Maternal intestinal flora and wheeze in early childhood.

BACKGROUND: Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood. OBJECTIVE: To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy. METHODS: A total of 60 pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children's health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log(10)colony-forming units (CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analysed as a secondary outcome. RESULTS: In multivariate models adjusted for breastfeeding, day care attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze. CONCLUSIONS AND CLINICAL RELEVANCE: In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.

Longitudinal relationship of early life immunomodulatory T cell phenotype and function to development of allergic sensitization in an urban cohort.

BACKGROUND: Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. OBJECTIVES: As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. METHODS: Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. RESULTS: The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.

Elevated allergen-induced IL-13 secretion predicts IgE elevation in children ages 2-5 years.

It is unclear if early immune responses to allergens, specifically Th1 and Th2 cytokine production, predict later immune responses, including increased IgE levels. In a group of children (n = 151) with a parental history of allergy or asthma followed from ages 2 through 5 years, we examined IL-13, IL-4, and IFN-gamma secretion by peripheral blood mononuclear cells in response to phytohemagglutinin (PHA), and to dust mite (Der f 1), cockroach (Bla g 2), and cat (Fel d 1) allergens in relation to elevated IgE. Elevated IgE was defined either as a positive IgE-specific response to at least one allergen (dust mite, cockroach, cat, and ovalbumin) or as an elevated total IgE level above a specified cut-off value. In multivariate logistic regression models including 181 observations made between the age of 2 through 5 years and accounting for repeated measures, we found an association between increased IL-13 secretion in response to Der f 1 and elevated IgE (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.09-1.34). Age did not modify this relationship. No association was found between allergen-induced IFN-gamma secretion and IgE production. Among the group of children with measurements made at age 4-5 (n = 70), IL-13 in response to Der f 1 (p = 0.046), and IL-4 in response to PHA (p = 0.04) were increased among children with elevated IgE. In a smaller subset of children with measurements made at both age 2-3 and age 4-5 (n = 36), IL-13 levels at age 2-3 were also significantly increased in response to Der f 1 (p = 0.01) and Fel d 1 (p = 0.002) among those with elevated IgE at age 4-5. In a group of children ages 2-5 years, there is an association between IL-13 and elevated IgE.

The protease inhibitor PI*S allele and COPD: a meta-analysis.

In many countries, the protease inhibitor (SERPINA1) PI*S allele is more common than PI*Z, the allele responsible for most cases of chronic obstructive pulmonary disease (COPD) due to severe alpha 1-antitrypsin deficiency. However, the risk of COPD due to the PI*S allele is not clear. The current authors located studies that addressed the risk of COPD or measured lung function in individuals with the PI SZ, PI MS and PI SS genotypes. A separate meta-analysis for each genotype was performed. Aggregating data from six studies, the odds ratio (OR) for COPD in PI SZ compound heterozygotes compared with PI MM (normal) individuals was significantly increased at 3.26 (95% confidence intervals (CI): 1.24-8.57). In 17 cross-sectional and case-control studies, the OR for COPD in PI MS heterozygotes was 1.19 (95%CI: 1.02-1.38). However, PI MS genotype was not associated with COPD risk after correcting for smoking. Furthermore, mean forced expiratory volume in one second, a measure of airflow obstruction and a defining feature of COPD, did not differ between PI MS and PI MM individuals. There were not enough cases to summarise the risk of COPD in PI SS homozygotes. In conclusion, the results show that the PI SZ genotype is a significant risk factor for chronic obstructive pulmonary disease. The risk of chronic obstructive pulmonary disease due to the PI MS genotype is not substantially elevated.

Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis.

BACKGROUND: Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial. METHODS: A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV(1)) in heterozygotes. RESULTS: In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV(1) as a continuous outcome there was no difference in mean FEV(1) between PI MM and PI MZ individuals. CONCLUSIONS: Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.