Publications by authors named "James E Gern"

291 Publications

Mechanisms and Treatment of the Diverse Presentations of Acute Wheezing and Asthma.

J Allergy Clin Immunol Pract 2021 07;9(7):2635-2637

Divisions of Pulmonary and Critical Care Medicine and Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2021.04.052DOI Listing
July 2021

Management of asthma in childhood: study protocol of a systematic evidence update by the Paediatric Asthma in Real Life (PeARL) Think Tank.

BMJ Open 2021 Jul 2;11(7):e048338. Epub 2021 Jul 2.

Department of Paediatrics, University of Turku, Turku, Finland.

Introduction: Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted.

Methods And Analysis: Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence.

Ethics And Dissemination: Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank.

Prospero Registration Numbers: CRD42020132990, CRD42020171624.
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http://dx.doi.org/10.1136/bmjopen-2020-048338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256789PMC
July 2021

Dual role of the miR-146 family in rhinovirus-induced airway inflammation and allergic asthma exacerbation.

Clin Transl Med 2021 Jun;11(6):e427

Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

Rhinovirus (RV) infections are associated with asthma exacerbations. MicroRNA-146a and microRNA-146b (miR-146a/b) are anti-inflammatory miRNAs that suppress signaling through the nuclear factor kappa B (NF-κB) pathway and inhibit pro-inflammatory chemokine production in primary human bronchial epithelial cells (HBECs). In the current study, we aimed to explore whether miR-146a/b could regulate cellular responses to RVs in HBECs and airways during RV-induced asthma exacerbation. We demonstrated that expression of miR-146a/b and pro-inflammatory chemokines was increased in HBECs and mouse airways during RV infection. However, transfection with cell-penetrating peptide (CPP)-miR-146a nanocomplexes before infection with RV significantly reduced the expression of the pro-inflammatory chemokines CCL5, IL-8 and CXCL1, increased interferon-λ production, and attenuated infection with the green fluorescent protein (GFP)-expressing RV-A16 in HBECs. Concordantly, compared to wild-type (wt) mice, Mir146a/b mice exhibited more severe airway neutrophilia and increased T helper (Th)1 and Th17 cell infiltration in response to RV-A1b infection and a stronger Th17 response with a less prominent Th2 response in house dust mite extract (HDM)-induced allergic airway inflammation and RV-induced exacerbation models. Interestingly, intranasal administration of CPP-miR-146a nanocomplexes reduced HDM-induced allergic airway inflammation without a significant effect on the Th2/Th1/Th17 balance in wild-type mice. In conclusion, the overexpression of miR-146a has a strong anti-inflammatory effect on RV infection in HBECs and a mouse model of allergic airway inflammation, while a lack of miR-146a/b leads to attenuated type 2 cell responses in mouse models of allergic airway inflammation and RV-induced exacerbation of allergic airway inflammation. Furthermore, our data indicate that the application of CPP-miR-146a nanocomplexes has therapeutic potential for targeting airway inflammation.
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http://dx.doi.org/10.1002/ctm2.427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161513PMC
June 2021

Experimental rhinovirus infection induces an antiviral response in circulating B cells which is dysregulated in patients with asthma.

Allergy 2021 Jun 25. Epub 2021 Jun 25.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: Rhinoviruses are the predominant cause of respiratory viral infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus infections, cellular aspects of this response are less well understood. Here, we investigated the antiviral response of circulating B cells upon experimental rhinovirus infection in healthy individuals and asthma patients.

Methods: We purified B cells from experimentally infected healthy individuals and patients with asthma and subjected them to total RNA-sequencing. Rhinovirus-derived RNA was measured in isolated B cells using a highly sensitive PCR. B cells were stimulated with rhinovirus in vitro to further study gene expression, expression of antiviral proteins and B-cell differentiation in response rhinovirus stimulation. Protein expression of pro-inflammatory cytokines in response to rhinovirus was assessed using a proximity extension assay.

Results: B cells isolated from experimentally infected subjects exhibited an antiviral gene profile linked to IFN-alpha, carried viral RNA in vivo and were transiently infected by rhinovirus in vitro. B cells rapidly differentiated into plasmablasts upon rhinovirus stimulation. While B cells lacked expression of interferons in response to rhinovirus exposure, co-stimulation with rhinovirus and IFN-alpha upregulated pro-inflammatory cytokine expression suggesting a potential new function of B cells during virus infections. Asthma patients showed extensive upregulation and dysregulation of antiviral gene expression.

