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1AbstractBackgroundRespiratory syncytial virus (RSV) is associated with acute respiratory infection. We sought to identify RSV variants associated with prolonged infection.MethodsAmong healthy term infants we identified those with prolonged RSV infection and conducted 1) a human GWAS to test the dependence of infection risk on host genotype, 2) a viral GWAS for association with prolonged RSV infection using RSV whole-genome sequencing, 3) an analysis of all viral public sequences, 4) an assessment of immunological responses, and 5) a summary of all major functional data. Analyses were adjusted for viral/human population structure and host factors associated with infection risk.ResultsWe identified p.E123K/D and p.P218T/S/L in G protein that were associated with prolonged infection (Padj= 0.01). We found no evidence of host genetic risk for infection. The RSV variant positions approximate sequences that could bind a putative viral receptor, heparan sulfate.ConclusionsUsing analysis of both viral and host genetics we identified a novel RSV variant associated with prolonged infection in healthy infants and no evidence supporting host genetic susceptibility to infection. As the capacity of RSV for chronicity and its viral reservoir are not defined, these findings are important for understanding the impact of RSV on chronic disease and endemicity.Key pointsUsing a comprehensive computational analysis of viral and host genetics we identified a novel RSV variant associated with prolonged infection and no evidence supporting host genetic infection susceptibility, findings important to understanding RSV contribution to chronic disease and viral endemicity.SummaryA comprehensive computational statistical analysis of both host and viral genetics provided compelling evidence for RSV viral persistence in healthy human infants, a finding of significant importance to understanding the impact of RSV on chronic disease and viral endemicity.

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

Whether children and people with asthma and allergic diseases are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection is unknown.Our aims were to determine the incidence of SARS-CoV-2 infection in households with children and to also determine whether self-reported asthma and/or other allergic diseases are associated with infection and household transmission.For 6 months, biweekly nasal swabs and weekly surveys were conducted within 1394 households (N = 4142 participants) to identify incident SARS-CoV-2 infections from May 2020 to February 2021, which was the pandemic period largely before a vaccine and before the emergence of SARS-CoV-2 variants. Participant and household infection and household transmission probabilities were calculated by using time-to-event analyses, and factors associated with infection and transmission risk were determined by using regression analyses.In all, 147 households (261 participants) tested positive for SARS-CoV-2. The household SARS-CoV-2 infection probability was 25.8%; the participant infection probability was similar for children (14.0% [95% CI = 8.0%-19.6%]), teenagers (12.1% [95% CI = 8.2%-15.9%]), and adults (14.0% [95% CI = 9.5%-18.4%]). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (adjusted hazard ratio [aHR] = 1.04 [95% CI = 0.73-1.46]), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR = 0.50 [95% CI = 0.32-0.81]); higher body mass index was associated with increased infection risk (aHR per 10-point increase = 1.09 [95% CI = 1.03-1.15]). The household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (adjusted odds ratio = 0.43 [95% CI = 0.19-0.96]; P = .04).Asthma does not increase the risk of SARS-CoV-2 infection. Food allergy is associated with lower infection risk, whereas body mass index is associated with increased infection risk. Understanding how these factors modify infection risk may offer new avenues for preventing infection.

In this cohort study of hospitalized patients with linked medical record data, we developed International Classification of Diseases (ICD) criteria that accurately identified laboratory-confirmed, severe influenza hospitalizations (positive predictive value [PPV] 80%, 95% confidence interval [CI] 71-87%), which we validated through medical record documentation. These criteria identify patients with clinically important influenza illness outcomes to inform evaluation of preventive and therapeutic interventions and public health policy recommendations.

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.

BACKGROUND Childhood asthma is a common chronic disease that likely has prenatal origins. Gestational diabetes alters maternal physiology and may influence fetal risk for childhood-onset disease. However, the association between gestational diabetes and child asthma is not well characterized. OBJECTIVE To investigate the association between gestational diabetes and wheeze/asthma at approximately 4 years of age in a racially diverse US cohort. METHODS We studied mother-child dyads enrolled prenatally in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study. Gestational diabetes was determined by medical chart review. At approximately 4 years of age, we assessed child respiratory outcomes including parent report of physician-diagnosed asthma (ever), current wheeze (symptoms within the past 12 months), and current asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used the modified Poisson regression to assess associations between gestational diabetes and child respiratory outcomes, adjusting for maternal age, race, prenatal smoking, pre-pregnancy body mass index, parity, asthma history, socioeconomic status, and infant sex. RESULTS Among 1107 women, 66% were African American/Black. Six percent (n = 62) had gestational diabetes documented during pregnancy. Gestational diabetes was associated with increased risk of physician-diagnosed asthma (adjusted risk ratio (RR) [95% Confidence Interval]: 2.13 [1.35, 3.38]; prevalence: 14%), current wheeze (RR: 1.85 [1.23, 2.78]; prevalence: 19%), and current asthma (RR: 2.01 [1.30, 3.10]; prevalence: 16%). CONCLUSIONS Gestational diabetes was associated with increased risk of asthma and wheeze outcomes. Additional studies are needed to elucidate modifiable pathways underlying this association.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Summary Background Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines. Methods We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the loge odds ratio (loge OR) scale. Findings From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR+ 2·45, 95% CI 1·23–4·88) compared with those that did not (4·17, 2·36–7·37), a significant difference (b 0·53, 95% CI 0·04–1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR+ 1·21, 95% CI 0·73–1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data. Interpretation Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses. Funding Bill & Melinda Gates Foundation.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Background Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs). Objective In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs. Methods We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex. Results Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis. Conclusion In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.

