Asthma, bronchial hyperresponsiveness, allergy and lung function development until early adulthood: A systematic literature review

University of Groningen

Asthma, bronchial hyperresponsiveness, allergy and lung function development until early

adulthood

Koefoed, Hans Jacob L; Zwitserloot, Annelies M; Vonk, Judith M; Koppelman, Gerard H

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Pediatric Allergy and Immunology

DOI:

10.1111/pai.13516

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Koefoed, H. J. L., Zwitserloot, A. M., Vonk, J. M., & Koppelman, G. H. (2021). Asthma, bronchial

hyperresponsiveness, allergy and lung function development until early adulthood: A systematic literature

review. Pediatric Allergy and Immunology. https://doi.org/10.1111/pai.13516

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Pediatr Allergy Immunol. 2021;00:1–17. wileyonlinelibrary.com/journal/pai 

|

DOI: 10.1111/pai.13516

O R I G I N A L A R T I C L E

Asthma, bronchial hyperresponsiveness, allergy and lung

function development until early adulthood: A systematic

literature review

Hans Jacob L. Koefoed

 | Annelies M. Zwitserloot

 | Judith M. Vonk

 |

Gerard H. Koppelman

This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.

© 2021 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

1_{Department of Pediatric Pulmonology}

and Pediatric Allergology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

2_{Groningen Research Institute for}

Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

3_{Department of Epidemiology, University}

Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence

Hans Jacob L. Koefoed, Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Centre Groningen (UMCG), Beatrix Kinderziekenhuis | UMCG, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Email: h.j.l.koefoed@umcg.nl

Editor: Ömer Kalaycı

Abstract

Background: It is unclear in which periods of life lung function deficits develop,

and whether these are affected by risk factors such as asthma, bronchial hyper- responsiveness (BHR) and allergic comorbidity. The goal of this systematic review was to identify temporal associations of asthma, BHR and allergic comorbidity with large and small lung function development from birth until peak function in early adulthood.

Methods: We searched MEDLINE, EMBASE, Web of Science and CINAHL for papers

published before 01.01.2020 on risk factors and lung function measurements of large and small airways. Studies were required to report lung function at any time point or interval from birth until peak lung function (age 21- 26) and include at least one can-didate risk factor.

Results: Of the 45 papers identified, 44 investigated cohorts and one was a clinical

trial with follow- up. Asthma, wheezing, BHR and allergic sensitization early in life and to multiple allergens were associated with a lower lung function growth of large and small airways during early childhood compared with the control populations. Lung function development after childhood in subjects with asthma or persistent wheeze, although continuing to grow at a lower level, largely tracked parallel to non- affected individuals until peak function was attained.

Clinical implications and future research: Deficits in lung function growth develop

in early childhood, and children with asthma, BHR and early- life IgE (poly)sensitiza-tion are at risk. This period is possibly a critical window of opportunity to identify at- risk subjects and provide treatment aimed at preventing long- term sequelae of lung function.

K E Y W O R D S

1  |  INTRODUCTION

Peak lung function is normally attained around the age of 22 for males

and slightly earlier for females,1 _{after which lung function remains}

stable for some years during a plateau phase before beginning to

de-cline.2,3 _{Children with asthma may reach a lower maximum lung}

func-tion in adulthood,3- 6 _{putting them at risk for development of future}

COPD. Different patterns of impaired lung function development from childhood to adulthood have been described in children with asthma, such as ‘normal growth’, ‘normal growth and early decline’, ‘reduced

growth’ and ‘reduced growth and early decline’.3 _{Growth of the lungs}

may not only be impaired during early childhood, but also throughout adolescence and early adulthood. Next to the growth of the large air-ways, growth of the small airways may be important, as accumulat-ing evidence suggests that many lung diseases, includaccumulat-ing asthma and

COPD, start in the small airways.7 _{Therefore, better knowledge on the}

predictors, place (small versus large airways) and timing of the devel-opment of low lung function may set the stage for future preventative measures aimed at improving lung function growth.

So far, conflicting results have been reported on lung growth in asthmatic children. Some studies suggested no association of mild or

transient asthma with reduced lung growth in the first years of life,5,8

whereas in another study, more severe asthma and persistent wheeze were associated with reduced lung growth throughout childhood and

adolescence.4 _{The presence of asthma, the timing of asthma onset,}

persistence and severity of symptoms and the presence of allergic co-morbidity may be important determinants of the maximally attained

FEV₁ in early adulthood (Figure 1).5,8- 12 _{Moreover, it has not been}

sys-tematically assessed whether these risk factors also relate to measures of small airway function growth. Thus, an important question remains when and where the lung function deficits develop: in the first years of life, in childhood, adolescence or early adulthood?

To identify the factors associated with lung function growth and their significance during different periods of development, this sys-tematic literature review investigated current literature on the tem-poral associations of asthma and allergy with lung function growth of small and large airways during childhood and adolescence up to the maximum lung function in early adulthood. Asthma is hetero-geneous disease with varying degrees of symptoms, comorbidities and clinical biomarkers. Candidate risk factors were therefore se-lected with the aim of capturing a valid representation of poten-tial factors associated with lung function growth in subjects with asthma or allergy. In addition to asthma and wheezing in early life, bronchial hyper- responsiveness (BHR), a hallmark of asthma, was in-cluded. Furthermore, we included allergic sensitization, rhinitis and blood eosinophils as candidate risk factors for a lower lung function growth from infancy until peak lung function in early adulthood.

2  |  METHODS

This systematic review (PROSPERO registration number: CRD42020172531) was conducted in accordance with guidelines

reported in the Preferred Reporting Items for Systematic reviews

and Meta- Analysis (PRISMA).13

2.1  |  Search strategy

We searched MEDLINE using the PubMed search engine, EMBASE, Web of Science (Clarivate) and CINAHL (EBSCO) for papers pub-lished before 01.01.2020 with search terms as outlined in Table 1 and Appendix S1. In addition to papers screened in MEDLINE, 52 pa-pers, retrieved from backward citation searching, were reviewed for eligibility of which 2 studies were selected for inclusion (Figure 2).

2.2  |  Study selection

Abstracts of all papers were screened independently by two re-searchers (HJLK and AMZ). Subsequently, full- text papers were as-sessed for eligibility. In case of disagreement, the study was asas-sessed by a third independent researcher (GHK). Papers were required to contain relevant primary data on studies performed in humans (inclusion criteria; see Table 2). We included longitudinal studies that provided data on temporal associations between candidate risk factors and lung function. This entails that in studies with lung function measured at one time point, the ascertainment of candi-date risk factors (eg asthma diagnosis) had to precede the measure-ment of lung function. In studies with multiple measuremeasure-ments of lung function, concurrent ascertainment of a candidate risk factor and lung function testing was permitted. We investigated the following candidate risk factors: asthma diagnosis, wheezing, BHR, markers related to allergy (rhinitis, specific IgE, skin prick tests) and blood eosinophils within asthmatic populations, non- asthmatic patients or in general population- based cohorts. These studies needed to re-port lung function at a point between infancy until maximum lung function was attained (age 21- 26). Studies presenting a mean lung function of subjects that had an age range >2 years were excluded to avoid aggregating lung function data from subjects at different stages of development. In studies reporting findings from two or more cohorts, in which not all cohorts matched the inclusion criteria, relevant data were extracted only from cohorts that matched our inclusion criteria. Letters to editors were not included in this system-atic review as this format would not allow us to verify the extensive inclusion criteria or perform a complete quality analysis. Backward

Key Message

Asthma, wheezing, BHR and allergic sensitization are as-sociated with a lower lung function growth of large and small airways during early childhood. Lung function de-velopment after childhood largely tracks parallel to non- asthmatic individuals.

citation search was performed by screening references (using title and abstract) in all full- text assessed papers for possible inclusion.