Conclusion: These findings add to the understanding of systemic effects of rhinovirus infections on B-cell responses in the periphery, show potential dysregulation in patients with asthma and might also have implications during infection with other respiratory viruses.
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http://dx.doi.org/10.1111/all.14985DOI Listing
June 2021

Trajectories of adiposity indicators and association with asthma and lung function in urban minority children.

J Allergy Clin Immunol 2021 Jun 22. Epub 2021 Jun 22.

Division of Pediatric Pulmonology, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, New York, NY.

Background: A relationship between adiposity and asthma has been described in some cohort studies, but little is known about trajectories of adiposity throughout early childhood among children at high risk for developing asthma in urban United States cities. Moreover, early life trajectories of adipokines that have metabolic and immunologic properties have not been comprehensively investigated.

Objective: Our objective was to characterize trajectories of adiposity in a longitudinal birth cohort of predominately Black and Latinx children (n = 418) using several different repeated measures including body mass index (BMI) z score, bioimpedance analysis, leptin, and adiponectin in the first 10 years of life.

Methods: In a longitudinal birth cohort of predominately Black and Latinx children, we used repeated annual measures of BMI, bioimpedance analysis (ie, percentage of body fat), leptin, and adiponectin to create trajectories across the first 10 years of life. Across those trajectories, we compared asthma diagnosis and multiple lung function outcomes, including spirometry, impulse oscillometry, and methacholine response.

Results: Three trajectories were observed for BMI z score, bioimpedance analysis, and leptin and 2 for adiponectin. There was no association between trajectories of BMI, percentage of body fat, leptin, or adipokine and asthma diagnosis or lung function (P > .05).

Conclusions: Trajectories of adiposity were not associated with asthma or lung function in children at high risk for developing asthma. Risk factors related to geography as well as social and demographic factors unique to specific populations could explain the lack of association and should be considered in obesity and asthma studies.
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http://dx.doi.org/10.1016/j.jaci.2021.06.015DOI Listing
June 2021

Loss of regulatory capacity in T regulatory cells upon rhinovirus infection.

J Allergy Clin Immunol 2021 Jun 18. Epub 2021 Jun 18.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. Electronic address:

Background: Respiratory infections with rhinoviruses (RV) are strongly associated with the development and exacerbations of asthma and pose an additional health risk for allergic subjects.

Objective: How RV infections and chronic allergic diseases are linked, and which role RV plays in the breaking of tolerance in T regulatory cells (Tregs) is unknown. Therefore this study aims to investigate the effects of RV on Tregs.

Methods: Tregs were isolated from asthmatic subjects and controls after experimental infection with RV16 and were analyzed with next-generation sequencing. Additionally, suppression assays, qPCRs, and protein quantifications were performed with Tregs after in vitro RV16 infection.

Results: RV16 induced a strong antiviral response in Tregs from asthmatic subjects and controls, including the upregulation of IFI44L, MX1, ISG15, IRF7, and STAT1. In asthmatic subjects, the inflammatory response was exaggerated and showed a dysregulated immune response compared to controls. Furthermore, asthmatic subjects failed to upregulate several immunosuppressive molecules such as CTLA4 and CD69 and upregulated the inflammasome related genes PYCARD and AIM2. Additionally, RV16 reduced the suppressive capacity of Tregs of healthy and asthmatic subjects in vitro and increased Th2-type cytokine production.

Conclusions: Tregs from healthy and asthmatic subjects displayed an anti-viral response after RV infection and showed reduced suppressive capacity. This data suggest that Treg function might be altered or impaired during RV infections, which might play an important role in the association between RV and the development of asthma and asthma exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2021.05.045DOI Listing
June 2021

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode.

Clin Exp Allergy 2021 Jun 1. Epub 2021 Jun 1.

Department of Paediatrics and Adolescent Medicine, University of Turku, Turku, Finland.

Background: Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta -agonist in this clinical scenario.

Objective: To study post hoc the short-term (up to 2 months) efficacy of inhaled beta -agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children.

Methods: The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2-4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences.

Results: Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p < .05), but no difference was detected in placebo arm (both p > .26).

