Advertisement

Lower respiratory illnesses in childhood are associated with the presence of air trapping in early adulthood

Open AccessPublished:November 25, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107062

      Abstract

      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 [
      • Lange P.
      • Celli B.
      • Agusti A.
      • et al.
      Lung-function trajectories leading to chronic obstructive pulmonary disease.
      ], 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 [
      • Polverino F.
      • Sam A.
      • Guerra S.
      COPD: to Be or not to Be, that is the question.
      ]. We, and others, have previously shown that individuals sustaining childhood respiratory infections [
      • Voraphani N.
      • Stern D.A.
      • Wright A.L.
      • Guerra S.
      • Morgan W.J.
      • Martinez F.D.
      Risk of current asthma among adult smokers with respiratory syncytial virus illnesses 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 [
      • Martinez F.D.
      • Morgan W.J.
      • Wright A.L.
      • Holberg C.J.
      • Taussig L.M.
      Diminished lung function as a predisposing factor for wheezing respiratory illness in infants.
      ]. 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 [
      • Ukil S.
      • Reinhardt J.M.
      Anatomy-guided lung lobe segmentation in X-ray CT images.
      ]. 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) [
      • Ukil S.
      • Reinhardt J.M.
      Anatomy-guided lung lobe segmentation in X-ray CT images.
      -]. 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 [
      • Robinson P.D.
      • Latzin P.
      • Verbanck S.
      • et al.
      Consensus statement for inert gas washout measurement using multiple- and single- breath tests.
      ,
      • Taussig L.M.
      • Wright A.L.
      • Holberg C.J.
      • Halonen M.
      • Morgan W.J.
      • Martinez F.D.
      Tucson children's respiratory study: 1980 to present.
      ]. 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 [
      • Robinson P.D.
      • Latzin P.
      • Verbanck S.
      • et al.
      Consensus statement for inert gas washout measurement using multiple- and single- breath tests.
      ,
      • Taussig L.M.
      • Wright A.L.
      • Holberg C.J.
      • Halonen M.
      • Morgan W.J.
      • Martinez F.D.
      Tucson children's respiratory study: 1980 to present.
      ]. 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.

      3. Results

      3.1 See Table 1 for participant characteristics

      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.
      CharacteristicsGroup/TypenMean %LAA-85695%CIp-value
      Early life factors:
      SexMale1818.512.9, 29.1
      Female2112.07.1, 16.80.071
      Race/EthnicityNHW2715.811.1, 20.5
      HW712.42.8, 21.9
      Other514.31.5, 27.00.773
      Maternal SmokingNo3215.110.8, 19.2
      (at enrollment)Yes714.65.8, 23.50.928
      Maternal AsthmaNo3415.211.2, 19.2
      (at enrollment)Yes513.60.7, 26.50.774
      LRI by age 3 yearsNo159.53.2, 15.70.018
      Yes1818.813.7, 23.9
      RSV-LRI by age 3 yearsNo159.53.2, 15.7
      RSV916.810.1, 23.5
      Non-RSV920.811.8, 29.80.047
      At age 26:
      SmokingNever1915.410.1, 20.6
      Ever2014.69.0, 20.20.831
      Respiratory SymptomsNo2217.011.7, 22.3
      (during the past year)Yes1712.47.2, 17.50.205
      nrho with %LAA-85695%CIp
      BMIinterval39−0.38−0.67, −0.090.017
      TLC, percent predictedinterval380.22−0.13, 0.560.191
      RV, percent predictedinterval380.10−0.23, 0.440.566
      Percent predicted (GLI), post-bronchodilator:
      FEV1interval39−0.24−0.57, 0.090.141
      FVCinterval39−0.02−0.36, 0.320.910
      FEV1/FVCinterval39−0.28−0.62, 0.050.080
      FEF25-75interval39−0.33−0.67, −0.0030.037
      CT Airway Measures at EELV
      Average - average wall thickness and average inner area at end expiratory volume for generation 3.
      :
      Wall Thicknessinterval39−0.18−0.49, 0.130.283
      Inner Areainterval390.03−0.28, 0.330.871
      Abbreviations: HRCT - high-resolution computed tomography; LRI - lower respiratory illness; RSV - respiratory syncytial virus; FEV1 - forced expiratory volume in 1 s; FVC - forced vital capacity; FEF25–75% - forced expiratory flow; BMI - body mass index; EELV - end expiratory volume; TLC - total lung capacity; GLI - global lung initiative.
      a Average - average wall thickness and average inner area at end expiratory volume for generation 3.
      Fig. 1
      Fig. 1Comparison of %LAA-856 levels by early life lower respiratory illness (LRI).
      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. 2
      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 [
      • Guerra S.
      • Lombardi E.
      • Stern D.A.
      • et al.
      Fetal origins of asthma: a longitudinal study from birth to age 36 years.
      ]. 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 [
      • Bhatt S.P.
      • Kim Y.I.
      • Wells J.M.
      • et al.
      FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices.
      ]. 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 [
      • Kjellberg S.
      • Houltz B.K.
      • Zetterstrom O.
      • Robinson P.D.
      • Gustafsson P.M.
      Clinical characteristics of adult asthma associated with small airway dysfunction.
      ] due to local peripheral conducting airway obstruction and/or reduced local elastance.
      Previous studies have found lung structure derangements, such as air trapping and emphysema, to be common in the general elderly population [
      • Oelsner E.C.
      • Hoffman E.A.
      • Folsom A.R.
      • et al.
      Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: a cohort study.
      ]. 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 [
      • Bhatt S.P.
      • Soler X.
      • Wang X.
      • et al.
      Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease.
      ]. 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.

