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.

Divergent maturational patterns of the infant bacterial and fungal gut microbiome in the first year of life are associated with inter-kingdom community dynamics and infant nutrition.

BACKGROUND: The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. RESULTS: We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40% of infants, which were characterized by differences in community composition, inter-kingdom dynamics, and microbe-derived metabolites in urine, suggestive of alterations in the timing of ecosystem transitions. Known microbiome-modifying factors, such as formula feeding and delivery by C-section, were associated with atypical bacterial, but not fungal, microbiome maturation patterns. Instead, fungal microbiome maturation was influenced by prenatal exposure to artificially sweetened beverages and the bacterial microbiome, emphasizing the importance of inter-kingdom dynamics in early-life colonization patterns. CONCLUSIONS: These findings highlight the ecological and environmental factors underlying atypical patterns of microbiome maturation in infants, and the need to incorporate multi-kingdom and individual-level perspectives in microbiome research to improve our understandings of gut microbiome maturation patterns in early life and how they relate to host health. Video Abstract.

Cohort profile: investigating SARS-CoV-2 infection and the health and psychosocial impact of the COVID-19 pandemic in the Canadian CHILD Cohort.

The coronavirus disease 2019 (COVID-19) pandemic has affected all Canadian families, with some impacted differently than others. Our study aims to: (1) determine the prevalence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among Canadian families, (2) identify predictors of infection susceptibility and severity of SARS-CoV-2, and (3) identify health and psychosocial impacts of the COVID-19 pandemic. This study builds upon the CHILD Cohort Study, an ongoing multi-ethnic general population prospective cohort consisting of 3,454 Canadian families with children born in Vancouver, Edmonton, Manitoba, and Toronto between 2009 and 2012. During the pandemic, CHILD households were invited to participate in the CHILD COVID-19 Add-On Study involving: (1) brief biweekly surveys about COVID-19 symptoms and testing; (2) quarterly questionnaires assessing COVID-19 exposure and testing, vaccination status, physical and mental health, and pandemic-driven life changes; and (3) in-home biological sampling kits to collect blood and stool. In total, 1,462 households (5,378 participants) consented to the CHILD COVID-19 Add-On Study: 2,803 children (mean±standard deviation [SD], 9.0±2.7 years; range, 0-17 years) and 2,576 adults (mean±SD, 43.0±6.5 years; range, 18-85 years). We will leverage the wealth of pre-pandemic CHILD data to identify risk and resilience factors for susceptibility and severity to the direct and indirect pandemic effects. Our short-term findings will inform key stakeholders and knowledge users to shape current and future pandemic responses. Additionally, this study provides a unique resource to study the long-term impacts of the pandemic as the CHILD Cohort Study continues.

Maturational patterns of the infant gut mycobiome are associated with early-life body mass index.

Unlike the bacterial microbiome, the role of early-life gut fungi in host metabolism and childhood obesity development remains poorly characterized. To address this, we investigate the relationship between the gut mycobiome of 100 infants from the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study and body mass index Z scores (BMIz) in the first 5 years of life. An increase in fungal richness during the first year of life is linked to parental and infant BMI. The relationship between richness pattern and early-life BMIz is modified by maternal BMI, maternal diet, infant antibiotic exposure, and bacterial beta diversity. Further, the abundances of Saccharomyces, Rhodotorula, and Malassezia are differentially associated with early-life BMIz. Using structural equation modeling, we determine that the mycobiome's contribution to BMIz is likely mediated by the bacterial microbiome. This demonstrates that mycobiome maturation and infant growth trajectories are distinctly linked, advocating for inclusion of fungi in larger pediatric microbiome studies.

Development of a Symptom-Based Tool for Screening of Children at High Risk of Preschool Asthma.

