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BACKGROUND: It is well known that homozygous deficiency of alpha(1)-antitrypsin, PiZZ, is associated with an increased risk of emphysema. However, studies evaluating associations between the heterozygous form PiMZ with emphysema and impaired lung function have provided conflicting results. STUDY OBJECTIVE: The goal of this study was to determine if the phenotype PiMZ is associated with an accelerated decline in diffusing capacity of the lung for carbon monoxide (Dlco). DESIGN AND METHODS: The Tucson Epidemiologic Study of Airway Obstructive Disease is a prospective, population-based cohort study initiated in 1972. Participants completed standardized questionnaires in up to 12 periodic surveys and Dlco assessments in up to 4 surveys. Random-effects models were used to determine the effects of alpha(1)-antitrypsin phenotypes on percentage of predicted (% predicted) Dlco levels among 1,075 subjects >/= 18 years old. RESULTS: % predicted Dlco declined more rapidly in subjects who smoked compared to nonsmoking subjects. Additionally, in smokers, the PiMZ phenotype was associated with borderline % predicted Dlco deficits at age 40 years (8.6%; p = 0.075) and significant % predicted Dlco deficits at age 60 years (15.2%; p = 0.001) and 80 years (21.9%; p = 0.003), as compared with the PiMM phenotype. CONCLUSIONS: Dlco may be a more sensitive indicator of the long-term effects of intermediate levels of alpha(1)-antitrypsin on lung function especially in subjects who smoke. [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]

BACKGROUND: For several years, asthma and COPD have been regarded as distinct entities, with distinct clinical courses. However, despite distinctive physiologic features at the time of diagnosis, and different risk factors, the two diseases over time may develop features that are quite similar. STUDY OBJECTIVE: To evaluate the association between physician-diagnosed asthma and the subsequent development of COPD in a cohort of 3,099 adult subjects from Tucson, AZ. DESIGN AND METHODS: A prospective observational study. Participants completed up to 12 standard respiratory questionnaires and 11 spirometry lung function measurements over a period of 20 years. Survival curves (with time to development of COPD as the dependent variable) were compared between subjects with asthma and subjects without asthma at the initial survey. RESULTS: Subjects with active asthma (n = 192) had significantly higher hazard ratios than inactive (n = 156) or nonasthmatic subjects (n = 2751) for acquiring COPD. As compared with nonasthmatics, active asthmatics had a 10-times-higher risk for acquiring symptoms of chronic bronchitis (95% confidence interval [CI], 4.94 to 20.25), 17-times-higher risk of receiving a diagnosis of emphysema (95% CI, 8.31 to 34.83), and 12.5-times-higher risk of fulfilling COPD criteria (95% CI, 6.84 to 22.84), even after adjusting for smoking history and other potential confounders. CONCLUSIONS: Physician-diagnosed asthma is significantly associated with an increased risk for CB, emphysema, and COPD. [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]

The objective of this study was to determine the limits for repeatability of FEV1, FVC, and PEF during spirometry test sessions in adult outpatients. A retrospective chart review of 18,000 consecutive patients, aged 20 to 90 years, referred to a large outpatient pulmonary function laboratory for testing was performed. Measurements included the differences between the highest and second-highest FVC (dFVC), FEV1 (dFEV1), and PEF (dPEF), from prebronchodilator spirometry, and anthropometric factors. Ninety percent of the patients were able to reproduce FEV1 within 120 ml (6.1%), FVC within 150 ml (5.3%), and PEF within 0.80 L (12%). Patient characteristics, such as sex, age, height, smoking status, and FEV1 (% predicted), had very little effect on repeatability, explaining only 2 to 4% of the variation in repeatability (expressed in milliliters). We conclude that the ability of patients to meet or exceed spirometry repeatability goals does not depend on patient characteristics when testing is performed by experienced personnel. The current American Thoracic Society repeatability goal of 200 ml for FEV1 and FVC may be too lenient. [ABSTRACT FROM AUTHOR]

Study Objectives: The Tucson Children's Assessment of Sleep Apnea (TuCASA) study is designed to investigate the prevalence and correlates of objectively measured sleep-disordered breathing (SDB) in preadolescent children. This article describes the parental report of sleep symptoms associated with SDB in Hispanic and white children.Design: A 13-question sleep habits screening questionnaire designed to assess the severity of sleep-related symptoms associated with SDB in children 4 to 11 years of age.Setting: Questionnaires were completed by the parents of children attending elementary school in the Tucson Unified School District, Tucson, AZ.Participants: There were 1,494 questionnaires returned, which comprised a sample of whites (38%), Hispanics (45%), and other races (17%). Of these questionnaires, 1,214 were returned for the children of white (45.8%; 556 children) or Hispanic (54.2%; 658 children) ethnicity only. The primary analysis was completed on these 613 boys (50.5%) and 601 girls (49.5%).Results: In the total sample of 1,494 children, parents were more likely to report excessive daytime sleepiness (EDS) in female children than in male children (p <.01), however, this association did not achieve significance in the sample of only white and Hispanic children (p <.07). Composite variables for EDS and witnessed apnea (WITAP) show that parents of Hispanic children were more likely to report EDS (p <.01) and WITAP (p <.007). Hispanic children were also more likely to have learning problems (LPs) [p <.03] and to snore frequently (SN) [p <.02] than were white children. There were no significant differences between boys and girls for SN or WITAP. Hispanic boys were more likely to have reports of EDS (p <.02) and LPs (p <.04) than white boys, however, there were no other significant differences in gender or ethnicity in reports of EDS or LPs for white or Hispanic boys and girls. Those children with frequent LPs were significantly more likely to have SN (p <.001), EDS (p <.001), and WITAP (p <.001). A logistic regression model predicting LP resulted in significant adjusted odds ratios (ORs) of 2.4 for SN, 2.5 for EDS, and 2.1 for children aged 8 to 11 years. A similar model for EDS resulted in significant adjusted ORs of 3.2 for SN, 5.7 for WITAP, and 1.6 for female gender. Ethnicity was not significant in either model.Conclusions: Hispanic children in the population-based TuCASA study experienced more frequent symptoms associated with SDB, such as SN, EDS, WITAP, and LPs, than did white children. Children with LPs are 2.4 times more likely to have SN, 2.5 times more likely to have EDS, and were 2.1 times more likely to be between the ages of 8 and 11 years. Children with EDS were 3.2 times more likely to have SN, 5.7 times more likely to have WITAP, and were 1.6 times more likely to be a girl. [ABSTRACT FROM AUTHOR]

