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Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33.Objectives: To identify a gene for BHR on chromosome 5q31-q33.Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry.Measurements and Main Results: In seven out of eight populations (n = 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages.Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR. [ABSTRACT FROM AUTHOR]

There is now clear evidence that asthma prevalence increased significantly, especially in developed countries, during the second part of the 20th century. What caused this increase is currently unknown. Recent reports from the United States and the United Kingdom suggest that asthma prevalence may have plateaued between 1995 and the first few years of the present century. This stabilization, and even some decrease in asthma prevalence, especially in countries with high baseline rates, was confirmed by the International Study of Asthma and Allergies in Children. The hospitalization rate for asthma (as a proportion of asthma patients) decreased significantly in the United States between 1980 and 1995, then remained stable between 2001 and 2004. However, the asthma death rate (as a proportion of subjects with asthma) did not decrease significantly during either of those periods. A better understanding of what determines the stable asthma death rate is urgently needed, especially since inhaled corticosteroids have been shown to prevent asthma deaths in persons who take them regularly. [ABSTRACT FROM AUTHOR]

Rationale: The effect of early life wheezing on respiratory function and continued symptoms through adolescence has not been fully described. Using data from a population-based birth cohort in Tucson, Arizona, we previously described four phenotypes based on the occurrence of wheezing lower respiratory illnesses before age 3 yr and active wheeze at age 6 yr: never wheezers (n = 425), transient early wheezers (n = 164), persistent wheezers (n = 113), and late-onset wheezers (n = 124).Objective: We sought to determine the prognosis for these phenotypes, with reference to lung function and symptoms, through adolescence.Methods: Current wheeze was assessed by questionnaire, lung function was measured by conventional spirometry, and atopy was determined by skin prick tests.Results: The prevalence of atopy and wheeze by age 16 yr was similar for never and transient wheezers and for persistent and late-onset wheezers. Both transient early, and persistent wheezers had significantly lower FEF(25-75) (-259 ml/s, p < 0.001, and -260 ml/s, p = 0.001, respectively), FEV1 (-75 ml, p = 0.02, and -87 ml, p = 0.03, respectively), and FEV1:FVC ratio (-1.9%, p = 0.002, and -2.5%, p = 0.001, respectively) through age 16 yr compared with never wheezers. Late-onset wheezers had levels of lung function similar to those of never wheezers through age 16 yr. There was no significant change in lung function among subjects with any of the four phenotypes, relative to their peers, from age 6 to 16 yr.Conclusion: Patterns of wheezing prevalence and levels of lung function are established by age 6 yr and do not appear to change significantly by age 16 yr in children who start having asthma-like symptoms during the preschool years. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has long been recognized that many children with asthma outgrow the disease after the onset of puberty, but little is known about genetic factors influencing this outcome. OBJECTIVES: The aim of the present study was to determine whether the polymorphisms at codons 16 and 27 of the beta2-adrenoceptor are significant predictors of the persistence of asthma during adolescence. DESIGN AND PARTICIPANTS: We used data from the prospective Tucson Children's Respiratory Study. Children were genotyped for the polymorphisms at codons 16 and 27. The presence of wheezing/asthma was assessed by questionnaire from age 6 years up to the reported onset of puberty (prepubertal period) and after the onset of puberty up to age 16 years (adolescence). RESULTS: Among children who wheezed in the prepubertal period (n = 168), subjects homozygous for Gly at codon 16 were at significantly increased risk for persistent wheezing after puberty, as compared with carriers of the other genotypes (relative risk [RR], 1.43; 95% confidence interval [CI], 1.06 to 1.92; p = 0.019). This relation was present among boys (RR, 2.17; 95% CI, 1.41 to 3.36) but not girls (RR, 0.85; 95% CI, 0.55 to 1.30), and increased linearly according to the frequency of wheezing episodes after the onset of puberty. These findings persisted after adjusting for ethnicity and other potential confounders and after selecting only white children. The polymorphism at codon 27 showed no relation with risk for persistent wheezing. CONCLUSIONS: This study provides evidence for a strong gender-specific effect of the Gly16 polymorphism on the persistence of asthma after the onset of puberty. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Farmers experience airway obstruction, which may be attributable in part to endotoxin inhalation. CD14 is a receptor for endotoxin. Materials and Methods: Based on our findings of increased circulating CD14 associated with the CD14/-159 T allele, we hypothesized that carriers of this allele would have decreased lung function among endotoxin-exposed individuals. CD14/-159TT farmers (n = 19) had significantly lower lung function as measured by FEV[1] (p = 0.028) and mean forced expiratory flow during the middle half of the FVC (FEF25-75) (p = 0.05) compared with farmers with the C allele (n = 78). Also, farmers with the CD14/-1619GG genotype (n =11) were associated with lower lung function (FEV[1], p = 0.008; FEF25-75, p = 0.009) compared with farmers with the A allele (n = 86). Results: No association between CD14/-550 and lung function was observed (FEV[1], p = 0.32; FEF25-75, p = 0.11). Increased prevalence of wheezing was reported in farmers homozygous for CD14/-159T (p = 0.013) or CD14/-1619G (p = 0.019) compared with farmers with the CC or AA genotype, respectively. No association was found between TLR4/Asp299Gly and lung function or wheeze. Conclusion: We conclude that the CD14/-159 or CD14/-1619 loci may play a role in modulating lung function and wheeze among agricultural workers. [ABSTRACT FROM AUTHOR]