2.3  |  Study population

The aim of this systematic review was to study the development of lung function in subjects with asthma or allergy compared with a non- affected population. We investigated lung function develop-ment between the ages of 0 and 26 as this period comprises lung growth from birth until peak lung function in early adulthood. Subjects could be derived from both hospital and population- based cohorts. As asthma and allergies are highly heterogeneous condi-tions, different candidate risk factors were chosen that characterize

these. These risk factors could be defined at a specific point in time (eg asthma at age 6) or could be based on longitudinal phenotype modelling. Comparison of lung function between affected and non- affected subjects could be performed within the same population, within a separate general population- based cohort or by utilizing standard reference values. Studies with outcome parameters de-rived from spirometry, forced oscillation technique (FOT), multiple- breath washout (MBW) and body plethysmography were included. Separate analyses were performed for outcome parameters

reflect-ing the large airways (eg FEV₁: forced expiratory volume in one

sec-ond, FVC: forced vital capacity, FEV₁/FVC) and the small airways (eg

FEF_{25- 75}: forced expiratory flow at 25%- 75% of FVC, sRaw: specific

airway resistance, MMEF: maximal mid- expiratory flow, R₅:

resist-ance at 5 Hz, f_res: resonance frequency). We classified sRaw and

F I G U R E 1 Lung function growth from childhood to adulthood. The green line represents normal lung function growth and levels. The red line represents low lung function growth and levels. The light green represents subjects with low lung function levels in early childhood and catch- up growth in adolescence and early adulthood. The pink line represents children with lower lung function levels in childhood and

reduced growth until early adulthood. Figure 1 is a conceptual illustration based on Agustí et al70

TA B L E 1 Search strategy using PubMed

Search strategy

We searched PubMed using the following key terms: PubMed (MESH terms)

Lung Volume Measurements/Respiratory Function Tests/Spirometry/Lung/growth and development/Allergy and Immunology/Hypersensitivity/ Eosinophils/Eosinophilia/Immunoglobulin E/Asthma/Respiratory Hypersensitivity/Rhinitis, Allergic/Predictive Value of Tests/Cohort Studies/ Case- Control Studies/Child/Infant/Adolescent/Young Adult/Age Distribution

Title and abstract search

lung growth/pulmonary growth/lung function meas*/spiromet*/plethysmography/forced oscillation technique*/lung clearance index/multiple breath washout/lung function*/allerg*/asthma*/hypersensit*/hypperresponsiv*/eosinophil/follow- up/followup/longitudinal/cohort/case- control/trajector*/pattern*/child*/infan*/prenatal*/fetal/pediatr*/paediatr*/school/preschool/adolscen*/teenager*/young adult*/younger adult*/young people/younger people / early life/early age/young age*/younger age*

MMEF as small airway parameters, although large airway obstruc-tion could also affect this outcome, thereby making it a mixed pa-rameter. VmaxFRC (maximum forced expiratory flow at functional residual capacity) derived from rapid chest compression in infancy was reported if the study met requirements of lung function testing later during development.

2.4  |  Data extraction

Information on study design, candidate risk factors and lung function outcomes was collected from included papers. Results were grouped according to which type of lung function outcome was presented:

estimated lung function trajectories using, for example, latent class analysis (LCA), calculated change in lung function over time (growth) and lung function levels at specific time points. If included studies provided sex- stratified associations, findings were included in the same manner in review. Definitions used for periods of development and phenotype development are provided in Appendix S3. Quality assessment of included studies was performed using a modified

Newcastle- Ottawa Quality Assessment Scale for cohort studies 14,15

(see Appendix S2). Information relating to quality assessment was collected from the included paper, the supplementary data or the official cohort profile. All studies with 6 or more stars were classified as high quality, while studies with 4- 5 stars were classified as moder-ate. In the quality assessment, the following criteria were reviewed:

F I G U R E 2 Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) flow diagram

Records idenfied through electronic database searches:

MEDLINE, EMBASE, Web of Science, CINAHL

(n = 7127 records),

Screening

Include

d

Eligibilit

y

Idenficaon

Unique records idenfied a„er removal of duplicates

(n = 4466)

Records excluded

(n = 4352)

Full-text papers assessed

for eligibility

(n = 114)

Full-text papers excluded (n = 71)

_{- Outside of age range (5)}

- Cross-seconal design (11)

- Outside scope (11)

- Age range of lung funcon

assessments exceeded 2 years

(37)

- Le”er to editor (4)

- Not original research (2)

- Publicaon not in English (1)

Backward citaons included

(n = 2)

Full text studies included

(n = 43)

Titles/abstracts screened

(n = 4466)

Total number of included

studies (n=45)

1. Representativeness of the exposed cohort (eg non- selected general population- based birth cohorts)

2. Selection of the non- exposed cohort (selection from the same co-hort as exposed subjects or a separate coco-hort).

3. Ascertainment of exposure/candidate risk factor (eg structured interview vs. self- reported observations).

4. Comparability of cohorts (degree of study control for the follow-ing confounders: age, height and sex)

5. Duration of follow- up (studies with more than 2- year follow- up were awarded a star)

6. Adequacy of follow- up (degree of follow- up and description of subjects lost to follow- up)

3  |  RESULTS

3.1  |  Search results

The literature search strategy identified 7127 records (Figure 2). After removal of duplicate records, 4466 records were reviewed using title and abstract. Of these, 114 full- text papers were assessed for eligibility resulting in 43 included studies. Backward citations from selected papers yielded an additional 2 studies bringing the total number of papers in the final analysis to 45.

3.2  |  Characteristics of studies

Of the 45 selected papers, 38 were population- based,4,5,16- 51 ₆

were clinical/hospital- based or high- risk cohorts,52- 57 _{and one was}

a clinical trial with observational follow- up.3 _{In total, 23 different}

cohorts were identified (Figure S1), of which 15 were birth cohorts

(Tables 3,4,S1). Seven studies reported lung function trajectories (Table 3). These studies mainly captured differences in lung function levels that remained stable throughout development. Next, 14 stud-ies reported associations with lung function growth during a defined period until early adulthood (Table 4), while 33 papers reported as-sociations with lung function levels (Table S1).

Separate lung function trajectories that capture differences in growth in an affected population relative to a control group were

identified in two studies.3,47 _{Small airway parameters were}

in-cluded in 22 studies,5,17,21,22,25- 29,31,33,35- 38,41,44,48,49,52,53,56 _{of which}

FEF_{25%- 75%} was the most frequently used. Of the 45 included stud-ies, one had a moderate level of quality, while the remaining had a high level (Appendix S2). Due to the overall high quality, differences in quality were not considered when reporting or interpreting find-ings from included studies. Different strategies in ascertainment of exposure, that is candidate risk factor, contributed to the greatest variation in quality amongst selected studies. The most frequent bi-ases were use of parental questionnaires and observations to ascer-tain the presence of a risk factor.

3.3  |  Asthma and wheezing

3.3.1  |  Lung function trajectories

Asthma and/or wheezing were associated with a lower- than- normal

lung function trajectory from childhood until adolescence 45,46 _and

until early adulthood.43,45,47,48 _{The trajectories identified differences}

in lung function level over time but not growth rate during develop-ment. Asthma in childhood was associated with lower lung function

trajectories for both small and large airways until early adulthood.48

TA B L E 2 Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

Longitudinal cohort studies and clinical trials with observational follow- up

Letter to editors, meeting abstracts, case reports and literature reviews Age of subjects 0- 26 y >2- yr age range for mean lung function measurement

Subjects from population- based cohorts or hospital- based cohorts Ascertainment of risk factor not preceding lung function measurement (cross- sectional studies only)

Papers published before 01.01.2020 Publications written in English Predictors of outcome: • Asthma/Wheezing • BHR