BackgroundDNA methylation of cytosines at CpG dinucleotides is a widespread epigenetic mark; but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays.ObjectiveTo explore this hidden portion of the epigenome, we combined whole-genome bisulfite sequencing (WGBS) with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. We focused these studies in airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk.MethodsWe identified differentially methylated regions (DMRs) from WGBS in nasal epithelial cell (NEC) DNA from 39 children with and without allergic asthma of both European and African ancestries. We selected CpGs from DMRs, previous allergy or asthma Epigenome-Wide Association Studies (EWAS), or Genome-Wide Association Study (GWAS) loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. Using both the Custom and EPIC arrays, we performed EWAS of allergic sensitization (AS) in NEC DNA from children in the URECA birth cohort and using the Custom array in the INSPIRE birth cohort. We assigned each CpG on the arrays to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes.ResultsCustom array CpGs were enriched for intermediate methylation (IM) levels compared to EPIC CpGs. IM CpGs were further enriched among those associated with AS and for eQTMs on both arrays.ConclusionsOur study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography.Clinical ImplicationsThese studies identified allergic sensitization-associated differentially methylated CpGs and their target genes in airway epithelium, providing potential epigenetic mechanisms in the development of allergic diseases and suggesting novel drug targets.Capsule SummaryThis study of previously unexplored regions of the airway epithelial methylome revealed novel epigenetic mechanisms regulating genes previously implicated in the pathogenesis of asthma and allergic diseases.

Postnatal exposures, including breastfeeding, may influence asthma development.To investigate the association between breastfeeding duration and child asthma.We studied 2021 mother-child dyads in the ECHO PATHWAYS consortium of prospective pregnancy cohorts (GAPPS, CANDLE, TIDES). Women reported the duration of any and exclusive breastfeeding and child asthma outcomes during follow-up at child age 4 to 6 years. Outcomes included current wheeze (previous 12 months), ever asthma, current asthma (having ≥2 of current wheeze, ever asthma, medication use in past 12-24 months), and strict current asthma (ever asthma with either or both current wheeze and medication use in past 12-24 months). We used multivariable logistic regression to assess associations (odds ratios and 95% confidence intervals) between breastfeeding and asthma outcomes adjusting for potential confounders. We assessed effect modification by mode of delivery, infant sex, and maternal asthma.Among women, 33%, 13%, 9%, and 45% reported 0 to less than 2, 2 to 4, 5 to 6, and more than 6 months of any breastfeeding, respectively. The duration of any breastfeeding had a protective linear trend with ever asthma but no other outcomes. There was a duration-dependent protective association of exclusive breastfeeding and child asthma outcomes (eg, current asthma adjusted odds ratio [95% confidence interval], 0.64 [0.41-1.02], 0.61 [0.38-0.98], and 0.52 (0.31-0.87) for 2to 4 months, 5 to 6 months, and more than 6 months, respectively, compared with2 months). For exclusive breastfeeding, protective associations were stronger in dyads with children born by vaginal vs cesarean delivery although interactions did not reach statistical significance (PLonger duration of exclusive breastfeeding had a protective association with child asthma.

