Clinical and molecular analysis of longitudinal rhinitis phenotypes in an urban birth cohort.

BACKGROUND: Chronic rhinitis symptoms cause significant health burden among children and can have a heterogeneous presentation. Defining phenotypes of childhood chronic rhinitis and associated pathobiology may lead to prevention or improved treatments. OBJECTIVES: We sought to identify longitudinal patterns of rhinitis symptoms in childhood and determine their associations with early life risk factors, allergic comorbidities, and nasal epithelial cell gene expression. METHODS: Chronic rhinitis symptoms were evaluated from ages 1 through 11 years in 485 urban children at high risk for allergic disease in the URECA (Urban Environment and Childhood Asthma) birth cohort. We identified longitudinal rhinitis phenotypes and their relationships to early life exposures, atopic comorbidities, and patterns of nasal epithelial gene expression at age 11 years. RESULTS: Chronic rhinitis symptoms started early in many children and were a risk factor for developing aeroallergen sensitization. We identified 4 longitudinal rhinitis phenotypes: low/minimal, persistent, persistent decreasing, and late increasing. Persistent rhinitis was most closely linked to allergic sensitization and asthma. Risk factors for persistent rhinitis included frequent colds (P < .001), antibiotic use (P < .001), and reduced exposure to common indoor aeroallergens (P = .003). Compared to low/minimal rhinitis phenotype, the other rhinitis phenotypes were associated with increased expression of canonical type 2 genes and decreased expression of immune response genes. CONCLUSIONS: In urban children, rhinitis symptoms often precede aeroallergen sensitization. Rhinitis phenotypes based on symptoms had distinct risk factors and nasal transcriptome. These results suggest that focusing on early life risk factors and distinct immune mechanisms may be a target to preventing chronic rhinitis in childhood.

Longitudinal relationships between early-life homelessness and school-aged asthma and wheezing.

BACKGROUND: Homelessness is a disruptive life event with profound impacts on children's health. It remains unclear, however, whether homelessness in early life has an enduring association with asthma and wheezing among school-aged children. OBJECTIVE: To test whether early-life homelessness is prospectively associated with asthma and wheezing during school-aged years. METHODS: We draw on data from 9242 children from the Avon Longitudinal Study of Parents and Children. Children were categorised as 'ever' or 'never' homeless based on maternal reports from the prenatal period through age 5 years. Children were assigned a binary indicator of asthma/wheezing based on maternal reports of asthma and wheezing at ages 6.8, 7.6 and 8.6 years. We used multilevel logistic regression models to test the association of interest in both bivariate analyses and models adjusted for a broad set of potential confounders. We conducted sensitivity analyses using generalised estimating equations and considering asthma and wheezing separately to test the robustness of the results. RESULTS: Between 12.1% and 14.3% of children had asthma or wheezing at ages 6.8, 7.6 and 8.6 years, and these conditions were more common among ever homeless participants. Ever-homeless children displayed higher odds of asthma or wheezing than never-homeless children (OR: 1.59, 95% CI 1.02 to 2.48) after adjustment for child, maternal and household risk factors. Sensitivity analyses yielded similar results. CONCLUSION: Early-life homelessness is prospectively associated with asthma and wheezing among school-aged children and should be prioritised by interventions promoting healthy child development.

Home and school pollutant exposure, respiratory outcomes, and influence of historical redlining.

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter [PM2.5], NO2) and respiratory outcomes (Composite Asthma Severity Index, lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N = 240) from 9 US cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of Composite Asthma Severity Index and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 parts per billion) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (P < .01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (P < .005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (P > .005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

Promoting Housing-Based Asset Building Programs in Healthcare.

OBJECTIVES: Wealth building programs remain underutilized, and Medical Financial Partnerships serve as a potential solution. We aimed to assess the reach and adoption of an underutilized asset building program, Family Self Sufficiency, with a national uptake of 3%, when integrated into a healthcare system. METHODS: First, a hospital-affiliated "known provider" introduced Family Self Sufficiency to clinic patients. Second, hospital staff unknown to families conducted outreach to clinic patients. For both pilots, we tracked eligibility, interest, and enrollment rates. We evaluated the pilots using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework in addition to reviewing the qualitative feedback from the staff who introduced the program. RESULTS: The reach of each pilot varied: the first pilot (n = 17) had an enrollment rate of 18%, whereas the second pilot (n = 69) had an enrollment rate of 1%. Adoption factors included prior relationship with the family and barriers to understanding the program families. However, adoption was limited by bandwidth of family to complete paperwork, staff to do outreach, and timing of the outreach to maximize benefit. CONCLUSIONS: Increasing uptake of underutilized asset building programs could be part of the solution to building wealth for families with low incomes. Healthcare partnerships may be an approach to increase reach and adoption by eligible populations. Areas to consider for successful future implementation include: (1) timeline of outreach, (2) families' relationship with individuals performing outreach, and (3) current bandwidth of the family. Systematic implementation trials are needed to study these outcomes in more detail.