Little is known about rates and predictors of remission of childhood asthma after the onset of puberty. We used data collected at ages 6, 8, 11, 13, and 16 years from the Tucson Children's Respiratory Study, a population-based birth cohort. The onset of puberty was defined as the age of appearance of the first pubertal signs as reported by parents. Information on wheezing both before and after onset of puberty (mean +/- SD follow-up from onset of puberty, 4.2 +/- 1 year) was available for 781 children. Of these, 166 had asthma (either frequent wheezing or a physician-confirmed diagnosis plus any wheezing) in at least one survey before puberty. In this group, 58% of the children (97 of 166) reported the presence of wheezing after the onset of puberty (unremitting asthma). In contrast, only 30% (39 of 131) of the children with infrequent wheezing before puberty experienced wheezing episodes after the onset of puberty (unremitting wheezing). In addition to frequent wheezing before puberty, obesity, early onset of puberty, active sinusitis, and skin test sensitization were significant and independent predictors of unremitting asthma after the onset of puberty. Our findings from a population-based longitudinal cohort challenge the commonly held view that asthma usually remits during adolescence. [ABSTRACT FROM AUTHOR]

It is unknown whether reduced production of IFNgamma in early life, before any lower respiratory tract illness, is a risk factor for recurrent wheezing in infancy. We followed 238 infants prospectively from birth to 1 year of age. At birth and at 3 months of age, IFNgamma production from polyclonally stimulated peripheral blood mononuclear cells and soluble CD14 (sCD14) levels in plasma were measured. The odds of developing recurrent wheezing (assessed by questionnaire) in the first year of life were up to 4.5 times higher for children in the lowest quartile of IFNgamma production at 3 months (p = 0.0005) and 3.2 times higher for children in the lowest quartile of sCD14 levels at birth (p = 0.004) as compared with children in the other 3 combined quartiles of IFNgamma and sCD14, respectively. Findings were confirmed in the multivariate analysis. IFNgamma production at 3 months and sCD14 levels at birth were correlated (r = 0.188, p = 0.031). Our findings from a longitudinal cohort suggest that impaired IFNgamma production at 3 months and reduced plasma-sCD14 levels at birth significantly increase the risk of developing recurrent wheezing in the first year of life. [ABSTRACT FROM AUTHOR]

Recent longitudinal studies have shed light on the pathogenesis and progression of asthma. The patterns of expression of childhood asthma that persist into adult life have been explored. Distinct asthma phenotypes (transient wheezing, nonatopic wheezing, and atopy-associated asthma) have been identified. Defining which children are at risk for persistent asthma could allow for better management and, potentially, for reduced morbidity and mortality. [ABSTRACT FROM AUTHOR]