Conclusions: In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.
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http://dx.doi.org/10.1111/cea.13960DOI Listing
June 2021

Inducible expression quantitative trait locus analysis of the MUC5AC gene in asthma in urban populations of children.

J Allergy Clin Immunol 2021 May 18. Epub 2021 May 18.

University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established.

Objectives: This study sought to assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma.

Methods: This study used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele-specific expression analyses in 2 cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort, and an exacerbation-prone asthma cohort. Inducible MUC5AC eQTLs were further investigated during incipient asthma exacerbations. Significant eQTLs SNPs were tested for associations with lung function measurements and their functional consequences were investigated in DNA regulatory databases.

Results: Two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression were identified. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, which is consistent with inducible expression. SNPs in 1 group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites, suggesting a mechanism of effect.

Conclusions: These findings demonstrate the applicability of organ-specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies.
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http://dx.doi.org/10.1016/j.jaci.2021.04.035DOI Listing
May 2021

A distributed geospatial approach to describe community characteristics for multisite studies.

J Clin Transl Sci 2021 Feb 5;5(1):e86. Epub 2021 Feb 5.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.
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http://dx.doi.org/10.1017/cts.2021.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111696PMC
February 2021

US Childhood Asthma Incidence Rate Patterns From the ECHO Consortium to Identify High-Risk Groups for Primary Prevention.

JAMA Pediatr 2021 May 17:e210667. Epub 2021 May 17.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Importance: Asthma is the leading chronic illness in US children, but most descriptive epidemiological data are focused on prevalence.

Objective: To evaluate childhood asthma incidence rates across the nation by core demographic strata and parental history of asthma.

Design, Setting, And Participants: For this cohort study, a distributed meta-analysis was conducted within the Environmental Influences on Child Health Outcomes (ECHO) consortium for data collected from May 1, 1980, through March 31, 2018. Birth cohort data of children from 34 gestational weeks of age or older to 18 years of age from 31 cohorts in the ECHO consortium were included. Data were analyzed from June 14, 2018, to February 18, 2020.

Exposures: Caregiver report of physician-diagnosed asthma with age of diagnosis.

Main Outcome And Measures: Asthma incidence survival tables generated by each cohort were combined for each year of age using the Kaplan-Meier method. Age-specific incidence rates for each stratum and asthma incidence rate ratios by parental family history (FH), sex, and race/ethnicity were calculated.

Results: Of the 11 404 children (mean [SD] age, 10.0 [0.7] years; 5836 boys [51%]; 5909 White children [53%]) included in the primary analysis, 7326 children (64%) had no FH of asthma, 4078 (36%) had an FH of asthma, and 2494 (23%) were non-Hispanic Black children. Children with an FH had a nearly 2-fold higher incidence rate through the fourth year of life (incidence rate ratio [IRR], 1.94; 95% CI, 1.76-2.16) after which the rates converged with the non-FH group. Regardless of FH, asthma incidence rates among non-Hispanic Black children were markedly higher than those of non-Hispanic White children during the preschool years (IRR, 1.58; 95% CI, 1.31-1.86) with no FH at age 4 years and became lower than that of White children after age 9 to 10 years (IRR, 0.67; 95% CI, 0.50-0.89) with no FH. The rates for boys declined with age, whereas rates among girls were relatively steady across all ages, particularly among those without an FH of asthma.

Conclusions And Relevance: Analysis of these diverse birth cohorts suggests that asthma FH, as well as race/ethnicity and sex, were all associated with childhood asthma incidence rates. Black children had much higher incidences rates but only during the preschool years, irrespective of FH. To prevent asthma among children with an FH of asthma or among Black infants, results suggest that interventions should be developed to target early life.
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http://dx.doi.org/10.1001/jamapediatrics.2021.0667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129904PMC
May 2021

Pediatric Asthma Incidence Rates in the United States from 1980 to 2017.

J Allergy Clin Immunol 2021 May 6. Epub 2021 May 6.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective.

Objective: Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history.

Methods: Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated.

Results: The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females.

Conclusions: US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.
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http://dx.doi.org/10.1016/j.jaci.2021.04.027DOI Listing
May 2021

Endotype of allergic asthma with airway obstruction in urban children.

