The re-emerging role of linoleic acid in paediatric asthma.

Asthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.

Mediating Role of Fine Particles Abatement on Pediatric Respiratory Health During COVID-19 Stay-at-Home Order in San Diego County, California.

Lower respiratory tract infections disproportionately affect children and are one of the main causes of hospital referral and admission. COVID-19 stay-at-home orders in early 2020 led to substantial reductions in hospital admissions, but the specific contribution of changes in air quality through this natural experiment has not been examined. Capitalizing on the timing of the stay-at-home order, we quantified the specific contribution of fine-scale changes in PM2.5 concentrations to reduced respiratory emergency department (ED) visits in the pediatric population of San Diego County, California. We analyzed data on pediatric ED visits (n = 72,333) at the ZIP-code level for respiratory complaints obtained from the ED at Rady Children's Hospital in San Diego County (2015-2020) and ZIP-code level PM2.5 from an ensemble model integrating multiple machine learning algorithms. We examined the decrease in respiratory visits in the pediatric population attributable to the stay-at-home order and quantified the contribution of changes in PM2.5 exposure using mediation analysis (inverse of odds ratio weighting). Pediatric respiratory ED visits dropped during the stay-at-home order (starting on 19 March 2020). Immediately after this period, PM2.5 concentrations, relative to the counterfactual values based in the 4-year baseline period, also decreased with important spatial variability across ZIP codes in San Diego County. Overall, we found that decreases in PM2.5 attributed to the stay-at-home order contributed to explain 4% of the decrease in pediatric respiratory ED visits. We identified important spatial inequalities in the decreased incidence of pediatric respiratory illness and found that brief decline in air pollution levels contributed to a decrease in respiratory ED visits.

Allergen Content and Protease Activity in Milk Feeds from Mothers of Preterm Infants.

Rationale: There is little information regarding the allergen content of milk feeds in the preterm population. Previous studies have not performed a broad analysis of the allergenic peptide content and protease activity of milk feeds in this population. Methods: To evaluate feasibility, we initially performed mass spectrometry on 4 human milk (HM) samples (2 term and 2 preterm) from the Mommy's Milk Human Milk Biorepository (HMB) and analyzed the results against the University of Nebraska FASTA database and UniProt for a total of 2,211 protein sequences. We then further analyzed five samples from the Microbiome, Atopy, and Prematurity (MAP) study including peptidomic and protease activity analysis. Results: Each HMB sample had between 806 and 1,007 proteins, with 37-44 nonhuman proteins/sample encompassing 26 plant and animal species. In the preterm MAP samples, 784 digested nonhuman proteins were identified, 30 were nonbovine in origin. Proteins from 23 different species including aeroallergens, food, and contact allergens were identified. Protease activity was highest in HM samples without human milk fortifier and lowest in preterm formula. Conclusions: These findings represent the first preterm milk feed mass spectrometry and protease analysis with identification of known allergenic proteins to food, contact, and aeroallergens. These results raise questions of whether the composition of milk feeds in the neonatal intensive care unit impact the development of atopic disease in the preterm population and whether the complex interaction between allergens, proteases, and other HM components can serve to induce sensitization or tolerance to allergens in infants. Clinical Trial Registration Number: NCT04835935.

Dose-dependent association between inhaled corticosteroid use and risk of obesity and metabolic syndrome in asthma.

Background: Inhaled corticosteroids (ICS) are widely prescribed medications. Some studies have reported that ICS may suppress the hypothalamic-pituitary-adrenal axis and induce systemic effects. Objective: To explore the possibility of a dose-dependent association between the long-term use of ICS and the risk of obesity and other markers of metabolic syndrome. Methods: A 5-year retrospective two-arm cohort study explored patients on asthma and not on ICS relative to patients with asthma who were on varying doses of ICS (low, medium, and high) and attributes such as body mass index (BMI) trajectory and prescription of antihypertensive, antidiabetic, and cholesterol-lowering medications. Results: A total of 229 subjects with asthma were in the control cohort, and 215 subjects with asthma were in the ICS cohort. The ICS cohort was subdivided into individuals on low- (n = 88), medium- (n = 107), or high- (n = 20) dose ICS throughout the 5-year study period. For every 1-year increase in time, the BMI in the high-dose ICS group increased at a rate of 0.25 kg/m² when compared with the subjects in the control group after controlling for age and gender. Also, for every 1-year increase in time, the BMI of those on medium-dose ICS increased by 0.06 kg/m² compared with those in the control group after controlling for age and gender. The subjects on ICS also had a statistically increased risk of being prescribed antihypertensive, antidiabetic, and cholesterol-lowering medications. Conclusion: ICS use in the subjects with asthma was associated with a dose-dependent risk of increasing BMI trajectories over time and an increased requirement for antidiabetic and cholesterol-lowering medications. One possible conclusion from this study is that long-term medium- and high-dose ICS have the potential to induce systemic effects.

