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• W3194017097 abstract "Dysanapsis refers to an anthropometric mismatch of airway tree caliber that was initially inferred from maximal expiratory airflow variation among healthy adults.1Green M. Mead J. Turner J.M. Variability of maximum expiratory flow-volume curves.J Appl Physiol. 1974; 37: 67-74Google Scholar CT-assessed dysanapsis among older adults is a major risk factor for COPD independent of standard risk factors (ie, tobacco exposures, air pollutants, asthma).2Smith B.M. Kirby M. Hoffman E.A. et al.Association of dysanapsis with chronic obstructive pulmonary disease among older adults.JAMA. 2020; 323: 2268-2280Google Scholar Although the mechanisms of dysanapsis are uncertain, factors that affect airway tree growth early in life1Green M. Mead J. Turner J.M. Variability of maximum expiratory flow-volume curves.J Appl Physiol. 1974; 37: 67-74Google Scholar,3Martin T.R. Feldman H.A. Fredberg J.J. Castile R.G. Mead J. Wohl M.E. Relationship between maximal expiratory flows and lung volumes in growing humans.J Appl Physiol. 1988; 65: 822-828Google Scholar and factors that affect airway tree homeostasis later in life have been implicated.4Rawlins E.L. Okubo T. Xue Y. et al.The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium.Cell Stem Cell. 2009; 4: 525-534Google Scholar,5Ito K. Barnes P.J. COPD as a disease of accelerated lung aging.Chest. 2009; 135: 173-180Google Scholar The present study tested the hypothesis that dysanapsis that is assessed directly by CT and its association with airflow obstruction are established by early adulthood, thus providing evidence that CT-assessed dysanapsis, at least in part, is due to early life factors. We conducted a cross-sectional study that included men and women aged 20 to 60 years old who were enrolled from the community at the University of Iowa. Exclusion criteria included participants who reported ever smoking (≥20 cigarettes in their lifetime), any diagnosed lung disease ever or medication for breathing, contraindication to spirometry or CT, or chest CT within 1 year. All procedures were approved by ethics committees of the University of Iowa and Columbia University. All participants provided written informed consent. Participants underwent inspiratory full-lung CT6Hammond E. Sloan C. Newell Jr., J.D. et al.Comparison of low- and ultralow-dose computed tomography protocols for quantitative lung and airway assessment.Med Phys. 2017; 44: 4747-4757Google Scholar according to a standardized protocol (Siemens SOMATOM Force scanner: 36 milliampere-seconds, 120 kilovoltage peak, thickness 0.75 mm, CareDose, [mean ± SD radiation dose, 1.04 ± 0.22 millisievert], advanced modeled iterative reconstruction kernel; Siemens Healthineers). Cross-sectional airway lumen diameters at 19 standard anatomic locations (trachea-to-subsegments) and total lung volume were measured from CT images with the use of Apollo software (VIDA Diagnostics).2Smith B.M. Kirby M. Hoffman E.A. et al.Association of dysanapsis with chronic obstructive pulmonary disease among older adults.JAMA. 2020; 323: 2268-2280Google Scholar Dysanapsis was quantified for each participant as the mean of airway lumen diameters in centimeters measured at 19 standard anatomic locations divided by the cube-root of total lung volume in cubic centimeters (airway-to-lung ratio). Lower values of airway-to-lung ratio indicate smaller airway tree caliber relative to lung size. Spirometry was performed according to American Thoracic Society standards.7Miller M.R. Hankinson J. Brusasco V. et al.Standardisation of spirometry.Eur Respir J. 2005; 26: 319-338Google Scholar Postbronchodilator spirometry was not performed. Airflow obstruction was quantified as the FEV1 divided by FVC. FEV1/FVC z-score was calculated with the Global Lung Initiative equation as an alternate approach to account for age, height, and sex differences in FEV1/FVC.8Quanjer P.H. Stanojevic S. Cole T.J. et al.Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations.Eur Respir J. 2012; 40: 1324-1343Google Scholar Age, sex, and race/ethnicity were self-reported. Body height and weight were measured with the use of a standardized protocol; BMI was calculated as weight in kilograms divided by height in square meters. CT-assessed emphysema was quantified as the percent lung volume ≤950 Hounsfield units (HU) and the lower 15th percentile of cumulative lung density distribution. The association between airway-to-lung ratio and FEV1/FVC was assessed by fitting a regression model adjusted for age, age squared, sex, height and height squared. Sensitivity analyses included models unadjusted, adjusted additionally for BMI, race/ethnicity, and emphysema measures, replacement of FEV1/FVC with FEV1/FVCz-score, addition of an age x airway-to-lung ratio interaction term, and restriction of the sample to the 20- to 30-year age range (early adulthood). To quantify the proportion of variation in FEV1/FVC explained by airway-to-lung ratio, the adjusted R2 was calculated from a regression model incrementally adjusted for age, age squared, height, height squared, sex, and airway-to-lung ratio. Analyses were performed with the use of SAS software (version 9.4; SAS Institute Inc). A two-sided probability value of <.05 was considered statistically significant. Among 101 participants (Table 1), the mean ± SD age was 41 ± 13 years (20 to 30 years old: n = 30); 56% were women; the mean FEV1/FVC was 0.80 ± 0.05, and airway-to-lung ratio was 0.031 ± 0.003.Table 1Participant CharacteristicsCharacteristicMeasureParticipants, No.101Participants by age range, No. 20-30 y30 31-40 y16 41-50 y22 51-60 y33Age, mean ± SD, y41 ± 13Sex, No. (%) Female56 (55) Male45 (45)Height, mean ± SD, cm171 ± 9BMI, mean ± SD, kg/m226 ± 4Race/ethnicity, No. (%) Non-Hispanic White83 (82) Non-Hispanic Black3 (3) Hispanic6 (6) Asian9 (9)Spirometry, mean ± SD FEV1/FVC0.80 ± 0.05 FEV1/FVCz-score−0.84 ± 0.99CT measures Airway-to-lung ratio,aAirway-to-lung ratio was quantified as the geometric mean of airway lumen diameters in centimeters measured at 19 standard locations divided by to cube root of lung volume in cubic centimeters. mean ± SD0.031 ± 0.003 Percent lung volume ≤950 Hounsfield units,bPercent lung volume below −950 Hounsfield units and the 15th percentile of cumulative lung density distribution are quantitative CT measures of emphysema-like lung. median (interquartile range), Hounsfield units0.04 (0.02 to 0.13) Lower 15th percentile of cumulative lung density distribution, mean ± SD, Hounsfield unitsbPercent lung volume below −950 Hounsfield units and the 15th percentile of cumulative lung density distribution are quantitative CT measures of emphysema-like lung.−758 ± 63a Airway-to-lung ratio was quantified as the geometric mean of airway lumen diameters in centimeters measured at 19 standard locations divided by to cube root of lung volume in cubic centimeters.b Percent lung volume below −950 Hounsfield units and the 15th percentile of cumulative lung density distribution are quantitative CT measures of emphysema-like lung. Open table in a new tab Smaller airway-to-lung ratio was associated with significantly lower FEV1/FVC independent of age, age squared, sex, height, and height squared (mean difference per 1-SD decrement in airway-to-lung ratio, -0.03; 95% CI, -0.04 to -0.02; P < .0001). Similar associations were observed in analyses unadjusted (P = .003); with additional adjustment for BMI (P < .0001); race/ethnicity (P < .0001); emphysema measures (percent lung volume ≤950 Hounsfield units, P < .0001; the lower 15th percentile of cumulative lung density distribution, P < .0001); restricted to participants 20 to 30 years old (P < .001), and FEV1/FVCz-score (P < .0001). Age did not modify the association between airway-to-lung ratio and FEV1/FVC (P-interaction = .17). The combination of age and age squared accounted for 15% of the variation in FEV1/FVC; height and height squared explained an additional 6%, and sex explained an additional 1%. The airway-to-lung ratio, when added to the aforementioned factors, explained an additional 20% of the variation in FEV1/FVC. Dysanapsis quantified directly by CT as the airway-to-lung ratio was evident among non-smoking adults free of clinical lung disease aged 20 to 60 years and was associated with FEV1/FVC independent of age, sex, and body size. Moreover, this association was evident among young adults (aged 20 to 30 years old) and did not differ by age from early-to-mid adulthood. These findings provide empiric evidence that CT-assessed dysanapsis among adults and its association with airflow obstruction, at least in part, are due to factors that occur at or before early adulthood. The variation in airway-to-lung ratio that was observed in early-to-mid adulthood (airway-to-lung-ratio SD, 0.003) was