• Allergic sensitization (IgE and SPT) • Rhinitis

• Blood eosinophils Lung function derived from: • Spirometry

• Forced oscillation technique • Multiple- breath washout • Body plethysmography

TA B LE 3  S tu di es o n l un g f un ct io n t ra je ct or ie s Fir st a ut ho r C oh or t Ty pe a nd a ge lun g f unc tio n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) Sch ult z 46 B A M SE ( n = 14 25 ) Pop ul at ion - ba se d bi rt h c oh or t Sp iro m et ry a t 8 an d 1 6 y Lu ng f un ct io n t ra je ct or y: Low Nor mal /h igh La rg e a ir w ay s: F EV 1 A sth m a/ w heez e S: e ar ly w he ez e a nd a st hm a e ve r t ill a ge 8 w er e a ss oc ia te d w ith a l ow F EV1 tr aj ec to ry (< 25 th p er ce nt ile a t 8 a nd 1 6 y o f a ge ). P re va le nc e o f e ar ly w he ez e: 2 5% i n l ow tr aj ec to ry a nd 1 2% i n n or m al /h ig h t ra je ct or y. P re va le nc e o f a st hm a: 2 3% i n l ow tr aj ec to ry a nd 1 4% i n n or m al /h ig h t ra je ct or y. N S: C ur re nt w he ez e a t a ge 8 w as n ot a ss oc ia te d w ith a l ow F EV1 tr aj ec to ry A ller gi c sen si tiz at io n (Ig E) N S: a lle rg ic s en si tiz at io n a t a ge 8 w as n ot a ss oc ia te d w ith a l ow F EV1 tr aj ec to ry ( <2 5t h pe rc en til e a t 8 a nd 1 6 y o f a ge ). B el gr av e 45 M A A S ( n = 10 46 ) Pop ul at ion - ba se d bi rt h c oh or t A LS PA C ( n = 13 90 ) Pop ul at ion - ba se d bi rt h c oh or t M A A S: _spiro m et ry a t 5, 8 , 1 1 a nd 16 y A LS PA C : Spir om et ry at 8 , 1 5 a nd 24 y ar s Lu ng f un ct io n t ra je ct or y: Pe rs is te nt ly h ig h N or mal B el ow a ve ra ge Pe rs is te nt ly l ow La rg e air w ay s: FE V1 A sth m a, w heez e S: a st hm a a nd w he ez e t hr ou gh ou t t he f ol lo w - u p p er io d w er e a ss oc ia te d w ith a pe rs is te nt ly l ow F EV1 tr aj ec to ry ( se e a pp en di x o f o rig in al p ap er f or e xa ct d at a) B H R ( ye s/ no ) S: B H R ( A LS PA C a t a ge s 1 5 a nd 2 4 a nd M A A S a t a ge s 5 , 8 , 1 1 a nd 1 6) w as a ss oc ia te d w ith a p er si st en tly l ow F EV 1 tr aj ec to ry . A ller gi c sen si tiz at io n (s ki n p ric k t es t) S: a lle rg ic s en si tiz at io n i n e ar ly c hi ld ho od i n M A A S w as a ss oc ia te d w ith a p er si st en tly lo w F EV 1 tr aj ec to ry . N S: a lle rg ic s en si tiz at io n i n a do le sc en ce ( M A A S) o r a t a ge 7 ( A LS PA C ) w as n ot as so ci at ed w ith a p er si st en tly l ow F EV1 tr aj ec to ry M cG ea ch ie 3 C A M P ( n = 68 4) Ran dom iz ed co nt rol le d t ria l w ith e xt en de d fo llo w - u p i n as th m at ic pat ie nt s Sp iro m et ry ( ag e 5/ 12 - 2 6/ 30 ) Lu ng f un ct io n t ra je ct or y: N or m al g ro w th Re du ce d g ro w th N or m al g ro w th , e ar ly d ec lin e Re du ce d g ro w th , e ar ly d ec lin e La rg e air w ay s: FE V1 B H R s ev er ity S: m or e s ev er e B H R ( at i nc lu si on ) w as a ss oc ia te d w ith a r ed uc ed F EV1 g ro w th p at te rn (O R f or r ed uc ed g ro w th c om pa re d w ith n or m al g ro w th : 0 .6 1 p er u ni t c ha ng e i n l og - tr an sf or m ed m g p er m L) A ller gi c sen si tiz at io n (s ki n p ric k t es t) S: s ub je ct s w ith a ‘ re du ce d g ro w th a nd e ar ly d ec lin e’ t ra je ct or y h ad a g re at er n um be r of p os iti ve s ki n p ric k t es ts a t e nr ol m en t c om pa re d w ith s ub je ct s w ith a ‘ no rm al gr ow th ’ t ra je ct or y ( O R f or ≥ 3 p os iti ve s ki n t es ts v s. < 3: 2. 42 ) Ra sm us se n 23 D un ed in , N ew Ze al an d ( n = 78 8) Pop ul at ion - ba se d bi rt h c oh or t Sp iro m et ry a t 1 8 an d 2 6 y Lu ng f un ct io n t ra je ct or y: Co ns is te nt ly n or m al V ar iab le Co ns is te nt ly lo w La rg e a ir w ay : ( FE V1 /VC ) A st hma S: a st hm a r ep or te d a t a ny t im e d ur in g t he s tu dy ( be tw ee n a ge 9 a nd 2 6) w as a ss oc ia te d w ith a c on si st en tly l ow F EV1 /V C t ra je ct or y b et w ee n a ge s 1 8 a nd 2 6. P re va le nc e of a st hm a: m al es : 6 8% i n c on si st en tly l ow a nd 3 0% i n c on si st en tly n or m al , f em al es : 82 % i n c on si st en tly l ow a nd 3 0% i n c on si st en tly n or m al B H R ( ye s/ no ) S: B H R a t a ge 9 w as a ss oc ia te d w ith a c on si st en tly l ow F EV1 /V C t ra je ct or y. P re va le nc e of B H R: m al es : 5 5% i n c on si st en tly l ow a nd 1 7% i n c on si st en tly n or m al , f em al es : 57 % i n c on si st en tly l ow a nd 1 4% i n c on si st en tly n or m al A ller gi c sen si tiz at io n (s ki n p ric k t es t) : H ou se d us t m ite C at _Atopy _IgE S: a lle rg ic s en si tiz at io n t o h ou se d us t m ite o r t o c at a t a ge 2 1 w as a ss oc ia te d w ith a co ns is te nt ly l ow F EV1 /V C t ra je ct or y. P re va le nc e o f h ou se d us t m ite s en si tiz at io n: m al es : 5 7% in c on si st en tly n or m al a nd 7 8% i n c on si st en tly l ow , f em al es : 5 1% i n co ns is te nt ly n or m al a nd 9 0% i n c on si st en tly l ow . P re va le nc e o f s en si tiz at io n t o ca t: m al es : 2 8% i n c on si st en tly n or m al a nd 4 8% i n c on si st en tly l ow , f em al es : 2 5% in c on si st en tly n or m al a nd 5 0% i n c on si st en tly l ow . H ig he r l ev el s o f I gE a t a ge s 1 1 an d 2 1 w er e a ls o a ss oc ia te d w ith a c on si st en tly l ow t ra je ct or y i n f em al es . A ge 1 1 Ig E: c on si st en tly n or m al 4 .6 ( ln ), c on si st en tly l ow 5 .6 ( ln ). A ge 2 1 I gE : c on si st en tly no rm al 3 .7 ( ln ), c on si st en tly l ow 5 .0 ( ln ). N S: a to py a t a ge 1 3 o r 2 1 ( at l ea st o ne S PT ≥ 2 m m ) w as n ot a ss oc ia te d w ith a co ns is te nt ly l ow F EV1 /V C t ra je ct or y. S en si tiz at io n t o h ou se d us t m ite a nd c at a t a ge 13 w as n ot a ss oc ia te d w ith a c on si st en tly l ow F EV1 /V C t ra je ct or y (Co nti nue s)