Background The roles of systemic and airway-specific epithelial energy metabolism in altering the developmental programming of airway epithelial cells (AECs) in early life are poorly understood. Objective Our aim was to assess carbohydrate metabolism in developing AECs among children with and without wheeze and test the association of infant plasma energy biomarkers with subsequent recurrent wheeze and asthma outcomes. Methods We measured cellular carbohydrate metabolism in live nasal AECs collected at age 2 years from 15 male subjects with and without a history of wheeze and performed a principal component analysis to visually assess clustering of data on AEC metabolism of glycolitic metabolites and simple sugars. Among 237 children with available year 1 plasma samples, we tested the associations of year 1 plasma energy biomarkers and recurrent wheeze and asthma by using generalized estimating equations and logistic regression. Results Children with a history of wheeze had lower utilization of glucose in their nasal AECs than did children with no wheeze. Systemically, a higher plasma glucose concentration at year 1 (within the normal range) was associated with decreased odds of asthma at age 5 years (adjusted odds ratio = 0.56; 95% CI = 0.35-0.90). Insulin concentration, glucose-to-insulin ratio, C-peptide concentration, and leptin concentration at year 1 were associated with recurrent wheeze from age 2 years to age 5 years. Conclusion These results suggest that there is significant energy metabolism dysregulation in early life, which likely affects AEC development. These pertubations of epithelial cell metabolism in infancy may have lasting effects on lung development that could render the airway more susceptible to allergic sensitization.

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

Background The potential for prenatal antibiotic exposure to influence asthma risk is not clear. We aimed to determine the effect of timing, dose, and spectrum of prenatal antibiotic exposure on the risk of childhood asthma. Methods We conducted a population-based cohort study of 84 214 mother–child dyads to examine the association of prenatal antibiotic exposure and childhood asthma using multivariable logistic regression models. Results Sixty-four percent of pregnant women received antibiotics. Prenatal antibiotic exposure was associated dose-dependently with increased odds of childhood asthma (adjusted odds ratio [aOR] for interquartile increase of 2 courses [interquartile range, 0–2], 1.26 [95% confidence interval {CI}, 1.20–1.33]). Among children exposed to at least 1 course in utero, the effect of timing at the first course was moderated by total maternal courses. Among pregnant women receiving a single antibiotic course, timing of exposure had no effect on childhood asthma risk. Among women receiving > 1 course, early exposure of the first course was associated with greater childhood asthma risk. Compared to narrow spectrum–only antibiotic use, broad spectrum–only antibiotic exposure was associated with increased odds of asthma (aOR, 1.14 [95% CI, 1.05–1.24]). There were effect modifications (P Conclusions Increased cumulative dose, early pregnancy first course, and broad-spectrum antibiotic exposure were associated with childhood asthma risk. Our study provides important evidence supporting judicious prenatal antibiotic use, particularly timing of use and choice of antibiotics, in preventing subsequent childhood asthma.

Anemia is an increasingly recognized problem in sub-Saharan Africa. To determine the magnitude, severity, and associated factors of anemia among hospitalized children aged 6–59 months, HIV-infected and HIV-exposed uninfected children (a child born to a known HIV-infected mother) with a documented fever or history of fever within the prior 24 hours of hospital admission (N = 413) were included in this analysis. Of 413 children enrolled, 364 (88%) were anemic, with 53% classified as mild anemia (hemoglobin [Hb] 7–9.9 g/dL). The most common diagnoses associated with hospital admission included acute respiratory illness (51%), malnutrition (47%), gastroenteritis/diarrhea (25%), malaria (17%), and bacteremia (13%). A diagnosis of malaria was associated with a decrease in Hb by 1.54 g/dL (P < 0.001). In HIV-infected patients, malaria was associated with a similar decrease in Hb (1.47 g/dL), whereas a dual diagnosis of bacteremia and malaria was associated with a decrease in Hb of 4.12 g/dL (P < 0.001). No difference was seen in Hb for patients on antiretroviral therapy versus those who were not. A diagnosis of bacteremia had a roughly 4-fold increased relative odds of death during hospitalization (adjusted odds ratio = 3.97; 95% CI: 1.61, 9.78; P = 0.003). The etiology of anemia in high-burden malaria, HIV, tuberculosis, and poor nutrition countries is multifactorial, and multiple etiologies may be contributing to one’s anemia at any given time. Algorithms used by physician and nonphysician clinicians in Mozambique should incorporate integrated and non–disease specific approaches to pediatric anemia management and should include improved access to blood culture.