Compelling evidence suggests a causal relation between exposure to parental cigarette smoking and respiratory symptoms during childhood. Still, the roles of prenatal versus postnatal parental smoking need clarification. In this study, the authors assessed the effects of passive smoking on respiratory symptoms in a cohort of over 1,000 children born during 1980-1984. The children were enrolled in the Tucson Children's Respiratory Study in Tucson, Arizona, and were followed from birth to age 11 years. The population was generally middle class and consisted of two main ethnic groups, non-Hispanic Whites (75%) and Hispanics (20%), reflecting Tucson's population. Information on parental smoking and on wheeze and cough in their children was elicited from parents by using questionnaires at five different surveys. Data were analyzed both cross-sectionally and by using the generalized estimation equation approach, a longitudinal mixed-effects model. The best-fitting model indicated that maternal prenatal but not postnatal smoking was associated with current wheeze (odds ratio = 2.3, 95% confidence interval 1.4-3.8) independently of a family history of asthma, socioeconomic factors, and birth weight. This effect was time dependent and significant only below age 3 years; although independent of gender, the association was stronger for girls (odds ratio = 3.6, 95% confidence interval 1.6-8.0). Cough was not associated with parental smoking during the first decade of life. This transitory effect of maternal prenatal smoking on wheezing could be due to changes that affect the early stages of lung development. [ABSTRACT FROM AUTHOR]

Background: Together with smoking, the lung function attained in early adulthood is one of the strongest predictors of chronic obstructive pulmonary disease. We aimed to investigate whether lung function in early adulthood is, in turn, affected by airway function measured shortly after birth.Methods: Non-selected infants were enrolled at birth in the Tucson Children's Respiratory Study between 1980 and 1984. We measured maximal expiratory flows at functional residual capacity (Vmax(FRC)) in 169 of these infants by the chest compression technique at a mean of 2.3 months (SD 1.9). We also obtained measurements of lung function for 123 of these participants at least once at ages 11, 16, and 22 years. Indices were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of FVC (FEF25-75), both before and after treatment with a bronchodilator (180 microg of albuterol).Findings: Participants who had infant Vmax(FRC) in the lowest quartile also had lower values for the FEV1/FVC ratio (-5.2%, p<0.0001), FEF25-75 (-663 mL/s, p<0.0001), and FEV1 (-233 mL, p=0.001) up to age 22, after adjustment for height, weight, age, and sex, than those in the upper three quartiles combined. The magnitude and significance of this effect did not change after additional adjustment for wheeze, smoking, atopy, or parental asthma.Interpretation: Poor airway function shortly after birth should be recognised as a risk factor for airflow obstruction in young adults. Prevention of chronic obstructive pulmonary disease might need to start in fetal life. [ABSTRACT FROM AUTHOR]

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are commonly triggered by rhinovirus (RV) infections with secondary bacterial infections. Risk factors for AECRS are not well understood., Objective: We sought to determine whether carriers of the minor allele rs6967330 (AA/AG) in the cadherin-related family member 3 (CDHR3) gene have an increased risk for RV infections in AECRS in vivo and identify CDHR3 genotype-dependent host responses to RV infection in differentiated nasal airway-liquid interface (ALI) cultures ex vivo., Methods: We performed a prospective year-long study of adult subjects with chronic rhinosinusitis by the rs6967330 genotype (AA/AG, n = 16; GG, n = 38). We contacted subjects every 2 weeks, and if they reported AECRS, then clinical data were collected. ALI cultures of adults with chronic rhinosinusitis (AG/AA, n = 19; GG, n = 19) were challenged with RV-A and RV-C. We measured viral copy numbers at 4 and 48 hours postinfection and RNA transcriptomes and cytokines at 48 hours postinfection., Results: Subjects with the minor allele had significantly higher rates of RV and bacterial infections than those with the major allele. ALI minor allele cultures had higher viral copy numbers of RV-A and RV-C after 48 hours compared with the major allele. Differentially expressed genes and pathways identified an upregulation of IL-10 and IL-4/IL-13 pathways and a significant downregulation of Toll-like receptor pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all differentially expressed genes suggested that allergic rhinitis had an additive effect on this response., Conclusions: The rs6967330 minor allele is associated with increased RV-A and RV-C replication, downregulation of Toll-like receptor-mediated responses, and increased type-2 and cytokine and chemokine responses during RV infection., Competing Interests: Disclosure statement This study was supported by grants from the National Institutes of Health (grant no. R01AI146131 to F.D.M. and E.H.C. and grant nos. R21 AI176305-01A1 and R01AI099108-11A1 to A.B.). Disclosure of potential conflict of interest: E. H. Chang is an advisor for Sanofi/Regeneron. A. Bosco is a cofounder, equity holder, and director of the startup company Respiradigm Pty Ltd and the subsidiary First Breath Health Pty Ltd, which are related to this work; and is the founder of the startup company INSiGENe Pty Ltd, which is related to this work. F. Martinez reports grants from NIH/NHLBI, grants from NIH/NIAID, grants from NIH/Office of the Director, grants from the ALA, and personal fees from OM Pharma. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: Identifying the root causes of racial disparities in childhood asthma is critical for health equity., Objectives: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP)., Methods: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates., Measurements and Main Results: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables., Conclusions: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