Importance: Despite advances in asthma therapeutics, the burden remains highest in preschool children; therefore, it is critical to identify primary care tools that distinguish preschool children at high risk for burdensome disease for further evaluation. Current asthma prediction tools, such as the modified Asthma Predictive Index (mAPI), require invasive tests, limiting their applicability in primary care and low-resource settings. Objective: To develop and evaluate the use of a symptom-based screening tool to detect children at high risk of asthma, persistent wheeze symptoms, and health care burden. Design, Setting, and Participants: The cohort for this diagnostic study included participants from the CHILD Study (n = 2511) from January 1, 2008, to December 31, 2012, the Raine Study from January 1, 1989, to December 31, 2012 (n = 2185), and the Canadian Asthma Primary Prevention Study (CAPPS) from January 1, 1989, to December 31, 1995 (n = 349), with active follow-up to date. Data analysis was performed from November 1, 2019, to May 31, 2022. Exposures: The CHILDhood Asthma Risk Tool (CHART) identified factors associated with asthma in patients at 3 years of age (timing and number of wheeze or cough episodes, use of asthma medications, and emergency department visits or hospitalizations for asthma or wheeze) to identify children with asthma or persistent symptoms at 5 years of age. Main Outcomes and Measures: Within the CHILD Study cohort, CHART was evaluated against specialist clinician diagnosis and the mAPI. External validation was performed in both a general population cohort (Raine Study [Australia]) and a high-risk cohort (CAPPS [Canada]). Predictive accuracy was measured by sensitivity, specificity, area under the receiver operating characteristic curve (AUROC), and positive and negative predicted values. Results: Among 2511 children (mean [SD] age at 3-year clinic visit, 3.08 [0.17] years; 1324 [52.7%] male; 1608 of 2476 [64.9%] White) with sufficient questionnaire data to apply CHART at 3 years of age, 2354 (93.7%) had available outcome data at 5 years of age. CHART applied in the CHILD Study at 3 years of age outperformed physician assessments and the mAPI in predicting persistent wheeze (AUROC, 0.94; 95% CI, 0.90-0.97), asthma diagnosis (AUROC, 0.73; 95% CI, 0.69-0.77), and health care use (emergency department visits or hospitalization for wheeze or asthma) (AUROC, 0.70; 95% CI, 0.61-0.78). CHART had a similar predictive performance for persistent wheeze in the Raine Study (N = 2185) in children at 5 years of age (AUROC, 0.82; 95% CI, 0.79-0.86) and CAPPS (N = 349) at 7 years of age (AUROC, 0.87; 95% CI, 0.80-0.94). Conclusions and Relevance: In this diagnostic study, CHART was able to identify children at high risk of asthma at as early as 3 years of age. CHART could be easily incorporated as a routine screening tool in primary care to identify children who need monitoring, timely symptom control, and introduction of preventive therapies.

Longitudinal body mass index trajectories at preschool age: children with rapid growth have differential composition of the gut microbiota in the first year of life.

BACKGROUND/OBJECTIVE: The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories. METHODS: BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed. RESULTS: Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium. CONCLUSION: This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.

Factors Affecting Cuff Extrusion of Tunneled Hemodialysis Catheters.

PURPOSE: To identify patient and procedural factors associated with extrusion of the Dacron cuff from the subcutaneous tunnel of tunneled hemodialysis catheters (THDCs). MATERIALS AND METHODS: Single center 5-year retrospective analysis of 625 catheters in 293 adult patients. Patient data included age, gender, body mass index (BMI), and common comorbidities. Procedural details included type of procedure (new insertion vs. exchange), operator seniority, side of insertion, catheter model and presence of catheter wings skin-sutures. Complications were reported as cumulative risk over time and Cox proportional hazards model was used to evaluate risk factors for cuff extrusion (CE). RESULTS: Median patient follow-up was 503 days (188,913 catheter-days) and median catheter survival 163 days. CE occurred in 23.8% of catheters, at a rate of 0.79 per 1,000 catheter-days and a median time of 64 days. It was more common than infection (14.6%) and inadequate flow (15.5%). The 1-month and 12-month risk of CE was 5.9% and 21.3% respectively. A first episode of CE was a strong predictor of future CE episodes. The only patient factor that affected the risk of CE was BMI (Hazard Ratio 2.36 for obese patients). Procedural factors that affected the risk of CE, adjusted for BMI, were catheter model, type of procedure (lower risk for new insertions) and catheter wings skin-sutures; the latter reduced the 30-day CE risk by 76% without increasing catheter-related infections. CONCLUSION: Cuff extrusion is common in long-term THDCs. The risk increases with obesity, history of previous cuff extrusion, certain catheter models and absence of wing-sutures.

Adenotonsillectomy, bronchoscopy and bronchoalveolar lavage in the management of preschool children with severe asthma: pilot study.