Fir st a ut ho r C oh or t Ty pe a nd a ge lun g f unc tio n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) B er ry 43 TC RS (n = 5 99 ) Pop ul at ion - ba se d bi rt h c oh or t Sp iro m et ry a t 1 1, 16 , 2 2, 2 6 a nd 32 y Lu ng f un ct io n t ra je ct or y: Pe rs is te nt ly l ow N or mal La rg e air w ay s: FE V1 /F VC A st hma S: a st hm a b et w ee n t he a ge s o f 6 a nd 3 2 ( su rv ey a ge 6 , 1 1, 2 2, 2 6 a nd 3 2) w as as so ci at ed w ith a p er si st en tly l ow F EV1 /F V C t ra je ct or y. P re va le nc e o f a st hm a ra ng ed f ro m 7 .7 % t o 1 8. 0% i n t he n or m al t ra je ct or y a nd f ro m 2 6. 4% t o 4 3. 9% i n t he pe rs is te nt ly l ow t ra je ct or y K ar m aus 48 Io W b ir th c oh or t (n = 1 15 7) Pop ul at ion - ba se d bi rt h c oh or t Sp iro m et ry a t 1 0, 18 a nd 2 6 y Lu ng f un ct io n t ra je ct or y: low high Larg e air w ay s: FV C , F EV1 , F EV1 /F VC : low high Lung f un ct io n t ra je ct or y: low med iu m hig h Sm al l a ir w ay s: FEF 25 - 7 5 A st hma Ma le s S: a st hm a a t a ge s 4 , 1 0, 1 8 a nd 2 6 w as a ss oc ia te d w ith a l ow F EV1 /F V C a nd F EF25 - 7 5 tr aj ec to ry . A st hm a a t a ge s 4 , 1 0 a nd 2 6 w as a ss oc ia te d w ith a l ow F EV 1 tr aj ec to ry . N S: a st hm a a t a ge s 4 , 1 0, 1 8 a nd 2 6 w as n ot a ss oc ia te d w ith a l ow F V C t ra je ct or y. A st hm a a t a ge 1 6 w as n ot a ss oc ia te d w ith a l ow F EV1 tr aj ec to ry Fe m ale s S: a st hm a a t a ge s 1 0, 1 8 a nd 2 6 w as a ss oc ia te d w ith a l ow F EV 1 /F V C a nd F EF25 - 7 5 tr aj ec to ry . A st hm a a t a ge 1 8 w as a ss oc ia te d w ith a l ow F EV 1 tr aj ec to ry ( se e ap pe nd ix o f o rig in al p ap er f or e xa ct d at a) . N S: a st hm a a t a ge 4 w as n ot a ss oc ia te d w ith a l ow F EV1 /F V C o r F EF25 - 7 5 tr aj ec to ry . A st hm a a t a ge s 4 , 1 0 o r 2 6 w as n ot a ss oc ia te d w ith a l ow F EV 1 tr aj ec to ry A ller gi c sen si tiz at io n (s ki n p ric k t es t) Ma le s S: a lle rg ic s en si tiz at io n a t a ge 4 w as a ss oc ia te d w ith a l ow F EV1 /F V C t ra je ct or y ( RR 1. 64 ). Fe m ale s S: A lle rg ic s en si tiz at io n a t a ge 4 w as a ss oc ia te d w ith a l ow F EV1, F V C a nd F EF25 - 7 5 tr aj ec to ry ( RR 1 .3 2) B ui 47 TA H S (n = 2 43 8) Pop ul at ion - ba se d bi rt h c oh or t Sp iro m et ry a t 7 , 13 , 1 8, 4 5, 5 0 an d 5 3 y Lu ng f un ct io n t ra je ct or y: Pe rs is te nt ly h ig h Av er ag e B el ow a ve ra ge Pe rs is te nt ly l ow Ea rly b el ow a ve ra ge , ac cel er at ed de cl in e Ea rly l ow , a cc el er at ed g ro w th , nor m al d ec line La rg e air w ay s: FE V1 A st hma S: c hi ld ho od a st hm a ( du rin g t he f irs t 7 y o f l ife ) w as a ss oc ia te d w ith t he p er si st en tly lo w ( O R 1 .7 c om pa re d w ith t he a ve ra ge t ra je ct or y) a nd t he e ar ly b el ow a ve ra ge , ac ce le ra te d d ec lin e ( O R 3 .1 c om pa re d w ith t he a ve ra ge t ra je ct or y) F EV1 tr aj ec to ry . N S: C hi ld ho od a st hm a w as n ot a ss oc ia te d w ith e ar ly l ow , a cc el er at ed g ro w th , n or m al de cl in e o r p er si st en tly h ig h F EV 1 tr aj ec to ry A lle rg ic rh in iti s S: a lle rg ic r hi ni tis ( du rin g t he f irs t 7 y o f l ife ) w as a ss oc ia te d w ith t he e ar ly b el ow av er ag e, a cc el er at ed d ec lin e F EV 1 tr aj ec to ry ( O R 2 .0 c om pa re d w ith t he a ve ra ge tr aj ec to ry ). N S: a lle rg ic r hi ni tis w as n ot a ss oc ia te d w ith t he o th er l un g f un ct io n t ra je ct or ie s. Fo od a lle rg y N S: f oo d a lle rg y ( du rin g t he f irs t 7 y o f l ife ) w as n ot a ss oc ia te d w ith a l un g f un ct io n tr aj ec to ry N ote : I n p ap er s r ep or tin g s ig ni fic an t a ss oc ia tio ns w ith ou t p ro vi di ng e st im at es , t he se e st im at es w er e r ec or de d a s m is si ng i n t he r es ul ts . A ll l un g f un ct io n o ut co m es a re p re - s al bu ta m ol u nl es s o th er w is e sp ecif ie d. A bb re vi at io ns : B H R , b ro nc hi al h yp er - r es po ns iv en es s; F EF25 - 7 5 , f or ce d e xp ira to ry f lo w a t 2 5% - 7 5% o f F V C ; F EV 1 , f or ce d e xp ira to ry v ol um e i n 1 s ; F V C , f or ce d v ita l c ap ac ity ; I gE , i m m un og lo bu lin G ; n , b as ed on n um be r o f s ub je ct s w ith l un g f un ct io n m ea su re m en t r el ev an t t o a na ly si s; N S, n ot s ig ni fic an t; O R , o dd s r at io ; R R , r is k r at io ; S , s ig ni fic an t; V C , v ita l c ap ac ity . TA B LE 3   (Co nti nue d)

