and newborn yet remain unrecognized in women who acquire the infection during gestation. In addition, in most countries, congenital infection and congenital toxoplasmosis in the newborn go undiagnosed, thereby predisposing to the occurrence of untoward sequelae of the infection, including decreased vision or blindness, decreased hearing or deafness, and mental and psychomotor retardation. The cost estimates for special care of children with congenital toxoplasmosis born each year in the United States alone is in the hundreds of millions of dollars.

Impact of visual impairment on measures of cognitive function for children with congenital toxoplasmosis: implications for compensatory intervention strategies.

OBJECTIVES. The purpose of this work was to determine whether visual impairment caused by toxoplasmic chorioretinitis is associated with impaired performance of specific tasks on standardized tests of cognitive function. If so, then we worked to determine whether there are patterns in these difficulties that provide a logical basis for development of measures of cognitive function independent of visual impairment and compensatory intervention strategies to facilitate learning for such children. METHODS. Sixty-four children with congenital toxoplasmosis with intelligence quotient scores ≥50 and visual acuity sufficient to cooperate with all of the intelligence quotient subscales had assessments of their vision, appearance of their retinas, and cognitive testing performed between 3.5 and 5 years of age. These evaluations took place between 1981 and 1998 as part of a longitudinal study to determine outcome of congenital toxoplasmosis. Children were evaluated at 3.5 or 5 (37 children) or both 3.5 and 5 (27 children) years of age. Cognitive function was measured using the Wechsler Preschool and Primary Scale of Intelligence-Revised. Wechsler Preschool and Primary Scale of Intelligence-Revised scale scores were compared for children grouped as those children who had normal visual acuity in their best eye (group 1), and those who had impaired vision in their best eye (acuity <20/40) because of macular disease (group 2). Demographic characteristics were compared for children in the 2 groups. Test scores were compared between groups using all of the 3.5-year-old visits, all of the 5-year-old visits, and using each childs “last” visit (ie, using the 5-year-old test results when a child was tested at both 3.5 and 5 years of age or only at 5 years, otherwise using the 3.5-year-old test results). The results were similar and, therefore, only the results from the last analysis are reported here. RESULTS. There were 48 children with normal visual acuity in their best eye (group 1) and 16 children with impaired vision because of macular involvement in their best eye (group 2). Ethnicity and socioeconomic scores were similar. There was a significantly greater proportion of males in group 2 compared with group 1 (81% vs 46%). There was no significant diminution in Wechsler Preschool and Primary Scale of Intelligence-Revised test scores between 3.5 and 5 years of age for the 27 children tested at both of these ages. Verbal intelligence quotient, performance intelligence quotient, full-scale intelligence quotient scores, and all of the scaled scores except arithmetic and block design were significantly lower for children in group 2 compared with group 1. The majority of the differences remained statistically significant or borderline significant after adjusting for gender. However, the difference in overall verbal scores does not remain statistically significant. Mean ± SD verbal (98 ± 20) and performance (95 ± 17) intelligence quotients were not significantly different for children in group 1. However, verbal (88 ± 13) and performance intelligence quotients (78 ± 17) were significantly different for children in group 2. For children in group 2, their lowest scale scores were in object assembly, geometric design, mazes, and picture completion, all timed tests that involved visual discrimination of linear forms with small intersecting lines. In the 2 scales scored that did not differ between groups 1 and 2, arithmetic and block design, timing and vision but not linear forms were components of the tasks. Children with monocular and binocular normal visual acuity did not differ in verbal, performance, or full-scale intelligence quotients or any of the subscale tests. Difficulty with sight or concomitant neurologic involvement also seemed to impact the ability to acquire information, comprehension skills, and vocabulary and performance in similarities testing. After controlling for gender, however, these differences were diminished, and there were no longer differences in overall verbal scores. As noted above, results were generally similar when all of the tests for 3.5-year-olds or 5-year-olds were analyzed separately. At the 3.5-year visit there were fewer significant differences between the 2 groups for the verbal components than at the 5-year visit. CONCLUSIONS. In children with congenital toxoplasmosis and bilateral macular disease (group 2) because of toxoplasmic chorioretinitis, scaled scores were lowest on timed tests that require discrimination of fine intersecting lines. Although the severity of ocular and neurologic involvement is often congruent in children with congenital toxoplasmosis, ophthalmologic involvement seems to account for certain specific limitations on tests of cognitive function. Children with such visual impairment compensate with higher verbal skills, but their verbal scores are still less than those of children with normal vision, and in some cases significantly so, indicating that vision impairment might affect other aspects of cognitive testing. Patterns of difficulties noted in the subscales indicate that certain compensatory intervention strategies to facilitate learning and performance may be particularly helpful for children with these impairments. These patterns also provide a basis for the development of measures of cognitive function independent of visual impairment.

Cytotoxic and microbicidal properties of macrophages.

Since the last Conference on Mononuclear Phagocytes, held in 1973, our laboratory has continued its work on the role of the macrophage in resistance to infection and tumors. Since we had considered that macrophages activated to effect a given function also had the capacity to effect all other functions that were attributed to activated macrophages, we began to use the tumor cell assay to determine whether a group of experimental mice were suitable for use in our studies, i.e., whether they possessed activated macrophages that should have the capacity to inhibit or kill toxoplasma. The first indication that our supposition equating the cytotoxic (against tumor target cells) and microbicidal functions of activated macrophages was incorrect, occurred during the course of a series of experiments designed to answer unrelated questions. A dichotomy between certain functions of activated macrophages was noted in studies in which the cytotoxic and microbicidal effects were examined in parallel. We will deal here with this dichotomy and with two related subjects: the specificity of the in vitro interaction of macrophages with tumor cells and microorganisms and the mechanisms of the microbicidal and cytotoxic effects of macrophages.

QUANTITATION OF DESTRUCTION OF TOXOPLASMA

Publisher Summary The persistence and multiplication of Toxoplasma gondii in mononuclear phagocytes in vitro provide a model in which the microbicidal or inhibitory capacity of infected cells can be evaluated. Methods used to quantitate the destruction of Toxoplasma include the visual observation of inhibition of multiplication or destruction of T. gondii, the measurement of nucleic acid synthesized by intracellular T. gondii, and the quantification of the number of organisms released from cells by plaquing techniques. Toxoplasma gondii is a class 2 pathogen, and the National Institutes of Health guidelines for work with class 2 pathogens should be followed. Non-immune pregnant women and immune-suppressed individuals should not work with this organism. Safety precautions for other healthy individuals include avoidance of skin puncture with needles contaminated with the trophozoite form of the parasite and avoidance of contact of trophozoites with breaks in skin or conjunctival or mucosal surfaces.

UNIT 19.3 Animal Models for Toxoplasma gondii Infection

Toxoplasma gondii is an obligate intracellular protozoan that commonly infects mammals and birds throughout the world. This unit describes murine models of acute T. gondii infection and toxoplasmic encephalitis. T. gondii infection in severe combined immunodeficient (SCID) mice, which lack T and B cells, has allowed for the study of T cell-independent mechanisms of defense against intracellular organisms, as described here. The establishment of temperature-sensitive mutant strains of T. gondii has allowed adoptive-transfer experiments without the concern for the transfer of the parasite at the same time. The temperature-sensitive mutant ts-4 strain disappears from tissues of immunocompetent mice without forming tissue cysts and induces protection against challenge with virulent strains of the parasite, and a protocol is provided for infection with this mutant strain. Support protocols present methodology for evaluation of progression of infection and immune response to the parasite, maintenance of T. gondii tissue cysts and tachyzoites, as well as preparation of T. gondii lysate antigens.