Patterns of allergenic food introduction in Los Angeles inner-city children.

Background: Early introduction of allergenic foods is recommended to reduce the risk of developing food allergies, but it is unclear whether recommendations are being followed. Objective: We examine patterns of allergenic food introduction in inner-city children enrolled in an academic pediatric practice in the greater Los Angeles area. Methods: This was a prospective study with patients ages 12 to 24 months recruited from the pediatrics continuity clinic at an inner-city tertiary medical center in the greater Los Angeles area. Caregivers were asked via anonymous surveys about their child's history of atopic diseases and at what age they first introduced egg, soy, wheat, peanut, tree nuts, fish, shrimp, and shellfish into their child's diet. Results: Two hundred caregivers responded to the survey. The average age of introduction of egg was 9.2 months, soy 10 months, wheat 9.3 months, peanut 10.5 months, tree nuts 10.9 months, fish 10.9 months, shrimp 11.3 months, and shellfish 11.5 months. Between ages 4-11 months, 65.3% of children were introduced egg, 19.1% soy, 55.8% wheat, 28.6% peanut, 17.1% tree nuts, 28.1% fish, 13.6% shrimp, and 7.0% shellfish. By age 24 months, 92% of children were introduced egg, 37.7% soy, 85.4% wheat, 67.3% peanut, 47.7% tree nuts, 67.8% fish, 48.2% shrimp, and 30.2% shellfish. Of the 14 children with eczema or egg allergy, 26.1% were introduced peanut by age 4-6 months and 50% by age 4-11 months. Conclusion: Despite recommendations, inner-city caregivers may not be introducing allergenic foods in a timely manner to their children.

A Perspective on Pediatric Respiratory Outcomes During California Wildfires Due to Smoke and PM2.5 Exposure.

As wildfires increase in prevalence and intensity across California and globally, it is anticipated that more children will be exposed to wildfire smoke, and thus face associated adverse health outcomes. Here, we provide a concise summary of the respiratory effects of California's wildfires on pediatric healthcare utilization, examine global examples of wildfire smoke exposure within the pediatric population and associated physiological effects, and assess the efficacy of metrics used to measure and communicate air quality during wildfires within the United States and elsewhere.

The impact of maternal asthma on the preterm infants' gut metabolome and microbiome (MAP study).

Preterm infants are at a greater risk for the development of asthma and atopic disease, which can lead to lifelong negative health consequences. This may be due, in part, to alterations that occur in the gut microbiome and metabolome during their stay in the Neonatal Intensive Care Unit (NICU). To explore the differential roles of family history (i.e., predisposition due to maternal asthma diagnosis) and hospital-related environmental and clinical factors that alter microbial exposures early in life, we considered a unique cohort of preterm infants born ≤ 34 weeks gestational age from two local level III NICUs, as part of the MAP (Microbiome, Atopic disease, and Prematurity) Study. From MAP participants, we chose a sub-cohort of infants whose mothers had a history of asthma and matched gestational age and sex to infants of mothers without a history of asthma diagnosis (control). We performed a prospective, paired metagenomic and metabolomic analysis of stool and milk feed samples collected at birth, 2 weeks, and 6 weeks postnatal age. Although there were clinical factors associated with shifts in the diversity and composition of stool-associated bacterial communities, maternal asthma diagnosis did not play an observable role in shaping the infant gut microbiome during the study period. There were significant differences, however, in the metabolite profile between the maternal asthma and control groups at 6 weeks postnatal age. The most notable changes occurred in the linoleic acid spectral network, which plays a role in inflammatory and immune pathways, suggesting early metabolomic changes in the gut of preterm infants born to mothers with a history of asthma. Our pilot study suggests that a history of maternal asthma alters a preterm infants' metabolomic pathways in the gut, as early as the first 6 weeks of life.

Fine Particles in Wildfire Smoke and Pediatric Respiratory Health in California.

