The association of infant urinary adrenal steroids with the risk of childhood asthma development.

BACKGROUND: Adrenal steroids play important roles in early-life development. However, our understanding of the effects of perinatal adrenal steroids on the development of childhood asthma is incomplete. OBJECTIVE: To evaluate the associations between early-life adrenal steroid levels and childhood asthma. METHODS: Participants included the Infant Susceptibility to Pulmonary Infections and Asthma following Respiratory Syncytial Virus Exposure birth cohort children with untargeted urinary metabolomics data measured during early infancy (n = 264) and nasal immune mediator data measured concurrently at age 2 to 6 months (n = 76). A total of 11 adrenal steroid compounds were identified using untargeted metabolomics and 6 asthma-relevant nasal immune mediators from multiplex assays were a priori selected. Current asthma at ages 5 and 6 years was ascertained using validated questionnaires. Associations were tested using logistic and linear regression with confounders adjustment. RESULTS: Pregnenetriol disulfate (adjusted odds ratio [aOR] = 0.20, 95% CI = 0.06-0.68) and 3a,21-dihydroxy-5b-pregnane-11,20-dione-21-glucuronide (aOR = 0.34, 95% CI = 0.14-0.75) were inversely associated with childhood asthma at 5 and 6 years after multiple testing adjustment. There was a significant interaction effect of pregnanediol-3-glucuronide by biological sex assigned at birth (aOR = 0.11, 95% CI = 0.02-0.51, for those with female sex) on childhood asthma. Pregnenetriol disulfate was inversely associated with granulocyte-macrophage colony-stimulating factor (ß = -0.45, q-value = 0.05). 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide was inversely associated with interleukin [IL]-4 (ß = -0.29, q-value = 0.02), IL-5 (ß = -0.35, q-value = 0.006), IL-13 (ß = -0.26, q-value = 0.02), granulocyte-macrophage colony-stimulating factor (ß = -0.35, q-value = 0.006), and fibroblast growth factor-ß (ß = -0.24, q-value = 0.01) after multiple testing adjustment. CONCLUSION: The inverse association between adrenal steroids downstream of progesterone and 17-hydroxypregnenolone and the odds of childhood asthma and nasopharyngeal type 2 immune biomarkers suggest that increased early-life adrenal steroids may suppress type 2 inflammation and protect against the development of childhood asthma.

Multi-Omics Analysis of Lung Tissue Demonstrates Changes to Lipid Metabolism during Allergic Sensitization in Mice.

Allergy and asthma pathogenesis are associated with the dysregulation of metabolic pathways. To understand the effects of allergen sensitization on metabolic pathways, we conducted a multi-omics study using BALB/cJ mice sensitized to house dust mite (HDM) extract or saline. Lung tissue was used to perform untargeted metabolomics and transcriptomics while both lung tissue and plasma were used for targeted lipidomics. Following statistical comparisons, an integrated pathway analysis was conducted. Histopathological changes demonstrated an allergic response in HDM-sensitized mice. Untargeted metabolomics showed 391 lung tissue compounds were significantly different between HDM and control mice (adjusted p < 0.05); with most compounds mapping to glycerophospholipid and sphingolipid pathways. Several lung oxylipins, including 14-HDHA, 8-HETE, 15-HETE, 6-keto-PGF1α, and PGE2 were significantly elevated in HDM-sensitized mice (p < 0.05). Global gene expression analysis showed upregulated calcium channel, G protein-signaling, and mTORC1 signaling pathways. Genes related to oxylipin metabolism such as Cox, Cyp450s, and cPla2 trended upwards. Joint analysis of metabolomics and transcriptomics supported a role for glycerophospholipid and sphingolipid metabolism following HDM sensitization. Collectively, our multi-omics results linked decreased glycerophospholipid and sphingolipid compounds and increased oxylipins with allergic sensitization; concurrent upregulation of associated gene pathways supports a role for bioactive lipids in the pathogenesis of allergy and asthma.

Black Mothers in Racially Segregated Neighborhoods Embodying Structural Violence: PTSD and Depressive Symptoms on the South Side of Chicago.

This study employs multi-level and mixed-methods approaches to examine how structural violence affects the health of low-income, single Black mothers. We use multilevel regression models to examine how feeling "trapped" in racially segregated neighborhoods with high levels of violence on the South Side of Chicago affects mothers' (N = 69) reports of posttraumatic stress disorder and depressive symptoms. The relationship between feeling "trapped" and variations in expression of mRNA for the glucocorticoid receptor gene NR3C1 using microarray assays was also examined. The regression models revealed that feeling "trapped" significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation. The mothers' voices revealed a nuanced understanding about how a lack of financial resources to move out of the neighborhood creates feelings of being "trapped" in dangerous situations.