TA B LE 4  S tu di es o n l un g f un ct io n g ro w th Fir st a ut ho r C oh or t A ge l un g f un ct io n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) H al lb er g 30 B A M SE ( n = 19 57 ) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 4 a nd 8 y Lu ng f un ct io n g ro w th (4 - 8 y ) La rg e air w ay s: PEF A sth m a ph en ot ype s: N ev er Tr an si en t Pe rs is te nt La te o ns et S: T ra ns ie nt a st hm a ( −5 .8 L /m in ) h ad a l ow er g ro w th i n P EF c om pa re d w ith ne ve r a st hm a. N S: p er si st en t o r l at on se t a st hm a w as n ot a ss oc ia te d w ith g ro w th i n P EF H al lb er g 41 B A M SE (n = 2 35 5) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 8 a nd 1 6 y Lu ng f un ct io n g ro w th (8 - 1 6 y) La rg e air w ay s: FE V1 , F V C , F EV 1 /F VC Sm al l a ir w ay s: FEF 50 A sth m a ph en ot ype s: N ev er Ea rly t ra ns ie nt Ea rly p er si st en t La te o ns et S: e ar ly p er si st en t ( FE V1 − 26 2 m L, F EF50 − 66 8 m L) a nd l at on se t a st hm a (FE V1 − 12 4 m L, F EF50 − 35 0 m L) h ad l ow er g ro w th i n F EV 1 a nd F EF50 , co m pa re d w ith n ev er a st hm a. E ar ly t ra ns ie nt a st hm a h ad l ow er g ro w th i n FEF 50 (− 22 1 m L) N S: e ar ly t ra ns ie nt a st hm a w as n ot a ss oc ia te d w ith g ro w th i n F EV1 . N o as th m a p he no ty pe s w er e a ss oc ia te d w ith g ro w th i n F EV 1 /F VC Bi sg aa rd 53 C O PS AC 2000 (n = 3 36 ) H ig ris k b ir th c oh or t (c hi ld re n f ro m as th m at ic m ot he rs ) Ra is ed v ol um e r ap id t ho ra ci c co m pr es si on i n n eo na ta l pe rio d. S pi ro m et ry a t ag e 7 Lu ng f un ct io n g ro w th (0 - 7 y ) La rg e air w ay s: FE V1 , F V C , F EV 1 /F VC Sm al l a ir w ay s: F EF50 A st hma S: a st hm a a t t he a ge o f 7 w as a ss oc ia te d w ith a l ow er g ro w th i n FE V1 ( sc or e − 0. 62 ) a nd F EF 50 (Z - s co re − 0. 69 ) f ro m in fa nc y u nt il t he a ge o f 7 c om pa re d w ith n o a st hm a B loo d eo si no ph ils N S: b lo od e os in op hi ls ( at a ge 6 ) w er e n ot a ss oc ia te d w ith l un g f un ct io n gr ow th b et w ee n t he a ge s o f 0 a nd 7 H all as 56 C O PS AC 2000 (n = 3 67 ) H ig ris k b ir th c oh or t (c hi ld re n f ro m as th m at ic m ot he rs ) Ra is ed v ol um e r ap id t ho ra ci c co m pr es si on i n n eo na ta l pe rio d. S pi ro m et ry h al f-ye ar ly b et w ee n 5 a nd 7 y an d a t 1 3 y . W ho le - b od y pl et hy sm og ra ph y h al f-ye ar ly b et w ee n 3 a nd 7 an d a t 1 3 y Lu ng f un ct io n g ro w th (0 - 1 3 y) La rg e air w ay s: FE V1 Sm al l a ir w ay s: M M EF , sR aw A sth m a ph en ot ype s: Ev er a st hm a, N ev er a st hm a A st hm a r em is si on N S: a st hm a d ur in g t he f irs t 1 3 y o f l ife w as n ot a ss oc ia te d w ith a l ow er l un g fu nc tio n g ro w th c om pa re d w ith n ev er a st hm a. A st hm a r em is si on w as n ot as so ci at ed w ith c at ch - u p g ro w th u p u nt il t he a ge o f 1 3 A st hm a a nd a lle rg ic se ns iti za tio n ( sk in pr ic k t es t, I gE ) N S: a st hm a a nd c on cu rr en t a lle rg ic s en si tiz at io n ( at a ge 1 3) w as n ot as so ci at ed w ith a l ow er l un g f un ct io n g ro w th ( FE V1, M M EF o r s Ra w ) f ro m 1 m on th u nt il a ge 1 3 c om pa re d w ith a st hm a a nd n o a lle rg ic s en si tiz at io n D uij ts 44 A LS PA C ( n = 72 78 ) Po pula tio ba se d bir th coh or t Sp iro m et ry a t a ge s 9 a nd 1 5 Lu ng f un ct io n g ro w th (9 - 1 5 y) La rg e air w ay s: FE V1 , F EV 1 /F VC Sm al l a ir w ay s: FEF 25 - 7 5 W heez in g ph en ot yp es : Tr an si en t e ar ly Pr olo ng ed e ar ly Inte rm ed iate o ns et La te o ns et Pe rs is te nt N ev er /i nf re qu en t S: P ro lo ng ed e ar ly ( FE V1 /F V C − 0. 23 S D U , F EF25 - 7 5 − 0 .1 0 S D U ) a nd p er si st en t (FE V1 /F V C − 0. 27 S D U , F EV1 − 0. 13 S D U ) w he ez in g h ad l ow er g ro w th i n FE V1 /F VC an d F EF25 - 7 5 c om pa re d w ith n ev er /i nf re qu en t w he ez in g N S: t ra ns ie nt , i nt er m ed ia te - o ns et o r l at on se t w he ez in g w as n ot a ss oc ia te d w ith a d iff er en t g ro w th i n F EV1 /F V C a nd F EF25 - 7 5 c om pa re d w ith n ev er / in fr eq ue nt w he ez in g. N o a ss oc ia tio n b et w ee n w he ez in g p he no ty pe s a nd gr ow th i n F EV1 w as f ou nd (Co nti nue s)

Fir st a ut ho r C oh or t A ge l un g f un ct io n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) B el gr av e 38 M A A S ( n = 10 51 ) Po pula tio ba se d bir th coh or t W ho le - bod y pl et hy sm og ra ph y a t a ge s 3, 5 , 8 a nd 1 1 Lu ng f un ct io n g ro w th (3 - 1 1 y) Sm al l a ir w ay s: s Ra w W heez in g ph en ot yp es : N o w he ez in g Tr an si en t e ar ly La te o ns et Pe rs is te nt S: P er si st en t w he ez in g h ad a l ar ge r i nc re as e i n s Ra w ( 0. 01 1 kP a/ s - 1 / y) o ve r tim e c om pa re d w ith n o w he ez in g. N S: t ra ns ie nt a nd l at on se t w he ez in g w er e n ot a ss oc ia te d w ith c ha ng e i n sR aw b et w ee n a ge s 3 a nd 1 1 A ller gi c sen si tiz at io n ph en ot yp es ( sk in pr ic k t es t a nd IgE ): N on - a to pic D us t m ite N on - d us t mi te M ult ip le e ar ly M ult ip le la te S: T he m ul tip le e ar ly ( 0. 01 1 kP a/ s - 1 / y) a nd m ul tip le l at e ( 0. 00 8 kP a/ s - 1 / y) tr aj ec to rie s h ad a l ar ge r i nc re as e i n s Ra w c om pa re d w ith n on - a to pi c Sh er rill 16 D un ed in , N ew Z ea la nd (n = 6 96 ) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 9 , 1 1, 1 3 a nd 15 y Lu ng f un ct io n g ro w th (9 - 1 5 y) La rg e air w ay s: FE V1, V C , F EV1 /VC W heez in g ph en ot yp es : Se ve re w heez in g Mo der at e wh ee zi ng O cc as io na l w he ez in g N w he ez in g S: m od er at e w he ez in g ( be tw ee n t he a ge s o f 3 a nd 1 5) ( −0 .0 53 L /y ) h ad a lo w er F EV1 g ro w th c om pa re d w ith n on - w he ez in g. O cc as io na l w he ez in g (0 .0 31 L /y ) h ad a g re at er V C g ro w th c om pa re d w ith n on - w he ez in g. Se ve re ( 0. 49 9% /y ) a nd m od er at e w he ez in g ( 0. 30 3% / y) h ad a h ig he r gr ow th i n F EV1 /V C c om pa re d w ith n on - w he ez in g. N S: s ev er e a nd o cc as io na l w he ez in g w er e n ot a ss oc ia te d w ith F EV1 g ro w th . Se ve re a nd m od er at e w he ez in g w er e n ot a ss oc ia te d w ith V C g ro w th BH R se ve rit y: Hy pe re sp on si ve Mi ldl y re sp on si ve N on - r es po ns iv e Co ns is te nt ly re sp on si ve Re m is si on N ew re sp on der s Co ns is te nt ly non - r es po ns iv e S: m ild ( −0 .0 32 L /y ) a nd h yp er - r es po ns iv e ( −0 .0 45 L /y ) B H R w er e a ss oc ia te d w ith a l ow er F EV1 g ro w th c om pa re d t o n on - r es po nd er s. M ild ly re sp on si ve B H R ( −0 .0 23 L /y ) w as a ss oc ia te d w ith a l ow er V C g ro w th . H yp er - r es po ns iv e B H R ( −0 .3 94 % /y ) w as a ss oc ia te d w ith a l ow er g ro w th in F EV1 /V C . C on si st en t r es po nd er s a nd n ew r es po nd er s h ad a l ow er FE V1 a nd F EV 1 /V C g ro w th c om pa re d w ith n ev er r es po nd er s ( m ea ns n ot pro vi de d) . N S: h yp er - r es po ns iv e B H R w as n ot a ss oc ia te d w ith a V C g ro w th . M ild ly re sp on si ve B H R w as n ot a ss oc ia te d w ith F EV1 /V C g ro w th . S ub je ct s w ho w en t i nt o r em is si on d id n ot h av e a d iff er en t l un g f un ct io n g ro w th co m pa re d w ith c on si st en tly n on - r es po ns iv e B H R Se ar s 4 D un ed in , N ew Z ea la nd (n = 6 13 ) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 9 , 1 1, 1 3, 1 5, 18 , 2 1 a nd 2 6 y Lu ng f un ct io n g ro w th (9 - 2 6 y ) La rg e air w ay s: FE V1 /F VC W heez in g ph en ot yp es : Pe rs is te nt f ro m o ns et Re la ps e Re m is si on Inte rm itte nt Tr an si en t N ev er wh ee ze N S: G ro w th i n F EV 1 /F V C w as n ot d iff er en t f or a ny w he ez in g p he no ty pe s co m pa re d w ith n ev er w he ez in g TA B LE 4   (Co nti nue d) (Co nti nue s)