      References

        • Lange P.
        • Celli B.
        • Agusti A.
        • et al.
        Lung-function trajectories leading to chronic obstructive pulmonary disease.
        N. Engl. J. Med. 2015; 373 ([doi]): 111-122https://doi.org/10.1056/NEJMoa1411532
        • Polverino F.
        • Sam A.
        • Guerra S.
        COPD: to Be or not to Be, that is the question.
        Am. J. Med. 2019; 132: 1271-1278https://doi.org/10.1016/j.amjmed.2019.04.047
        • Voraphani N.
        • Stern D.A.
        • Wright A.L.
        • Guerra S.
        • Morgan W.J.
        • Martinez F.D.
        Risk of current asthma among adult smokers with respiratory syncytial virus illnesses in early life.
        Am. J. Respir. Crit. Care Med. 2014; 190: 392-398https://doi.org/10.1164/rccm.201311-2095OC
        • Martinez F.D.
        • Morgan W.J.
        • Wright A.L.
        • Holberg C.J.
        • Taussig L.M.
        Diminished lung function as a predisposing factor for wheezing respiratory illness in infants.
        N. Engl. J. Med. 1988; 319: 1112-1117https://doi.org/10.1056/NEJM198810273191702
        • Ukil S.
        • Reinhardt J.M.
        Anatomy-guided lung lobe segmentation in X-ray CT images.
        IEEE Trans. Med. Imag. 2009; 28: 202-214https://doi.org/10.1109/TMI.2008.929101
        • Robinson P.D.
        • Latzin P.
        • Verbanck S.
        • et al.
        Consensus statement for inert gas washout measurement using multiple- and single- breath tests.
        Eur. Respir. J. 2013; 41: 507-522https://doi.org/10.1183/09031936.00069712
        • Taussig L.M.
        • Wright A.L.
        • Holberg C.J.
        • Halonen M.
        • Morgan W.J.
        • Martinez F.D.
        Tucson children's respiratory study: 1980 to present.
        J. Allergy Clin. Immunol. 2003; 111 (quiz 676): 661-675https://doi.org/10.1067/mai.2003.162
        • Guerra S.
        • Lombardi E.
        • Stern D.A.
        • et al.
        Fetal origins of asthma: a longitudinal study from birth to age 36 years.
        Am. J. Respir. Crit. Care Med. 2020; 202: 1646-1655https://doi.org/10.1164/rccm.202001-0194OC
        • Bhatt S.P.
        • Kim Y.I.
        • Wells J.M.
        • et al.
        FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices.
        Ann. Am. Thorac. Soc. 2014; 11: 335-341https://doi.org/10.1513/AnnalsATS.201308-251OC
        • Kjellberg S.
        • Houltz B.K.
        • Zetterstrom O.
        • Robinson P.D.
        • Gustafsson P.M.
        Clinical characteristics of adult asthma associated with small airway dysfunction.
        Respir. Med. 2016; 117: 92-102https://doi.org/10.1016/j.rmed.2016.05.028
        • Oelsner E.C.
        • Hoffman E.A.
        • Folsom A.R.
        • et al.
        Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: a cohort study.
        Ann. Intern. Med. 2014; 161 (2023010 [pii]): 863-873https://doi.org/10.7326/M13-2570
        • Bhatt S.P.
        • Soler X.
        • Wang X.
        • et al.
        Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 2016; 194: 178-184https://doi.org/10.1164/rccm.201511-2219OC