Association of citrulline concentration at birth with lower respiratory tract infection in infancy: Findings from a multi-site birth cohort study.

Assessing the association of the newborn metabolic state with severity of subsequent respiratory tract infection may provide important insights on infection pathogenesis. In this multi-site birth cohort study, we identified newborn metabolites associated with lower respiratory tract infection (LRTI) in the first year of life in a discovery cohort and assessed for replication in two independent cohorts. Increased citrulline concentration was associated with decreased odds of LRTI (discovery cohort: aOR 0.83 [95% CI 0.70-0.99], p = 0.04; replication cohorts: aOR 0.58 [95% CI 0.28-1.22], p = 0.15). While our findings require further replication and investigation of mechanisms of action, they identify a novel target for LRTI prevention and treatment.

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

Exclusive breast-feeding, the early-life microbiome and immune response, and common childhood respiratory illnesses.

BACKGROUND: The impact of breast-feeding on certain childhood respiratory illnesses remains controversial. OBJECTIVE: We sought to examine the effect of exclusive breast-feeding on the early-life upper respiratory tract (URT) and gut microbiome, the URT immune response in infancy, and the risk of common pediatric respiratory diseases. METHODS: We analyzed data from a birth cohort of healthy infants with prospective ascertainment of breast-feeding patterns and common pediatric pulmonary and atopic outcomes. In a subset of infants, we also characterized the URT and gut microbiome using 16S ribosomal RNA sequencing and measured 9 URT cytokines using magnetic bead-based assays. RESULTS: Of the 1949 infants enrolled, 1495 (76.71%) had 4-year data. In adjusted analyses, exclusive breast-feeding (1) had an inverse dose-response on the ⍺-diversity of the early-life URT and gut microbiome, (2) was positively associated with the URT levels of IFN-α, IFN-γ, and IL-17A in infancy, and (3) had a protective dose-response on the development of a lower respiratory tract infection in infancy, 4-year current asthma, and 4-year ever allergic rhinitis (odds ratio [95% CI] for each 4 weeks of exclusive breast-feeding, 0.95 [0.91-0.99], 0.95 [0.90-0.99], and 0.95 [0.92-0.99], respectively). In exploratory analyses, we also found that the protective association of exclusive breast-feeding on 4-year current asthma was mediated through its impact on the gut microbiome (P = .03). CONCLUSIONS: Our results support a protective causal role of exclusive breast-feeding in the risk of developing a lower respiratory tract infection in infancy and asthma and allergic rhinitis in childhood. They also shed light on potential mechanisms of these associations, including the effect of exclusive breast-feeding on the gut microbiome.

Upper respiratory tract bacterial-immune interactions during respiratory syncytial virus infection in infancy.

BACKGROUND: The risk factors determining short- and long-term morbidity following acute respiratory infection (ARI) due to respiratory syncytial virus (RSV) in infancy remain poorly understood. OBJECTIVES: Our aim was to examine the associations of the upper respiratory tract (URT) microbiome during RSV ARI in infancy with the acute local immune response and short- and long-term clinical outcomes. METHODS: We characterized the URT microbiome by 16S ribosomal RNA sequencing and assessed the acute local immune response by measuring 53 immune mediators with high-throughput immunoassays in 357 RSV-infected infants. Our short- and long-term clinical outcomes included several markers of disease severity and the number of wheezing episodes in the fourth year of life, respectively. RESULTS: We found several specific URT bacterial-immune mediator associations. In addition, the Shannon ⍺-diversity index of the URT microbiome was associated with a higher respiratory severity score (ß =.50 [95% CI = 0.13-0.86]), greater odds of a lower ARI (odds ratio = 1.63 [95% CI = 1.10-2.43]), and higher number of wheezing episodes in the fourth year of life (ß = 0.89 [95% CI = 0.37-1.40]). The Jaccard ß-diversity index of the URT microbiome differed by level of care required (P = .04). Furthermore, we found an interaction between the Shannon ⍺-diversity index of the URT microbiome and the first principal component of the acute local immune response on the respiratory severity score (P = .048). CONCLUSIONS: The URT microbiome during RSV ARI in infancy is associated with the acute local immune response, disease severity, and number of wheezing episodes in the fourth year of life. Our results also suggest complex URT bacterial-immune interactions that can affect the severity of the RSV ARI.

Association between asthma status and prenatal antibiotic prescription fills among women in a Medicaid population.

