Background The association between vitamin D status at birth and childhood allergic outcomes is uncertain. The desert climate of Tucson offers a unique setting for studying the health effects of higher exposure to vitamin D. Objective To assess relations between cord blood 25-hydroxyvitamin D (25[OH]D) levels and allergic outcomes through age 5 years. Methods Cord blood 25(OH)D levels were measured in 219 participants in the Tucson Infant Immune Study, a population-based birth cohort. Plasma total IgE and specific IgE to 6 aeroallergens were measured at 1, 2, 3 and 5 years. Skin-prick test (SPT) positivity (wheal ≥ 3mm), and physician-diagnosed active allergic rhinitis and asthma were assessed at age 5. Longitudinal models were used to assess relations between 25(OH)D and IgE outcomes. Logistic regression models were used to assess relations with SPT positivity, allergic rhinitis and asthma. Results The median cord blood 25(OH)D level was 64 nmol/L (interquartile range, 49 to 81 nmol/L). Relative to the reference group (50–74.9 nmol/L), both low (<50 nmol/L) and high (≥ 100 nmol/L) levels were associated with increased total IgE (coef.=0.27, P=0.006; and coef.=0.27, P=0.04, respectively) and inhalant specific IgE (OR=2.4, P=0.03; and OR=4.0, P=0.01, respectively) through age 5 years. High 25(OH)D levels also were associated with increased SPT positivity (OR=4.0, P=0.02). By contrast, 25(OH)D level was not significantly associated with allergic rhinitis or asthma. Conclusion Both low and high levels of cord blood 25(OH)D were associated with increased aeroallergen sensitization. The association between vitamin D status and actual allergic diseases merits further study.

Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective To assess whether the trajectory to asthma begins already at birth and epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used Methylated CpG Island Recovery Assay (MIRA)-chip to survey DNA methylation in cord blood mononuclear cells (CBMC) from 36 children (18 non-asthmatic, 18 asthmatic by age 9) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n=60) and in two replication cohorts (The Manchester Asthma and Allergy Study, n=30, and the Childhood Origins of ASThma Study, n=28) was analyzed by bisulfite sequencing or Illumina 450K arrays. CBMC-derived IL-1β was measured by ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions (DMRs) that distinguished IIS children who did and did not develop asthma by age 9. In all three cohorts, methylation in SMAD3, the most connected node within the network of asthma-associated DMRs, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and pro-inflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

The Community Health Worker model is recognized nationally as a means to address glaring inequities in the burden of adverse health conditions that exist among specific population groups in the United States. This study explored Arizona CHW involvement in advocacy beyond the individual patient level into the realm of advocating for community level change as a mechanism to reduce the structural underpinnings of health disparities. A survey of CHWs in Arizona found that CHWs advocate at local, state and federal political levels as well as within health and social service agencies and business. Characteristics significantly associated with advocacy include employment in a not for profit organization, previous leadership training, and a work environment that allows flexible work hours and the autonomy to start new projects at work. Intrinsic characteristics of CHWs associated with advocacy include their belief that they can influence community decisions, self perception that they are leaders in the community, and knowledge of who to talk to in their community to make change. Community-level advocacy has been identified as a core CHW function and has the potential to address structural issues such as poverty, employment, housing, and discrimination. Agencies utilizing the CHW model could encourage community advocacy by providing a flexible working environment, ongoing leadership training, and opportunities to collaborate with both veteran CHWs and local community leaders. Further research is needed to understand the nature and impact of CHW community advocacy activities on both systems change and health outcomes.

Rationale: Innate immune responses marked by increases in tumor necrosis factor (TNF)-a have been associated with asthma but whether such alterations are evident before symptoms is not yet clear. Objectives: To determine if prevalence of childhood asthma or asthma-related traits is predicted by perinatal innate immune status and if maternal factors related to pregnancy influence asthma prevalence and innate immune status. Methods: In the Tucson Infant Immune Study (a nonselected birth cohort), presence of eczema and wheezing in the child's first year and physician-diagnosed asthma through age 9 and asthma in the parents was obtained from parent-completed questionnaires. TNF-a, IL-6, IL-10, and IL-12 were measured in supernatants of LPSstimulated peripheral blood mononuclear cells at birth and 3 months as was TNF-a in plasma. TNF-a single nucleotide polymorphisms were genotyped by Sequenom. Percent predicted FEV 1 /FVC was measured at age 9. Maternal weight gain during pregnancy and prepregnancy weight were ascertained from medical records. Measurements and Main Results: Infants with persistently elevated LPS-induced TNF-a at birth and 3 months were at increased risk for childhood asthma (odds ratio [OR], 4.1; confidence interval [CI], 1.9-8.8; n ¼ 233; P ¼ 0.0003) and had decreased FEV 1 /FVC ratios at age 9. Children with mothers in the top tertile for pregnancy weight gain had increased risk for asthma (OR, 3.4; CI,; n ¼ 225; P ¼ 0.001) and persistently elevated TNF-a in early life (OR, 2.9; CI, 1.4-8.2; n ¼ 195; P ¼ 0.013). These relations were independent of maternal asthma and rhinitis. Conclusions: Persistently elevated LPS-induced TNF-a production early in life acts as a predictive biomarker for childhood asthma, and excess pregnancy weight gain in the mother seems to contribute to both. Keywords: biomarker; innate cytokines; asthma etiologyAsthma is the most common chronic disease of childhood and has increased in prevalence over the last several decades in much of the industrialized world (1, 2). Pathways leading to asthma in childhood seem to be initiated early in infancy, possibly even in utero (3, 4), but searches for predictive biomarkers of asthma development have not been successful (5). Although myriad studies support immune-related alterations after asthma is established, whether immune differences precede asthma is much less clear. More than one line of evidence suggests that asthma and allergy may develop by different pathways. Burrows and coworkers (6) found that parental IgE levels (although well established to provide risk for IgE in the child) did not provide risk for asthma in the child, a finding confirmed in a birth cohort, the Children's Respiratory Study (7). From the Tucson Infant Immune Study (IIS), early-life type-2 cytokine patterns were found to differ in nature and in temporal pattern in relation to childhood asthma and IgE levels (8). Several genome-wide association studies implicate different patterns of genetic variation for asthma and IgE regulation (9) and point toward th...

