Microbial colonization programs are structured by breastfeeding and guide healthy respiratory development.

Breastfeeding and microbial colonization during infancy occur within a critical time window for development, and both are thought to influence the risk of respiratory illness. However, the mechanisms underlying the protective effects of breastfeeding and the regulation of microbial colonization are poorly understood. Here, we profiled the nasal and gut microbiomes, breastfeeding characteristics, and maternal milk composition of 2,227 children from the CHILD Cohort Study. We identified robust colonization patterns that, together with milk components, predict preschool asthma and mediate the protective effects of breastfeeding. We found that early cessation of breastfeeding (before 3 months) leads to the premature acquisition of microbial species and functions, including Ruminococcus gnavus and tryptophan biosynthesis, which were previously linked to immune modulation and asthma. Conversely, longer exclusive breastfeeding supports a paced microbial development, protecting against asthma. These findings underscore the importance of extended breastfeeding for respiratory health and highlight potential microbial targets for intervention.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Antibiotics taken within the first year of life are linked to infant gut microbiome disruption and elevated atopic dermatitis risk.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in both pediatric and adult populations. The development of AD has been linked to antibiotic usage, which causes perturbation of the microbiome and has been associated with abnormal immune system function. However, imbalances in the gut microbiome itself associated with antibiotic usage have been inconsistently linked to AD. OBJECTIVES: This study aimed to elucidate the timing and specific factors mediating the relationship between systemic (oral or intravenous) antibiotic usage and AD. METHODS: We used statistical modeling and differential analysis to link CHILD Cohort Study participants' history of antibiotic usage and early-life gut microbiome alterations to AD. RESULTS: Here we report that systemic antibiotics during the first year of life, as compared to later, are associated with AD risk (adjusted odds ratio [aOR] = 1.81; 95% CI: 1.28-2.57; P < .001), with an increased number of antibiotic courses corresponding to a dose response-like increased risk of AD risk (1 course: aOR: 1.67; 95% CI: 1.17-2.38; 2 or more courses: aOR: 2.16; 95% CI: 1.30-3.59). Further, we demonstrate that microbiome alterations associated with both AD and systemic antibiotic usage fully mediate the effect of antibiotic usage on the development of AD (ßindirect = 0.072; P < .001). Alterations in the 1-year infant gut microbiome of participants who would later develop AD included increased Tyzzerella nexilis, increased monosaccharide utilization, and parallel decreased Bifidobacterium and Eubacterium spp, and fermentative pathways. CONCLUSIONS: These findings indicate that early-life antibiotic usage, especially in the first year of life, modulates key gut microbiome components that may be used as markers to predict and possibly prevent the development of AD.

From Fetus to Eight: the CHILD Cohort Study.

The CHILD Cohort Study is an active multi-center longitudinal, prospective, population pregnancy cohort study following Canadian infants from fetal life until adulthood. We hypothesized that early life physical and psychosocial environments interact with biological factors (e.g. immunologic, genetic, physiologic, and metabolic) influencing burdensome non-communicable disease outcomes, including asthma and allergic disorders, growth and development, cardio-metabolic health, and neurodevelopmental outcomes that manifest during the life-course. Detailed clinical and physiologic phenotyping at strategic intervals was complemented by environmental sampling, actigraphy and global positioning system measures, biological sampling including gut, breastmilk and nasal microbiome, nutritional studies, genetics, and epigenetic profiling. Of 3,454 families recruited from 2008 to 2012, study retention was 96.0% at 1-year, 93.2% at 5-years and 90.7% at 8-years. Data collection during the SARS-2 COVID-19 pandemic was partially completed via virtual visits. A sub-cohort was implemented, capturing detailed information on the prevalence and predictors of SARS-CoV-2 infection and the health and psychosocial impact of the pandemic on Canadian families. The 13-year clinical assessment launched in 2022 will be completed in 2025. Ultimately, the CHILD Cohort Study provides a data science platform designed to enable a deep understanding of early life factors associated with the development of chronic non-communicable diseases and multimorbidity.

Pre-labor and post-labor cesarean delivery and early childhood adiposity in the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study.