J Allergy Clin Immunol 2021 Mar 10. Epub 2021 Mar 10.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States.

Objectives: This study sought to identify specific respiratory phenotypes of health and disease in this population, associations with early life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease.

Methods: The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through 10 years of age. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at 11 years of age.

Results: Of the 6 identified respiratory phenotypes, a high wheeze, high atopy, low lung function group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high-atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in the high wheeze, high atopy, low lung function group. In contrast, a medium wheeze, low atopy group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways.

Conclusions: In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and nonallergic asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.02.040DOI Listing
March 2021

Maternal stress and depression are associated with respiratory phenotypes in urban children.

J Allergy Clin Immunol 2021 Jul 10;148(1):120-127. Epub 2021 Mar 10.

Department of Pediatrics, University of Wisconsin - Madison, Madison, Wis.

Background: Prenatal and early-life exposure to maternal stress and depression is linked to development of recurrent wheezing in young children.

Objective: We sought to determine whether maternal stress and depression in early life are associated with nonatopic wheezing phenotype in urban children.

Methods: The Urban Environment and Childhood Asthma Study examined a birth cohort of children at high risk for asthma in low-income neighborhoods. Prenatal and postnatal (through age 3 years) maternal stress and depression scores were compared with respiratory phenotypes through age 10 years (multinomial regression), self-reported colds (linear regression), and detection of respiratory viruses (Poisson regression).

Results: Scores for maternal depression, and, to a lesser extent, maternal perceived stress, were positively related to multiple wheezing phenotypes. In particular, cumulative measures of maternal depression in the first 3 years were related to the moderate-wheeze-low-atopy phenotype (odds ratio, 1.13; [1.05, 1.21]; P < .01). Considering indicators of respiratory health that were used to identify the phenotypes, there were multiple positive associations between early-life scores for maternal stress and depression and increased wheezing illnesses, but no consistent relationships with lung function and some inverse relationships with allergic sensitization. Cumulative maternal stress and depression scores were associated with cumulative number of respiratory illnesses through age 3 years.

Conclusions: Among high-risk, urban children, maternal stress and depression in early life were positively associated with respiratory illnesses and a moderate-wheeze-low-atopy phenotype. These results suggest that treating stress and depression in expectant and new mothers could reduce viral respiratory illnesses and recurrent wheeze during the preschool years and some forms of childhood asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273133PMC
July 2021

Cockroach-induced IL9, IL13, and IL31 expression and the development of allergic asthma in urban children.

J Allergy Clin Immunol 2021 May 9;147(5):1974-1977.e3. Epub 2021 Mar 9.

University of Washington Department of Medicine, Seattle, Wash; Benaroya Research Institute Systems Immunology Division, Seattle, Wash. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113125PMC
May 2021

Ensemble Analysis Identifies Nasal 15-Keto-PGE2 as a Predictor of Recovery in Experimental Rhinovirus Colds.

J Infect Dis 2021 Mar 3. Epub 2021 Mar 3.

Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Background: Symptom intensity during a common cold is highly variable, particularly after the illness peaks, contributing to delay in recovery. Rhinoviruses frequently cause colds and, during acute infections, generate leukotriene B4 and prostaglandin E2 (PGE2). PGE2 is known to initiate oxylipin class switching and resolution of acute inflammation. Thus, we hypothesized that during acute rhinovirus colds, oxylipins with pro-resolving capabilities reduce symptom severity and speed recovery.

Methods: Four groups of healthy volunteers were inoculated with placebo or 3 different doses of rhinovirus A16. Participants kept daily records of symptoms and contributed serial nasal lavage fluid samples. We collected semi-quantitative mass spectrometry data for 71 oxylipins in these acute samples from all participants. An ensemble analysis approach was used to further reduce this dataset.

Results: Levels of 15-keto-PGE2 at day 3 of the cold were consistently among the top candidates in these models of recovery symptoms. 15-keto-PGE2 was the only oxylipin with an interaction between inoculum dose and time. Acute 15-keto-PGE2 levels were inversely associated with symptoms during cold recovery in a multivariable analysis (P = .0043).

Conclusions: These findings show that high 15-keto-PGE2 levels during the acute cold are associated with fewer symptoms during recovery.
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http://dx.doi.org/10.1093/infdis/jiab015DOI Listing
March 2021

Wisconsin Upper Respiratory Symptom Survey for Kids: Validation of an Illness-specific Quality of Life Instrument.