Background: It is well-known that the homozygous deficiency of alpha(1)-antitrypsin, phenotype PiZZ, is associated with an increased risk of COPD. However, studies evaluating the association between the heterozygous forms of the alpha(1)-antitrypsin phenotype PiMZ and rapid decline in lung function, both in patient and community populations, have yielded conflicting results.Study Objective: To assess the relationship between alpha(1)-antitrypsin phenotypes and decline in FEV(1) values of 2,016 adult subjects in a community population in Tucson, AZ.Design and Methods: Prospective cohort study. Standardized questionnaires and lung function measurements were administered 1.5 to 2 years apart during 12 surveys.Results: The frequency distribution for PiMM, PiMS, and PiMZ phenotypes did not differ significantly by physician-confirmed diagnoses of emphysema, chronic bronchitis, or asthma. There was no statistically significant difference in mean FEV(1) slope values between PiMM, PiMS, and PiMZ phenotypes (-22.5, -21, and -7 mL per year, respectively). After controlling for smoking and other potential confounders, the FEV(1) slope was associated with an initial FEV(1) level and age for the initial questionnaire but not with the different phenotypes. Selecting cutoff values, we identified rapidly declining and nondeclining subgroups, based on the percent predicted changes in FEV(1). They also were not associated with alpha(1)-antitrypsin phenotypes.Conclusions: We conclude that the data from this longitudinal community study suggest that having the PiMZ phenotype is not a significant risk factor for an accelerated decline in FEV(1). [ABSTRACT FROM AUTHOR]

OBJECTIVES: Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age. PATIENTS AND METHODS: We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured. RESULTS: Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production. CONCLUSIONS: Interferon gamma responses of school-aged children are impacted by parental smoking. [ABSTRACT FROM AUTHOR]

Background: The single breath nitrogen (SBN 2 ) test was proposed for early detection of "small airways disease" in the seventies. Few longitudinal studies have subsequently evaluated the relationships between SBN 2 test measurements and lung function decline or COPD incidence., Aim: This study evaluates whether SBN 2 test abnormalities may be significant predictors of lung function decline and COPD incidence over an 8-year follow-up., Study Design and Methods: In this longitudinal study, 907 adults (20+ years old; 56% males) from the prospective Po River Delta epidemiological study underwent SBN 2 test at baseline and spirometry testing at both baseline and follow-up 8-year apart. Multinomial and multiple regression models were used to assess associations of SBN 2 indexes and rates of FEV 1 decline or risk of COPD incidence over time, after adjusting for sex, height and baseline age, FEV 1 and smoking status. COPD was defined according to either GOLD or ATS-ERS criteria., Results: Among SBN 2 indexes, only the slope of alveolar plateau (N 2 -slope) was significantly associated with rates of FEV 1 decline (7.93 mL/year for a one-unit change in N 2 -slope, p<0.0001), and with an increased risk of developing COPD as defined by GOLD (RR 1.81, 95%CI 1.29-2.52, mild; RR 2.78, 95%CI 1.70-4.53, moderate or severe obstruction) and ATS-ERS criteria (RR 1.62, 95%CI 1.14-2.29, mild; RR 3.40, 95%CI 1.72-6.73, moderate or severe obstruction)., Conclusion: In this population-based study, N 2 -slope from SBN 2 test is a significant predictor of lung function decline and COPD incidence over an 8-year follow-up, confirming the role of the "small airways disease" in the natural history of COPD., Competing Interests: Conflict of interest All the authors have no conflicts of interest to declare in relation to the present manuscript., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

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.)

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.