BACKGROUND/OBJECTIVES: Delivery by cesarean section (CS) compared to vaginal delivery has been associated with increased risk of overweight in childhood. Our study examined if the presence or absence of labor events in CS delivery altered risk of overweight in early childhood (1-5 years) compared to vaginal delivery and if this association differed according to infant sex. SUBJECTS/METHODS: The study included 3073 mother-infant pairs from the CHILD Cohort Study in Canada. Data from birth records were used to categorize infants as having been vaginally delivered, or delivered by CS, with or without labor events. Age and sex adjusted weight-for-length (WFL) and body mass index (BMI) z scores were calculated from height and weight data from clinic visits at 1, 3 and 5 years and used to classify children as overweight. Associations between delivery mode and child overweight at each timepoint were assessed using regression models, adjusting for relevant confounding factors including maternal pre-pregnancy BMI. Effect modification by infant sex was tested. RESULTS: One in four infants (24.6%) were born by CS delivery; 13.0% involved labor events and 11.6% did not. Infants born by CS without labor had an increased odds of being overweight at age 1 year compared to vaginally delivered infants after adjustment for maternal pre-pregnancy BMI, maternal diabetes, smoking, infant sex and birthweight-for-gestational age (aOR 1.68 [95% CI 1.05-2.67]). These effects did not persist to 3 or 5 years of age and, after stratification by sex, were only seen in boys (aOR at 1 year 2.21 [95% CI 1.26-3.88]). CONCLUSION AND RELEVANCE: Our findings add to the body of evidence that CS, in particular CS without labor events, may be a risk factor for overweight in early life, and that this association may be sex-specific. These findings could help to identify children at higher risk for developing obesity.

Early prediction of pediatric asthma in the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort using machine learning.

BACKGROUND: Early identification of children at risk of asthma can have significant clinical implications for effective intervention and treatment. This study aims to disentangle the relative timing and importance of early markers of asthma. METHODS: Using the CHILD Cohort Study, 132 variables measured in 1754 multi-ethnic children were included in the analysis for asthma prediction. Data up to 4 years of age was used in multiple machine learning models to predict physician-diagnosed asthma at age 5 years. Both predictive performance and variable importance was assessed in these models. RESULTS: Early-life data (≤1 year) has limited predictive ability for physician-diagnosed asthma at age 5 years (area under the precision-recall curve (AUPRC) < 0.35). The earliest reliable prediction of asthma is achieved at age 3 years, (area under the receiver-operator curve (AUROC) > 0.90) and (AUPRC > 0.80). Maternal asthma, antibiotic exposure, and lower respiratory tract infections remained highly predictive throughout childhood. Wheezing status and atopy are the most important predictors of early childhood asthma from among the factors included in this study. CONCLUSIONS: Childhood asthma is predictable from non-biological measurements from the age of 3 years, primarily using parental asthma and patient history of wheezing, atopy, antibiotic exposure, and lower respiratory tract infections. IMPACT: Machine learning models can predict physician-diagnosed asthma in early childhood (AUROC > 0.90 and AUPRC > 0.80) using ≥3 years of non-biological and non-genetic information, whereas prediction with the same patient information available before 1 year of age is challenging. Wheezing, atopy, antibiotic exposure, lower respiratory tract infections, and the child's mother having asthma were the strongest early markers of 5-year asthma diagnosis, suggesting an opportunity for earlier diagnosis and intervention and focused assessment of patients at risk for asthma, with an evolving risk stratification over time.

Clinical characteristics and management of pediatric egg-induced anaphylaxis: A cross-sectional study.

BACKGROUND: Egg is the third most common food allergy in children; however, data on pediatric egg-induced anaphylaxis are sparse. OBJECTIVE: To describe the clinical characteristics, management, and outcomes of pediatric egg-induced anaphylaxis. METHODS: Children presenting with anaphylaxis were recruited from 13 emergency departments as part of the Cross-Canada Anaphylaxis Registry, from which data on anaphylaxis triggered by egg were extracted. Multivariate logistic regression was used to determine factors associated with prehospital epinephrine autoinjector (EAI) use and to compare anaphylaxis triggered by egg with other triggers of food-induced anaphylaxis (FIA). RESULTS: We recruited 302 children with egg-induced anaphylaxis. The mean age was 2.6 years (SD = 3.6), and 55.3% were male. Only 39.4% had previously been diagnosed with an egg allergy. Prehospital EAI use was 32.1%, but this was not significantly lower than in other triggers of FIA (P = .26). Only 1.4% of patients required hospital admission. Relative to other triggers of FIA, patients with egg-induced anaphylaxis were significantly younger (P < .001) and exhibited more vomiting (P = .0053) and less throat tightness (P = .0015) and angioedema (P < .001). CONCLUSION: To the best of our knowledge, this is the largest published cohort of pediatric egg-induced anaphylaxis. In this cohort, prehospital EAI use was very low. In addition, we identified certain symptoms that distinguish egg-induced from other triggers of FIA. Taken together, high suspicion is crucial in identifying egg-induced anaphylaxis, given the younger patient demographic and frequent lack of FIA history.