Associations of household unmet basic needs and health outcomes among very low birth weight children.

OBJECTIVE: We examined associations of past year household hardships (housing, energy, food, and healthcare hardships) with postnatal growth, developmental risk, health status, and hospitalization among children 0-36 months born with very low birth weight (VLBW) and the extent that these relationships differed by receipt of child supplemental security income (SSI). STUDY DESIGN: We examined cross-sectional data from 695 families. Growth was measured as weight-for-age z-score change. Developmental risk was defined as ≥1 concerns on the "Parents' Evaluation of Developmental Status" screening tool. Child health status was categorized as excellent/good vs. fair/poor. Hospitalizations excluded birth hospitalizations. RESULTS: Compared to children with no household hardships, odds of developmental risk were greater with 1 hardship (aOR 2.0 [1.26, 3.17]) and ≥2 hardships (aOR) 1.85 [1.18, 2.91], and odds of fair/poor child health (aOR) 1.59 [1.02, 2.49] and hospitalizations (aOR) 1.49 [1.00, 2.20] were greater among children with ≥2 hardships. In stratified analysis, associations of hardships and developmental risk were present for households with no child SSI and absent for households with child SSI. CONCLUSION: Household hardships were associated with developmental risk, fair/poor health status, and hospitalizations among VLBW children. Child SSI may be protective against developmental risk among children living in households with hardships.

Critical windows of susceptibility for the effects of prenatal exposure to heat and heat variability on gestational growth.

BACKGROUND: Studies have shown that prenatal heat exposure may impact fetal growth, but few studies have examined the critical windows of susceptibility. As extreme heat events and within season temperature variability is expected to increase in frequency, it is important to understand how this may impact gestational growth. OBJECTIVES: We investigated associations between various measures of weekly prenatal heat exposure (mean and standard deviation (SD) of temperature and heat index (HI), derived using temperature in °C and dew point) and term birthweight or odds of being born small for gestational age (SGA) to identify critical windows of susceptibility. METHODS: We analyzed data from mother-child dyads (n = 4442) in the Boston-based Children's HealthWatch cohort. Birthweights were collected from survey data and electronic health records. Daily temperature and HI values were obtained from 800 m gridded spatial climate datasets aggregated by the PRISM Climate Group. Distributed lag-nonlinear models were used to assess the effect of the four weekly heat metrics on measures of gestational growth (birthweight, SGA, and birthweight z-scores). Analyses were stratified by child sex and maternal homelessness status during pregnancy. RESULTS: HI variability was significantly associated with decreased term birthweight during gestational weeks 10-29 and with SGA for weeks 9-26. Cumulative effects for these time periods were -287.4 g (95% CI: -474.1 g, -100.8 g for birthweight and 4.7 (95% CI: 1.6, 14.1) for SGA. Temperature variability was also significantly associated with decreased birthweight between weeks 15 and 26. The effects for mean heat measures on term birthweight and SGA were not significant for any gestational week. Stratification by sex revealed a significant effect on term birthweight in females between weeks 23-28 and in males between weeks 9-26. Strongest effects of HI variability on term birthweight were found in children of mothers who experienced homelessness during pregnancy. Weekly HI variability was the heat metric most strongly associated with measures of gestational growth. The effects observed were largest in males and those who experienced homelessness during pregnancy. DISCUSSION: Given the impact of heat variability on birthweight and risk of SGA, it is important for future heat warnings to incorporate measure of heat index and temperature variability.

The maternal prenatal and offspring early-life gut microbiome of childhood asthma phenotypes.