Introduction: Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population., Methods: We evaluated 403 participants from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) who at enrollment were aged 28-55 years and completed lung function tests. During follow-up, the 403 participants completed on average 7.2 lung function tests per subject for a total of 2908 observations over a mean period of 14.7 years. We tested CMV serology in serum samples from enrollment and categorized participants into low, medium, and high CMV serology based on tertiles. The relation of CMV serology at enrollment to lung function levels and decline during follow-up was tested in multivariate random coefficients models., Results: After full adjustment, participants in the highest CMV serology tertile had faster declines of forced expiratory volume in 1 s (FEV 1 ) and FEV 1 /forced vital capacity (FVC) compared with subjects in the lowest tertile (by -7.9 ml/year 95% confidence interval [-13.9 ml/year, -1.93 ml/year], and by -0.13%/year [-0.23%/year, -0.026%/year], respectively). These CMV effects were additive with those of cigarette smoking. No associations were found between CMV serology and FVC, indicating specific effects of CMV seropositivity on airflow limitation., Conclusion: High CMV serology in young to mid-adult life may be linked to increased COPD risk through an accelerated decline of lung function., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF)., Methods: We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV 1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV 1 and FEV 1 /FVC% predicted levels between ages 7-16 using mixed models., Results: Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV 1 /FVC and, marginally, FEV 1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations)., Conclusions: Serum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF., Competing Interests: Declaration of Competing Interest MJE, EEB, KJB, MH, RLG, MR, SDS, MJB, WJM, and SG report receiving grant support through their institution for the present work. SDS reports receiving honoraria from DKBMed. WJM reports receiving consulting fees from the Cystic Fibrosis Foundation, receiving speaker honoraria from the American College of Chest Physicians, and participating on the CFF DSMB., (Copyright © 2022. Published by Elsevier B.V.)

Background: Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV 1 /FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life., Methods: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV 1 /FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV 1 /FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV 1 /FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants., Findings: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction., Interpretation: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden., Funding: National Institutes of Health., Competing Interests: Declaration of interests WJM has received grant funding for this work from the National Institutes of Health; funding from the National Institutes of Health and the Cystic Fibrosis Foundation outside of the submitted work; and personal fees from the Cystic Fibrosis Foundation, the American Thoracic Society, and the American College of Chest Physicians outside of the submitted work. AC has received personal fees from Novartis, Thermo Fisher Scientific, Philips, Sanofi, Stallergenes Greer, and AstraZeneca outside of the submitted work. AS and CSM are supported by the NIHR Manchester Biomedical Research Centre. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Rationale: Deficits in infant lung function-including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)-have been linked to increased risk for childhood asthma. Objectives: To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life. Methods: One hundred eighty participants in the Tucson Children's Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models. Measurements and Main Results: After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% ( P  = 0.001) and 55% ( P  = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26. Conclusions: These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.

Background: Positive serology for cytomegalovirus (CMV) has been associated with all-cause mortality risk but its role in COPD mortality is unknown. The objective of the present study was to assess the relationship between CMV serology and COPD mortality., Methods: We analysed data from 806 participants in the Tucson Epidemiological Study of Airway Obstructive Disease who, at enrolment, were aged 28-70 years and had completed lung function tests. We tested CMV serology in sera from enrolment and defined "high CMV serology" as being in the highest tertile. Vital status, date and cause of death were assessed through death certificates and/or linkage with the National Death Index up to January 2017. The association of CMV serology with all-cause and cause-specific mortality risk was tested in Cox models adjusted for age, sex, level of education, body mass index, smoking status and pack-years., Results: High CMV serology was marginally associated with all-cause mortality (p=0.071) but the effect was inversely dependent on age, with the association being much stronger among participants <55 years than among participants ≥55 years at enrolment (p-value for CMV-by-age interaction <0.001). Compared with low CMV serology, high CMV serology was associated with mortality from COPD among all subjects (adjusted hazard ratio (HR) 2.38, 95% CI 1.11-5.08; p=0.025) and particularly in subjects <55 years old at enrolment (HR 5.40, 95% CI 1.73-16.9; p=0.004). Consistent with these results, high CMV serology also predicted mortality risk among subjects who already had airflow limitation at enrolment (HR 2.10, 95% CI 1.20-3.68; p=0.009)., Conclusions: We report a strong relationship between CMV serology and the risk of dying from COPD, and thus identify a novel risk factor for COPD mortality., Competing Interests: Conflict of interest: R. Nenna has nothing to disclose. Conflict of interest: J. Zhai has nothing to disclose. Conflict of interest: S.E. Packard reports grants from the NIH during the conduct of the study. Conflict of interest: A. Spangenberg has nothing to disclose. Conflict of interest: D.L. Sherrill has nothing to disclose. Conflict of interest: F.D. Martinez reports grants HL139054, HL132523, HL091889, HL130045, HL098112 and HL056177 from NIH/NHLBI, grant ES006614 from NIH/NIEHS, grant AI126614 from NIH/NIAID, grant OD023282 from NIH/Office of Director, grant UA009253-0001 from Johnson & Johnson, and personal fees for consultancy from Copeval and Commense Inc., outside the submitted work. Conflict of interest: M. Halonen reports grants from the NIH during the conduct of the study. Conflict of interest: S. Guerra reports grants from the NIH during the conduct of the study., (Copyright ©ERS 2020.)

In a population-based study, higher circulating levels of L1-ORF1p were associated with lower lung function levels and increased risk for airflow limitation among former smokers http://bit.ly/2ZEIjNv., Competing Interests: Conflict of interest: S. Guerra reports grants from the NIH during the conduct of the study. Conflict of interest: M.M. Vasquez has nothing to disclose. Conflict of interest: P. Bojang Jr has patent WO2017172839A1 (Use of biomarkers associated with LINE-1) issued. Conflict of interest: I.N. Ramos has nothing to disclose. Conflict of interest: D.L. Sherrill has nothing to disclose. Conflict of interest: F.D. Martinez reports grants from the National Institutes of Health (NIH)/National Heart, Lung and Blood Institute (HL139054, HL056177, HL132523, HL091889, HL130045 and HL098112), NIH/National Institute of Environmental Health Sciences (ES006694), NIH/National Institute of Allergy and Infectious Diseases (AI126694), NIH/Office of Director (OD023282) and Johnson & Johnson (UA009253-0001), and personal fees for consultancy from Copeval and Commense Inc., outside the submitted work. Conflict of interest: M. Halonen reports grants from the National Institutes of Health during the conduct of the study. Conflict of interest: K.S. Ramos reports grants from the National Institutes of Health during the conduct of the study. He holds patent W02017172839A1 (Use of biomarkers associated with LINE-1) and patent 2019 62/787444 (Systems and methods for characterizing and treating disease)., (Copyright ©ERS 2019.)

