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Background Epidemiologic studies have shown that Alzheimer's disease (AD) and related dementias (ADRD) are seen more frequently with asthma, especially with greater asthma severity or exacerbation frequency. Objective To examine the changes in brain structure that may underlie this phenomenon, we examined diffusion-weighted magnetic resonance imaging (dMRI) and blood-based biomarkers of AD (phosphorylated tau 181, p-Tau181), neurodegeneration (neurofilament light chain, NfL), and glial activation (glial fibrillary acidic protein, GFAP). Methods dMRI data were obtained in 111 individuals with asthma, ranging in disease severity from mild to severe, and 135 healthy controls. Regression analyses were used to test the relationships between asthma severity and neuroimaging measures, as well as AD pathology, neurodegeneration, and glial activation, indexed by plasma p-Tau181, NfL, and GFAP, respectively. Additional relationships were tested with cognitive function. Results Asthma participants had widespread and large-magnitude differences in several dMRI metrics, which were indicative of neuroinflammation and neurodegeneration, and which were robustly associated with GFAP and, to a lesser extent, NfL. The AD biomarker p-Tau181 was only minimally associated with neuroimaging outcomes. Further, asthma severity was associated with deleterious changes in neuroimaging outcomes, which in turn were associated with slower processing speed, a test of cognitive performance. Conclusions Asthma, particularly when severe, is associated with characteristics of neuroinflammation and neurodegeneration, and may be a potential risk factor for neural injury and cognitive dysfunction. There is a need to determine how asthma may affect brain health and whether treatment directed toward characteristics of asthma associated with these risks can mitigate these effects.

Background Various clinical, biologic, or physiologic markers of asthma have been used to identify patient clusters and potential targets for therapy. However, these identifiers frequently overlap among the different asthma groups. For instance, both eosinophil and neutrophil counts are often increased in the airways of asthmatic patients despite their typical association with type 2 and type 17 immune response, respectively. Objectives We sought to determine whether inflammatory gene expression is related to patterns of airway inflammation and lung function and identify molecular markers for neutrophilic asthma. Methods Expression levels of 17 genes characterizing type 1, type 2, and type 17 lymphocytes were measured in sputum samples from 48 participants with asthma. The relationships between gene expression levels and sputum cell differentials or measures of pulmonary function were examined by using partial least squares regression. Results Gene expression levels were strongly associated with cell differentials, explaining 71% of variation in eosinophil counts and 64% of variation in neutrophil counts. The 3 genes with the strongest relationships to sputum neutrophil counts were IL1R1 (standardized regression coefficient [β] = +0.27, P = .005), IL1RAP (β = +0.32, P = .0004), and IL4R (β = +0.29, P = .002). Higher expression levels of IL1R1 , IL1RAP , and IL4R were associated with reduced FEV 1 /forced vital capacity ratio (β = −0.11, −0.08, and −0.10; P = .005, .07, and .05). Conclusion IL-1 receptor appears to be a marker of neutrophilic inflammation and airflow obstruction in patients with asthma, who have a wide range of disease severity. The IL-1 pathway might contribute to airway neutrophilia and is a potential therapeutic target in patients with neutrophilic asthma.

Background Farm exposures may reduce the risk of atopic dermatitis (AD) in children, but this is controversial and US data are limited. Objective This study was conducted to identify patterns of farm exposure in Wisconsin family farms that modify AD incidence and prevalence in early childhood. Methods Environmental exposures, health history, and clinical outcomes were prospectively recorded for 111 farm families and 129 non–farm families enrolled in the Wisconsin Infant Study Cohort birth cohort study. Exposures from the prenatal and early postnatal (2-month) visits were evaluated together with parental report of AD diagnosis by a health care provider through age 24 months. Latent class analysis was performed with prenatal and early postnatal farm-exposure variables to assign farm children to 3 classes. Results Overall, children of farm families had reduced AD incidence (P = .03). Within farm families, exposures including poultry (3% vs 28%; P = .003), pig (4% vs 25%; P = .04), feed grain (13% vs 34%; P = .02), and number of animal species were inversely associated with AD incidence. Among the latent class groups, children in families with diverse or more intense farm exposures (classes A and B) had reduced AD incidence, whereas low-exposure (class C) infants had AD incidence similar to that in nonfarm children. Conclusions Infants in Wisconsin farm families had reduced AD incidence, and patterns of farm exposures further defined AD risk. These findings suggest that exposure to diverse farm animals, feed, and bedding during the prenatal period and in early infancy reduce the risk of early-onset AD, a phenotype associated with multiple other atopic diseases.

