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. 2019 Jun 5;220(1):151-162.
doi: 10.1093/infdis/jiz072.

Effects of Child and Maternal Histo-Blood Group Antigen Status on Symptomatic and Asymptomatic Enteric Infections in Early Childhood

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Effects of Child and Maternal Histo-Blood Group Antigen Status on Symptomatic and Asymptomatic Enteric Infections in Early Childhood

Josh M Colston et al. J Infect Dis. .

Abstract

Background: Histo-blood group antigens (HBGAs) such as fucosyltransferase (FUT)2 and 3 may act as innate host factors that differentially influence susceptibility of individuals and their offspring to pediatric enteric infections.

Methods: In 3 community-based birth cohorts, FUT2 and FUT3 statuses were ascertained for mother-child dyads. Quantitative polymerase chain reaction panels tested 3663 diarrheal and 18 148 asymptomatic stool samples for 29 enteropathogens. Cumulative diarrhea and infection incidence were compared by child (n = 520) and mothers' (n = 519) HBGA status and hazard ratios (HRs) derived for all-cause diarrhea and specific enteropathogens.

Results: Children of secretor (FUT2 positive) mothers had a 38% increased adjusted risk of all-cause diarrhea (HR = 1.38; 95% confidence interval (CI), 1.15-1.66) and significantly reduced time to first diarrheal episode. Child FUT2 and FUT3 positivity reduced the risk for all-cause diarrhea by 29% (HR = 0.81; 95% CI, 0.71-0.93) and 27% (HR = 0.83; 95% CI, 0.74-0.92), respectively. Strong associations between HBGAs and pathogen-specific infection and diarrhea were observed, particularly for noroviruses, rotaviruses, enterotoxigenic Escherichia coli, and Campylobacter jejuni/coli.

Conclusions: Histo-blood group antigens affect incidence of all-cause diarrhea and enteric infections at magnitudes comparable to many common disease control interventions. Studies measuring impacts of interventions on childhood enteric disease should account for both child and mothers' HBGA status.

Keywords: Escherichia coli infections; antibodies, bacterial; bacterial vaccines; colonization factor antigens; controlled human infection model; diarrhea, prevention and control; fimbriae proteins; immunization, passive; milk proteins, immunology; randomized controlled clinical trial.

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Figures

Figure 1.
Figure 1.
Hypothesized pathways through which maternal and child fucosyltransferase (FUT)2 and FUT3 expression alter susceptibility to enteric infection. 2’-FL, 2’-fucosyllactose; LDFT, lactodifucotetraose; LNDFH I, lacto-N-difucohexaose I; LNFP I, lacto-N-fucopentaose I [38, 43–45].
Figure 2.
Figure 2.
Pathway of histo-blood group antigen synthesis with assignment of phenotype (Lewis and secretor status) in accordance with the presence of a functional phenotype or allele for the FUT2 gene (encoding α (1,2) fucosyltransferase) and FUT3 gene (encoding enzyme with α(1,3) and α(1,4) fucosyltransferase activities).
Figure 3.
Figure 3.
Kaplan-Meier plot of cumulative incidence of diarrhea of any etiology by age for phenotype positive and negative subjects by fucosyltransferase (FUT) gene and for child’s and mother’s status with hazard ratios (HRs) comparing phenotype positive to negative status from univariate Cox regression models (with 95% confidence interval [CI] [***, P < .001, **, P = .001–.01, and *, P = .01–.05] and significance level). Maternal FUT2 status consistently had the largest association with the risk of all-cause diarrhea, with risk ratios greatest between 3 and 12 months of age but significant until 24 months of age.
Figure 4.
Figure 4.
Hazard ratios for diarrhea and for infection with common enteric pathogens comparing phenotype positive to negative status from multivariate Cox models that adjusted for mothers’ fucosyltransferase (FUT)2 and FUT3 status (for child estimates) and child’s FUT2 and FUT3 (for maternal estimates) and covariates stratified by diarrheal (green) and surveillance (purple) stool samples. Statistically significant estimates (P ≤ .05) are represented by solid markers and labeled with the hazard ratio (with 95% confidence interval; ***, P < .001, **, P = .001–.01, and *, P = .01–.05) and significance level.
Figure 5.
Figure 5.
Hazard ratios (HRs) for infection with common virus strains comparing phenotype positive to negative status from multivariate Cox models that adjusted for child and mothers’ fucosyltransferase (FUT)2 and FUT3 status and covariates stratified by diarrheal (green) and surveillance (purple) stool samples. Statistically significant estimates (P ≤ .05) are represented by solid markers and labeled with the HR (with 95% confidence interval; ***, P < .001, **, P = .001–.01, and *, P = .01–.05) and significance level. Diarrhea was not noted in children who were Lewis positive with G1 rotavirus infections, thus a HR was undefined. (Just 1 case each of G1 and G2 rotavirus diarrhea was observed in nonsecretor infants, and no cases of G1 rotavirus diarrhea were observed in Lewis null infants, so it was not possible to calculate HRs for those associations.)

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