Milk-induced anaphylaxis among children presenting to Canadian emergency departments.

BACKGROUND: Cow's milk is one of the most common and burdensome allergens in pediatrics, and it can induce severe anaphylactic reactions in children. However, data on cow's milk-induced anaphylaxis are sparse. OBJECTIVE: To describe the epidemiology of pediatric cow's milk-induced anaphylaxis and to determine risk factors for repeat emergency department (ED) epinephrine administration. METHODS: Between April 2011 and May 2023, data were collected on children with anaphylaxis presenting to 10 Canadian EDs. A standardized form documenting symptoms, triggers, treatment, and outcome was used. Multivariate logistic regression was used. RESULTS: Of 3118 anaphylactic reactions, 319 milk-induced anaphylaxis cases were identified (10%). In the prehospital setting, 54% of patients with milk-induced anaphylaxis received intramuscular epinephrine. In those with milk-induced anaphylaxis, receiving epinephrine before presenting to the ED was associated with a reduced risk of requiring 2 or more epinephrine doses in the ED (adjusted odds ratio, 0.95 [95% CI, 0.90-0.99]). Children younger than 5 years of age were more likely to experience a mild reaction compared with that in older children, who experienced a moderate reaction more often (P < .0001). Compared with other forms of food-induced anaphylaxis, children presenting with milk-induced anaphylaxis were younger; a greater proportion experienced wheezing and vomiting, and less experienced angioedema. CONCLUSION: Prehospital epinephrine in pediatric milk-induced anaphylaxis is underused; however, it may decrease risk of requiring 2 ED epinephrine doses. Milk-induced anaphylaxis in children younger than 5 years of age may be less severe than in older children. Wheezing and vomiting are more prevalent in milk-induced anaphylaxis compared with that of other foods.

Management of anaphylaxis after pre-hospital epinephrine use in children with food-induced anaphylaxis.

BACKGROUND: Previous guidelines recommend prompt epinephrine administration, followed by observation in the emergency department (ED). The need for transfer in all cases of anaphylaxis has recently been challenged. OBJECTIVE: To evaluate the need for additional ED treatment among children with anaphylaxis who received prehospital epinephrine. METHODS: Between 2011 and 2023, data were collected on symptoms, triggers, comorbidities, and prehospital and in-hospital management from children (<18 years) with food-induced anaphylaxis who received at least 1 dose of prehospital epinephrine presenting at 7 pediatric EDs. Multivariable logistic regression assessed factors associated with the use of 2 or more prehospital epinephrine autoinjectors (EAIs), epinephrine use in the ED, and hospital admission. RESULTS: Of the 1127 children (mean 8.1 ± 5.3 years; 60.6% male sex) with food-induced anaphylaxis who used at least 1 EAI prehospital, the most common trigger was peanuts (25.3%). There were 209 (18.5%) children who received additional epinephrine in the ED, most of whom (88.0%) received 1 dose. A total of 30 (2.7%) patients were admitted to hospital. Among all patients, severe reactions (cardiovascular instability/cyanosis/loss of consciousness) (adjusted odds ratio [aOR] 1.22; 95% CI 1.12-1.33) and reactions to tree nuts (aOR 1.09; 95% CI 1.03-1.16) were associated with increased odds of in-hospital epinephrine use. Prehospital inhaled ß-agonists (aOR 1.08; 95% CI 1.01-1.16) use and severe reactions (aOR 1.13; 95% CI 1.05-1.22) were associated with the use of 2 or more EAI prehospital. CONCLUSION: A minority of anaphylaxis cases that used prehospital EAIs required additional treatment, supporting that shared decision making about transfer to ED works for most patients.

Stress and anxiety during pregnancy and length of gestation: a federated study using data from five Canadian and European birth cohorts.