OBJECTIVE: Pregnant women with asthma have increased frequency of respiratory viral infections and exacerbations. Because of these risks, women with asthma may be subject to increased surveillance during pregnancy and may, therefore, be at increased risk of antibiotic receipt. The objective of this study was to assess the relationship between maternal asthma and outpatient prenatal antibiotic prescription fills to inform antibiotic stewardship. METHODS: We included women who delivered a singleton, term, non-low birthweight, and otherwise healthy infant enrolled in the Tennessee Medicaid Program. Maternal asthma and prenatal antibiotic fills were ascertained from healthcare encounters and outpatient pharmacy claims. We examined the association between maternal asthma and prenatal antibiotic fills using modified Poisson regression. RESULTS: Our study population included 168354 pregnant women, 4% of whom had asthma. Women with asthma had an increased risk of filling at least one prenatal antibiotic prescription (adjusted risk ratio [aRR] 1.27, 95% confidence interval [CI] 1.25-1.28) and had an increased number of fills during pregnancy (aRR 1.54, 95% CI 1.51-1.57) compared to women without asthma. Among those who filled at least one antibiotic prescription, women with asthma had earlier first prenatal antibiotic prescription fill and increased likelihood of filling at least one course of broad-spectrum antibiotics during pregnancy (versus narrow-spectrum). CONCLUSIONS: Pregnant women with asthma had more outpatient antibiotic prescription fills than pregnant women without asthma. These findings highlight that pregnant women with asthma disproportionately fill more antibiotic prescriptions during pregnancy, providing data that may inform antibiotic stewardship.

Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes.

Respiratory syncytial virus (RSV) causes respiratory illness in children, immunosuppressed individuals and the elderly. However, the viral factors influencing the clinical outcome of RSV infections remain poorly defined. Defective viral genomes (DVGs) can suppress virus replication by competing for viral proteins and by stimulating antiviral immunity. We studied the association between detection of DVGs of the copy-back type and disease severity in three RSV A-confirmed cohorts. In hospitalized children, detection of DVGs in respiratory samples at or around the time of admission associated strongly with more severe disease, higher viral load and a stronger pro-inflammatory response. Interestingly, in experimentally infected adults, the presence of DVGs in respiratory secretions differentially associated with RSV disease severity depending on when DVGs were detected. Detection of DVGs early after infection associated with low viral loads and mild disease, whereas detection of DVGs late after infection, especially if DVGs were present for prolonged periods, associated with high viral loads and severe disease. Taken together, we demonstrate that the kinetics of DVG accumulation and duration could predict clinical outcome of RSV A infection in humans, and thus could be used as a prognostic tool to identify patients at risk of worse clinical disease.

Transcriptomic analyses of black women in neighborhoods with high levels of violence.

Chronic stress threatens an individual's capacity to maintain psychological and physiological homeostasis, but the molecular processes underlying the biological embedding of these experiences are not well understood. This is particularly true for marginalized groups, presenting a fundamental challenge to decreasing racial, economic, and gender-based health disparities. Physical and social environments influence genome function, including the transcriptional activity of core stress responsive genes. We studied the relationship between social experiences that are associated with systemic inequality (e.g., racial segregation, poverty, and neighborhood violence) and blood cell (leukocytes) gene expression, focusing on the activation of transcription factors (TF) critical to stress response pathways. The study used data from 68 women collected from a convenience sample in 2013 from the Southside of Chicago. Comparing single, low-income Black mothers living in neighborhoods with high levels of violence (self-reported and assessed using administrative police records) to those with low levels of violence we found no significant differences in expression of 51 genes associated with the Conserved Transcriptional Response to Adversity (CTRA). Using TELiS analysis of promoter TF-binding motif prevalence we found that mothers who self-reported higher levels of neighborhood stress showed greater expression of genes regulated by the glucocorticoid receptor (GR). These findings may reflect increased cortisol output from the hypothalamic-pituitary-adrenal (HPA) axis, or increased GR transcriptional sensitivity. Transcript origin analyses identified monocytes and dendritic cells as the primary cellular sources of gene transcripts up-regulated in association with neighborhood stress. The prominence of GR-related transcripts and the absence of sympathetic nervous system-related CTRA transcripts suggest that a subjective perception of elevated chronic neighborhood stress may be associated with an HPA-related defeat-withdrawal phenotype rather than a fight-or-flight phenotype. The defeat-withdrawal phenotype has been previously observed in animal models of severe, overwhelming threat. These results demonstrate the importance of studying biological embedding in diverse environments and communities, specifically marginalized populations such as low-income Black women.

Unconjugated bilirubin is associated with protection from early-life wheeze and childhood asthma.