BACKGROUND: The infant fecal microbiome is known to impact subsequent asthma risk, but the environmental exposures impacting this association, the role of the maternal microbiome, and how the microbiome impacts different childhood asthma phenotypes are unknown. METHODS: Our objective was to identify associations between features of the prenatal and early-life fecal microbiomes and child asthma phenotypes. We analyzed fecal 16 s rRNA microbiome profiling and fecal metabolomic profiling from stool samples collected from mothers during the third trimester of pregnancy (n = 120) and offspring at ages 3-6 months (n = 265), 1 (n = 436) and 3 years (n = 506) in a total of 657 mother-child pairs participating in the Vitamin D Antenatal Asthma Reduction Trial. We used clinical data from birth to age 6 years to characterize subjects with asthma as having early, transient or active asthma phenotypes. In addition to identifying specific genera that were robustly associated with asthma phenotypes in multiple covariate-adjusted models, we clustered subjects by their longitudinal microbiome composition and sought associations between fecal metabolites and relevant microbiome and clinical features. RESULTS: Seven maternal and two infant fecal microbial taxa were robustly associated with at least one asthma phenotype, and a longitudinal gut microenvironment profile was associated with early asthma (Fisher exact test p = .03). Though mode of delivery was not directly associated with asthma, we found substantial evidence for a pathway whereby cesarean section reduces fecal Bacteroides and microbial sphingolipids, increasing susceptibility to early asthma. CONCLUSION: Overall, our results suggest that the early-life, including prenatal, fecal microbiome modifies risk of asthma, especially asthma with onset by age 3 years.

Household unmet basic needs in the first 1000 days and preterm birth status.

OBJECTIVE: To examine the relationship of individual and composite number of unmet basic needs (housing, energy, food, and healthcare hardships) in the past year with preterm birth status among children aged 0-24 months. STUDY DESIGN: We examined cross-sectional 2011-18 data of 17,926 families with children aged 0-24 months. We examined children born <31 weeks', 31-33 weeks', and 34-36 weeks' gestation versus term (≥37 weeks) using multivariable multinomial logistic regression. RESULTS: At least 1 unmet basic need occurred among ≥60% of families with preterm children, compared to 56% of families with term children (p = 0.007). Compared to term, children born ≤30 weeks' had increased odds of healthcare hardships (aOR 1.28 [1.04, 1.56]) and children born 34-36 weeks' had increased odds of 1 (aOR 1.19 [1.05, 1.35]) and ≥2 unmet needs (aOR 1.15 [1.01, 1.31]). CONCLUSION: Unmet basic needs were more common among families with preterm, compared to term children.

Association of the gut microbiome and metabolome with wheeze frequency in childhood asthma.

BACKGROUND: While the microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma. OBJECTIVE: In this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we analyzed the gut microbiome and metabolome of wheeze frequency in children with asthma. METHODS: Bacterial 16S ribosomal RNA microbiome and untargeted metabolomic profiling were performed on fecal samples collected from 3-year-old children with parent-reported physician-diagnosed asthma. We analyzed wheeze frequency by calculating the proportion of quarterly questionnaires administered between ages 3 and 5 years in which parents reported the child had wheezed (wheeze proportion). Taxa and metabolites associated with wheeze were analyzed by identifying log fold changes with respect to wheeze frequency and correlation/linear regression analyses, respectively. Microbe-metabolite and microbe-microbe correlation networks were compared between subjects with high and low wheeze proportion. RESULTS: Specific taxa, including the genus Veillonella and histidine pathway metabolites, were enriched in subjects with high wheeze proportion. Among wheeze-associated taxa, Veillonella and Oscillospiraceae UCG-005, which was inversely associated with wheeze, were correlated with the greatest number of fecal metabolites. Microbial networks were similar between subjects with low versus high wheeze frequency. CONCLUSION: Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

Trajectories of adiposity indicators and association with asthma and lung function in urban minority children.