Background Sex influences the risk of wheezing illnesses and the prevalence of asthma throughout childhood. Objective To better understand the mechanisms of these effects, we analyzed longitudinal relationships between sex, lung physiology, and asthma in the Childhood Origins of ASThma birth cohort study. Methods Childhood Origins of ASThma birth cohort study children were followed prospectively from birth and assessed annually. Results of spirometry, fractional exhaled nitric oxide (Feno), mannitol provocation testing, and 3 He gas magnetic resonance imaging were assessed by sex using multivariate models including age, asthma diagnosis, and wheezing histories. Results Girls had higher prebronchodilator forced expiratory volume in 0.5 seconds/forced vital capacity values than did boys (mean difference, 0.017; 95% CI, 0.000-0.034; P = .05) of equivalent age. Postbronchodilator findings were more pronounced, with boys demonstrating reduced forced expiratory volume in 0.5 seconds/forced vital capacity values than did girls of equivalent age (mean difference, 0.032; 95% CI, 0.014-0.049; P = .0005). Conversely, girls were noted to have higher ventilation defects on 3 He magnetic resonance imaging than did boys ( P = .01). No differences were noted in the rate of positive responses to mannitol provocation or Feno measurements. Conclusions Lower airflow values are present by spirometry for prepubertal boys than for age-matched girls; however, greater 3 He ventilation defects were noted in girls. This could represent a greater degree of subclinical air trapping in prepubertal girls because residual volumes are not detected on standard spirometric readings. No differences were noted between the 2 sexes with airway hyperresponsiveness (mannitol provocation testing) or inflammation (Feno). Prospective peripubertal follow-up will determine whether these differences persist or change with the de novo expression and remission of asthma based on sex and age.

Background Quantitative computed tomographic (QCT) biomarkers of airway morphology hold potential for understanding and monitoring regional airway remodeling in asthmatic patients. Objective We sought to determine whether the change in airway lumen area between total lung capacity (TLC) and functional residual capacity (FRC) lung volumes measured from CT imaging data was correlated with severe outcomes in asthmatic patients. Methods We studied 152 asthmatic patients (90 female and 62 male patients) and 33 healthy subjects (12 female and 21 male subjects) using QCT. Postprocessing of airways at generations 1 to 5 (1 = trachea) was performed for wall area percentage, wall thickness percentage (WT%), lumen area at baseline total lung capacity (LA TLC ), lumen area at baseline functional residual capacity (LA FRC ), and low attenuation area at FRC. A new metric (reflecting remodeling, distal air trapping, or both), Delta Lumen, was determined as follows: Percentage difference in lumen area (LA TLC − LA FRC )/LA TLC × 100. Results Postprocessing of 4501 airway segments was performed (3681 segments in the 152 patients with asthma and 820 segments in the 33 healthy subjects; range, 17-28 segments per subject). Delta Lumen values were negatively correlated with WT% and low attenuation area ( P P Conclusion Reduced Delta Lumen value in the central airways measured by using QCT is a promising exploratory biomarker of unstable refractory asthma that warrants further study.

Background Obesity has been proposed to be a risk factor for the development of childhood asthma. Objective We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years. Methods Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years. Results No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05). Conclusion In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma.

Ventilation defect percent (VDP) measured in asthmatics with hyperpolarized helium-3 MRI was more strongly associated with ED visits and hospitalizations due to asthma exacerbation than were conventional biomarkers of lung function and inflammation.

Background There is evidence that CD4 + CD25 high T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited. Objective To test the hypothesis that greater numbers and function of CD4 + CD25 high T cells are associated with a reduced risk of childhood allergies and wheezing. Methods A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4 + CD25 high and CD4 + CD25 int T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis. Results Factors positively associated with % CD4 + CD25 high /CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4 + CD25 high /total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4 + CD25 + T cells ( r = –0.45; P = .034). The percentage of CD4 + CD25 int /CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring ( P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 ( P ≤ .001 for all). Conclusion Our findings suggest that blood CD4 + CD25 high cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure. Clinical implications Seasonal increases in CD4CD25 high expression in children with allergy may represent systemic immune activation caused by pollen exposures.