BACKGROUND: Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood. OBJECTIVES: We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma. METHODS: We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma. RESULTS: Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (ß = 0.87; 95% CI, 0.74-1.02) and 22% (ß = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (ß = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization. CONCLUSIONS: We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.

Dose, Timing, and Spectrum of Prenatal Antibiotic Exposure and Risk of Childhood Asthma.

BACKGROUND: The potential for prenatal antibiotic exposure to influence asthma risk is not clear. We aimed to determine the effect of timing, dose, and spectrum of prenatal antibiotic exposure on the risk of childhood asthma. METHODS: We conducted a population-based cohort study of 84 214 mother-child dyads to examine the association of prenatal antibiotic exposure and childhood asthma using multivariable logistic regression models. RESULTS: Sixty-four percent of pregnant women received antibiotics. Prenatal antibiotic exposure was associated dose-dependently with increased odds of childhood asthma (adjusted odds ratio [aOR] for interquartile increase of 2 courses [interquartile range, 0-2], 1.26 [95% confidence interval {CI}, 1.20-1.33]). Among children exposed to at least 1 course in utero, the effect of timing at the first course was moderated by total maternal courses. Among pregnant women receiving a single antibiotic course, timing of exposure had no effect on childhood asthma risk. Among women receiving > 1 course, early exposure of the first course was associated with greater childhood asthma risk. Compared to narrow spectrum-only antibiotic use, broad spectrum-only antibiotic exposure was associated with increased odds of asthma (aOR, 1.14 [95% CI, 1.05-1.24]). There were effect modifications (P < .001) by maternal asthma on total courses, and on timing of the first course, significant only among those without maternal asthma. CONCLUSIONS: Increased cumulative dose, early pregnancy first course, and broad-spectrum antibiotic exposure were associated with childhood asthma risk. Our study provides important evidence supporting judicious prenatal antibiotic use, particularly timing of use and choice of antibiotics, in preventing subsequent childhood asthma.

Involving Urban Single Low-Income African American Mothers in Genomic Research: Giving Voice to How Place Matters in Health Disparities and Prevention Strategies.

This article describes the process of using principles from community-based participatory action research to involve low-income, single, African American mothers on the south side of Chicago in genomic research, including as citizen scientists. The South Chicago Black Mothers' Resiliency Project used a mixed methods design to investigate how the stress of living in neighborhoods with high levels of violence affects mothers' mental and physical health. This article seeks to serve as a model for physicians and scholars interested in successfully involving low-income African American mothers in genomic research, and other health-related activities in ways that are culturally sensitive and transformative. The lives of Black mothers who struggle under interlocking systems of oppression that are often hidden from view of most Americans are at the center of this article. Therefore, we provide extensive information about the procedures used to collect the various types of data, the rationale for our procedures, the setting, the responses of mothers in our sample and methodological challenges. This study also has implications for the current COVID-19 pandemic and the need to train a corps of citizen scientists in health and wellness to avoid future extreme loss of life such as the 106,195 lives lost in the United States as of June 1, 2020.

Dose, Timing, and Type of Infant Antibiotic Use and the Risk of Childhood Asthma.

BACKGROUND: Aspects of infant antibiotic exposure and its association with asthma development have been variably explored. We aimed to evaluate comprehensively and simultaneously the impact of dose, timing, and type of infant antibiotic use on the risk of childhood asthma. METHODS: Singleton, term-birth, non-low-birth-weight, and otherwise healthy children enrolled in the Tennessee Medicaid Program were included. Infant antibiotic use and childhood asthma diagnosis were ascertained from prescription fills and healthcare encounter claims. We examined the association using multivariable logistic regression models. RESULTS: Among 152 622 children, 79% had at least 1 antibiotic prescription fill during infancy. Infant antibiotic use was associated with increased odds of childhood asthma in a dose-dependent manner, with a 20% increase in odds (adjusted odds ratio [aOR], 1.20 [95% confidence interval {CI}, 1.19-1.20]) for each additional antibiotic prescription filled. This significant dose-dependent relationship persisted after additionally controlling for timing and type of the antibiotics. Infants who had broad-spectrum-only antibiotic fills had increased odds of developing asthma compared with infants who had narrow-spectrum-only fills (aOR, 1.10 [95% CI, 1.05-1.19]). There was no significant association between timing, formulation, anaerobic coverage, and class of antibiotics and childhood asthma. CONCLUSIONS: We found a consistent dose-dependent association between antibiotic prescription fills during infancy and subsequent development of childhood asthma. Our study adds important insights into specific aspects of infant antibiotic exposure. Clinical decision making regarding antibiotic stewardship and prevention of adverse effects should be critically assessed prior to use during infancy.

