The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty.

RATIONALE: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. OBJECTIVES: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). METHODS: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates. MEASUREMENTS AND MAIN RESULTS: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables. CONCLUSIONS: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Prenatal exposure to RSV season influences first-year risk of RSV lower respiratory illness and RSV-specific immune responses assessed at birth.

Maternal-to-fetal transmission of respiratory syncytial virus (RSV) has been shown to occur but whether late prenatal exposure to RSV season influences offspring postnatal RSV-lower respiratory illness (LRI) risk in early life or RSV immune status at birth is unclear. In this study, the duration of third trimester RSV season exposure was determined for 1,094 newborns of the Tucson Children's Respiratory Study (TCRS) and found to show an inverse relation to risk for first RSV-LRI in the first year. Cord blood anti-RSV antibody is related to third trimester RSV season exposure but not to first year RSV-LRI risk. In a separate birth cohort (the Infant Immune Study), supernatants from cord blood mononuclear cells stimulated with the recall antigen, UV-inactivated RSV, were assayed for IFN-γ and IL-4. The frequency of detectable IFN-γ (but not IL-4) was increased for those with at least 2 mo of third trimester RSV season exposure, suggestive of a fetal immune response to RSV. IMPORTANCE Our study found that duration of third trimester exposure to RSV season related inversely to subsequent risk of postnatal RSV-LRI in the first year, thus implicating this exposure as an important factor in reducing risk of postnatal RSV-LRIs, a risk reduction that appears to be independent of maternally transferred anti-RSV antibody level. The increase in frequency of detectable IFN-γ and not IL-4 in response to UV-inactivated RSV in cord blood immune cells for infants with greater third trimester exposure to RSV season is suggestive of a Type-1 immune response to RSV occurring in utero.

Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life.

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.

Pediatric asthma incidence rates in the United States from 1980 to 2017.

BACKGROUND: Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective. OBJECTIVE: Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history. METHODS: Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated. RESULTS: The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females. CONCLUSIONS: US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.

Fetal Origins of Asthma: A Longitudinal Study from Birth to Age 36 Years.

Rationale: Deficits in infant lung function-including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)-have been linked to increased risk for childhood asthma.Objectives: To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life.Methods: One hundred eighty participants in the Tucson Children's Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models.Measurements and Main Results: After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% (P = 0.001) and 55% (P = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26.Conclusions: These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

CC16 Levels into Adult Life Are Associated with Nitrogen Dioxide Exposure at Birth.

Rationale: Lung function and growth are adversely associated with nitrogen dioxide (NO2) exposure. Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function. NO2 exposure may induce epithelial damage in lungs and alter club cell proliferation and morphology.Objectives: To determine if increased ambient NO2 levels at participants' home addresses in early life were associated with decreased levels of CC16 from age 6 to 32 years.Methods: Participants were enrolled at birth in the Tucson Children's Respiratory Study and had circulating CC16 measured at least once between age 6 and 32. Linear mixed models were used to determine the association between estimated ambient NO2 exposure at participants' home address at birth or age 6 with CC16 levels from age 6 to 32.Measurements and Main Results: NO2 exposures at birth or age 6 were available for 777 children with one or more CC16 measurement. We found a negative association between NO2 exposure and CC16 levels, with a 4.7% (95% confidence interval, -8.6 to -0.7) decrease in CC16 levels from age 6 to 32 per interquartile range increase in NO2 exposure (6.0 ppb) at the participants' birth address. We observed modification by race (p interaction = 0.04), with stronger associations among participants with at least one black parent (-29.6% [95% confidence interval, -42.9% to -13.2%] per interquartile range). NO2 at participant's age 6 address was not significantly associated with CC16 levels (-1.9%; 95% confidence interval, -6.3 to 2.6).Conclusions: Higher exposure to NO2 at birth is associated with persistently low levels of CC16 from 6 to 32 years.

Club Cell Secretory Protein Deficiency Leads to Altered Lung Function.

RATIONALE: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases. OBJECTIVES: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions. METHODS: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway. MEASUREMENTS AND MAIN RESULTS: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness. CONCLUSIONS: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.

Non-atopic rhinitis at age 6 is associated with subsequent development of asthma.

BACKGROUND: It has been postulated that the association between allergic rhinitis and asthma is attributable to the progressive clinical expression of respiratory inflammation during childhood. The role of non-allergic rhinitis in early life in relation to subsequent asthma has not been extensively explored. OBJECTIVE: We sought to determine whether rhinitis in early life was associated with risk of asthma development into adulthood, and whether this relationship is independent of allergic sensitization. METHODS: Participants were identified from the Tucson Children's Respiratory Study, a non-selected birth cohort. Allergy skin prick testing was performed at age 6 years using house dust mix, Bermuda, mesquite, olive, mulberry, careless weed, and Alternaria aeroallergens. Atopy was defined as ≥1 positive tests. Physician-diagnosed active asthma from age 6 to 32 and physician-diagnosed rhinitis at age 6 were determined by questionnaire. Participants with asthma or active wheezing at age 6 were excluded from analyses. Risk estimates were obtained with Cox regression. RESULTS: There were 521 participants who met inclusion criteria. The hazard ratio for subsequently acquiring a diagnosis of asthma between the ages of 8 and 32 for those with non-atopic rhinitis was 2.1 (95% CI: 1.2, 3.4, P = 0.005), compared with the non-atopic no rhinitis group, after adjusting for sex, ethnicity, maternal asthma, maternal education and smoking, and history of 4+ colds per year at age 6. Among the atopic participants, both the active and no rhinitis groups were more likely to develop and have asthma through age 32. The relation between non-atopic rhinitis and asthma was independent of total serum IgE levels at age 6. CONCLUSION AND CLINICAL RELEVANCE: Childhood rhinitis, even in the absence of atopy, confers significant risk for asthma development through adulthood. These findings underscore the importance of non-allergic mechanisms in the development of asthma.