Background Sex and age are known to influence the clinical expression of asthma and allergic diseases. Objective We sought to evaluate whether immune response profiles also vary by sex and age. Methods We performed a prospective birth cohort study (Childhood Origins of Asthma) designed to evaluate interactions among age, sex, immune responses, and virus infections on the development of asthma and allergic diseases. Two hundred eighty-nine subjects were enrolled at birth, and 275 maintained prospective follow-up for 3 years. Cytokine response profiles at birth, 1, and 3 years of age; rates of wheezing, atopic dermatitis, and viral illnesses; and biomarkers of atopy, including total and specific IgE levels and peripheral eosinophil counts, were evaluated. Results PHA-induced IFN-γ responses were higher in boys at 1 year of age (median, 35 vs 19 pg/mL; P P = .07). Among children who wheezed during the third year of life, boys had increased IFN-γ, IL-5, and IL-13 responses at age 3 years ( P P = .008, and P = .01, respectively). Boys also demonstrated increased rates of sensitization ( P = .05 at year 1), total IgE levels ( P = .03 at year 1 and P = .006 at year 3), and peripheral eosinophil counts (2.62 vs 1.85; P = .05 at year 3). Conclusion Sex-specific differences in immune responses develop during early childhood; some of these differences developmentally proceed, whereas others occur in parallel to the clinical expression of various atopic phenotypes. Clinical implications The differential expression of atopic diseases between boys and girls in early childhood is accompanied by sex-specific differences in immune response profiles.

Background Coagulation Factor XIII (FXIII) plays an important role in wound healing by stabilizing fibrin clots and cross-linking extracellular matrix proteins. FXIII is expressed in cells of the monocyte/macrophage and dendritic cell lineages in response to type 2 cytokines. Objective We sought to determine the association between FXIII and asthma pathobiology. Methods We analyzed the expression of FXIII mRNA and protein levels in bronchoalveolar lavage samples obtained before and after segmental allergen challenge from patients with mild asthma and in induced sputum samples collected from patients with mild-to-moderate and severe asthma. Results FXIII mRNA and protein levels were highly upregulated in bronchoalveolar cells and fluid after allergen challenge and mRNA levels correlated with protein levels. In sputum of asthmatic patients, FXIII expression was positively correlated with type 2 immune response and dendritic cell markers (CD209 and CD207). FXIII expression was also associated with increased airflow limitation (FEV 1 /forced vital capacity and residual volume/total lung capacity ratios) and greater reversibility to β-agonists. Conclusions FXIII expression was upregulated in the airways of asthmatic patients after allergen exposure. Expression in the sputum of asthmatic patients correlated with the type 2 immune response and airflow limitation. Excessive activity of FXIII could contribute to the pathophysiology of airway obstruction in asthmatic patients.

Background Detection of either viral or bacterial pathogens is associated with wheezing in children; however, the influence of both bacteria and viruses on illness symptoms has not been described. Objective We evaluated bacterial detection during the peak rhinovirus season in children with and without asthma to determine whether an association exists between bacterial infection and the severity of rhinovirus-induced illnesses. Methods Three hundred eight children (166 with asthma and 142 without asthma) aged 4 to 12 years provided 5 consecutive weekly nasal samples during September and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis were performed on all nasal samples. Results Detection rates were 53%, 17%, and 11% for H influenzae , S pneumoniae , and M catarrhalis , respectively, with detection of rhinovirus increasing the risk of detecting bacteria within the same sample (odds ratio [OR], 2.0; 95% CI, 1.4-2.7; P P = .02). In the absence of rhinovirus, S pneumoniae was associated with increased cold symptoms (mean, 2.7 [95% CI, 2.0-3.5] vs 1.8 [95% CI, 1.5-2.2]; P = .006) and moderate asthma exacerbations (18% [95% CI, 12% to 27%] vs 9.2% [95% CI, 6.7% to 12%]; P = .006). In the presence of rhinovirus, S pneumoniae was associated with increased moderate asthma exacerbations (22% [95% CI, 16% to 29%] vs 15% [95% CI, 11% to 20%]; P = .01). Furthermore, M catarrhalis detected alongside rhinovirus increased the likelihood of experiencing cold symptoms, asthma symptoms, or both compared with isolated detection of rhinovirus (OR, 2.0 [95% CI, 1.0-4.1]; P = .04). Regardless of rhinovirus status, H influenzae was not associated with respiratory symptoms. Conclusion Rhinovirus infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M catarrhalis and S pneumoniae contribute to the severity of respiratory tract illnesses, including asthma exacerbations.

Background Maternal asthma and child's sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve nonclassical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases but has not been investigated for a role in asthma or allergic disease. Objective We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared with children of mothers without asthma, or to sons compared with daughters. We further hypothesized that rates of MMc differ between children with and without asthma. Methods We tested these hypotheses in 317 subjects from 3 independent cohorts by using a real-time quantitative PCR assay to detect a noninherited HLA allele in the child. Results MMc was detected in 20.5% of the subjects (range 16.8%-27.1% in the 3 cohorts). We observed lower rates of asthma among MMc-positive subjects than among MMc-negative subjects (odds ratio, 0.38; 95% CI, 0.19-0.79; P = .029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child ( P = .81 and .15, respectively). Conclusions Our results suggest for the first time that MMc may protect against the development of asthma.