Summary Background Findings from studies of the relation between early antibiotic use and subsequent asthma have been inconsistent, which may be attributable to methodologic issues. Objective Our objective was to assess the impact of confounding by indication on the relation of early antibiotic use to childhood asthma through age 5 in a non-selected birth cohort (n = 424). Methods Oral antibiotic use was assessed by frequent nurse interviews in the first 9 months of life. Physician-diagnosed active asthma and eczema were assessed by questionnaire at 1, 2, 3, and 5 years, and were considered as ever asthma or ever eczema if positive at any age. Allergen-specific IgE was assessed in plasma at 1, 2, 3, and 5 years. Confounding by indication was investigated by considering the relation of asthma to antibiotic use while controlling for the number of illness visits to a physician in early life. Results There was no statistically significant relation of early antibiotic use with physician-diagnosed eczema or allergen-specific IgE. A dose–response relation was evident for antibiotic use with ever asthma (odds ratio [OR] = 1.5, P = 0.047). Ever asthma also increased significantly with the number of illness visits to a physician (P<0.001). After adjustment for number of illness visits, antibiotic use showed no relation with asthma. Conclusions The relation of asthma to antibiotics in this cohort appears to be an artefact of the strong relation of number of physician visits for illness with both antibiotic use and risk for asthma.

Background While it has been postulated that allergic disease is associated with a predominance of Th2 cells, whether IgE levels and asthma might differ in their relations with early life cytokine production is not known. Objective To assess relations between first year adaptive immune cytokine production with asthma and total IgE levels through age 5 years in a non-selected birth cohort. Methods Mitogen (ConA/PMA) stimulated IL-4, IL-5, IL-13 and IFN-γ were measured in supernatants from cord and peripheral blood mononuclear cells at birth, 3 months and 12 months. Total serum IgE and physician-diagnosed active asthma were assessed at 1, 2, 3 and 5 years. Longitudinal models that adjust for both Th1 and Th2 cytokine production were used to determine relations of outcomes. Results Relations of cytokines with total IgE and asthma were strikingly different. Total IgE through age 5 years was positively associated with 12-month IL-4 (p < 0.001), IL-5 (p < 0.001) and IL-13 (p = 0.02) levels when adjusted for IFN-γ, and inversely associated with 12-month IFN-γ after IL-4 adjustment (p = 0.01). Active asthma through age 5 was positively associated with 3-month IL-13 adjusted for IFN-γ (Odds ratio (OR) = 2.6, p <0.001), and inversely associated with 3-month IFN-γ adjusted for IL-13 (OR = 0.5, p = 0.001). These relations were strongest for non-atopic asthma. Conclusion Total IgE and active asthma through age 5 are associated with adaptive cytokine production in early life, though relations vary temporally and with regard to the relative importance of individual cytokines.

Background-Variation in TLR2 gene (TLR2/−16934) is associated with allergic diseases amongst farmers' children, but not amongst children not living on farms.

Little is known about whether maternal immune status during pregnancy influences asthma development in the child. We measured cytokine production in supernatants from mitogen-stimulated peripheral blood immune cells collected during and after pregnancy from the mothers of children enrolled in the Tucson Infant Immune Study, a nonselected birth cohort. Physician-diagnosed active asthma in children through age 9 and a history of asthma in their mothers were assessed through questionnaires. Maternal production of each of the cytokines IL-13, IL-4, IL-5, IFN-γ, IL-10, and IL-17 during pregnancy was unrelated to childhood asthma. However, IFN-γ/IL-13 and IFN-γ/IL-4 ratios during pregnancy were associated with a decreased risk of childhood asthma (n = 381; odds ratio [OR], 0.33; 95% confidence interval [CI], 0.17-0.66; P = 0.002; and n = 368; OR, 0.36; 95% CI, 0.18-0.71; P = 0.003, respectively). The inverse relations of these two ratios with childhood asthma were only evident in mothers without asthma (n = 309; OR, 0.18; 95% CI, 0.08-0.42; P = 0.00007; and n = 299; OR, 0.17; 95% CI, 0.07-0.39; P = 0.00003, respectively) and not in mothers with asthma (n = 72 and 69, respectively; P for interaction by maternal asthma = 0.036 and 0.002, respectively). Paternal cytokine ratios were unrelated to childhood asthma. Maternal cytokine ratios in mothers without asthma were unrelated to the children's skin-test reactivity, total IgE, physician-confirmed allergic rhinitis at age 5, or eczema in infancy. To our knowledge, this study provides the first evidence that cytokine profiles in pregnant mothers without asthma relate to the risk for childhood asthma, but not allergy, and suggests a process of asthma development that begins in utero and is independent of allergy.