Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission

BACKGROUND: Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. METHODS: We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. RESULTS: In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37-120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with >0.16% predicted probabilities [lower quartile for eligible infants]). CONCLUSIONS: We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis

Association of citrulline concentration at birth with lower respiratory tract infection in infancy: Findings from a multi-site birth cohort study

Assessing the association of the newborn metabolic state with severity of subsequent respiratory tract infection may provide important insights on infection pathogenesis. In this multi-site birth cohort study, we identified newborn metabolites associated with lower respiratory tract infection (LRTI) in the first year of life in a discovery cohort and assessed for replication in two independent cohorts. Increased citrulline concentration was associated with decreased odds of LRTI (discovery cohort: aOR 0.83 [95% CI 0.70-0.99], p = 0.04; replication cohorts: aOR 0.58 [95% CI 0.28-1.22], p = 0.15). While our findings require further replication and investigation of mechanisms of action, they identify a novel target for LRTI prevention and treatment

Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis

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

The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aβ 0.05 [95% CI 0.03, 0.07]; replication: aβ 0.04 [95% CI 0.006, 0.06]; C2: discovery: aβ 0.04 [95% CI 0.003, 0.08]; replication: aβ 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1–3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns

Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood. The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats. Nicotine (0, 0.05, 0.2&nbsp;mg/kg, s.c.) and tranylcypromine (3&nbsp;mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field. Nicotine (0.2&nbsp;mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2&nbsp;mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment. There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors

Personalized Infant Risk Prediction for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection Requiring Intensive Care Unit Admission

Background:Currently, there are no available tools to identify infants at the highest risk of significant morbidity and mortality from respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) who would benefit most from RSV prevention products. The objective was to develop and internally validate a personalized risk prediction tool for use among all newborns that uses readily available birth/postnatal data to predict RSV LRTI requiring intensive care unit (ICU) admission. Methods:We conducted a population-based birth cohort study of infants born from 1995 to 2007, insured by the Tennessee Medicaid Program, and who did not receive RSV immunoprophylaxis during the first year of life. The primary outcome was severe RSV LRTI requiring ICU admission during the first year of life. We built a multivariable logistic regression model including demographic and clinical variables available at or shortly after birth to predict the primary outcome. Results:In a population-based sample of 429 365 infants, 713 (0.2%) had severe RSV LRTI requiring ICU admission. The median age of admission was 66 days (interquartile range, 37–120). Our tool, including 19 variables, demonstrated good predictive accuracy (area under the curve, 0.78; 95% confidence interval, 0.77-0.80) and identified infants who did not qualify for palivizumab, based on American Academy of Pediatrics guidelines, but had higher predicted risk levels than infants who qualified (27% of noneligible infants with &gt;0.16% predicted probabilities [lower quartile for eligible infants]). Conclusions:We developed a personalized tool that identified infants at increased risk for severe RSV LRTI requiring ICU admission, expected to benefit most from immunoprophylaxis.</p

Associations between Smoking and Smoking Cessation during Pregnancy and Newborn Metabolite Concentrations: Findings from PRAMS and INSPIRE Birth Cohorts

Newborn metabolite perturbations may identify potential biomarkers or mechanisms underlying adverse, smoking-related childhood health outcomes. We assessed associations between third-trimester smoking and newborn metabolite concentrations using the Tennessee Pregnancy Risk Assessment Monitoring System (PRAMS, 2009–2019) as the discovery cohort and INSPIRE (2012–2014) as the replication cohort. Children were linked to newborn screening metabolic data (33 metabolites). Third-trimester smoking was ascertained from birth certificates (PRAMS) and questionnaires (INSPIRE). Among 8600 and 1918 mother–child dyads in PRAMS and INSPIRE cohorts, 14% and 13% of women reported third-trimester smoking, respectively. Third-trimester smoking was associated with higher median concentrations of free carnitine (C0), glycine (GLY), and leucine (LEU) at birth (PRAMS: C0: adjusted fold change 1.11 [95% confidence interval (CI) 1.08, 1.14], GLY: 1.03 [95% CI 1.01, 1.04], LEU: 1.04 [95% CI 1.03, 1.06]; INSPIRE: C0: 1.08 [95% CI 1.02, 1.14], GLY: 1.05 [95% CI 1.01, 1.09], LEU: 1.05 [95% CI 1.01, 1.09]). Smoking cessation (vs. continued smoking) during pregnancy was associated with lower median metabolite concentrations, approaching levels observed in infants of non-smoking women. Findings suggest potential pathways underlying fetal metabolic programming due to in utero smoke exposure and a potential reversible relationship of cessation

Electronic cigarette use during pregnancy and the risk of adverse birth outcomes: A cross-sectional surveillance study of the US Pregnancy Risk Assessment Monitoring System (PRAMS) population.

BackgroundResearch on health effects and potential harms of electronic cigarette (EC) use during pregnancy is limited. We sought to determine the risks of pregnancy EC use on pregnancy-related adverse birth outcomes and assess whether quitting ECs reduces the risks.MethodsWomen with singleton live births who participated in the US Pregnancy Risk Assessment Monitoring System (PRAMS) survey study 2016-2020 were classified into four mutually exclusive groups, by their use of ECs and combustible cigarettes (CCs) during pregnancy: non-use, EC only use, CC only use, and dual use. We determined the risk of preterm birth, low birth weight, and small-for-gestational-age (SGA) by comparing cigarette users to non-users with a modified Poisson regression model adjusting for covariates. In a subset of women who all used ECs prior to pregnancy, we determined whether quitting EC use reduces the risk of preterm birth, low birth weight, and SGA by comparing to those who continued its use. All analyses were weighted to account for the PRAMS survey design and non-response rate.ResultsOf the 190,707 women (weighted N = 10,202,413) included, 92.1% reported cigarette non-use, 0.5% EC only use, 6.7% CC only use, and 0.7% dual use during pregnancy. Compared with non-use, EC only use was associated with a significantly increased risk of preterm birth (adjusted risk ratio [aRR]: 1.29, 95% confidence interval [CI]: 1.00, 1.65) and low birth weight (aRR: 1.38, 95%CI: 1.09, 1.75), but not SGA (aRR: 1.04, 95%CI: 0.76, 1.44). Among 7,877 (weighted N = 422,533) women EC users, quitting use was associated with a significantly reduced risk of low birth weight (aRR: 0.76, 95%CI: 0.62, 0.94) and SGA (aRR: 0.77, 95%CI: 0.62, 0.94) compared to those who continued to use ECs during pregnancy.ConclusionsPregnancy EC use, by itself or dual use with CC, is associated with preterm birth and low birth weight. Quitting use reduces that risk. ECs should not be considered as a safe alternative nor a viable gestational smoking cessation strategy

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

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