While its etiology is not fully elucidated, preterm birth represents a major public health concern as it is the leading cause of child mortality and morbidity. Stress is one of the most common perinatal conditions and may increase the risk of preterm birth. In this paper we aimed to investigate the association of maternal perceived stress and anxiety with length of gestation. We used harmonized data from five birth cohorts from Canada, France, and Norway. A total of 5297 pregnancies of singletons were included in the analysis of perceived stress and gestational duration, and 55,775 pregnancies for anxiety. Federated analyses were performed through the DataSHIELD platform using Cox regression models within intervals of gestational age. The models were fit for each cohort separately, and the cohort-specific results were combined using random effects study-level meta-analysis. Moderate and high levels of perceived stress during pregnancy were associated with a shorter length of gestation in the very/moderately preterm interval [moderate: hazard ratio (HR) 1.92 (95%CI 0.83, 4.48); high: 2.04 (95%CI 0.77, 5.37)], albeit not statistically significant. No association was found for the other intervals. Anxiety was associated with gestational duration in the very/moderately preterm interval [1.66 (95%CI 1.32, 2.08)], and in the early term interval [1.15 (95%CI 1.08, 1.23)]. Our findings suggest that perceived stress and anxiety are associated with an increased risk of earlier birth, but only in the earliest gestational ages. We also found an association in the early term period for anxiety, but the result was only driven by the largest cohort, which collected information the latest in pregnancy. This raised a potential issue of reverse causality as anxiety later in pregnancy could be due to concerns about early signs of a possible preterm birth.

Organophosphate ester flame retardants and plasticizers in house dust and mental health outcomes among Canadian mothers: A nested prospective cohort study in CHILD.

Organophosphate ester flame retardants and plasticizers (OPEs) are common exposures in modern built environments. Toxicological models report that some OPEs reduce dopamine and serotonin in the brain. Deficiencies in these neurotransmitters are associated with anxiety and depression. We hypothesized that exposure to higher concentrations of OPEs in house dust would be associated with a greater risk of depression and stress in mothers across the prenatal and postpartum periods. We conducted a nested prospective cohort study using data collected on mothers (n = 718) in the CHILD Cohort Study, a longitudinal multi-city Canadian birth cohort (2008-2012). OPEs were measured in house dust sampled at 3-4 months postpartum. Maternal depression and stress were measured at 18 and 36 weeks gestation and 6 months and 1 year postpartum using the Centre for Epidemiologic Studies for Depression Scale (CES-D) and Perceived Stress Scale (PSS). We used linear mixed models to examine the association between a summed Z-Score OPE index and continuous depression and stress scores. In adjusted models, one standard deviation increase in the OPE Z-score index was associated with a 0.07-point (95% CI: 0.01, 0.13) increase in PSS score. OPEs were not associated with log-transformed CES-D (ß: 0.63%, 95% CI: -0.18%, 1.46%). The effect of OPEs on PSS score was strongest at 36 weeks gestation and weakest at 1 year postpartum. We observed small increases in maternal perceived stress levels, but not depression, with increasing OPEs measured in house dust during the prenatal and early postpartum period in this cohort of Canadian women. Given the prevalence of prenatal and postpartum anxiety and the ubiquity of OPE exposures, additional research is warranted to understand if these chemicals affect maternal mental health.

Examining psychosocial pathways to explain the link between breastfeeding practices and child behaviour in a longitudinal cohort.

OBJECTIVE: Breastfeeding is associated with reduced postpartum depression, stronger parent-child relationships, and fewer behavioral disorders in early childhood. We tested the mediating roles of postpartum depression and parent-child relationship in the association between breastfeeding practices and child behavior. STUDY DESIGN: We used standardized questionnaire data from a subset of the CHILD Cohort Study (n = 1,573) to measure postpartum depression at 6 months, 1 year and 2 years, parent-child relationship 1 year and 2 years, and child behavior at 5 years using the Child Behavior Checklist (range 0-100). Breastfeeding practices were measured at 3 months (none, partial, some expressed, all direct at the breast), 6 months (none, partial, exclusive), 12 months, and 24 months (no, yes). Confounders included birth factors, maternal characteristics, and socioeconomic status. RESULTS: Breast milk feeding at 3 or 6 months was associated with - 1.13 (95% CI: -2.19-0.07) to -2.14 (95% CI: -3.46, -0.81) lower (better) child behavior scores. Reduced postpartum depression at 6 months mediated between 11.5% and 16.6% of the relationship between exclusive breast milk feeding at 3 months and better child behavior scores. Together, reduced postpartum depression at 1 year and reduced parent-child dysfunction at 2 years mediated between 21.9% and 32.1% of the relationship between breastfeeding at 12 months and better child behavior scores. CONCLUSION: Postpartum depression and parent-child relationship quality partially mediate the relationship between breastfeeding practices and child behavior. Breastfeeding, as well as efforts to support parental mental health and parent-child relationships, may help to improve child behavior.

Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries. CONCLUSIONS: This study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.

Correction: Gestational age at birth and body size from infancy through adolescence: An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies.

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].

Early sex-dependent differences in metabolic profiles of overweight and adiposity in young children: a cross-sectional analysis.

BACKGROUND: Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. METHODS: Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). RESULTS: In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. CONCLUSIONS: Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.

The Relationship Between Diet, Gut Microbiota, and Serum Metabolome of South Asian Infants at 1 Year.

BACKGROUND: Diet is known to affect the gut microbiota and the serum metabolome in adults, but this has not been fully explored in infants. Infancy is an important developmental period that may influence a person's long-term health. Infant development can be affected by diet, which also interacts with the developing gut microbiota. OBJECTIVES: This study aimed to explore the associations between diet, the gut microbiota, and the serum metabolome of 1-y-old infants with the overarching goal of identifying serum biomarkers of diet and/or the gut microbiota. METHODS: We derived dietary patterns of 1-y-old infants (n = 182) participating in the Canadian South Asian Birth Cohort (START) study. We compared gut microbiota α-diversity and ß-diversity and taxa relative abundance from 16S rRNA gene profiles with dietary patterns (PERMANOVA, Envfit) and investigated diet-serum metabolite associations using a multivariate analysis (partial least squares-discriminant analysis) and univariate analysis (t test). We explored the effect of nondietary factors on diet-serum metabolite relationships by incorporating diet, the gut microbiota, and maternal, perinatal, and infant characteristics in a multivariable forward stepwise regression. We replicated this analysis in White European infants, from the CHILD Cohort Study (n = 81). RESULTS: A dietary pattern characterized by formula consumption and negatively associated with breastfeeding most strongly predicted variation in the gut microbiota (R2 = 0.109) and serum metabolome (R2 = 0.547). Breastfed participants showed higher abundance of microbes from the genera Bifidobacterium (3.29 log2-fold) and Lactobacillus (7.93 log2-fold) and higher median concentrations of the metabolites S-methylcysteine (1.38 µM) and tryptophan betaine (0.43 µM) than nonbreastfed participants. Formula consuming infants showed higher median concentrations of branched-chain/aromatic amino acids (average 48.3 µM) than non-formula-consuming infants. CONCLUSIONS: Formula consumption and breastfeeding most strongly predicted the serum metabolites of 1-y-old infants, even when the gut microbiota, solid food consumption, and other covariates were considered.

Prehospital epinephrine administration for treating anaphylaxis among those with comorbid asthma: A scoping review.

BACKGROUND: Prompt and correct use of epinephrine for treating anaphylaxis is considered essential in reducing the risk of fatal outcomes from anaphylaxis. Nevertheless, prehospital use of epinephrine remains low. Although asthma is a common comorbidity in individuals experiencing severe allergic reactions, little attention has been given to whether asthma functions as a predictor of prehospital epinephrine administration. OBJECTIVE: To perform a scoping review of the extant literature on using epinephrine to manage anaphylaxis in patients with comorbid asthma before presenting to the emergency department. METHODS: Per Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review guidelines, peer-reviewed articles published in English or French were searched for within the Medline, Cumulative Index to Nursing and Allied Health Literature, and Embase databases between June 11 and June 18, 2021. We excluded studies that did not contain primary data. RESULTS: The literature search yielded 1022 articles that were screened at the title and abstract level by 2 independent reviewers. Of these, 90 (8.8%) advanced to full-text review, and ultimately, 8 studies (0.8% of all articles; 8.9% of full-text articles) were included in the analysis. Overall, the association between comorbid asthma and epinephrine use in the prehospital setting for managing anaphylaxis was inconsistently reported in the literature. Three studies reported a positive association, whereas 2 others suggested a link, but their results were no longer significant when controlling for other study variables. Three studies described no significant association. CONCLUSION: Although asthma is frequently comorbid in individuals experiencing anaphylaxis, the association between comorbid asthma and prehospital epinephrine treatment rates remains an understudied area of patient care.

Managing anaphylaxis: Epinephrine, antihistamines, and corticosteroids: More than 10 years of Cross-Canada Anaphylaxis REgistry data.