PURPOSE: This is a pilot study that describes the feasibility and clinical course of a cohort of preschool children with severe asthma undergoing a combined adenotonillectomy (TA), bronchoscopy (B), and bronchoalveolar lavage (BAL) procedure. METHODS: A retrospective cohort study of preschool patients with severe asthma who underwent a combined TA-B-BAL procedure between 2012 and 2019. Subjects were treated at a tertiary care asthma clinic and had a diagnosis of preschool asthma according to the Canadian Thoracic Society Guidelines. Data on demographics, clinical characteristics, medication use, virology and microbiology from bronchoalveolar lavage, and asthma control questionnaires were collected. Variables were analyzed using paired t test. RESULTS: Eighteen preschool subjects (mean age 3.19 ± 1.13 years) with severe asthma were identified through the asthma clinic. Patients treated with standard asthma care and a combined  TA-B-BAL procedure  experienced a decrease in the number of oral steroid courses (p = 0.017), emergency department visits (p = 0.03) and wheezing exacerbations (p = 0.026) following the procedure. Ten patients experienced clinically meaningful improvements in TRACK scores after the procedure (p < 0.001). CONCLUSION: This pilot study provides early evidence that a combined TA-B-BAL procedure is feasible in preschool children with severe asthma and that the procedure may reduce asthma medication use and hospital visits.

Reduced peanut sensitization with maternal peanut consumption and early peanut introduction while breastfeeding.

New guidelines for peanut allergy prevention in high-risk infants recommend introducing peanut during infancy but do not address breastfeeding or maternal peanut consumption. We assessed the independent and combined association of these factors with peanut sensitization in the general population CHILD birth cohort (N = 2759 mother-child dyads). Mothers reported peanut consumption during pregnancy, timing of first infant peanut consumption, and length of breastfeeding duration. Child peanut sensitization was determined by skin prick testing at 1, 3, and 5 years. Overall, 69% of mothers regularly consumed peanuts and 36% of infants were fed peanut in the first year (20% while breastfeeding and 16% after breastfeeding cessation). Infants who were introduced to peanut early (before 1 year) after breastfeeding cessation had a 66% reduced risk of sensitization at 5 years compared to those who were not (1.9% vs. 5.8% sensitization; aOR 0.34, 95% CI 0.14-0.68). This risk was further reduced if mothers introduced peanut early while breastfeeding and regularly consumed peanut themselves (0.3% sensitization; aOR 0.07, 0.01-0.25). In longitudinal analyses, these associations were driven by a higher odds of outgrowing early sensitization and a lower odds of late-onset sensitization. There was no apparent benefit (or harm) from maternal peanut consumption without breastfeeding. Taken together, these results suggest the combination of maternal peanut consumption and breastfeeding at the time of peanut introduction during infancy may help to decrease the risk of peanut sensitization. Mechanistic and clinical intervention studies are needed to confirm and understand this "triple exposure" hypothesis.

Persistent ventilation inhomogeneity after an acute exacerbation in preschool children with recurrent wheezing.

BACKGROUND: Preschool children with recurrent wheezing suffer high morbidity. It is unclear whether objective measures of asthma control, such as pulmonary function tests (PFTs), provide additional information to the clinical assessment. METHODS: We recruited children between 3 and 6 years old, with a history of recurrent wheezing in the preceding year and treated for acute wheezing exacerbation in the emergency department (ED) into an observational cohort study. Children attended two outpatient visits: the first study visit within five days of discharge from the ED and the second study visit 12 weeks after the ED visit. We performed standardized symptom score (test for respiratory and asthma control in kids (TRACK)), multiple breath washout (MBW), spirometry, and clinical assessment at both visits. RESULTS: Seventy-four children, mean (standard deviation (SD)) age of 4.32 years (0.84), attended both visits. Paired FEV0.75 and lung clearance index (LCI) measurements at both time points were obtained in 37 and 34 subjects, respectively. Feasibility for all tests improved at visit 2 and was not age-dependent. At the second study visit, a third had controlled asthma based on the TRACK score, and the mean lung clearance index (LCI) improved from 9.86 to 8.31 (P = .003); however, 46% had an LCI in the abnormal range. FEV0.75 z-score improved from -1.66 to -1.17 (P = .05) but remained in the abnormal range in 24%. LCI was abnormal in more than half of the children with "well-controlled" asthma based on the TRACK score. There was no correlation between PFT measures and TRACK scores at either visit. CONCLUSIONS: Lung clearance index demonstrates a persistent deficit post-exacerbation in a large proportion of preschoolers with recurrent wheezing, highlighting that symptom scores alone may not suffice for monitoring these children.