BACKGROUND: A relationship between adiposity and asthma has been described in some cohort studies, but little is known about trajectories of adiposity throughout early childhood among children at high risk for developing asthma in urban United States cities. Moreover, early life trajectories of adipokines that have metabolic and immunologic properties have not been comprehensively investigated. OBJECTIVE: Our objective was to characterize trajectories of adiposity in a longitudinal birth cohort of predominately Black and Latinx children (n = 418) using several different repeated measures including body mass index (BMI) z score, bioimpedance analysis, leptin, and adiponectin in the first 10 years of life. METHODS: In a longitudinal birth cohort of predominately Black and Latinx children, we used repeated annual measures of BMI, bioimpedance analysis (ie, percentage of body fat), leptin, and adiponectin to create trajectories across the first 10 years of life. Across those trajectories, we compared asthma diagnosis and multiple lung function outcomes, including spirometry, impulse oscillometry, and methacholine response. RESULTS: Three trajectories were observed for BMI z score, bioimpedance analysis, and leptin and 2 for adiponectin. There was no association between trajectories of BMI, percentage of body fat, leptin, or adipokine and asthma diagnosis or lung function (P > .05). CONCLUSIONS: Trajectories of adiposity were not associated with asthma or lung function in children at high risk for developing asthma. Risk factors related to geography as well as social and demographic factors unique to specific populations could explain the lack of association and should be considered in obesity and asthma studies.

The Association of Prenatal Vitamin D Sufficiency With Aeroallergen Sensitization and Allergic Rhinitis in Early Childhood.

BACKGROUND: The role of prenatal vitamin D sufficiency and supplementation in the development of childhood aeroallergen sensitization and allergic rhinitis remains uncertain. OBJECTIVE: To describe the association of prenatal vitamin D sufficiency with childhood allergic outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial, a randomized controlled trial of prenatal vitamin D supplementation. METHODS: We included 414 mother-offspring pairs with offspring aeroallergen sensitization data available at age 6 years in this analysis. We examined the association between prenatal vitamin D sufficiency status, based on vitamin D levels measured in the first and third trimesters, or vitamin D supplementation treatment assignment with the outcomes of aeroallergen sensitization, parent-reported clinical allergic rhinitis, parent-reported clinical allergic rhinitis with aeroallergen sensitization, food sensitization, any sensitization, eczema, and total IgE at ages 3 and 6 years. RESULTS: Compared with early and late insufficiency, early prenatal vitamin D insufficiency with late sufficiency was associated with reduced development of clinical allergic rhinitis with aeroallergen sensitization at 3 years (adjusted odds ratio [aOR] = 0.34; 95% confidence interval [CI], 0.13-0.82; P = .02) and 6 years (aOR = 0.54; 95% CI, 0.29-0.98; P = .05). At 6 years, clinical allergic rhinitis with sensitization was significantly decreased in offspring whose mothers received high-dose vitamin D (aOR = 0.54; 95% CI, 0.32-0.91; P = .02) compared with offspring whose mothers who received low-dose vitamin D. Associations of prenatal vitamin D with aeroallergen sensitization were strengthened among children who also developed asthma or who had a maternal history of atopy. CONCLUSIONS: Among mothers with first-trimester vitamin D insufficiency, we detected a protective effect of third-trimester prenatal vitamin D sufficiency on the development of clinical allergic rhinitis with aeroallergen sensitization at ages 3 and 6 years.

Screening Discordance and Characteristics of Patients With Housing-Related Social Risks.

INTRODUCTION: Healthcare systems are increasingly interested in identifying patients' housing-related risks, but minimal information exists to inform screening question selection. The primary study aim is to evaluate discordance among 5 housing-related screening questions used in health care. METHODS: This was a cross-sectional multisite survey of social risks used in a convenience sample of adults seeking care for themselves or their child at 7 primary care clinics and 4 emergency departments across 9 states (2018-2019). Housing-related risks were measured using 2 questions from the Accountable Health Communities screening tool (current/anticipated housing instability, current housing quality problems) and 3 from the Children's HealthWatch recommended housing instability screening measures (prior 12-month: rent/mortgage strain, number of moves, current/recent homelessness). The 2-sided Fisher's exact tests analyzed housing-related risks and participant characteristics; logistic regression explored associations with reported health (2019-2020). RESULTS: Of 835 participants, 52% screened positive for ≥1 housing-related risk (n=430). Comparing the tools, 32.8% (n=274) screened discordant: 11.9% (n=99) screened positive by Children's HealthWatch questions but negative by Accountable Health Communities, and 21.0% (n=175) screened positive by the Accountable Health Communities tool but negative by Children's HealthWatch (p<0.001). Worse health was associated with screening positive for current/anticipated housing instability (AOR=0.56, 95% CI=0.32, 0.96) or current/recent homelessness (AOR=0.57, 95% CI=0.34, 0.96). CONCLUSIONS: The 5 housing questions captured different housing-related risks, contributed to different health consequences, and were relevant to different subpopulations. Before implementing housing-related screening initiatives, health systems should understand how specific measures surface distinct housing-related barriers. Measure selection should depend on program goals and intervention resources.