BACKGROUND AND OBJECTIVES: Exposure to airborne fine particles with diameters ≤2.5 µm (PM2.5) pollution is a well-established cause of respiratory diseases in children; whether wildfire-specific PM2.5 causes more damage, however, remains uncertain. We examine the associations between wildfire-specific PM2.5 and pediatric respiratory health during the period 2011-2017 in San Diego County, California, and compare these results with other sources of PM2.5. METHODS: Visits to emergency and urgent care facilities of Rady's Children Hospital network in San Diego County, California, by individuals (aged ≤19 years) with ≥1 of the following respiratory conditions: difficulty breathing, respiratory distress, wheezing, asthma, or cough were regressed on daily, community-level exposure to wildfire-specific PM2.5 and PM2.5 from ambient sources (eg, traffic emissions). RESULTS: A 10-unit increase in PM2.5 (from nonsmoke sources) was estimated to increase the number of admissions by 3.7% (95% confidence interval: 1.2% to 6.1%). In contrast, the effect of PM2.5 attributable to wildfire was estimated to be a 30.0% (95% confidence interval: 26.6% to 33.4%) increase in visits. CONCLUSIONS: Wildfire-specific PM2.5 was found to be ∼10 times more harmful on children's respiratory health than PM2.5 from other sources, particularly for children aged 0 to 5 years. Even relatively modest wildfires and associated PM2.5 resolved on our record produced major health impacts, particularly for younger children, in comparison with ambient PM2.5.

Screening Social Determinants of Health in a Multidisciplinary Severe Asthma Clinical Program.

Asthma is the most common cause of chronic disease in children and has high healthcare utilization costs. Minority children living in poverty have a higher asthma burden. These health disparities are associated with the social determinants of health (SDH). A severe asthma clinic was implemented at Rady Children's Hospital in San Diego to determine whether a multidisciplinary approach, including an asthma home visit addressing SDH, would lead to decreased healthcare utilization in terms of emergency department (ED) visits and hospitalizations. METHODS: Patients with 2 or more ED visits in the past 6 months or 2 or more hospitalizations in the previous year were recruited to Rady Children's Hospital Severe Asthma Clinic. A multidisciplinary team evaluated each patient systematically. A subset of patients on capitated Medicaid insurance plans also had a comprehensive asthma home visit with community health workers as part of the Community Approach to Severe Asthma (CASA) program. RESULTS: A significant reduction in ED visits (75%, P < 0.001) and hospitalization days (73%, P < 0.001) was demonstrated in 74 Severe Asthma Clinic participants with 1 year of pre-/postdata to analyze. In a subset of 12 patients in the CASA program, further reductions in ED visits (90%, P = 0.002) were also demonstrated. Basic needs, including shelter, food, and assistance with utilities, were the most common domain of SDH identified and addressed in CASA participants. CONCLUSION: We demonstrate that a novel pediatric severe asthma clinic with a multidisciplinary approach, including actively addressing SDH, is associated with decreasing health care utilization.

Increase in Pediatric Respiratory Visits Associated with Santa Ana Wind-Driven Wildfire Smoke and PM2.5 Levels in San Diego County.

Rationale: There is significant evidence of increased healthcare utilization from cardiopulmonary causes in adults from exposure to wildfire smoke, but evidence in pediatric age groups is limited.Objectives: To quantify and examine the healthcare utilization effects of the December 2017 Lilac Fire in San Diego County among pediatric patients at the Rady Children's Hospital (RCH) emergency department and urgent care (UC) clinics.Methods: Using data from 2011 to 2017, including data on daily particulate matter <2.5 µm (PM2.5) in an inverse-distance interpolation model and RCH electronic medical records, we retrospectively analyzed pediatric respiratory visits at the RCH emergency department and UC clinics during the Santa Ana wind (SAW)-driven Lilac Fire from December 7 to 16, 2017. An interrupted time series study design was applied as our primary analysis to compare the observed pediatric respiratory visits from December 7 to 16, 2017 to what would have occurred in a counterfactual situation, namely, if the Lilac Fire had not occurred. A complementary descriptive spatial analysis was also used to evaluate the geographic distribution of respiratory visits in relationship to satellite imaging of the Lilac Fire and the associated wind pattern.Results: The Lilac Fire was associated with 16.0 (95% confidence interval [CI], 11.2-20.9) excess respiratory visits per day at the RCH emergency department across all pediatric age groups. Children aged 0 to 5 years had the highest absolute excess respiratory visits per day with 7.3 (95% CI, 3.0-11.7), whereas those aged 6 to 12 years had the highest relative increase in visits, with 3.4 (95% CI, 2.3-4.6). RCH UC clinics had similar results. The top five ZIP codes in San Diego County with the highest standard deviations of age-adjusted respiratory visits were all located generally downwind of the fire perimeter, as expected for the SAW pattern.Conclusions: We have demonstrated an increase in pediatric respiratory visits during the SAW-driven Lilac Fire in San Diego County in a patterned geographic distribution that is attributable to an increase in PM2.5 exposure. Younger children were particularly affected. Climate change is expected to result in more frequent and extensive wildfires in the region and will require greater preparedness and adaptation efforts to protect vulnerable populations, such as young children.