Background Viral bronchiolitis is a common respiratory infection that often affects term, otherwise healthy infants. A small literature suggests maternal stress during pregnancy is associated with bronchiolitis. However, the association between maternal exposure to lifetime traumatic stress, including traumatic events occurring in childhood or throughout the life course, and bronchiolitis has not been studied previously. Objectives To investigate the association between maternal exposure to total lifetime and childhood traumatic stress events and infant bronchiolitis. Methods We studied mother-infant dyads enrolled in a prospective prenatal cohort, recruited 2006-2011, and Tennessee Medicaid. During pregnancy, we assessed maternal lifetime exposure to types of traumatic events by questionnaire. We captured bronchiolitis diagnoses in term, non-low birthweight infants' first 12 months using linked Medicaid data. In separate models, we assessed the association of maternal lifetime traumatic events (0 to 20 types) and a subset of traumatic events that occurred during childhood (0 to 3: family violence, sexual, and physical abuse) and infant bronchiolitis using multivariable log-binomial models. Results Of 629 women, 85% were African American. The median count (interquartile range) of lifetime traumatic events was 3 (2, 5); 42% reported ≥1 childhood traumatic event. Among infants, 22% had a bronchiolitis diagnosis (0 to 2 lifetime traumatic events: 24%; 3 events: 20%; 4 to 5 events: 18%; 6 or more events: 24%). Total maternal lifetime traumatic events were not associated with bronchiolitis in multivariable analyses. For maternal childhood traumatic events, the risk of infant bronchiolitis increased with number of event types reported: adjusted Risk ratios were 1.12 (95% confidence interval [CI] 0.80, 1.59), 1.31 (95% CI 0.83, 2.07), and 2.65 (95% CI 1.45, 4.85) for 1, 2, and 3 events, respectively, vs none. Conclusions Infants born to women reporting multiple types of childhood trauma were at higher risk for bronchiolitis. Further research is needed to explore intergenerational effects of traumatic experiences.

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.

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

Background Altered mental status (AMS) is a priority presenting sign that must be assessed in HIV-infected, febrile children, yet diagnosis is difficult in areas with limited diagnostic capacity. Malaria and bacterial meningitis have been reported as the most common causes of AMS in febrile children presenting to the hospital in sub-Saharan Africa. However, in an HIV-infected child, central nervous system manifestations are diverse. Methods We conducted a clinical observational study of HIV-infected febrile children, aged 0–59 months, hospitalized in Mozambique and prospectively followed. Within this cohort, a nested study was designed to characterize children admitted with AMS and to assess factors associated with mortality. Univariate and multivariable analysis were performed comparing characteristics of the cohort by AMS status and evaluated demographic and clinical factors by in-hospital mortality outcome. Results In total, 727 children were enrolled between April 2016 and February 2019, 16% had AMS at admission. HIV-infected, febrile children, who presented with AMS and who had a diagnosis of bacteremia, had a 4-fold increased relative odds of in-hospital mortality, and children who presented with neurologic symptoms on admission had a roughly 8-fold higher odds of in-hospital mortality relative to children without presenting neurologic findings. Conclusions Mozambique has a pressing need to expand local diagnostic capacity. Our results highlight the critical need for clinicians to incorporate a broader differential into their potential causes of AMS, and to develop a Ministry of Health approved diagnostic and management algorithm, which is standardly used, to manage patients for whom reliable and relevant diagnostic services are not available.

This study identified a genotype of respiratory syncytial virus (RSV) associated with increased acute respiratory disease severity in a cohort of previously healthy term infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4th position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild-type A2 strain G gene (one stop codon preceding a wild-type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the recombinant A4G (rA4G) RSV mutant resulted in transcriptional readthrough and lower G and fusion (F) protein levels than for the wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational readthrough. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naive BALB/c mice compared to that for wild-type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of preexisting immunity than rA4G RSV. Together, these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains. IMPORTANCE Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4th position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity than a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and, potentially, immune evasion.

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

Rationale: Recurrent wheeze and asthma are thought to result from alterations in early life immune development following respiratory syncytial virus (RSV) infection. However, prior studies of the n...

OBJECTIVES: Viral bronchiolitis is the most common cause of infant hospitalization. Folic acid supplementation is important during the periconceptional period to prevent neural tube defects. An area of investigation is whether higher prenatal folate is a risk factor for childhood respiratory illnesses. We investigated the association between maternal 2(nd) trimester plasma folate levels and infant bronchiolitis. METHODS: We conducted a retrospective cohort analysis in a subset of mother-infant dyads (n=676) enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study and Tennessee Medicaid. Maternal folate status was determined using 2(nd) trimester (16–28 weeks) plasma samples. Bronchiolitis diagnosis in the first year of life was ascertained using International Classification of Diagnosis-9 codes from Medicaid administrative data. We used multivariable logistic regression to assess the adjusted association of prenatal folate levels and infant bronchiolitis outcome. RESULTS: Half of the women in this lower-income and predominately African-American (84%) study population had high levels of folate (median 2(nd) trimester level 19.2 ng/mL) and 21% of infants had at least one bronchiolitis healthcare visit. A relationship initially positive then reversing between maternal plasma folate and infant bronchiolitis was observed that did not reach statistical significance (p(overall)=0.112, p(nonlinear effect)=.088). Additional adjustment for dietary methyl donor intake did not significantly alter the association. CONCLUSIONS FOR PRACTICE: Results did not confirm a statistically significant association between maternal 2(nd) trimester plasma folate levels and infant bronchiolitis. Further work is needed to investigate the role of folate, particularly higher levels, in association with early childhood respiratory illnesses.