Rationale: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases., Objectives: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions., Methods: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16 -/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway., Measurements and Main Results: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16 -/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16 -/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness., Conclusions: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.

Alcohol intake has been inconsistently associated with lung function levels in cross-sectional studies. The goal of our study was to determine whether longitudinally assessed light-to-moderate alcohol intake is associated with levels and decline of lung function. We examined data from 1333 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease. Alcohol intake was assessed with four surveys between 1972 and 1992. Subjects who completed at least two surveys were classified into longitudinal drinking categories ("never", "inconsistent", or "persistent drinker"). Spirometric lung function was measured in up to 11 surveys between 1972 and 1992. Random coefficient models were used to test for differences in lung function by drinking categories. After adjustment for sex, age, height, education, BMI categories, smoking status, and pack-years, as compared to never-drinkers, persistent drinkers had higher FVC (coefficient: 157 mL, p < 0.001), but lower FEV 1 /FVC ratio (-2.3%, p < 0.001). Differences were due to a slower decline of FVC among persistent than among never-drinkers (p = 0.003), and these trends were present independent of smoking status. Inconsistent drinking showed similar, but weaker associations. After adjustment for potential confounders, light-to-moderate alcohol consumption was associated with a significantly decreased rate of FVC decline over adult life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Hospitalization of patients with chronic obstructive pulmonary disease creates a huge healthcare burden. Positive airway pressure therapy is sometimes used in patients with chronic obstructive pulmonary disease, but the possible impact on hospitalization risk remains controversial. We studied the hospitalization risk of patients with chronic obstructive pulmonary disease before and after initiation of various positive airway pressure therapies in a "real-world" bioinformatics study., Methods: We performed a retrospective analysis of administrative claims data of hospitalizations in patients with chronic obstructive pulmonary disease who received or did not receive positive airway pressure therapy: continuous positive airway pressure, bilevel positive airway pressure, and noninvasive positive pressure ventilation using a home ventilator., Results: The majority of 1,881,652 patients with chronic obstructive pulmonary disease (92.5%) were not receiving any form of positive airway pressure therapy. Prescription of bilevel positive airway pressure (1.5%), continuous positive airway pressure (5.6%), and noninvasive positive pressure ventilation (<1%) in patients with chronic obstructive pulmonary disease demonstrated geographic-, sex-, and age-related variability. After adjusting for confounders and propensity score, noninvasive positive pressure ventilation (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.13-0.27), bilevel positive airway pressure (OR, 0.42; 95% CI, 0.39-0.45), and continuous positive airway pressure (OR, 0.70; 95% CI, 0.67-0.72) were individually associated with lower hospitalization risk in the 6 months post-treatment when compared with the 6 months pretreatment but not when compared with the baseline period between 12 and 6 months before treatment initiation. Stratified analysis suggests that comorbid sleep-disordered breathing, chronic respiratory failure, heart failure, and age less than 65 years were associated with greater benefits from positive airway pressure therapy., Conclusion: Initiation of positive airway pressure therapy was associated with reduction in hospitalization among patients with chronic obstructive pulmonary disease, but the causality needs to be determined by randomized controlled trials., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess longitudinal change in refractive, keratometric, and internal astigmatism in a sample of students from a population with a high prevalence of with-the-rule (WTR) astigmatism and to determine the optical origins of changes in refractive astigmatism., Methods: A retrospective analysis of longitudinal measurements of right eye refractive and keratometric astigmatism in Tohono O'odham Native American children was conducted. Changes in refractive and keratometric astigmatism per year were compared in a younger cohort (n = 1594, 3 to <11 years old) and an older cohort (n = 648, 11 to <19 years old). Data were analyzed in clinical notation (Cyl) and vector notation (J0, J45)., Results: On average, refractive astigmatism (means: 1.19 diopters [D] Cyl, +0.54 J0, +0.03 J45) resulted primarily from WTR corneal astigmatism (means: +0.85 J0, -0.02 J45) and against-the-rule (ATR) internal astigmatism (means: -0.31 J0, +0.05 J45). Mean longitudinal changes in astigmatism were statistically significant (younger cohort -0.02 D/y Cyl; older cohort +0.06 D/y Cyl). In the younger cohort, astigmatism decreased with age in low and moderate astigmats (<3.00 D) and increased with age in high astigmats (≥3.00 D). In the older cohort, astigmatism increased with age across all levels of astigmatism. Longitudinal changes in keratometric and internal astigmatism were negatively correlated in both cohorts., Conclusions: Cross-sectional data suggest the presence of a constant ATR contribution from internal astigmatism (0.60 D Cyl) that is close to the 0.50 D ATR constant reported by Javal and others. Highly astigmatic 3- to <11-year-old children and children older than age 11 years show a small (not clinically significant) increase in astigmatism with age. A negative correlation between changes in keratometric astigmatism and internal astigmatism suggests an active compensation that may contribute to the stability of astigmatism in Tohono O'odham children., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To determine the accuracy and stability of accommodation in uncorrected children during visual task performance., Methods: Subjects were second- to seventh-grade children from a highly astigmatic population. Measurements of noncycloplegic right eye spherical equivalent (Mnc) were obtained while uncorrected subjects performed three visual tasks at near (40 cm) and distance (2 m). Tasks included reading sentences with stimulus letter size near acuity threshold and an age-appropriate letter size (high task demands) and viewing a video (low task demand). Repeated measures ANOVA assessed the influence of astigmatism, task demand, and accommodative demand on accuracy (mean Mnc) and variability (mean SD of Mnc) of accommodation., Results: For near and distance analyses, respectively, sample size was 321 and 247, mean age was 10.37 (SD 1.77) and 10.30 (SD 1.74) years, mean cycloplegic M was 0.48 (SD 1.10) and 0.79 diopters (D) (SD 1.00), and mean astigmatism was 0.99 (SD 1.15) and 0.75 D (SD 0.96). Poor accommodative accuracy was associated with high astigmatism, low task demand (video viewing), and high accommodative demand. The negative effect of accommodative demand on accuracy increased with increasing astigmatism, with the poorest accommodative accuracy observed in high astigmats (≥3.00 D) with high accommodative demand/high hyperopia (1.53 D and 2.05 D of underaccommodation for near and distant stimuli, respectively). Accommodative variability was greatest in high astigmats and was uniformly high across task condition. No/low and moderate astigmats showed higher variability for the video task than the reading tasks., Conclusions: Accuracy of accommodation is reduced in uncorrected children with high astigmatism and high accommodative demand/high hyperopia, but improves with increased visual task demand (reading). High astigmats showed the greatest variability in accommodation., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Background: YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers., Aim: To determine the longitudinal relation of circulating YKL-40 to levels and decline of lung function in the general population., Methods: We used longitudinal data from up to 13 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972 and 1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function., Results: Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p = 0.05) faster than subjects in the third quartile, 5 ml/yr (p = 0.02) faster than subjects in the second quartile, and 10 ml/yr (p < 0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined, the top YKL-40 quartile was associated with a 9 ml/yr (p = 0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p = 0.35)., Conclusions: Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To describe change in spherical equivalent (M) in a longitudinal sample of Tohono O'odham students ages 3 to 18 years and to test the hypothesis that astigmatism creates complex cues to emmetropization, resulting in increased change in M in the direction of increasing myopia and increased occurrence of myopia., Methods: Subjects were 777 Tohono O'odham Native American children on whom cycloplegic right eye autorefraction was measured on at least two study encounters between ages 3 and 18 years (first encounter prior to age 5.5 years, final encounter ≥3 years later). Regression lines were fit to individual subjects' longitudinal M data to estimate rate of change in M (regression slope, D/yr). Regression was also used to predict if a subject would be myopic (≤-0.75 D M) by age 18 years. Analysis of covariance was used to assess the relation between M slope and magnitude of baseline M and astigmatism. Chi-square analyses were used to assess the relation between predicted myopia onset and magnitude of baseline M and astigmatism., Results: Mean M slope was significantly more negative for hyperopes (M ≥ +2.00) than for myopes (M ≤ -0.75) or for subjects neither hyperopic nor myopic (NHM, M > -0.75 and < +2.00), but there was no significant difference between the myopic and NHM groups. Chi-square analysis indicated that final myopia status varied across level of baseline astigmatism. Subjects with high astigmatism were more likely to be predicted to have significant myopia by age 18 years., Conclusions: The association between greater shift in M towards myopia with age in subjects who were hyperopic at baseline is consistent with continued emmetropization in the school years. Results regarding predicted myopia development imply that degradation of image quality due to refractive astigmatism creates complex cues to emmetropization, resulting in increased occurrence of myopia.

