Custovic, A

Fontanella, S

American Journal of Respiratory and Critical Care Medicine

Spiral - Imperial College Digital Repository

regular preventer treatment in mild to moderate asthma: findings fromthe PRACTICAL study, a randomised clinical trial. Eur Respir J 2020;55:1902073.7. Krings JG, Gerald JK, Blake KV, Krishnan JA, Reddel HK, Bacharier LB,et al. A call for the United States to accelerate the implementation ofreliever combination ICS-formoterol inhalers in asthma. Am J Respir CritCare Med 2022;207:390–405.8. Baggott C, Hardy JK, Sparks J, Sabbagh D, Beasley R, Weatherall M,et al. Epinephrine (adrenaline) compared to selective beta-2-agonist inadults or children with acute asthma: a systematic review and meta-analysis. Thorax 2022;77:563–572.9. Rogliani P, Ritondo BL, Ora J, Cazzola M, Calzetta L. SMART andas-needed therapies in mild-to-severe asthma: a network meta-analysis.Eur Respir J 2020;56:2000625.10. Kearns N, Bruce P, Williams M, Doppen M, Black M, Weatherall M, et al.Repeated dose budesonide/formoterol compared to salbutamol in adultasthma: a randomised cross-over trial. Eur Respir J [online ahead ofprint] 3 Feb 2022; DOI: 10.1183/13993003.02309-2021.11. Rea HH, Scragg R, Jackson R, Beaglehole R, Fenwick J, Sutherland DC.A case-control study of deaths from asthma. Thorax 1986;41:833–839.Copyright © 2023 by the American Thoracic SocietyEvolution of Lung Function within Individuals: Clinical Insightsand Data-driven MethodsSpirometric impairments at the physiological peak in early adulthoodare associated with adverse health outcomes through the life course(1), including poor respiratory health and a higher risk of chronicobstructive pulmonary disease (2), but also cardiovascular andcerebrovascular events into middle age (3). Among children withasthma, reduced lung function predicts the persistence of severedisease to adulthood (4). These studies identified diminished lunggrowth in childhood as an important indicator of poor health inadulthood and highlighted the importance of interventions topreserve/improve lung function during childhood to prevent theonset and progression of ill health. However, it remains unansweredhow best to identify individuals at risk and which preventivemeasures to apply.In recent years, a substantial effort has been devoted toidentifying lifetime trajectories of different spirometric measures oflung function and their predictors using data-driven methods (5–10).These models can quickly process large amounts of data and identifypatterns humans cannot easily observe. Because of the limitedavailability of repeated spirometry in children, relatively few studiesapplied analytical modeling to childhood lung function (5–7).Twomulticohort studies reported age-specific prevalence ofspirometric impairments from childhood to peak in early adulthood,with airway obstruction ranging from 3% to 11% and restrictivepattern from 2% to 8% (11, 12). Longitudinal models identifiedbetween two (6) and four (5, 7) distinct trajectories extending fromschool age into adolescence/early adulthood, characterized byapparently stable lung function through childhood, depicted byparallel lines. These findings are usually interpreted as lung functiontracking through childhood. Of note, these data-driven analysesrevealed no evidence of latent classes/clusters of children withdeclining (or improving) lung function. In contrast, clinicalexperience and visualization of within-individual trajectories suggestconsiderable variability between children, with lung functionimproving in some and declining in others. Furthermore, oneprevious study, which modeled childhood lung function trajectoriesusing repeated measures of specific airway resistance rather thanspirometry, reported that children with persistent wheeze, frequentexacerbations, and early atopy are at risk of a decline in lung functionbetween ages 3 and 11 years and that these effects are more marked inboys (13). Modeling of spirometry data extending to later adulthood(45–55 yr) described six trajectories, four of which were strikinglysimilar to childhood trajectories (8). One additional trajectory wascharacterized by an accelerated decline in later adulthood andanother by early low lung function but with accelerated growth (8).So, why are clusters of children with declining and improvingspirometry not readily identified using data-driven methodologies?Is spirometry too blunt a tool to detect subtle but potentiallyimportant temporal trends (13), or is the follow-up to early adulthoodtoo short (8), or is the proportion of decliners and improvers throughchildhood too small to be detected in relatively small sample sizeswith repeated spirometry available in birth cohorts? And why wouldit be important?We would argue that understanding the associates oflung function decline and improvement through childhood is of keyimportance to developing actionable