Early life risk factors for chronic sinusitis: A longitudinal birth cohort study.

BACKGROUND: Chronic sinusitis is a commonly diagnosed condition in adults who frequently present with late-stage disease and irreversible changes to the sinus mucosa. Understanding the natural history of chronic sinusitis is critical in developing therapies designed to prevent or slow the progression of disease. OBJECTIVE: We sought to determine early life risk factors for adult sinusitis in a longitudinal cohort study (Tucson Children's Respiratory Study). METHODS: Physician-diagnosed sinusitis was reported at age 6. Adult sinusitis between 22 and 32 years was defined as self-reported sinusitis plus physician-ordered sinus radiologic films. Atopy was assessed by skin prick test. Individuals were grouped into 4 phenotypes: no sinusitis (n = 621), transient childhood sinusitis only (n = 57), late-onset adult sinusitis only (n = 68), and early onset chronic sinusitis (childhood and adult sinusitis, n = 26). RESULTS: Sinusitis was present in 10.8% of children and 12.2% of adults. Childhood sinusitis was the strongest independent risk factor for adult sinusitis (odds ratio = 4.2; 95% CI: 2.5-7.1; P < .0001; n = 772). Early onset chronic sinusitis was associated with increased serum IgE levels as early as at 9 months of age, atopy (assessed by skin prick test reactivity), childhood eczema and allergic rhinitis, frequent childhood colds, maternal asthma, and with increased prevalence of concurrent asthma. No association was found between late-onset adult sinusitis and any of the early life risk factors studied. CONCLUSIONS: We identified an early onset chronic sinusitis phenotype associated with a predisposition to viral infections/colds in early life, allergies, and asthma. Elucidation of the molecular mechanisms for this phenotype may lead to future therapies to prevent the progression of the disease into adult sinusitis.

Maternal Cytokine Profiles during Pregnancy Predict Asthma in Children of Mothers without Asthma.

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.

Alternaria sensitisation at age 6 years is associated with subsequent airway hyper-responsiveness in non-asthmatics.

In the non-selected birth cohort Tucson Children's Respiratory Study, early sensitisation to Alternaria was associated with increased airway hyper-responsiveness (AHR) into adult life among non-asthmatics. The increase in AHR was of a similar magnitude to that seen for Alternaria sensitised asthmatics and was primarily evident among those who were overweight or obese. In contrast, there was no significant association between early sensitisation to aeroallergens other than Alternaria and AHR among non-asthmatics. Why this group of Alternaria sensitised individuals without asthma demonstrated increased AHR of a magnitude similar to asthmatics is unknown and requires further investigation.

Protective effect of breastfeeding on recurrent cough in adulthood.

RATIONALE: Breastfeeding protects from respiratory infections in early life but its relationship to recurrent cough and other respiratory outcomes in adult life is not well established. METHODS: Infant feeding practices were assessed prospectively in the Tucson Children's Respiratory Study, a non-selected birth cohort and categorised into formula from birth or introduced <1 month, formula introduced ≥1 to <4 months and exclusive breastfeeding for ≥4 months. Infant feeding was assessed as an ordinal variable representing an increasing dose of breastmilk across the three categories. Recurrent cough was defined at 22, 26 and 32 years as ≥2 episodes of cough without a cold lasting 1 week during the past year. Covariates included participant sex, race/ethnicity and smoking as well as parental smoking, education, age and asthma. Covariates were evaluated as potential confounders for the relation between infant feeding and adult outcomes. RESULTS: Of the 786 participants, 19% breastfed <1 month, 50% breastfed ≥1 to <4 months and 31% breastfed ≥4 months. The prevalence of recurrent cough at 22, 26 and 32 years was 17%, 15% and 16%, respectively. Each ordinal increase in breastfeeding duration was associated with a decreased risk of recurrent cough in adult life: adjusted OR=0.71, (95% CI: 0.56 to 0.89), p=0.004. Additional adjustment for concurrent adult asthma, wheeze, smoking and lung volume did not change these results. CONCLUSION: Longer duration of breastfeeding reduces the risk of recurrent cough in adult life, regardless of smoking and other respiratory symptoms, suggesting long-term protective effects on respiratory health.