Maternal stress and depression are associated with respiratory phenotypes in urban children.

BACKGROUND: Prenatal and early-life exposure to maternal stress and depression is linked to development of recurrent wheezing in young children. OBJECTIVE: We sought to determine whether maternal stress and depression in early life are associated with nonatopic wheezing phenotype in urban children. METHODS: The Urban Environment and Childhood Asthma Study examined a birth cohort of children at high risk for asthma in low-income neighborhoods. Prenatal and postnatal (through age 3 years) maternal stress and depression scores were compared with respiratory phenotypes through age 10 years (multinomial regression), self-reported colds (linear regression), and detection of respiratory viruses (Poisson regression). RESULTS: Scores for maternal depression, and, to a lesser extent, maternal perceived stress, were positively related to multiple wheezing phenotypes. In particular, cumulative measures of maternal depression in the first 3 years were related to the moderate-wheeze-low-atopy phenotype (odds ratio, 1.13; [1.05, 1.21]; P < .01). Considering indicators of respiratory health that were used to identify the phenotypes, there were multiple positive associations between early-life scores for maternal stress and depression and increased wheezing illnesses, but no consistent relationships with lung function and some inverse relationships with allergic sensitization. Cumulative maternal stress and depression scores were associated with cumulative number of respiratory illnesses through age 3 years. CONCLUSIONS: Among high-risk, urban children, maternal stress and depression in early life were positively associated with respiratory illnesses and a moderate-wheeze-low-atopy phenotype. These results suggest that treating stress and depression in expectant and new mothers could reduce viral respiratory illnesses and recurrent wheeze during the preschool years and some forms of childhood asthma.

Endotype of allergic asthma with airway obstruction in urban children.

BACKGROUND: Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States. OBJECTIVES: This study sought to identify specific respiratory phenotypes of health and disease in this population, associations with early life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease. METHODS: The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through 10 years of age. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at 11 years of age. RESULTS: Of the 6 identified respiratory phenotypes, a high wheeze, high atopy, low lung function group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high-atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in the high wheeze, high atopy, low lung function group. In contrast, a medium wheeze, low atopy group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways. CONCLUSIONS: In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and nonallergic asthma.

Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels.

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life.

Housing Intervention For Medically Complex Families Associated With Improved Family Health: Pilot Randomized Trial.

The effects of housing instability and homelessness on child and adult health are well documented. However, few studies have explored health and housing interventions for families with children with the objective of health improvement. Housing Prescriptions as Health Care is a randomized controlled trial that is investigating the impact on physical and mental health of integrating priority placement in affordable housing and the provision of services (case management, financial, and legal), compared to the standard of care (providing resource guides and hospital-based social work or care navigation services). In 2016-19 seventy-eight homeless or housing-unstable families defined as "medically complex"-with a child or adult member who used more health services than usual or had a chronic disease or disability-were enrolled in the trial, and sixty-seven completed a six-month follow-up. A difference-in-differences analysis at six months showed decreases in the share of children in fair or poor health and in average anxiety and depression scores among parents in the intervention group, relative to the control group. Findings suggest that a population-specific model that integrates health, housing, legal, and social services can improve health-related outcomes at the household level.

Home Visits for Children With Asthma Reduce Medicaid Costs.

We conducted a multicomponent, low-cost, home intervention for children with uncontrolled asthma, the Reducing Ethnic/Racial Asthma Disparities in Youth (READY) study, to evaluate its effect on health outcomes and its return on investment. From 2009 through 2014 the study enrolled 289 children aged 2 to 13 years with uncontrolled asthma and their adult caregivers in Boston and Springfield, Massachusetts. Community health workers (CHWs) led in-home asthma management and environmental trigger remediation education over 5 visits spanning 6 months. Asthma health outcomes and indoor environment data were collected via survey, and health use costs were accessed through Massachusetts Medicaid (MassHealth). Results showed significant improvements in asthma control, health care use, and environmental trigger reduction and a positive return on investment (1.34) for participants who had 2 or more emergency department visits 1 year prior to the first home visit. The CHW asthma home visiting intervention improved trigger management, clinical outcomes, and Medicaid cost savings, demonstrating that asthma home visits improve health quality and reduce costs.