interventions to improve lungfunction growth.In this issue of the Journal, Wang and colleagues (pp. 406–415)report the analysis of lung function development from childhood toearly adulthood in two unselected birth cohorts, which used a data-drivenMarkovian dependent mixture model to identify five lungfunction states (very low, low, normal, high, and very high) at threecross-sectional points through childhood (14). The model used in thisstudy, like many others, is a simplification of reality, but a morecomplicated model must be balanced against interpretability. Furtherfrequentist analyses suggested that some participants in the low lungfunction states had catch-up to normal but that growth failureoccurred in some participants with initial normal/high lung function.Longitudinal lung function through childhood to early adulthood andmeticulous follow-up of study participants are some of the strengthsof the study. However, there are unavoidable weaknesses.Although lung function states were derived using data-drivenmethods, the definition of catch-up and growth failure trajectoriesThis article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202212-2226EDon December 14, 2022Editorials 379EDITORIALSwas reconstructed by investigators a posteriori, in that individualsmoving from the low/very low to normal/high/very high stateswere assigned to a catch-up group, whereas those transitioningfrom normal/high/very high to the low/very low states wereassigned to a growth failure. This does not fully account for theindividual variability in transition patterns between the states atdifferent time points, nicely illustrated at the individual level inthe alluvial graph in Figure E1 in the online supplement. Thisdefinition also assumes that the transition from low to high hasthe same impact as that from very low to very high states, thatindividuals who transition from normal to high/very high statesdo not have a catch-up, and does not consider transitions fromhigh/very high states to normal as growth failure. Although thedefinitions of improvement and decline in lung function may notfully reflect the structure in the dataset, the results add to evidencethat within-individual changes over time (including improvementand worsening) do occur. Lung function catch-up and growthfailure, as defined by investigators, were observed in a smallproportion of participants, suggesting that a much larger samplewith longitudinal spirometry would be required to detect suchsmall clusters using data-driven techniques. We, therefore, agreewith the authors that large-scale collaboration involving multiplecohorts will be needed for such analyses.Should we wait for such analyses to derive more precisely stableand homogenous clusters of decliners and improvers and theirpredictors before we consider possible interventions?We believe thatwe should triangulate available evidence now and then put this intothe context of the modeling results in the forthcoming largemulticohort analyses. In the study byWang and colleagues, subjectsin the very low lung function state were more likely to be male, beborn prematurely, be exposed to higher air pollution, and haverespiratory infections in early life (14). Previous studies have reportedthat similar in utero and early-life factors influence lung functiontrajectories through childhood, including nutritional deficits duringpregnancy, preterm birth, poor intrauterine growth and low birthweight, early-life respiratory infections, early allergic sensitization,persistent wheezing, and exposure to tobacco smoke in utero.The adverse impact of air pollution on lung function is also wellestablished (15), highlighting the importance of developing andapplying policies to address exposures that impact lifelong health andpromote transportation and environmental justice (16). There is areason for hope that environmental policies targeting a reduction inair pollution may lead to population-level improvement in lungfunction (17).Previous analysis in the large United Kingdom birth cohortsuggested that catch-up growth is possible around puberty andthat later onset and higher velocity of pubertal growth areassociated with higher peak lung function (18). Given theestablished relationships between the early onset of puberty witha child’s obesity and maternal obesity and gestational weight gain(19), we fully agree with the earlier editorial in the Journal thatargued that a combination of interventions tackling childhoodobesity to protect current generations, and obesity in pregnancyto protect future generations, may have a substantial impact onoverall health (20). This should be coupled with measures tominimize adverse environmental exposures such as tobacco smokeand air pollution. We should advocate that all these interventionsshould happen at the population level now. We can then use datafrom large-scale multiple-cohort collaborations to