Background Magnetic resonance imaging (MRI) with 3 He does not require ionizing radiation and has been shown to detect regional abnormalities in lung ventilation and structure in adults with asthma, but the method has not been extended to children with asthma. Measurements of regional lung ventilation and microstructure in subjects with childhood asthma could advance our understanding of disease mechanisms. Objective We sought to determine whether 3 He MRI in children can identify abnormalities related to the diagnosis of asthma or prior history of respiratory illness. Methods Forty-four children aged 9 to 10 years were recruited from a birth cohort at increased risk of asthma and allergic diseases. For each subject, a time-resolved 3-dimensional image series and a 3-dimensional diffusion-weighted image were acquired in separate breathing maneuvers. The numbers and sizes of ventilation defects were scored, and regional maps and statistics of average 3 He diffusion lengths were calculated. Results Children with mild-to-moderate asthma had lower average root-mean-square diffusion length ( X r m s ¯ ) values ( P = .004), increased regional SD of diffusion length values ( P = .03), and higher defect scores ( P = .03) than those without asthma. Children with histories of wheezing illness with rhinovirus infection before the third birthday had lower X r m s ¯ values ( P = .01) and higher defect scores ( P = .05). Conclusion MRI with 3 He detected more and larger regions of ventilation defect and a greater degree of restricted gas diffusion in children with asthma compared with those seen in children without asthma. These measures are consistent with regional obstruction and smaller and more regionally variable dimensions of the peripheral airways and alveolar spaces.

Rationale Interleukin-10 (IL-10) response profiles and the timing and nature of environmental exposures may contribute to the development of allergic sensitization during early childhood. Methods Cord blood obtained from infants enrolled in the COAST project were stimulated in vitro with phytohemagglutinin (PHA) for 24 hours, and supernatant fluids were analyzed for IL-10 by ELISA. Values for IL-10 secretion were compared to allergen-specific IgE results evaluated at age 2 years for the following antigens: D. farinae, D. pteronyssinus, Alternaria alternata , dog dander, cat dander, milk, egg, peanut, and soy. Results Infants who were sensitized to any aeroallergen had significantly lower levels of IL-10 than those that were not (median 89.7 vs 107.4 pg/ml, p=0.04). When individual allergens were evaluated, IL-10 secretion profiles were not associated with sensitization to mites or Alternaria , but were significantly lower with both dog (median 73.7 vs 107.0 pg/ml, p=0.001) and cat (median 71.4 vs 107.3 pg/ml, p=0.007) sensitization. IL-10 secretion profiles were not associated with the development of food allergen sensitization (median 97.9 vs 104.6 pg/ml, p=0.18). Conclusions Reduced IL-10 responses at birth are associated with increased risk for the development of sensitization to some, but not all, allergens following early life exposures.

Background Few trials of sublingual immunotherapy (SLIT) in the United States have been reported. Objective This randomized, placebo-controlled feasibility SLIT study compared the safety and physiologic effects of high- versus low-dose Dermatophagoides farinae vaccine. Methods Thirty-one D farinae –sensitive adults with allergic rhinitis with or without mild intermittent asthma were eligible for randomization to high-dose maintenance vaccine (n = 10, 4200 allergen units [approximately 70 μg of Der f 1/d]), low-dose maintenance vaccine (n = 10; 60 allergen units [approximately 1 μg of Der f 1/d]), or placebo (n = 11) over 12 to 18 months. Medication-symptom scores and adverse events were monitored, serum D farinae –specific IgE and IgG4 levels were measured, and bronchial reactivity to D farinae was determined at baseline and 6-month intervals. Results Of the 31 randomized subjects, 6 withdrew because of non–treatment-ascribed events. Four withdrew because of treatment-ascribed effects: high-dose group, 1 of 10 (gastrointestinal symptoms); low-dose group, 1 of 10 (gastrointestinal symptoms); and placebo group, 2 of 11 (headache and increased nasal symptoms). Thus 21 subjects completed the study: high-dose group, 9; low-dose group, 7; and placebo group, 5. Eleven of the 21 subjects experienced mild-to-moderate gastrointestinal symptoms, throat irritation, or both (high-dose group, 5/9; low-dose group, 4/7; and placebo group, 2/5). No severe systemic reactions were noted. No differences in symptom-medication scores were found. High-dose SLIT increased the bronchial threshold to allergen challenge and increased serum D farinae –specific IgG4 levels, whereas low-dose SLIT and placebo had no significant effect. Conclusions High-dose D farinae SLIT was generally tolerable, increased serum D farinae –specific IgG4 levels, and improved the bronchial threshold to allergen challenge. Larger US trials are warranted.