Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009)

Abstract

Background: Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types.

Methods: ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined.

Results: Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment.

Conclusions: Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment.

Clinical trials registration: NCT00004317.

Figure 1.

National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS) patients with antibodies to GRA6 and GRA7 peptides from type II or type I/III parasites or both based on decade of birth. A, Distribution of NCCCTS patients with serologic responses designated as type II and not exclusively II (NE-II). The cutoff value for a positive reaction in the enzyme-linked immunosorbent assay was 1.4 [5]. II indicates those persons who have reactivity only to type II GRA6/7 alleles. NE-II indicates all other persons with antibodies to GRA6/7 alleles. B, Distribution of NCCCTS patients with serologic responses designated as II, IIa, II = I/III, I/IIIa, and I/III. I/III indicates those persons who have reactivity only to type I/III GRA6/7 alleles. For persons who possessed antibodies to both II and non-II peptides, but in whom one or the other was clearly more abundant, these serotypes were designated as IIa (reactivity ≥1.4; II > I/III) or I/IIIa (reactivity ≥1.4; I/III > II), respectively. For persons who possessed antibodies to both II and non-II peptides with near-equivalent reactivities to one or the other type, these were designated II = I/III. Rx indicates persons in the NCCCTS cohort who were diagnosed in the perinatal period and treated during the first year of life [–18]; No Rx, persons in the NCCCTS cohort who missed being treated in the first year of life and were referred to the NCCCTS after that time [16, 19, 20]; All, persons in the Rx plus No Rx cohorts; All decades, 1980–2009 and earlier for a few persons in the No Rx cohort. Specifically, there were 2 untreated persons born between 1940 and 1949, 2 born between 1960 and 1969, and 2 born between 1970 and 1979. There was only 1 untreated person born between 2000 and 2009 with a II = I/III parasite serotype; no histogram is presented for this person. P values are for comparisons of serotype distribution across decades for the All, Rx, or No Rx cohorts and are from χ² tests or Fisher exact tests. ^aThe numbers outside parentheses represent the number of persons with the parasite serotype born in each time period for each treatment category (all, treated, or untreated persons). Numbers within parentheses represent the percentage of persons with parasite serotype among those born in each time period and the treatment category. No significant variation for distribution of parasite serotypes across decades was found.

Figure 2.

Distribution of parasite serotypes in the United States with locations mapped according to birthplace. A, Climate regions, following designations of the Pacific Northwest National Laboratory and Oak Ridge National Library (2010). Guide to Determining Climate Regions by County. Building America Best Practices Series (7.1). Retrieved from http://apps1.eere.energy.gov/buildings/publications/ pdfs/building_america/ba_climateguide_7_1.pdf. B, Serotypes and US regions. US regions were derived from the 10 standard federal regions as established by the Office of Management and Budget: East (regions I, II, and III); Southeast (region IV); South (region VI); Central (regions V, VII, and VIII); West (region IX); and Pacific Northwest (region X). The serotypes II, IIa, II = I/III, I/IIIa, I/III, and NE-II serotypes are defined in the Methods section and the Figure 1 legend. Pie graphs: Percentage = [number of persons born in climate or geographic region with parasite serotype/total number of persons with parasite serotype] × 100.

Figure 3.

Distribution of parasite serotypes by birth month. In total, 38% of persons with not exclusively II (NE-II) serotype were born from November to January. Percentage = [number of persons born in month with parasite serotype/total number of persons with parasite serotype]. The serotypes II and NE-II are defined in the Methods section and the Figure 1 legend.

Figure 4.

Parasite serotype and outcomes later in life in our cohort and in literature data. Rx indicates persons in the National Collaborative Chicago-based Congenital Toxoplasmosis Study cohort who were diagnosed in the perinatal period and treated during the first year of life [6–18]; No Rx, literature [27]. The II and NE-II serotypes are defined in the Methods and the Figure 1 legend.