investigategenetic associates and gene–environment interactions contributingto the loss or growth in lung function during childhood to derivestratified interventions. Author disclosures are available with the text of this article atwww.atsjournals.org.Adnan Custovic, M.D., Ph.D.Sara Fontanella, Ph.D.National Heart and Lung InstituteImperial College LondonLondon, United KingdomORCID ID: 0000-0001-5218-7071 (A.C.).References1. Agustı A, Noell G, Brugada J, Faner R. Lung function in early adulthoodand health in later life: a transgenerational cohort analysis.Lancet Respir Med 2017;5:935–945.2. Lange P, Celli B, Agustı A, Boje Jensen G, Divo M, Faner R, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease.N Engl J Med 2015;373:111–122.3. Cuttica MJ, Colangelo LA, Dransfield MT, Bhatt SP, Rana JS, Jacobs DR Jr,et al. Lung function in young adults and risk of cardiovascular events over29 years: the CARDIA study. J Am Heart Assoc 2018;7:e010672.4. Izadi N, Baraghoshi D, Curran-Everett D, Zeiger RS, Szefler SJ, Covar RA;Childhood Asthma Management Program Research Group. Factorsassociated with persistence of severe asthma from late adolescence toearly adulthood. Am J Respir Crit Care Med 2021;204:776–787.5. Belgrave DCM, Granell R, Turner SW, Curtin JA, Buchan IE, Le Sou€ef PN,et al. Lung function trajectories from pre-school age to adulthood andtheir associations with early life factors: a retrospective analysis of threepopulation-based birth cohort studies. Lancet Respir Med 2018;6:526–534.6. Berry CE, Billheimer D, Jenkins IC, Lu ZJ, Stern DA, Gerald LB, et al.A distinct low lung function trajectory from childhood to the fourthdecade of life. Am J Respir Crit Care Med 2016;194:607–612.7. Karmaus W, Mukherjee N, Janjanam VD, Chen S, Zhang H, Roberts G,et al. Distinctive lung function trajectories from age 10 to 26years in menand women and associated early life risk factors—a birth cohort study.Respir Res 2019;20:98.8. Bui DS, Lodge CJ, Burgess JA, Lowe AJ, Perret J, Bui MQ, et al.Childhood predictors of lung function trajectories and future COPD risk:a prospective cohort study from the first to the sixth decade of life.Lancet Respir Med 2018;6:535–544.9. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML,et al. Patterns of growth and decline in lung function in persistentchildhood asthma. N Engl J Med 2016;374:1842–1852.10. Weber P, Menezes AMB, Gonçalves H, Perez-Padilla R, Jarvis D,de Oliveira PD, et al. Characterisation of pulmonary function trajectories:results from a Brazilian cohort. ERJ Open Res 2020;6:00065-2020.11. Voraphani N, Stern DA, Zhai J, Wright AL, Halonen M, Sherrill DL, et al.The role of growth and nutrition in the early origins of spirometricrestriction in adult life: a longitudinal, multicohort, population-basedstudy. Lancet Respir Med 2022;10:59–71.12. Wang G, Hallberg J, Charalampopoulos D, Sanahuja MC,Breyer-Kohansal R, Langhammer A, et al. Spirometric phenotypesfrom early childhood to young adulthood—a CADSET (chronic airwaydisease early stratification) study. Eur Respir J 2021;6:00457-2021.13. Belgrave DC, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A.Trajectories of lung function during childhood. Am J Respir Crit CareMed 2014;189:1101–1109.14. Wang G, Hallberg J, Faner R, Koefoed HJ, Kebede Merid S,Klevebro S, et al. Plasticity of individual lung function states380 American Journal of Respiratory and Critical Care Medicine Volume 207 Number 4 | February 15 2023EDITORIALSfrom childhood to adulthood. Am J Respir Crit Care Med 2022;207:406–415.15. Wooding DJ, Ryu MH, H€uls A, Lee AD, Lin DTS, Rider CF, et al. Particledepletion does not remediate acute effects of traffic-related air pollutionand allergen. A randomized, double-blind crossover study. Am J RespirCrit Care Med 2019;200:565–574.16. Beamer PI, Lothrop N. Before the first breath: prenatal ultrafineparticulate exposure and incident asthma. Am J Respir Crit Care Med2021;204:747–748.17. Xue T, Han Y, Fan Y, Zheng Y, Geng G, Zhang Q, et al. Associationbetween a rapid reduction in air particle pollution and improved lungfunction in adults. Ann Am Thorac Soc 2021;18:247–256.18. Mahmoud O, Granell R, Tilling K, Minelli C, Garcia-Aymerich J, Holloway JW,et al. Association of height growth in puberty with lung function.A longitudinal study. Am J Respir Crit Care Med 2018;198:1539–1548.19. Zhou J, Zhang F, Zhang S, Li P, Qin X, Yang M, et al. Maternal pre-pregnancy body mass index, gestational weight gain, and pubertaltiming in daughters: a systematic review and meta-analysis of cohortstudies. Obes Rev 2022;23:e13418.20. Bush A. Growing, growing, gone: the double whammy of early deprivationand impaired evolution of lung function. Am J Respir Crit Care Med2021;204:745–746.Copyright © 2023 by the American Thoracic SocietyRemodeling Phenotypes Take Center Stage in the Predictionof Preschool Wheeze AttacksAirway inflammation and structural