Fir st a ut ho r C oh or t A ge l un g f un ct io n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) A rsha d 37 Io W b ir th c oh or t (n = 1 81 a t a ge 1 8) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 1 0 a nd 1 8 y Lu ng f un ct io n g ro w th (1 18 y ) La rg e air w ay s: FE V1 , F V C Sm al l a ir w ay s: FEF 25 - 7 5 A st hma gr ou ps : Pe rs is te nt Re m is si on Ma le s S: R em is si on o f a st hm a ( 2. 6 L ) w as a ss oc ia te d w ith a h ig he r g ro w th i n FE V1 (b et w ee n 1 0 a nd 1 8 y ) c om pa re d w ith p er si st en t a st hm a ( 2. 4 L ). Re m is si on o f a st hm a ( 2. 7 L ) w as a ss oc ia te d w ith a h ig he r g ro w th i n FEF 25 - 7 5 c om pa re d w ith p er si st en t a st hm a ( 2. 1 L ). N S: N o a st hm a g ro up s w er e a ss oc ia te d w ith g ro w th i n F V C . Fe m ale s N S: Re m is si on of a st hm a w as no t a ss oc ia te d w ith a di ff er en ce in lu ng fu nc tio n gr ow th c om pa re d t o s ub je ct s w ith p er si st en t a st hm a K ur uk ula ar at ch y 33 Io W b ir th c oh or t (n = 4 18 , m al e 1 86 , fe m al e 2 32 ) Po pula tio ba se d bir th coh or t Sp iro m et ry a t 1 0 a nd 1 8 y Lu ng f un ct io n g ro w th (1 18 y ) La rg e air w ay s: FE V1 , F V C , F EV 1 /F VC Sm al l a ir w ay s: FEF 25 - 7 5 A st hma gr ou ps : A do le sc en on se t N ev er - a st hm a Ma le s N S: s ub je ct s w ith a do le sc en on se t a st hm a d id n ot h av e a d iff er en t g ro w th i n lu ng f un ct io n c om pa re d w ith n ev er a st hm a. Fe m ale s S: s ub je ct s w ith a do le sc en on se t a st hm a ( 1. 36 L ) h ad a l ow er g ro w th i n F EV1 (b et w ee n 1 0 a nd 1 8 y c om pa re d w ith n ev er a st hm a ( 1. 52 L ). N S: a st hm a g ro up s w er e n ot a ss oc ia te d w ith g ro w th o f F V C , F EV1 /F V C a nd FEF 25 - 7 5 M or gan 5 TC RS ( n = 82 6) Po pula tio ba se d bir th coh or t Pa rt ia l e xp ira to ry f lo w vo lu m e m an oe uv re a t ag e 6 . Sp iro m et ry a t a ge s 1 1 a nd 1 6 Lu ng f un ct io n g ro w th (6 - 1 6 y ) La rg e air w ay s: Vm ax FR C Sm al l a ir w ay s: FEF 25 - 7 5 W heez in g ph en ot yp es : N ev er Tr an si en t e ar ly La te o ns et Pe rs is te nt N S: N on e o f t he w he ez in g p he no ty pe s h ad a d iff er en t l un g f un ct io n g ro w th co m pa re d w ith n ev er w he ez in g Jȩ dr ych ow sk i 21 K ra ko w , P ol an d (n = 1 00 1) Pop ul at ion - ba se d coh or t Sp iro m et ry a t 9 a nd 1 1 Lu ng f un ct io n g ro w th (9 - 1 1 y ) ( bi na ry : sl ow l un g f un ct io n gr ow th (S LFG )= low es t qu in til e o f g ro w th ) La rg e air w ay s: FE V1 , F V C Sm al l a ir w ay s: FEF 25 - 7 5 A sth m a/ w heez in g ph en ot yp es : H ea lthy N ew c as es C on tin ue d Re m is si on S: C on tin ue d a st hm a b et w ee n t he a ge o f 9 a nd 1 1 w as a ss oc ia te d w ith a hi gh er p re va le nc e o f S LF G ( FE V1 O R 3 .4 6, F V C O R 3 .4 0 a nd F EF25 - 7 5 O R 5 .8 4) c om pa re d w ith h ea lth y s ub je ct s. N ew s ym pt om s o f a st hm a be tw ee n t he a ge o f 9 a nd 1 1 w er e a ss oc ia te d w ith S LF G f or F EV 1 (O R 1. 46 ) b et w ee n t he a ge o f 9 a nd 1 1. R em is si on o f a st hm a s ym pt om s w as as so ci at ed w ith S LF G f or F EF25 - 7 5 (O R 2 .6 3) . N S: r em is si on o f a st hm a s ym pt om s w as n ot a ss oc ia te d w ith S LF G f or F EV1 o r FVC N ak ad ate 18 Ib ar ak i, J ap an ( n = 32 5) Pop ul at ion - ba se d coh or t Sp iro m et ry a t 1 0 a nd 1 4 Lu ng f un ct io n g ro w th (1 14 y ) La rg e a ir w ay s: F EV1 , F V C Sm al l a ir w ay s: F EF50 , FEF 25 A st hm a c at eg or ie s: C at eg or y A : a st hm a a t fir st s ur ve y ( 10 y ) C at eg or y B : br on ch iti s o r pn eu m on ia a t f irs t su rv ey ( 10 y ) C at eg or y C : n o as th m a, br on ch iti s or p neu m on ia a t an y t im e d ur in g fo llo w - u p S: C at eg or y A ( −7 9 m L/ s y ea r) w as a ss oc ia te d w ith a l ow er a nn ua l g ro w th i n FEF 25 c om pa re d w ith C at eg or y C ( 8 m L/ s/ y) . N S: c at eg or y A w as n ot a ss oc ia te d w ith a d iff er en t g ro w th i n F EV1 , F V C o r FEF 50 c om pa re d w ith C at eg or y C TA B LE 4   (Co nti nue d) (Co nti nue s)

3.3.2  |  Lung function growth

Asthma and/or wheezing before the age of 7 30,53 _{and later in}

child-hood 21 _{were associated with a lower lung function growth during}

childhood. Asthma and/or wheezing during childhood 18,41 _and

dur-ing adolescence 16,17 _{were associated with a lower lung function}

growth during adolescence. Adolescent- onset asthma was

associ-ated with a lower FEV₁ growth in females between ages 10 and 18,

but not in males.33 _{Interestingly, remission of asthma in males during}

the same period of development was associated with a greater gain

in FEV₁ and FEF_{25- 75} from childhood to early adulthood when

com-pared to subjects with a persistent asthma phenotype.37 _However,

another study reported that remission of asthma during childhood was not associated with catch- up growth from infancy until the age

of 13.56 _{Asthma and/or wheezing was significantly associated with}

lower growth of large and small airway parameters during

child-hood in three out of four studies 17,21,53 _{; one study did not confirm}

this.33 _{Lower lung function growth during childhood in subjects with}

asthma 56 _{and wheezing} 38 _{using sRaw (ie higher sRaw) and small}

airways expiratory flows (higher MMEF) during childhood 56 _was

re-ported in two independent studies. Wheezing phenotypes

A persistent wheezing phenotype was associated with a larger increase in specific airway resistance (sRaw) during childhood compared with

the never- wheezing subjects.38 _{Early transient,}41 _{prolonged early,}44

persistent 41,44 _{and late- onset} 41 _{wheeze were associated with a lower}

lung function growth from childhood until adolescence. The associa-tion for persistent wheezing was reported in studies using both LCA and a hypothesis- driven approach combined with asthma treatment records for phenotype development. In contrast, one study found that

growth of FEF_{25- 75} from age 6 until 16 in subjects with any of the

re-ported wheezing phenotypes was not significantly different from non-

wheezing subjects.5 _{Although phenotype definition was also defined}

a priori, this study differed from Hallberg et al in that persistence of wheeze was based solely on reporting during the first 6 years of life. Another study that incorporated reporting of wheeze between the

ages of 9 and 26 reported no difference in the change in FEV₁/FVC

between the ages 9 and 26 between subjects with any wheezing

phe-notype compared with the never- wheeze reference group.4

3.3.3  |  Lung function at distinct stages of

development

Asthma and wheezing

A history of asthma or wheezing before the age of 7 22,26,30,39- 41,51

and later in childhood 20,28,39,52 _{was associated with lower lung}

func-tion levels during childhood. Childhood asthma was associated with a lower lung function in adolescence, which persisted into