Background: Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults., Methods: We used data from the prospective birth cohort, the Tucson Children's Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participant's birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 μg of albuterol at YR11, YR16, YR22 and YR26., Results: Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV1/FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25-75) and FEF25-75/FVC (all p values between 0.03 and <0.001)., Conclusions: Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.

In order to raise public awareness of the importance of early detection of airway obstruction and to enable many people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004-2009. Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. Nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLN) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for diagnosing and grading airway obstruction were used. Of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0 ± 18.4 yrs; 25.5% smokers; 5.5% asthmatic). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria. Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. Relative risk ratio and 95% confidence interval for LLN stage I, for example, was 2.9 (2.0-4.1) for the youngest age (≤ 19 yrs), 1.9 (1.2-3.0) for the oldest age (≥ 80 yrs), 2.4 (2.0-2.9) for current smokers and 2.8 (2.2-3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a leading cause of hospitalizations in the United States and the major cost driver of COPD. This study determined the national inpatient burden of AECOPD and assessed the association of co-morbidities and hospital characteristics with inpatient costs and mortality. Discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample for 2006 was utilized. Outcomes of costs and mortality were assessed for AECOPD hospitalizations in cases ≥40 years of age. Multivariate regression analyses using a generalized linear model framework were conducted to determine predictors of inpatient costs and mortality controlling for patient demographics, primary payer, co-morbidity index, length of stay, hospital region, mechanical ventilation, and admission period. Overall, 1,254,703 hospitalizations for AECOPD were observed with mean costs of $9545(±12,700) and total costs of $11.9 billion. In-hospital mortality was 4.3% (N = 53,748). Discharges averaged 70.6 (±11.9) years of age. The majority were female (52.8%) and of white race (83.6% of reported race). Several co-morbidities were significantly associated with both costs and mortality (p < 0.001): acute myocardial infarction; congestive heart failure; cerebrovascular disease; lung cancer; cardiac arrhythmias; pulmonary circulation disorders; and weight loss. Significantly higher costs (p < 0.001) were associated with large and urban hospitals. The importance of co-morbidities in AECOPD is indicated in their association with prognosis and inpatient costs. Future research should determine if better management of these conditions can favorably impact the COPD disease burden.