wall abnormalities(remodeling) are considered the two hallmark pathologicalfeatures of asthma. For more than 15 years, we have knownthat airway remodeling is present very early, in the first 5 yearsof life, in preschool children with severe recurrent wheezing.There is evidence of subepithelial reticular basement membrane(RBM) thickening (1), increased bronchial smooth muscle(BSM), angiogenesis, and epithelial damage (2). However, littlerelationship is apparent between clinical wheeze phenotypes (viralwheezing or multiple-trigger wheezing) and remodeling (3) orbetween inflammation and remodeling (4) in early life. Follow-upof preschoolers with severe wheezing has shown that features ofremodeling, including BSM (5) and reticular basement membranethickness (6), rather than eosinophilic inflammation, predictprogression to asthma at school age.What has not been investigated to date is the relevanceof airway remodeling in predicting shorter-term outcomes forpreschool wheezers. Although unbiased analyses of lower airwayinflammation have revealed distinct preschool wheeze clusterswith relationships to therapeutic response (7), we did not haveevidence for the role of remodeling in determining moreimmediate outcomes.In this issue of the Journal, Fayon and colleagues (pp. 416–426)have, for the first time, demonstrated the role of a cluster of featuresof remodeling that predict exacerbations of severe wheeze in the yearafter biopsy (8). They have incorporated epithelial integrity, RBMthickness, mucus glands, fibrosis, BSM area, density of blood vessels,and RBM–BSM distance as markers of remodeling. Using latent classanalyses, they identified a two-class model; the class that wascharacterized by increased RBM thickness, smooth muscle, and bloodvessel density and reduced mucus glands, fibrosis, and RBM–BSMdistance was associated with significantly more exacerbations and ashorter time to first exacerbation over the subsequent 12 months.There were no clinical features that distinguished the children in eachlatent class before the bronchoscopy. The mean age at bronchoscopywas 2.3 years, and, as has been shown previously for severe recurrentwheezers, only approximately one-quarter had aeroallergensensitization, despite a median of six oral corticosteroid bursts everfor wheezing.An important aspect of the study is the young age of thechildren included, highlighting that even during such earlywheezing, remodeling is a complex process that involves structuralmodifications in virtually all components of the airway wall and thatthere is no single aspect of airway remodeling that appears to precedethe others. The main histological changes observed in the airwaysof the children who went on to have wheeze attacks consistedof increased RBM thickness (due to collagen deposition in thelamina reticularis) with a concurrent increase in BSM area, thusreducing the distance between the epithelial and the smoothmuscle compartments. Increased thickness of the smooth musclelayer measured on biopsy sections may result either from moremuscle cells (hyperplasia), larger muscle cells (hypertrophy), and/or more extracellular matrix within the smooth muscle layer (9).Because BSM area was measured in sections stained specifically todetect smooth muscle actin, the present results would suggest adirect involvement of smooth muscle cell abnormalities. Reducedfibrosis, but increased subepithelial RBM thickness, suggestsdistinct mechanistic processes and types of collagen are involvedin the submucosal layer compared with the subepithelial layer. Anincreased density of blood vessels in the airways was also observedat this early stage and was associated with exacerbations at 1-yearfollow-up. Changes in vascularity may be due to both dilatationand congestion of existing vessels but also to the formation ofnew vessels (neoangiogenesis), possibly as a response to growthfactors released from other injured airway structures, such as theepithelium or the smooth muscle (10). Because increasedvascularity may then contribute to the amplification of airwayinflammation, it is conceivable that vascular changes associatewith an exacerbation-prone phenotype.A significant strength of the study was the inclusion of aprospective cohort of children (n = 56) in whom the latentThis article is open access and distributed under the terms of theCreative Commons Attribution Non-Commercial No DerivativesLicense 4.0. For commercial usage and reprints, please e-mailDiane Gern (dgern@thoracic.org).Originally Published in Press as DOI: 10.1164/rccm.202209-1833EDon September 28, 2022Editorials 381EDITORIALS

Evolution of lung function within individuals: clinical insights and data-driven methods

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Evolution of lung function within individuals: clinical insights and data-driven methods

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