adult-hood in two studies.20,52 _{Persistence of asthma from childhood to}

adulthood was associated with lower FEV₁ during early adulthood.37

Fir st a ut ho r C oh or t A ge l un g f un ct io n m eas ur em en t( s) En po in ts Pr ed ic to rs o f ou tc ome M ain fin din gs (S : sig ni fic an t, N S: n on - sig ni fic an t) We is s 17 B os to n, U SA ( n = 60 2) Pop ul at ion - ba se d coh or t Sp iro m et ry a nn ua lly d ur in g th e 1 y o f f ol lo w - u p st ar tin g a t e nr ol m en t (a ge 5 - 9 ) Lu ng fu nc tio n gr ow th 9 to 1 22 y ) La rg e air w ay s: FE V1 , F V C Sm al l a ir w ay s FEF 25 - 7 5 A st hm a c at eg or ie s: A ct iv e a st hm a Ina ct iv e as th ma N o a st hm a Ma le s S: a ct iv e a st hm a ( −4 .1 8% / y) w as a ss oc ia te d w ith a l ow er g ro w th i n F EF25 - 7 5 % pr ed ic te d c om pa re d w ith n o a st hm a. A ct iv e a st hm a ( 2. 45 % / y) w as as so ci at ed w ith a h ig he r g ro w th i n F V C % p re di ct ed c om pa re d w ith n o as th m a. N S: N o a ss oc ia tio n w as s ee n f or g ro w th i n F EV1 . Fe m ale s S: a ct iv e a st hm a ( −2 .1 2% / y) w as a ss oc ia te d w ith a l ow er g ro w th i n F EV1 % pr ed ic te d c om pa re d w ith n o a st hm a. A ct iv e a st hm a ( −5 .7 5% / y) w as as so ci at ed w ith a l ow er g ro w th i n F EF25 - 7 5 % p re di ct ed c om pa re d w ith n o as th m a. N S: n o s ig ni fic an t a ss oc ia tio n w as s ee n f or g ro w th i n F V C . N S: i na ct iv e a st hm a w as n ot a ss oc ia te d w ith d iff er en ce s i n l un g f un ct io n gr ow th c om pa re d w ith n o a st hm a N ote : I n p ap er s r ep or tin g s ig ni fic an t a ss oc ia tio ns w ith ou t p ro vi di ng e st im at es , t he se e st im at es w er e r ec or de d a s m is si ng i n t he r es ul ts . A ll l un g f un ct io n o ut co m es a re p re - s al bu ta m ol u nl es s o th er w is e sp ecif ie d. A bb re vi at io ns : B H R: b ro nc hi al h yp er - r es po ns iv en es s; F EF25 - 7 5 : f or ce d e xp ira to ry f lo w a t 2 5% a nd 7 5% o f F V C ; F EV 1 : f or ce d e xp ira to ry v ol um e i n 1 s ; F V C : f or ce d v ita l c ap ac ity ; I gE : i m m un og lo bu lin G ; M M EF : m ax im al m id - e xp ira to ry f lo w ; n : b as ed o n n um be r o f s ub je ct s w ith l un g f un ct io n m ea su re m en t r el ev an t t o a na ly si s; N S: n ot s ig ni fic an t; P EF : p ea k e xp ira to ry f lo w ; S : s ig ni fic an t; s Ra w : s pe ci fic ai rw ay r es is ta nc e; V C : v ita l c ap ac ity ; V m ax FR C : m ax im um f or ce d e xp ira to ry f lo w a t f un ct io na l r es id ua l c ap ac ity . TA B LE 4   (Co nti nue d)

Remission of asthma during adolescence was associated with higher

FEV₁/FVC level in early adulthood when compared to subjects with

persistent asthma.54 _{We identified no studies investigating the}

dif-ference in lung function levels between subjects with asthma remis-sion and never asthma.

Wheezing phenotypes

Transient 19,36 _{and persistent} 36 _{wheezing phenotypes were}

associ-ated with a lower lung function in infancy. An association between wheezing phenotype and lung function for transient wheezing was observed in studies using both LCA and a hypothesis- driven ap-proach for phenotype development, while an association for persis-tent wheezing was only reported in the ALSPAC cohort using LCA. At age 3, persistent wheezing was associated with a higher sRaw (ie higher resistance) when compared to non- wheezers at age 3. At age 5, both transient and persistent wheezing phenotypes were

associ-ated with a higher sRaw.27

Later in childhood, (early) transient,5,19,24,25,27,29,31,32,35,36,40,49

persistent,5,19,24,25,27,29,31,32,35,36,40,49 _{prolonged early} 29 _{and late-}

onset wheezing 25,29,35,40 _{were associated with lower lung}

func-tion levels when compared to non- affected control subjects. Associations with lung function for (early) transient, late- onset and persistent wheezing were observed in studies using both a

hypothesis- driven approach 5,19,24,25,27,31 _{and LCA.}29,32,35,36,40,49

Transient (early),5,44 _{prolonged early,}44 _{intermediate- onset,}44 _late-

onset 44 _{and persistent} 5,44 _{wheezing phenotypes were also}

asso-ciated with lower lung function levels in adolescence. Transient wheezing was the only phenotype developed using both LCA and a hypothesis- driven approach to be associated with a lower lung func-tion level in adolescence. Granell et al found that phenotypes with early childhood- onset wheezing persisting into adolescence were

associated with FEV₁/FVC and FEF_{25- 75}; however, no association

was seen for FEV₁.50 _{In one study, a persistent wheezing}

pheno-type was associated with lower lung function levels in adulthood.4

Ten studies included both small and large airway parameters in their analysis with asthma and/or wheezing (including longitudinal

phe-notypes thereof).5,25,28,29,33,35,36,41,49,52 _{All these papers found that}

asthma and/or wheezing were associated with both reduced large and small airway parameters.

3.4  |  Bronchial hyper- responsiveness

3.4.1  |  Lung function trajectories

BHR, measured in childhood, adolescence and adulthood, was associated with a lower- than- normal lung function trajectory in

childhood, up to early adulthood.23,45 _{One study reported that}

more severe BHR in childhood was associated with a reduced

lung function growth trajectory based on FEV₁.3 _{No studies}

re-ported the association between BHR and trajectories of the small airways.

3.4.2  |  Lung function growth

More severe BHR measured in childhood and adolescence was

as-sociated with a lower growth of FEV₁, FEV₁/VC and VC from age

9 to 15 until adolescence.16 _{Adolescent- onset BHR was associated}

with a lower growth pattern of FEV₁ in adolescence compared

with subjects without BHR,16 _{whereas remission of BHR was not}

associated with lower lung function growth until adolescence

compared with subjects who were never– BHR- responsive.16 _No

studies analysed the association between BHR and small airway growth.

3.4.3  |  Lung function at distinct stages of

development

The presence of BHR in childhood and until adulthood was

associ-ated with a lower FEV₁ and FEV₁/FVC level in early adulthood.20,23

No studies reported associations between BHR and small airway lung function.