Pediatr Res 2021 Feb 24. Epub 2021 Feb 24.

Department of Family Medicine and Community Health, University of Wisconsin-Madison, Madison, WI, USA.

Background: Acute respiratory infections (ARIs) are the most common illness seen in the pediatric ambulatory setting. Research in this area is hampered by the lack of validated ARI measures. The aim of this study was to assess the reliability and validity of the Wisconsin Upper Respiratory Symptom Survey for Kids (WURSS-K), a 15-item instrument, which measures illness-specific symptoms and impact on quality of life during an ARI.

Methods: WURSS-K was administered to two populations: (1) children aged 4-10 years recruited from the local community and (2) 9- and 10-year-old children from an ongoing study, the Urban Environment and Childhood Asthma.

Results: Overall, 163 children with 249 ARI episodes completed WURSS-K. WURSS-K was analyzed using multiple models to evaluate reliability and validity for a two-factor structure (symptom and functionality) and a single global structure. These models provided evidence of reliability and validity with omega of 0.72 and 0.91 for symptoms and functionality along with the single structure with omega of 0.90.

Conclusions: WURSS-K shows strong psychometric properties for validity and reliability as either a single global factor or a two-factor structure. This instrument will be useful in both therapeutic trials and observational studies among children with ARI in ambulatory settings.

Impact: WURSS-K is a valid and reliable illness-specific quality of life instrument that evaluates the impacts of ARIs on children. WURSS-K is designed for children 4-10 years of age, for whom there is a lack of validated assessment tools. This now validated instrument will be useful for future observational studies and therapeutic trials among children with ARIs in ambulatory settings.
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http://dx.doi.org/10.1038/s41390-021-01395-9DOI Listing
February 2021

Development of nasal allergen challenge with cockroach in children with asthma.

Pediatr Allergy Immunol 2021 Jul 20;32(5):971-979. Epub 2021 Mar 20.

Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma.

Methods: Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells.

Results: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated.

Conclusion: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.
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http://dx.doi.org/10.1111/pai.13480DOI Listing
July 2021

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

Am J Respir Crit Care Med 2021 04;203(7):864-870

Asthma and Airway Disease Research Center.

Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored. To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry. Data from seven U.S. birth cohorts ( = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) ( = 1,308) and, for the first time, in African American (AA) ( = 620) children. The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children. These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.
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http://dx.doi.org/10.1164/rccm.202003-0820OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017591PMC
April 2021

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

J Allergy Clin Immunol 2021 Jul 10;148(1):128-138. Epub 2021 Jan 10.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address:

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% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 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 (β = 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.
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http://dx.doi.org/10.1016/j.jaci.2020.12.639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271087PMC
July 2021

Single-Cell Mapping of Progressive Fetal-to-Adult Transition in Human Naive T Cells.

Cell Rep 2021 01;34(1):108573

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, Division of Neonatology, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological "layer" of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid cells, myeloid cells, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity-with a substantial degree of inter-individual variation at the time of birth-rather than via a transition between discrete waves. These findings have important implications for the design of strategies for prophylaxis against infection in the newborn and for the use of umbilical cord blood (UCB) in the setting of transplantation.
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http://dx.doi.org/10.1016/j.celrep.2020.108573DOI Listing
January 2021

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.

Am J Respir Crit Care Med 2021 04;203(7):822-830

George Washington University, Washington, DC.

Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection. In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits ( < 0.001, χ) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A;  < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age ( < 0.0001), genotype ( < 0.05), and wheezing illnesses ( < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time. Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.
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http://dx.doi.org/10.1164/rccm.202010-3753OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017585PMC
April 2021

FUT2-ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses.

Nat Commun 2020 12 16;11(1):6398. Epub 2020 Dec 16.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), P = 2.6 × 10) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
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http://dx.doi.org/10.1038/s41467-020-19814-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744576PMC
December 2020

Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma.

J Allergy Clin Immunol 2021 Jun 13;147(6):2108-2117. Epub 2020 Nov 13.

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Background: Young children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk.

Objective: We aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk.

Methods: As part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years.

Results: Of 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusmicrobiomeT2; endotype B, virusmicrobiomeT2; endotype C, virusmicrobiomeT2; and endotype D, virusmicrobiomeT2. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03).