Infant Respiratory Syncytial Virus Bronchiolitis and Subsequent Risk of Pneumonia, Otitis Media, and Antibiotic Utilization.

Infant respiratory syncytial virus (RSV) bronchiolitis in the first 6 months of life was associated with increased odds of pneumonia, otitis media, and antibiotic prescription fills in the second 6 months of life. These data suggest a potential value of future RSV vaccination programs on subsequent respiratory health.

The current state of omics technologies in the clinical management of asthma and allergic diseases.

OBJECTIVE: To review the state of omics science specific to asthma and allergic diseases and discuss the current and potential applicability of omics in clinical disease prediction, treatment, and management. DATA SOURCES: Studies and reviews focused on the use of omics technologies in asthma and allergic disease research and clinical management were identified using PubMed. STUDY SELECTIONS: Publications were included based on relevance, with emphasis placed on the most recent findings. RESULTS: Omics-based research is increasingly being used to differentiate asthma and allergic disease subtypes, identify biomarkers and pathological mediators, predict patient responsiveness to specific therapies, and monitor disease control. Although most studies have focused on genomics and transcriptomics approaches, increasing attention is being placed on omics technologies that assess the effect of environmental exposures on disease initiation and progression. Studies using omics data to identify biological targets and pathways involved in asthma and allergic disease pathogenesis have primarily focused on a specific omics subtype, providing only a partial view of the disease process. CONCLUSION: Although omics technologies have advanced our understanding of the molecular mechanisms underlying asthma and allergic disease pathology, omics testing for these diseases are not standard of care at this point. Several important factors need to be addressed before these technologies can be used effectively in clinical practice. Use of clinical decision support systems and integration of these systems within electronic medical records will become increasingly important as omics technologies become more widely used in the clinical setting.

Sex-specific association between prenatal life stress exposure and infant pro-inflammatory cytokine levels during acute respiratory infection.

BACKGROUND: Prenatal life stress exposure is linked to dysregulated immune function and chronic inflammatory disease in offspring, but we know little about its effects on infant immune response during viral infection. METHOD: To address this issue, we examined associations between prenatal life stress exposure and infant upper-airway inflammatory markers during acute respiratory infection (ARI) using data from a prospective, population-based birth-cohort study (N = 180). Infant inflammation was measured as a continuous latent factor within a structural equation modeling framework using nasal wash concentrations of interleukin-1ß, interleukin-6, and tumor necrosis factor-α. We hypothesized that infants exposed to prenatal life stress would have greater levels of nasal inflammation during ARI and increased risk for ARI-related morbidity in early childhood. RESULTS: Our findings contradicted these hypotheses and provided evidence of sexually dimorphic effects of prenatal stress exposure on infant immune functioning during ARI. Among boys, but not girls, prenatal stress was negatively associated with nasal inflammation and indirectly associated with both lower ARI severity and reduced likelihood of subsequent ARI-related hospitalization in the 2nd and 3rd years of life. CONCLUSION: These data suggest that prenatal stress exposure may be beneficial for infant boys in the context of respiratory viral infections; however, it will be critical to determine if these benefits are offset by increased risk for chronic inflammatory diseases in later childhood. As the participants in this cohort are being followed longitudinally through age 8, we will be able to evaluate long-term health outcomes in future studies.

Association of newborn screening metabolites with risk of wheezing in childhood.

BACKGROUND: There are critical gaps in our understanding of the temporal relationships between metabolites and subsequent asthma development. This is the first study to examine metabolites from newborn screening in the etiology of early childhood wheezing. METHODS: One thousand nine hundred and fifty one infants enrolled between 2012 and 2014 from pediatric practices located in Middle Tennessee in the population-based birth cohort study, the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE), were linked with metabolite data from the Tennessee Newborn Screening Program. The association between the levels of 37 metabolites and the number of wheezing episodes in the past 12 months was assessed at 1, 2, and 3 years of life. RESULTS: Several metabolites were significantly associated with the number of wheezing episodes. Two acylcarnitines, C10:1 and C18:2, showed robust associations. Increasing levels of C10:1 were associated with increasing number of wheezing episodes at 2 years (OR 2.11, 95% CI 1.41-3.17) and 3 years (OR 2.56, 95% CI 1.59-4.11), while increasing levels of C18:2 were associated with increasing number of wheezing episodes at 1 year (OR 1.38, 95% CI 1.12-1.71) and 2 years (OR 1.47, 95% CI 1.17-1.84). CONCLUSIONS: Identification of specific metabolites and associated pathways involved in wheezing pathogenesis offer insights into potential targets to prevent childhood asthma morbidity.