Background: Familial aggregation of specific response to allergens and asthma adjusted for age and sensitization to multiple allergens was assessed in two large population cohorts., Methods: Allergen skin prick tests (SPTs) were administered to 1151 families in the Tucson Children's Respiratory Study (CRS) and 435 families in the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD). Sensitization was defined by wheal size ≥3 mm; physician-diagnosed asthma at age ≥8 yr was based on questionnaires. Using S.A.G.E. 6.1 software ASSOC and FCOR, familial correlations of crude and adjusted phenotypes were evaluated., Results: Crude estimates of parent-offspring (P-O) and sibling correlations were statistically significant for most allergens, ranging from 0.03 to 0.29. After adjusting for age of assessment and 'other atopy' (SPT-positive response to additional allergens), correlations were reduced by 14-71%. Sibling correlations for specific response to allergens were consistently higher than P-O correlations, but this difference was significant only for dust mite and weed mix in the TESAOD population. Familial correlation for atopic status (any positive SPTs vs. none) tended to be higher than for specific allergens. Asthma, with and without adjustment, showed greater familial correlation than either specific or general SPT response and significantly higher sibling correlation in TESAOD than in CRS, probably due to the older age of the siblings and the longer period of ascertainment., Conclusions: Significant familial aggregation of specific response to allergen after adjustment for other atopy appears to reflect a genetic propensity toward atopy, dependent on shared familial exposures. Results also suggest that inheritance of asthma is independent of atopic sensitization., (© 2011 John Wiley & Sons A/S.)

The overall goal of this study was to assess the longitudinal changes in bone strength in women reporting rheumatoid arthritis (RA; n=78) compared with nonarthritic control participants (n=4779) of the Women's Health Initiative bone mineral density (WHI-BMD) subcohort. Hip structural analysis program was applied to archived dual-energy X-ray absorptiometry scans (baseline, years 3, 6, and 9) to estimate bone mineral density (BMD) and hip structural geometry parameters in 3 femoral regions: narrow neck (NN), intertrochanteric (IT), and shaft (S). The association between RA and hip structural geometry was tested using linear regression and random coefficient models. Compared with the nonarthritic control, the RA group had a lower BMD (p=0.061) and significantly lower outer diameter (p=0.017), cross-sectional area (p=0.004), and section modulus (p=0.035) at the NN region in the longitudinal models. No significant associations were seen at the IT regions or S regions, and the association was not modified by age, ethnicity, glucocorticoid use, or time. Within the WHI-BMD, women with RA group had reduced BMD and structural geometry at baseline, and this reduction was seen at a fixed rate throughout the 9 yr of study., (Copyright © 2012 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Study Objective: The Epworth Sleepiness Scale (ESS) has been used to detect patients with potential sleep disordered breathing (SDB). Recently, a 4-Variable screening tool was proposed to identify patients with SDB, in addition to the STOP and STOP-Bang questionnaires. This study evaluated the abilities of the 4-Variable screening tool, STOP, STOP-Bang, and ESS questionnaires in identifying subjects at risk for SDB., Methods: A total of 4,770 participants who completed polysomnograms in the baseline evaluation of the Sleep Heart Health Study (SHHS) were included. Subjects with RDIs ≥ 15 and ≥ 30 were considered to have moderate-to-severe or severe SDB, respectively. Variables were constructed to approximate those in the questionnaires. The risk of SDB was calculated by the 4-Variable screening tool according to Takegami et al. The STOP and STOP-Bang questionnaires were evaluated including variables for snoring, tiredness/sleepiness, observed apnea, blood pressure, body mass index, age, neck circumference, and gender. Sleepiness was evaluated using the ESS questionnaire and scores were dichotomized into < 11 and ≥ 11., Results: The STOP-Bang questionnaire had higher sensitivity to predict moderate-to-severe (87.0%) and severe (70.4%) SDB, while the 4-Variable screening tool had higher specificity to predict moderate-to-severe and severe SDB (93.2% for both)., Conclusions: In community populations such as the SHHS, high specificities may be more useful in excluding low-risk patients, while avoiding false positives. However, sleep clinicians may prefer to use screening tools with high sensitivities, like the STOP-Bang, in order to avoid missing cases that may lead to adverse health consequences and increased healthcare costs.