Conclusions: Integrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.
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http://dx.doi.org/10.1016/j.jaci.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116357PMC
June 2021

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma.

Commun Biol 2020 11 13;3(1):678. Epub 2020 Nov 13.

Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.

There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.
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http://dx.doi.org/10.1038/s42003-020-01411-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666152PMC
November 2020

Developmental patterns in the nasopharyngeal microbiome during infancy are associated with asthma risk.

J Allergy Clin Immunol 2021 May 19;147(5):1683-1691. Epub 2020 Oct 19.

Department of Pediatrics, University of Wisconsin-Madison, Madison, Wis. Electronic address:

Background: Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma.

Objectives: In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma.

Methods: Children participating in the Childhood Origins of Asthma study (N = 285) provided nasopharyngeal mucus samples in the first 2 years of life, during routine healthy study visits (at 2, 4, 6, 9, 12, 18, and 24 months of age), and during episodes of respiratory illnesses, all of which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and we correlated these with presence of asthma at 6, 8, 11, 13, and 18 years of age.

Results: Of the 4 microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood.

Conclusion: In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571460PMC
May 2021

Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels.

Epigenetics 2021 Jun 30;16(6):662-676. Epub 2020 Sep 30.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life.
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http://dx.doi.org/10.1080/15592294.2020.1817290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143220PMC
June 2021

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial.

JAMA 2020 08;324(8):752-760

Division of Pulmonary Medicine, Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania.

Importance: Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.

Objective: To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels.

Design, Setting, And Participants: The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019.

Interventions: Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old), or 220 μg/d (12-16 years old).

Main Outcomes And Measures: The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.

Results: Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).

Conclusions And Relevance: Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02687815.
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http://dx.doi.org/10.1001/jama.2020.12384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448830PMC
August 2020

Reply.

J Allergy Clin Immunol 2020 11 14;146(5):1214-1215. Epub 2020 Aug 14.

Department of Medicine, University of Washington, Seattle, Wash; Benaroya Research Institute, Systems Immunology Division, Seattle, Wash.

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http://dx.doi.org/10.1016/j.jaci.2020.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427546PMC
November 2020

Immune responses to rhinoviruses and asthma: Are we 3 steps closer to the door?

Authors:
James E Gern

J Allergy Clin Immunol 2020 09 14;146(3):513-514. Epub 2020 Jul 14.

Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wis. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.06.031DOI Listing
September 2020

Patterns of farm exposure are associated with reduced incidence of atopic dermatitis in early life.

J Allergy Clin Immunol 2020 12 7;146(6):1379-1386.e6. Epub 2020 Jul 7.

University of Wisconsin School of Medicine and Public Health, Madison, Wis. Electronic address:

Background: Farm exposures may reduce the risk of atopic dermatitis (AD) in children, but this is controversial and US data are limited.

Objective: This study was conducted to identify patterns of farm exposure in Wisconsin family farms that modify AD incidence and prevalence in early childhood.

Methods: Environmental exposures, health history, and clinical outcomes were prospectively recorded for 111 farm families and 129 non-farm families enrolled in the Wisconsin Infant Study Cohort birth cohort study. Exposures from the prenatal and early postnatal (2-month) visits were evaluated together with parental report of AD diagnosis by a health care provider through age 24 months. Latent class analysis was performed with prenatal and early postnatal farm-exposure variables to assign farm children to 3 classes.

Results: Overall, children of farm families had reduced AD incidence (P = .03). Within farm families, exposures including poultry (3% vs 28%; P = .003), pig (4% vs 25%; P = .04), feed grain (13% vs 34%; P = .02), and number of animal species were inversely associated with AD incidence. Among the latent class groups, children in families with diverse or more intense farm exposures (classes A and B) had reduced AD incidence, whereas low-exposure (class C) infants had AD incidence similar to that in nonfarm children.

Conclusions: Infants in Wisconsin farm families had reduced AD incidence, and patterns of farm exposures further defined AD risk. These findings suggest that exposure to diverse farm animals, feed, and bedding during the prenatal period and in early infancy reduce the risk of early-onset AD, a phenotype associated with multiple other atopic diseases.
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http://dx.doi.org/10.1016/j.jaci.2020.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721989PMC
December 2020