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

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: We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. METHODS: We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) 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 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1ß levels were measured by means of ELISA. RESULTS: Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, 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-1ß, an innate inflammatory mediator. CONCLUSIONS: The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life.

RATIONALE: Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline. OBJECTIVES: We aimed to determine if there were individuals with a distinct, persistently low lung function trajectory in the CRS (Tucson Children's Respiratory Study). METHODS: The CRS, an ongoing birth cohort study, enrolled 1,246 participants between 1980 and 1984. Latent class linear mixed effects modeling of the ratio of FEV1 to FVC was used to identify distinct lung function trajectories among participants with two or more spirometry measurements between ages 11 and 32 years. MEASUREMENTS AND MAIN RESULTS: Among 599 participants with 2,142 observations, a model with two distinct trajectories (a low trajectory [n = 56; 9.3%] and a normal trajectory) fit the data significantly better than a model with only one trajectory (P = 0.0007). As compared with those with a normal trajectory, participants with a persistently low trajectory were more likely to have a history of maternal asthma (20.0% vs. 9.9%; P = 0.02); early life lower respiratory illness caused by respiratory syncytial virus (41.2% vs. 21.4%; P = 0.001); and physician-diagnosed active asthma at age 32 years (43.9% vs. 16.2%; P < 0.001). Individuals with a persistently low trajectory also demonstrated lower lung function as measured by average maximal expiratory flow at functional residual capacity during infancy and at age 6 years. CONCLUSIONS: A distinct group of individuals in a nonselected population demonstrates a persistently low lung function trajectory that may be partly established at birth and predisposes them to chronic obstructive pulmonary disease later in life.

Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays.

BACKGROUND: Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent. METHODS: With an antibody array (RayBiotech, Norcross, GA, USA), the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema, and wheeze. RESULTS: In the antibody array, four proteins had rank differences between asthma and non-asthma groups (FDR <0.1). By ELISA, mean log (±s.e.m.) erythropoietin (EPO) level (IU/l) was lower (0.750 ± 0.048 vs. 0.898 ± 0.035; p = 0.006) and mean (±s.e.m.) soluble GP130 (sGP130) level (ng/ml) was higher in the asthma vs. the non-asthma group (302 ± 13 vs. 270 ± 8; p = 0.041). The other 2 array proteins (galactin-3 and eotaxin-3) did not differ by ELISA by asthma. EPO related to the asthma risk factor, first year eczema, whereas sGP130 related to first year wheeze. CONCLUSIONS: Through two independent assessments, age 3 plasma levels of EPO and sGP130 were found related to childhood asthma.

Risk of current asthma among adult smokers with respiratory syncytial virus illnesses in early life.

RATIONALE: Risk of subsequent asthma-like symptoms after early-life lower respiratory illness (LRI) caused by respiratory syncytial virus (RSV) is increased during the first decade of childhood and diminished thereafter by adolescence. OBJECTIVES: To determine the relation of early-life RSV-LRI on adult asthma-like symptoms and its interactive role with adult smoking. METHODS: A total of 1,246 nonselected infants were enrolled at birth and prospectively followed. Virologically confirmed RSV-LRIs were assessed during the first 3 years of life. At age 22, 24, 26, and 29 years, current asthma and smoking behavior were evaluated by questionnaire. Peak flow variability was assessed at age 26 and expressed as amplitude % mean. A longitudinal analysis was used to investigate the relation of RSV-LRI and active smoking to adult outcomes. MEASUREMENTS AND MAIN RESULTS: Neither RSV-LRI nor active smoking were directly associated with increased current adult asthma or peak flow variability. However, there was a significant interaction between RSV-LRI and active smoking in relation to current asthma (P for interaction = 0.004) and peak flow variability (P for interaction = 0.04). Among subjects with early RSV-LRI, those who actively smoked were 1.7 times more likely to have current asthma (95% confidence interval, 1.2-2.3; P = 0.003) and had greater amplitude % mean (10.0% vs. 6.4%; P = 0.02) than nonsmokers. Among subjects without early RSV-LRI, there was no difference in asthma risk or peak flow variability between active smokers and nonsmokers. CONCLUSIONS: Smoking is associated with increased risk of having asthma in young adults who had RSV-LRI in early life but not among subjects without these illnesses.

Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

Perinatal tumor necrosis factor-α production, influenced by maternal pregnancy weight gain, predicts childhood asthma.

RATIONALE: Innate immune responses marked by increases in tumor necrosis factor (TNF)-α 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-α, IL-6, IL-10, and IL-12 were measured in supernatants of LPS-stimulated peripheral blood mononuclear cells at birth and 3 months as was TNF-α in plasma. TNF-α single nucleotide polymorphisms were genotyped by Sequenom. Percent predicted FEV1/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-α 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 = 233; P = 0.0003) and had decreased FEV1/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, 1.7-6.9; n = 225; P = 0.001) and persistently elevated TNF-α in early life (OR, 2.9; CI, 1.4-8.2; n = 195; P = 0.013). These relations were independent of maternal asthma and rhinitis. CONCLUSIONS: Persistently elevated LPS-induced TNF-α 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.