Rationale: Several studies have reported associations between indicators of birth size and postnatal growth rates with levels of pulmonary function achieved as adults. The objective of this study was to determine if levels and/or rates of weight gain, measured in early life (birth-6 years), are associated with FVC or FEV1 levels achieved in young adulthood and if these associations differ by early childhood wheezing phenotypes., Methods: We used data from participants in the Tucson Children's Respiratory Study (CRS), a prospective birth cohort study. Weight was measured quarterly up to age 3 years and again at age 6 years. Pulmonary function was assessed at ages 16 and 22. Mean weight and slope of weight growth between 3 and 6 years were estimated using standardized residuals. Longitudinal models were used to determine predictors of FVC and FEV1 at ages 16 and 22 years., Results: There were 127 non-Hispanic white subjects that had at least four weight measures and one or more pulmonary function measures as young adults. After adjusting for sex, height, and age, the standardized slope of weight growth (between 3 and 6 years) was positively associated with higher levels of FVC at age 16 and 22 years (P = 0.0001) among subjects who did not have preschool wheezing. However, this association was completely absent among subjects who had wheezing lower respiratory tract illnesses in the first 3 years of life. Similar trends were found for FEV1., Conclusion: The rate of weight gain between 3 and 6 years is significantly positively related to adult FVC and FEV1 and this association is modified by early wheezy phenotypes., (Copyright © 2011 Wiley-Liss, Inc.)

Study Objective: To determine the impact of lower amounts of childhood sleep assessed by polysomnogram on development of obesity, being anxious or depressed, or having learning problems 5 years later., Design: Prospective cohort., Participants: Subjects were 304 community participants from the Tucson Children's Assessment of Sleep Apnea study, aged 6-12 years old at baseline., Measurements and Results: Children were classified according to baseline sleep as those who slept ≥ 9 h/night, those who slept > 7.5 to < 9 h/night, and those who slept ≤ 7.5 h/night. Odds of overweight/obese (≥ 85(th) BMI percentile), obese (≥ 95(th) BMI percentile), anxious or depressed, and learning problems at follow-up were assessed according to baseline sleep categories. Children who slept ≤ 7.5 h/night had higher odds of being obese (OR = 3.3, P < 0.05) at follow-up than children who slept ≥ 9 h/night. Borderline significance for overweight/obese (OR = 2.2, P < 0.1), anxious or depressed (OR = 3.3, P < 0.1), and having learning problems (OR = 11.1, P < 0.1) were seen for children who slept ≤ 7.5 h/night as compared to those who slept ≥ 9 h/night. A mean increase in BMI of 1.7 kg/m(2) (P = 0.01) over the 5 years of follow-up was seen for children who slept ≤ 7.5 h/night compared to those who slept ≥ 9 h/night. These relationships did not differ between Hispanic and Caucasian children., Conclusions: Children with reduced amounts of sleep (≤ 7.5 h/night) had an increased risk for higher body weight in early adolescence. Similarly, children who slept ≤ 7.5 h/night had higher risk of being anxious or depressed or having learning problems in early adolescence.

In this study, we examined the role of neprilysin (NEP), a key membrane-bound endopeptidase, in the inflammatory response induced by diesel exhaust emissions (DEE) in the airways through a number of approaches: in vitro, animal, and controlled human exposure. Our specific aims were (1) to examine the role of NEP in inflammatory injury induced by diesel exhaust particles (DEP) using Nep-intact (wild-type) and Nep-null mice; (2) to examine which components of DEP are associated with NEP downregulation in vitro; (3) to determine the molecular impact of DEP exposure and decreased NEP expression on airway epithelial cells' gene expression in vitro, using a combination of RNA interference (RNAi) and microarray approaches; and (4) to evaluate the effects on NEP activity of human exposure to DEE. We report four main results: First, we found that exposure of normal mice to DEP consisting of standard reference material (SRM) 2975 via intratracheal installation can downregulate NEP expression in a concentration-dependent manner. The changes were accompanied by increases in the number of macrophages and epithelial cells, as well as proinflammatory cytokines, examined in bronchoalveolar lavage (BAL) fluid and cells. Nep-null mice displayed increased and/or additional inflammatory responses when compared with wild-type mice, especially in response to exposure to the higher dose of DEP that we used. These in vivo findings suggest that loss of NEP in mice could cause increased susceptibility to injury or exacerbate inflammatory responses after DEP exposure via release of specific cytokines from the lungs. Second, we found evidence, using in vitro studies, that downregulation of NEP by DEP in cultured human epithelial BEAS-2B cells was mostly attributable to DEP-adsorbed organic compounds, whereas the carbonaceous core and transition metal components of DEP had little or no effect on NEP messenger RNA (mRNA) expression. This NEP downregulation was not a specific response to DEP or its contents because the change also occurred after exposure to urban dust (SRM 1649a), which differs in physical and chemical composition from DEP. Third, we also collected the transcriptome profiles of the concentration-effects of SRM 2975 in cultured BEAS-2B cells through a 2 X 3 factorial design. DEP exposure upregulated 151 genes and downregulated 59 genes. Cells with decreased NEP expression (accomplished by transfecting an NEP-specific small interfering RNA [siRNA]) substantially altered the expression of genes (upregulating 17 and downregulating 14) associated with DNA/protein binding, calcium channel activities, and the cascade of intracellular signaling by cytokines. Data generated from the combined RNAi and microarray approaches revealed that there is a complex molecular cascade mediated by NEP in different subcellular compartments, possibly influencing the inflammatory response. Fourth, in a controlled human exposure study, we observed significant increases in soluble NEP in sputum after acute exposure to DEE, with an average net increase of 31%. We speculate that the change in NEP activity in sputum, if confirmed in larger epidemiologic investigations at ambient exposure levels to DEE, may provide a useful endpoint and promote insight into the mechanism of DEE-induced airway alterations.