Background: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life., Objectives: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children., Methods: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV 1 /forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life., Results: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV 1 /FVC and FEV 1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV 1 % predicted in all adult cohorts (meta-analyzed FEV 1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10 -16 ). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV 1 and FEV 1 /FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV 1 and FEV 1 /FVC (P = .01 and .001)., Conclusions: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation., (© 2024. The Author(s).)

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation., Competing Interests: Declaration of interests LL has given lectures sponsored by Chiesi, a non-profit organisation facilitating lifelong learning for health-care providers, and received consulting fees from AstraZeneca, all paid to Ghent University. EM has received lecture fees from Airsonett, ALK, AstraZeneca, Chiesi, and Sanofi. AA has received lecture fees from AstraZeneca, Chiesi, GSK, Menarini, MSD, Sanofi, and Zambon; and research grants from AstraZeneca, GSK, Menarini, and Sanofi. SS has received lecture fees from Vyaire Medical, and consulting fees from Chiasi and NDD. JG-A's institution has received consulting and lecture fees from AstraZeneca (not related to this study); JGA has received lecture fees from Esteve and Chiesi (not related to this study). SCD has received investigator-initiated grants from GlaxoSmithKline and AstraZeneca. HP has received lecture fees (not related to this review) from Teva and Sandoz. AC reports personal fees from Novartis, Sanofi, Stallergenes Greer, AstraZeneca, GlaxoSmithKline, and La Roche-Posay, outside the submitted work. LEGWV has received lecture fees and advisory board fees from GlaxoSmithKline, AstraZeneca, Chiesi, Boehringer, Pulmonx, and Menarini. RF has received lecture fees Chiesi, AstraZeneca, and Zambon, advisory board fees from AstraZeneca, and research grants from AstraZeneca, GSK, Menarini, and Sanofi. JPA has received lecture fees from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Importance: Exposure to outdoor air pollution contributes to childhood asthma development, but many studies lack the geographic, racial and ethnic, and socioeconomic diversity to evaluate susceptibility by individual-level and community-level contextual factors., Objective: To examine early life exposure to fine particulate matter (PM2.5) and nitrogen oxide (NO2) air pollution and asthma risk by early and middle childhood, and whether individual and community-level characteristics modify associations between air pollution exposure and asthma., Design, Setting, and Participants: This cohort study included children enrolled in cohorts participating in the Children's Respiratory and Environmental Workgroup consortium. The birth cohorts were located throughout the US, recruited between 1987 and 2007, and followed up through age 11 years. The survival analysis was adjusted for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, neighborhood characteristics, and cohort. Statistical analysis was performed from February 2022 to December 2023., Exposure: Early-life exposures to PM2.5 and NO2 according to participants' birth address., Main Outcomes and Measures: Caregiver report of physician-diagnosed asthma through early (age 4 years) and middle (age 11 years) childhood., Results: Among 5279 children included, 1659 (31.4%) were Black, 835 (15.8%) were Hispanic, 2555 (48.4%) where White, and 229 (4.3%) were other race or ethnicity; 2721 (51.5%) were male and 2596 (49.2%) were female; 1305 children (24.7%) had asthma by 11 years of age and 954 (18.1%) had asthma by 4 years of age. Mean values of pollutants over the first 3 years of life were associated with asthma incidence. A 1 IQR increase in NO2 (6.1 μg/m3) was associated with increased asthma incidence among children younger than 5 years (HR, 1.25 [95% CI, 1.03-1.52]) and children younger than 11 years (HR, 1.22 [95% CI, 1.04-1.44]). A 1 IQR increase in PM2.5 (3.4 μg/m3) was associated with increased asthma incidence among children younger than 5 years (HR, 1.31 [95% CI, 1.04-1.66]) and children younger than 11 years (OR, 1.23 [95% CI, 1.01-1.50]). Associations of PM2.5 or NO2 with asthma were increased when mothers had less than a high school diploma, among Black children, in communities with fewer child opportunities, and in census tracts with higher percentage Black population and population density; for example, there was a significantly higher association between PM2.5 and asthma incidence by younger than 5 years of age in Black children (HR, 1.60 [95% CI, 1.15-2.22]) compared with White children (HR, 1.17 [95% CI, 0.90-1.52])., Conclusions and Relevance: In this cohort study, early life air pollution was associated with increased asthma incidence by early and middle childhood, with higher risk among minoritized families living in urban communities characterized by fewer opportunities and resources and multiple environmental coexposures. Reducing asthma risk in the US requires air pollution regulation and reduction combined with greater environmental, educational, and health equity at the community level.