similar to that reported in two community-based samples of older adults (the Canadian Cohort of Obstructive Lung Disease [airway-to-lung ratio SD, 0.003] and the Multi-Ethnic Study of Atherosclerosis Lung study [airway-to-lung ratio SD, 0.004]).2Smith B.M. Kirby M. Hoffman E.A. et al.Association of dysanapsis with chronic obstructive pulmonary disease among older adults.JAMA. 2020; 323: 2268-2280Google Scholar Moreover, the proportion of variation in FEV1/FVC explained by airway-to-lung ratio in the present study (adjusted R2, 20%) is consistent with that observed in older adult community-based samples (Canadian Cohort of Obstructive Lung Disease, 19%; Multi-Ethnic Study of Atherosclerosis Lung study, 17%).2Smith B.M. Kirby M. Hoffman E.A. et al.Association of dysanapsis with chronic obstructive pulmonary disease among older adults.JAMA. 2020; 323: 2268-2280Google Scholar The findings are also consistent with a previous lung function trajectory study that showed that a substantial proportion of older adults with COPD manifest low lung function in early adulthood9Lange P. Celli B. Agusti A. Lung-function trajectories and chronic obstructive pulmonary disease.N Engl J Med. 2015; 373: 1575Google Scholar and that dysanapsis inferred from spirometry is evident in childhood.3Martin T.R. Feldman H.A. Fredberg J.J. Castile R.G. Mead J. Wohl M.E. Relationship between maximal expiratory flows and lung volumes in growing humans.J Appl Physiol. 1988; 65: 822-828Google Scholar The present study did not assess mechanism. Although direct observation of dysanapsis among young adults in the absence of smoking or clinical lung disease implies that etiologic factors must be present at or before early adulthood,1Green M. Mead J. Turner J.M. Variability of maximum expiratory flow-volume curves.J Appl Physiol. 1974; 37: 67-74Google Scholar,3Martin T.R. Feldman H.A. Fredberg J.J. Castile R.G. Mead J. Wohl M.E. Relationship between maximal expiratory flows and lung volumes in growing humans.J Appl Physiol. 1988; 65: 822-828Google Scholar they do not exclude subsequent contributions by factors related to airway homeostasis/injury later in life.4Rawlins E.L. Okubo T. Xue Y. et al.The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium.Cell Stem Cell. 2009; 4: 525-534Google Scholar,5Ito K. Barnes P.J. COPD as a disease of accelerated lung aging.Chest. 2009; 135: 173-180Google Scholar Dysanapsis was initially inferred among healthy individuals with the use of spirometry,1Green M. Mead J. Turner J.M. Variability of maximum expiratory flow-volume curves.J Appl Physiol. 1974; 37: 67-74Google Scholar,3Martin T.R. Feldman H.A. Fredberg J.J. Castile R.G. Mead J. Wohl M.E. Relationship between maximal expiratory flows and lung volumes in growing humans.J Appl Physiol. 1988; 65: 822-828Google Scholar which is a safe and reproducible procedure. In clinical populations, however, various pathophysiologies may impair maximum expiratory flow (eg, emphysema, small airways disease, dysanapsis). Imaging may facilitate clinical endotyping2Smith B.M. Kirby M. Hoffman E.A. et al.Association of dysanapsis with chronic obstructive pulmonary disease among older adults.JAMA. 2020; 323: 2268-2280Google Scholar,10Galban C.J. Han M.K. Boes J.L. et al.Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression.Nat Med. 2012; 18: 1711-1715Google Scholar by quantifying the extent of each these abnormalities in the setting of obstructive lung disease. The cross-sectional design is a limitation, though we note that (1) longitudinal CT imaging among young adults free of clinical disease has radiation risk and (2) the main inference that dysanapsis and its association with airflow obstruction are manifest in early adulthood does not require longitudinal design. In summary, CT-assessed dysanapsis and its association with FEV1/FVC are evident from early adulthood. These findings provide empiric evidence that dysanapsis and its association with airflow obstruction, at least in part, are due to factors that occur at or before early adulthood. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript." @default.
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• W3194017097 date "2022-02-01" @default.
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• W3194017097 title "CT-Assessed Dysanapsis and Airflow Obstruction in Early and Mid Adulthood" @default.
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