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Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, 85719, USAPulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
Several factors occurring in early life, including lower respiratory tract illnesses (LRIs), are involved in determining lung structure and function in adulthood, but the effects of these factors on lung development remain largely unknown. Hereby, we evaluated the parameters from computed tomography (CT) scans performed at the age of 26 years in 39 subjects from the birth cohort of the Tucson Children's Respiratory Study (TCRS) in order to determine the relationship between early childhood factors and lung structural changes in young adult life. We found that participants with LRIs in childhood had increased air trapping at the age of 26 suggesting an association between childhood infections and lung development.
1. Introduction
Large longitudinal cohorts have shown that about half of the individuals who will develop COPD in their adult life do not reach their expected maximal lung function in early adulthood [
], but the etiology of the various lung function trajectories is unclear. Structural studies using computed tomography (CT) carry complementary information that is not captured by spirometry, offering the opportunity to elucidate the structure-function relationships underpinning the trajectories of lung function development.
Multiple factors are involved in determining lung structure and function in adulthood, including genetics, pre- and peri-natal smoke exposure, preterm birth, and lower respiratory tract illnesses (LRIs) in early life [
] are at increased risk of reduced adult lung function.
So far, the effects of pre- and peri-natal factors on lung structural development remain largely unknown because no prospective study has determined whether early-life risk factors are associated with structural alterations in adult life. In the current study, we used the data from the Tucson Children's Respiratory Study (TCRS) cohort to determine the relation between early childhood factors and imaging-based lung structural changes in young adult life.
2. Methods
Between 1980 and 1984, 1246 healthy infants were enrolled in the TCRS Study, a non-selected birth cohort study of the early origins of respiratory diseases followed to date [
]. At age 26 years, 39 non-selected participants, prioritized based upon whether they had lung function testing during infancy, completed post-bronchodilator high-resolution chest CT scans. Lung masks were used to segment the lungs and the percentage of gas trapping [
]. The percentage of gas trapping was calculated as the percentage of lung voxels with attenuation less than −856 Hounsfield Units (%LAA-856) at end-expiratory lung volume (EELV) [
-]. Respiratory symptoms during the past year, lung function, total lung capacity (TLC) by nitrogen washout at the time of the CT scan, and lung clearance index (LCI) were assessed. Physician-diagnosed asthma with symptoms during the past year was ascertained by parentcompleted questionnaire at ages 6, 8, 11, 13, and 16. Lung function parameters Scond and Sacin, indices of peripheral airway function sensitive to the conduction-diffusion wavefront in the terminal bronchioles, were also measured and multiplied by tidal volume (*Vt) to adjust for lung volume and breathing pattern [
]. LRI from birth to age 3 years, and smoking history from adolescence to age 26 were determined prospectively. The occurrence of respiratory syncytial virus (RSV)-LRI was determined by viral culture [
]. Analysis of variance, multiple linear regression, contingency tables with Fisher exact test, and Spearman correlation with 95%CI calculated using the bootstrap method were used for data analysis. P-values <0.05 were considered significant. Data were analyzed using STATA 16.
The demographic composition (sex, race/ethnicity, parental smoking at enrollment, history of parental asthma), as well as the frequency of current symptoms, smoking and lung function of the group of participants with CT data, were similar to the participants without CT at age 26.
CT-assessed %LAA-856 values ranged from 0.2% to 38.0% (median = 14.3%, IQR: 3.2%–22.3%).
Thirty-three participants had complete LRI data from birth through age 3 years, of whom 18 (54.6%) had at least one LRI. A history of LRI was associated with greater %LAA-856 (Table 1 and Fig. 1). Mean %LAA-856 was 18.8% (95%CI: 13.7, 23.9) for those with a history of LRI and 9.5% (95%CI: 3.2, 15.7) for those without a history of LRI (p = 0.018).
Table 1Bivariate relation of participant characteristics to %LAA-856. Participants were enrolled in the study at birth and HRCT was performed at age 26 years.
After adjusting for sex and body mass index (BMI), participants with a history of LRI had significantly greater %LAA-856 compared to participants without a history of LRI (adjusted beta coefficient: 7.4%, [95%CI: 0.35%, 14.5%], p = 0.040). The relation between LRI and %LAA-856 was not appreciably changed by adjustment for smoking at age 26 as ‘never smoker’ and ‘ever smoker’ categories (adjusted beta coefficient: 7.3% [95%CI: 0.1%, 14.6%] p = 0.047) or respiratory symptoms during the past year (adjusted beta coefficient: 8.3%, [95%CI: 1.2%, 15.3%], p = 0.023). The %LAA-856 was similar for those with RSV compared to those with non-RSV LRIs (p = 0.848). There was no significant interaction between sex and LRI on %LAA-856 (interaction p = 0.710) after adjusting for BMI.