Single-cell genomic technologies hold great potential to advance our understanding of lung development and disease. A major limitation lies in accessing intact cells from primary lung tissues for profiling human airway health. Sampling methods such as endotracheal aspiration that are compatible with clinical interventions could enable longitudinal studies, the enrollment of large cohorts, and the development of novel diagnostics. To explore single-cell RNA sequencing profiling of the cell types present at birth in the airway lumen of extremely premature neonates (<28 wk gestation), we isolated cells from endotracheal aspirates collected from intubated neonates within the first hour after birth. We generated data on 10 subjects, providing a rich view of airway luminal biology at a critical developmental period. Our results show that cells present in the airways of premature neonates primarily represent a continuum of myeloid differentiation, including fetal monocytes (25% of total), intermediate myeloid populations (48%), and macrophages (2.6%). Applying trajectory analysis to the myeloid populations, we identified two trajectories consistent with the developmental stages of interstitial and alveolar macrophages, as well as a third trajectory presenting an alternative pathway bridging the distinct macrophage precursors. The three trajectories share many dynamic genes ( N  = 5,451), but also have distinct transcriptional changes (259 alveolar-specific, 666 interstitial-specific, and 285 bridging-specific). Overall, our results define cells isolated within the so-called "golden hour of birth" in extremely premature neonate airways, representing complex lung biology, and can be used in studies of human development and disease.

BACKGROUND: Methods to determine whether a toddler is likely to develop asthma are of value to parents and clinical trialists testing primary prevention strategies. The Pediatric Asthma Risk Score (PARS) is a 14-point score of six factors designed to predict asthma in early life. PARS was developed and validated in relatively homogenous populations, so its generalizability is unknown. METHODS: We computed PARS using the six factors of self-declared race (parent-reported as “Black” or “not Black”), parental asthma, eczema, any wheezing, wheezing without a cold, and polysensitization in 5634 children from birth to 3 years of age. The primary outcome of our analysis was the ability of PARS to predict asthma development at 5 to 10 years of age using the area under the receiver operating curve in each cohort and across all cohorts with varying ethnicity, sex, cohort type, birth decades, missing PARS factors, and polysensitization definition. We also performed a meta-analysis across all the cohorts. Finally, we compared PARS predictive ability with the binary Asthma Predictive Index (API). RESULTS: Across 10 cohorts, the area under the receiver operating curve for PARS was 0.76. PARS performance did not differ by ethnicity, sex, cohort type, enrollment decade, missing PARS factors, or polysensitization definition (all P>0.05). The weights of each factor in the meta-analysis were similar to the original PARS weights. PARS and API equally identified children at high risk for developing asthma or not; API missed 31% of children at moderate asthma risk. CONCLUSIONS: PARS provided robust estimates of asthma risk in children from a wide range of ethnicities, backgrounds, and susceptibility. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1 ) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2 ) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P  < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P  < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P  < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.