Estimating Cost-Effectiveness of Confirmatory Oral Food Challenges in the Diagnosis of Children With Food Allergy.

Introduction. Food allergies affect 8% of the pediatric population in the United States with an estimated annual cost of US$25 billion. The low specificity of some of the main food allergy tests used in diagnosis may generate false positives incurring unnecessary costs. We examined the cost-effectiveness of oral food challenges (OFC) as confirmatory tests in the diagnosis of food allergy. Methods. We constructed a decision tree with a Markov model comparing the long-term (15 years) cost and effectiveness-in the form of quality-adjusted life years (QALY)-of confirmatory OFCs compared with immediate allergenic food elimination (FE) after a skin prick test or blood immunoglobulin E (IgE) level in children with suspected food allergy. For costs, we included the costs of OFCs and the reported annual costs of having a food allergy, including direct medical costs and costs borne by families. Results. The cost of OFC strategy was $8671 compared with $18 012 for the FE strategy for the length of the model. Also, the OFC strategy had a total QALY of 21.942 compared with 21.740 for the FE strategy. In the OFC strategy, the total cost was $9341 less than FE and the increase in QALY after OFCs led to a 0.202 higher effectiveness in the OFC strategy. Conclusion. In conclusion, our study shows that the confirmatory OFC strategy dominated the FE strategy and that a confirmatory OFC for children, within a year of diagnosis, is a cost-effective strategy that decreases costs and appears to improve quality of life.

Effect of inhaled corticosteroid use on weight (BMI) in pediatric patients with moderate-severe asthma.

OBJECTIVES: Assess the relationship between inhaled corticosteroid use (ICS) and weight (BMI) in pediatric patients with moderate-severe asthma. Assess if the number of emergency department (ED) visits correlates with overall BMI trajectory. Assess the trend of prescribing biologic therapy in pediatric patients with moderate-severe asthma and determine its relationship with weight (BMI). METHODS: A retrospective chart review was performed on 93 pediatric patients with moderate-severe asthma to determine the relationship between ICS use and weight (BMI), biologic therapy and BMI, and number of ED visits and BMI trajectory. A mixed effects model was employed with the correlation between repeated measures accounted for through the random effects. RESULTS: There is a statistically significant increase of 0.369 kg/m2 in BMI trajectory per year in subjects on high-dose steroids compared to an increase of 0.195 kg/m2 in the low dose group (p < 0.05). The BMI of subjects initiated on biologic therapy (omalizumab or mepolizumab) had a statistically significant decrease in BMI trajectory of 0.818 kg/m2 per year (p < 0.05). Subjects with ≥5 ED visits due to asthma exacerbations had a significantly higher BMI trajectory (p < 0.05). CONCLUSIONS: The potency of ICS use in pediatric patients with moderate-severe asthma affects BMI trajectory; the higher the dose, the greater the projected BMI increase per year. Initiation of biologic therapy decreased BMI trajectory over time. Lastly, those with frequent ED visits had a higher BMI trend. Future prospective studies are warranted that further evaluate the potential metabolic impacts of ICS and assess the effects of biologic therapy on BMI.

Human immunodeficiency virus type 1 Vpr protein does not modulate surface expression of the CD4 receptor.

The CD4 receptor is required for the entry of human immunodeficiency virus (HIV) into target cells. It has long been known that Nef, Env, and Vpu participate in the removal of the viral receptor from the cell surface. Recently, it has been proposed that the HIV type 1 (HIV-1) Vpr protein may also play a role in the downmodulation of CD4 from the surfaces of infected cells (L. Conti, B. Varano, M. C. Gauzzi, P. Matarrese, M. Federico, W. Malorani, F. Belardelli, and S. Gessani, J. Virol. 74:10207-10211, 2000). To investigate the possible role of Vpr in the downregulation of the viral receptor Vpr alleles from HIV-1 and simian immunodeficiency virus were transiently expressed in transformed T cells and in 293T fibroblasts, and their ability to modulate surface CD4 was evaluated. All Vpr alleles efficiently arrested cells in the G(2) stage of the cell cycle. However, none of the tested Vpr proteins altered the expression of CD4 on the cell surface. In comparison, HIV-1 Nef efficiently downmodulated surface CD4 in all the experimental settings. Transformed T cells and primary lymphocytes were challenged with wild-type, Nef-defective, and Vpr-defective viruses. A significant reduction in the HIV-induced downmodulation of surface CD4 was observed in viruses lacking Nef. However, Vpr-deletion-containing viruses showed no defect in their ability to remove CD4 from the surfaces of infected cells. Our results indicate that Vpr does not play a role in the HIV-induced downmodulation of the CD4 receptor.