There was an inverse correlation between %LAA-856 and % predicted post-bronchodilator FEF25-75 (Table 1). We also found a moderate association between height-, weight- and sex-adjusted values of Scond*VT and %LAA-856 (rho = 0.57, p = 0.018; n = 17) (Fig. 2). Physician-diagnosed asthma, found in 11 of the 39 participants, did not affect the relation between LRI and %LAA-856.
Fig. 2Association between LCI Scond*VT and %LAA-856. The association persisted after removing the outlier with LCI z-score below −2.
In an additional analysis of the relation between the factors shown in Table 1 to LRI, we found no significant differences in the prevalence of LRI by sex, race/ethnicity, maternal smoking or maternal asthma. Additionally, LRI was not related to ever smoking, BMI, FEV1/FVC ratio, FEF25-75, CT airway measures, ppRV, or symptom score at age 26. However, those with LRI had a trend towards lower FEV1 (p = 0.05), FVC (p = 0.06), and ppTLC (p = 0.07) compared to those without LRI.
4. Discussion
The TCRS cohort is the only existing long-term birth cohort followed into the fourth decade of life with HRCT scans performed in young adulthood. We recently showed, in this same population, that a lower time to peak tidal expiratory flow/expiratory time ratio (TPTEF/TE) compatible with longer respiratory system time constants at birth is associated with reduced airway caliber at EELV at age 26 [
]. We now show an association between LRIs in the first three years of life and increased lung lucency as %LAA856, commonly interpreted as gas trapping [
]. Accordingly, Scond*Vt was moderately correlated with increased lung lucency. Increases in Scond*Vt is believed to be related to increased convection-dependent inhomogeneity in the conducting airway zone and have shown to be increased in airway obstructive diseases such as asthma. This suggests that subtle gas trapping may have contributed to the increased %LAA-856 [
]. However, these studies did not address potential effects by pre- and peri-natal exposures. Our findings provide evidence that LRI in childhood is associated with changes in lung structure.
This study has some limitations. First, it is not possible to determine whether the association between LRI and structural changes on CT is due to lung structural damage caused by the respiratory infection itself or to preexisting deficits in lung structure in young children in whom LRI develops. Nonetheless, air trapping on CT is associated with further lung function decline, and hence is an important finding [
]. Also, it is difficult to extrapolate whether the observed increase in %LAA-856 in subjects who had LRI in childhood was associated with parenchymal structural changes since none of the subjects had a clear emphysematous pattern. However, it is plausible that alveolar simplification could be a consequence of RSV-LRI or a risk factor for symptomatic LRI due to less recoil maintaining small airway patency.
These observations provide the first evidence of structural lung abnormalities associated with LRIs earlier in life. Further studies are needed in order to clarify the prognostic significance of these findings on CT in a population-based sample, and to shed light onto the physiology of lung structural changes over the course of life.
CRediT authorship contribution statement
Francesca Polverino: Conceptualization, Supervision, Writing - original draft, Writing - review & editing. Debra A. Stern: Formal analysis. Fernando D. Martinez: Formal analysis. Stefano Guerra: Formal analysis, Writing – original draft. Wayne J. Morgan: Formal analysis, Writing – original draft.
Declaration of competing interest
FP is supported by NIH grant RO1 HL149744, has received an unrestricted grant from Boehringer Ingelheim and is section editor for the European Respiratory Journal. SPB is supported by NIH grants R01HL151421 and UH3HL155806. He has received consulting fees from Boehringer Ingelheim and Sanofi and CME fees from IntegrityCE. S. Guerra, D. A. Stern, W. J. Morgan, and F. D. Martinez received support for this research from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) (grant no. 132523). S. Guerra reports grants from NIH/NHLBI, NIH/National Institute of Allergy and Infectious Diseases (NIAID), and the Cystic Fibrosis Foundation. W. J. Morgan reports grants from NIH/NHLBI, NIH/NIAID, and the Cystic Fibrosis Foundation; personal fees from the Cystic Fibrosis Foundation; and personal fees from Genentech. F. D. Martinez reports grants from NIH/NHLBI, NIH/NIAID, NIH/National Institute of Environmental Health Sciences, NIH/Office of the Director, and Johnson & Johnson. He was also a consultant for Commense INC and Copeval. The rest of the authors declare that they have no relevant conflicts of interest.
Acknowledgments
This study was supported by awards AI135108 from National Institute of Allergy and Infectious Diseases and HL132523 from National Heart, Lung, and Blood Institute, US National Institutes of Health. We gratefully acknowledge the contributions of Lynn M. Taussig who started the Tucson Children's Respiratory Study in 1980. We thank Per M. Gustafsson for assistance with MBW measurements, and our study nurses and technicians for data collection and participant follow-up. We would like to thank the TCRS study participants and their parents for their continued support and enthusiasm.
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