Background: Recent studies have suggested that a restrictive pattern assessed with a single spirometric test is associated with increased morbidity and mortality. This study was undertaken to determine demographic, clinical and mortality profiles of subjects with either a recurrent or an inconsistent restrictive spirometric pattern assessed prospectively., Methods: Data from 2048 adult participants in the population-based TESAOD study were analysed. Normal (forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) ratio >or=70% and FVC >or=80% predicted), restrictive (FEV(1)/FVC >or=70% and FVC <80% predicted) and obstructive (FEV(1)/FVC <70%) patterns were assessed at the enrollment survey in 1972 and in 11 subsequent follow-up surveys up to 1996. Demographic and clinical characteristics were measured at enrollment and vital status and cause of death were assessed at January 2005., Results: Overall, 12% of participants had a restrictive spirometric pattern at enrollment. They were less likely to be male, to smoke and to have asthma, and had lower IgE levels than subjects in the obstructive group. Among subjects with a restrictive pattern at enrollment, 38% developed an obstructive pattern during follow-up. The remaining 62% had either a recurrent (restrictive pattern >or=50% of follow-up surveys) or inconsistent (restrictive pattern <50% of follow-up surveys) longitudinal restrictive pattern. The recurrent and inconsistent restrictive groups had increased mortality risk for all-cause (adjusted HR 1.7 (95% CI 1.3 to 2.3) and 1.9 (95% CI 1.4 to 2.6), respectively), heart disease (2.0 (95% CI 1.3 to 3.1) and 2.7 (95% CI 1.7 to 4.3)), stroke (2.4 (95% CI 0.9 to 6.3) and 3.5 (95% CI 1.2 to 9.8)) and diabetes (8.0 (95% CI 2.9 to 21.8) and 6.0 (95% CI 1.9 to 19.2))., Conclusions: The restrictive spirometric pattern identifies a pulmonary condition that is distinguishable from obstructive lung disease and is associated with an increased risk of life-threatening comorbidities.

Background: Previous studies on the relationship of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. This study sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality and serum levels of C-reactive protein (CRP) and interleukin-8 (IL-8), and whether subjects' age influences these relationships., Methods: 1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrolment (1972-1973) were 21-80 years old and had FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) > or = 70% and no asthma were identified. Chronic bronchitis was defined as cough and phlegm production on most days for > or = 3 months in two or more consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV(1)/FVC <70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrolment survey., Results: After adjusting for covariates, chronic bronchitis at enrolment significantly increased the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (HR 2.2, 95% CI 1.3 to 3.8; and HR 2.2, 95% CI 1.3 to 3.8; respectively), but not among subjects > or = 50 years old (HR 0.9, 95% CI 0.6 to 1.4; and HR 1.0, 95% CI 0.7 to 1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old., Conclusions: Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.

Background: The treatment of Nocardia species found in the sputum of cystic fibrosis patients is of unknown value., Methods: We conducted a retrospective analysis of the impact of directed oral antibiotic therapy against Nocardia spp. isolated from the sputum of 17 cystic fibrosis patients over a 10-year period. Pulmonary Function Tests were used as the clinical indicator of the disease state and the data were analyzed by general linear mixed model statistics with univariate analysis., Results: Pulmonary Function Test values of all patients studied showed no significant difference before, during, or after the antibiotic treatment period. Treatment groups did not differ from non-treatment groups. This held true for Forced Expiratory Volume over 1 s and Functional Vital Capacity analysis. In addition, individual patient analysis did not reveal any trends or outliers., Conclusions: Oral antibiotic therapy of cystic fibrosis patients colonized with Nocardia does not appear to affect clinical outcome. This suggests that deferring therapy may be an acceptable alternative and justifies conducting a future placebo controlled trial. In addition, this study model may be useful in analyzing the effect of therapy on other rare and difficult organisms, such as fungi and mycobacteria in the cystic fibrosis population.

Rationale: Most patients who develop persistent airflow limitation do so either as a manifestation of chronic obstructive pulmonary disease that is largely related to smoking or as a consequence of persistent asthma. We sought to compare the natural course of lung function associated with persistent airflow limitation in subjects with and without asthma from early to late adult life., Methods: We studied 2552 participants aged 25 or more who had multiple questionnaire and lung function data from the long-term prospective population-based Tucson Epidemiological Study of Airway Obstructive Disease. Persistent airflow limitation was defined as FEV(1)/FVC ratio consistently < 70% in all completed surveys subsequent to the first survey with airflow limitation. Participants were divided into nine groups based on the combination of their physician-confirmed asthma status (never, onset < or = 25 years, or onset > 25 years) and the presence of airflow limitation during the study follow-up (never, inconsistent, or persistent)., Results: Among subjects with an asthma onset < or = 25 years, blood eosinophilia increased significantly the odds of developing persistent airflow limitation (adjusted ORs: 3.7, 1.4-9.5), whereas cigarette smoking was the strongest risk factor for persistent airflow limitation among non-asthmatics and among subjects with asthma onset after age 25 years. Among subjects with persistent airflow limitation, the natural course of lung function differed between subjects with asthma onset < or = 25 years and non-asthmatics, with the former having lower FEV(1) levels at age 25 (predicted value for a 175-cm tall male of 3400 versus 4090 ml, respectively; p<0.001) and the latter having greater FEV(1) loss between age 25 and 75 (1590 versus 2140 ml; p=0.003)., Conclusion: In subjects who have asthma onset before 25 years of age and persistent airflow limitation in adult life, the bulk of the FEV(1) deficit is already established before age 25 years.