BACKGROUND: Epinephrine is the first-line treatment for anaphylaxis but is often replaced with antihistamines or corticosteroids. Delayed epinephrine administration is a risk factor for fatal anaphylaxis. Convincing data on the role of antihistamines and corticosteroids in anaphylaxis management are sparse. OBJECTIVE: To establish the impact of prehospital treatment with epinephrine, antihistamines, and/or corticosteroids on anaphylaxis management. METHODS: Patients presenting with anaphylaxis were recruited prospectively and retrospectively in 10 Canadian and 1 Israeli emergency departments (EDs) between April 2011 and August 2022, as part of the Cross-Canada Anaphylaxis REgistry. Data on anaphylaxis cases were collected using a standardized form. Primary outcomes were uncontrolled reactions (>2 doses of epinephrine in ED), no prehospital epinephrine use, use of intravenous fluids in ED, and hospital admission. Multivariate regression was used to identify factors associated with primary outcomes. RESULTS: Among 5364 reactions recorded, median age was 8.8 years (IQR, 3.78-16.9); 54.9% of the patients were males, and 52.5% had a known food allergy. In the prehospital setting, 37.9% received epinephrine; 44.3% received antihistamines, and 3.15% received corticosteroids. Uncontrolled reactions happened in 250 reactions. Patients treated with prehospital epinephrine were less likely to have uncontrolled reactions (adjusted odds ratio [aOR], 0.955 [95% CI, 0.943-0.967]), receive intravenous fluids in ED (aOR, 0.976 [95% CI, 0.959-0.992]), and to be admitted after the reaction (aOR, 0.964 [95% CI, 0.949-0.980]). Patients treated with prehospital antihistamines were less likely to have uncontrolled reactions (aOR, 0.978 [95% CI, 0.967-0.989]) and to be admitted after the reaction (aOR, 0.963 [95% CI, 0.949-0.977]). Patients who received prehospital corticosteroids were more likely to require intravenous fluids in ED (aOR, 1.059 [95% CI, 1.013-1.107]) and be admitted (aOR, 1.232 [95% CI, 1.181-1.286]). CONCLUSION: Our findings in this predominantly pediatric population support the early use of epinephrine and suggest a beneficial effect of antihistamines. Corticosteroid use in anaphylaxis should be revisited.

Ethnicity Associations With Food Sensitization Are Mediated by Gut Microbiota Development in the First Year of Life.

BACKGROUND AND AIMS: Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. METHODS: In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. RESULTS: Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13-7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75-22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. CONCLUSIONS: This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.

Childhood body mass index and associations with infant gut metabolites and secretory IgA: findings from a prospective cohort study.

BACKGROUND/OBJECTIVES: Differences in gut microbiota, metabolites and immune markers have been observed between individuals with and without obesity. Our study determined the temporal association between infant fecal gut metabolites, sIgA and body mass index (BMI) z score of preschool children, independent of pre/postnatal factors. SUBJECTS/METHODS: The study includes a subset of 647 infants from the CHILD Cohort Study (recruited between January 1, 2009, and December 31, 2012). Fecal metabolites and sIgA were measured at 3-4 months of age, and age and sex adjusted BMI z scores at 1 and 3 years of age. Associations between the metabolites, IgA, and child BMI z scores at age 1 and 3 years were tested using linear regression adjusted for pre/postnatal factors (breastfeeding, birthweight-for-gestational age, birthmode and IAP, solid food introduction). RESULTS: Mean BMI z score for all infants was 0.34 (SD 1.16) at 1 year (N = 647) and 0.71 (SD 1.06) at 3 years (N = 573). High fecal formate in infancy was associated with a significantly lower BMI z score (adjusted mean difference -0.23 (95% CI -0.42, -0.04)) and high butyrate was associated with a higher BMI z score (adjusted mean difference 0.21 (95% CI 0.01, 0.41)) at age 3 years only. The influence of formate and butyrate on BMI z score at age 3 were seen only in those that were not exclusively breastfed at stool sample collection (adjusted mean difference for high formate/EBF- group: -0.33 (95%CI -0.55, -0.10) and 0.25 (95% CI 0.02, 0.47) for high butyrate/EBF- group). No associations were seen between sIgA and BMI z score at age 1 or 3 years in adjusted regression models. CONCLUSION AND RELEVANCE: Differences in fecal metabolite levels in early infancy were associated with childhood BMI. This study identifies an important area of future research in understanding the pathogenesis of obesity.