3.4.4  |  Atopic sensitization

Allergic sensitization between the ages of 3 and 11 was associated

with a persistently low FEV₁ trajectory until adolescence,45,48 _but

this association was not seen for sensitization in adolescence.45

Another study also reported no association between allergic sen-sitization at age 8 and a low lung function trajectory during

adoles-cence.46 _{A higher number of positive skin prick tests in childhood}

were associated with a lower FEV₁ trajectory until adulthood

com-pared to subjects with a normal trajectory.3 _{Allergic sensitization}

in adulthood to house dust mite or to cat in adulthood was

associ-ated with a consistently lower FEV₁/VC trajectory in adulthood,23

whereas food allergy was not associated with any lung function

tra-jectory.47 _{Allergic rhinitis was associated with an ‘early below average,}

accelerated decline’ trajectory.47 _{Allergic sensitization in early}

child-hood was associated with both small and large airway trajectories in

females.48 _{In males, allergic sensitization at age 4 was only}

associ-ated with a low FEV₁/FVC trajectory but not with the trajectory of

the small airway parameter (ie FEF_{25- 75}).48

Lung function growth

Sensitization to multiple allergens early in life was associated with an increase in sRaw between the ages of 3 and 11 compared with

non- atopic subjects.38 _{Asthma with concurrent allergic sensitization,}

measured at age 13, was not associated with a lower degree of lung function growth in large and small airway parameters from infancy until the age of 13, compared to subjects with asthma without

aller-gic sensitization.56 _{None of the papers assessed the role of allergic}

Lung function at distinct stages of development

At age 3, a positive skin prick test was associated with a higher sRaw in non- wheezing subjects compared with the non- atopic

non- wheezing group.22 _{A combined wheezing and atopic}

pheno-type in childhood was associated with a lower FEV₁ and FEV₁/FVC

at age 7.57 _{In two separate cohorts, sensitivity to a wide variety of}

allergens, including mite, pollens, cat and dog around age 10/11,

was associated with a lower FEV₁ and FEV₁/FVC.34 _Early

sensitiv-ity to mite, grass and tree pollens with later onset of sensitivsensitiv-ity to

pets was associated with a lower FEV₁ at age 11 (based on

sensitiv-ity testing at ages 1, 3, 5, 8 and 11).34 _{Allergic sensitization to cat}

dander at age 13 was associated with a lower FEV₁ level between

the ages of 9 and 15.16 _{In one study, atopic wheeze was associated}

with lower lung function parameters of both large and small

air-ways (FEV₁, FEV₁/FVC, FEF₇₅ and FEF₂₅) at age 7 compared with

no wheeze.28 _{For subjects with early- onset timothy grass}

sensiti-zation and a dust mite sensitisensiti-zation trajectory (based on

sensitiza-tion profiles at ages 5, 8 and 11 years), a lower FEV₁ was reported

at age 11.42 _{At ages 8- 9, a late- onset allergic rhinitis phenotype}

was associated with lower FEV₁ and FEF_{25- 75} compared with the

reference group.49 _{Atopic wheeze was associated with lower FEV}

1,

FEV₁/FVC, FEF₇₅ and FEF₂₅ at age 7 compared with no

wheez-ing.28 _{A late- onset allergic rhinitis phenotype was associated with}

lower large and small airway parameters (FEV₁, FEF_{25- 75} and FEV₁/

FVC).49

Blood eosinophils

Only one study reported associations of blood eosinophils with lung function outcomes. No association between blood eosinophils at

age 6 and lung function growth (FEV₁, FVC, FEV₁/FVC and FEF₅₀)

between 0 and 7 years was found for either large or small airway

parameters.53

4  |  DISCUSSION

4.1  |  Main findings

Asthma and different patterns of wheezing are associated with a low lung function trajectory in childhood, adolescence and up to

early adulthood.43,45- 48 _{Additionally, BHR is a strong risk factor for}

low lung function in childhood up to adolescence.3,45 _{Most studies}

report this for large airways parameters (FEV₁, FEV₁/FVC), with a

paucity of studies of the small airways. In asthmatic and wheezing children, reduced lung function growth appears to occur mainly in early childhood, after which lung function often tracks at a

paral-lel, but lower level to that of non- affected individuals.4,5,43 _Allergic

sensitization 45 _{and allergic rhinitis} 47 _{are also associated with lower-}

than- normal lung function trajectories, yet results varied. The timing of allergic sensitization (preschool age) and the level of sensitization (polysensitization) appeared to be strongly predictive of low lung

function growth.3,34,38

4.2  |  Lung function development until peak

function in subjects with asthma or wheezing

Many children with asthma or wheezing have a lower lung func-tion level and lower lung funcfunc-tion growth, and reach a lower peak lung function in early adulthood compared with a control

population,43,45- 48 _{possibly predisposing them to COPD.}3 _{This is}

likely attributed to a lower degree of lung function growth

dur-ing early childhood 30,53 _{after which lung function growth tracks}

parallel to non- asthmatic controls.4,5 _{Consequently, early}

child-hood should be identified as a key period of development in which exposure to risk factors such as asthma and wheezing play an in-tegral role in lung function growth. Despite this, the association of adolescent- onset BHR with a lower lung function growth pat-tern suggests that lung function development can change after

childhood as well.16 _{This is further emphasized by the}

improve-ment in lung function in early adulthood in subjects with asthma

remission, relative to subjects with persistent asthma.37,54 _These

observations were done in mainly population- based studies that include children with mild asthma. Thus, future studies should also address lung growth in children with persistent, moderate- to- severe asthma, since evidence suggests that lung growth up to the

plateau may be limited.3 _{The heterogeneity of lung function}

de-velopment is further increased by sex- related differences,17,33,48

and future research should therefore incorporate sex- stratified analyses to further explore these differences.

Asthma is a highly heterogeneous condition, which can present as several phenotypes with varying degrees of severity. Based on findings presented in this systematic review, a greater disease se-verity, manifested by earlier onset and persistence of asthma and or wheezing, was associated with lung function deficits throughout development compared with the control population. In addition to an earlier onset and persistence of symptoms, the number of exacer-bations may be important as well in subjects with asthma. In this sys-tematic review, we did not include exacerbations as a candidate risk factor for lung function growth. However, the number of exacerba-tions in children with asthma and wheezing has been reported to be predictive of a lower lung function throughout childhood compared

to children with asthma and no exacerbations.38,58 _{As such, accurate}

recognition of asthma exacerbations and timely intervention to treat and prevent exacerbations may be warranted to preserve optimal lung function growth.

4.3  |  Preschool asthma, wheezing phenotypes and

lung function

Asthma predominantly starts in preschool life, often as recurrent wheezing episodes. Different patterns of wheeze were associ-ated with low lung function in childhood and adolescence. After

the seminal publication by Martinez et al,19 _{describing transient}

childhood, these patterns of wheezing onset and persistence have been confirmed in other cohorts and by machine learning approac hes.29,32,35,36,38,40,44,49,59,60 _{Children with an early transient wheeze}

had a lower lung function compared with persistent, late- onset and never- wheezing phenotypes at the age of 2 months, prior to onset of wheezing and that lung function remained at a lower level

dur-ing childhood in this group,19 _{with a replication study yielding}

con-flicting results.25 _{Direct comparison is made difficult by different}

approaches in establishing the wheezing phenotypes. Later in child-hood, transient wheeze phenotypes were still associated with lower

lung function levels.5,19,24,25,27,29,31,32,35,36,40,49 _{This supports the}

hy-pothesis that transient wheeze early in life is likely the clinical pres-entation of congenitally narrow airways predisposing to wheeze, especially during viral infections. Following growth of airway calibre, wheezing resolves in most subjects; however, a lower lung function remains.

The early persistent, intermediate and late- onset wheezing phe-notypes have also been associated with low lung function growth

until adolescence and early adulthood.59 _{Furthermore, the}

associ-ation of persistent,32,59 _intermediate 32,44,59 _{and late- onset}

wheez-ing phenotypes 32,44,59 _{with a later diagnosis of asthma in childhood}

suggests that these wheezing phenotypes have a stronger relation to asthma and reflect ongoing inflammatory airway disease. Children with persistent wheeze had a lower lung function in infancy

com-pared with never- wheezing subjects in the SWS study,36 _{but this was}

not replicated for persistent or late- onset wheeze phenotypes in the

Tucson study.19 _{A direct comparison is, however, not possible due to}

differences in phenotype modelling. Low lung function in early life may be a reflection of a more severe asthma phenotype with earlier onset, thereby being both causally and consequentially related to a lower lung function growth. Since almost all studies were done in general populations, it is likely that these observations reflected milder asthma, as severe asthma has a low prevalence in the general

population.61

4.4  |  Risk factors for lung function development:

BHR, atopy and eosinophils

BHR is a universally recognized hallmark of asthma and has been

associated with lower lung function in childhood,62,63 _adolescence

16 _{and adulthood,}4,20,23,64 _{making it a prime risk factor for adverse}

lung function growth. The notion of BHR as strong predictor of lower lung function growth is supported by the association of adolescent- onset BHR with a lower lung function growth pattern

in that period of life.16 _{In parallel, improvement in lung function}

growth, which may be seen as catch- up growth, was observed in

adolescent subjects with BHR remission.16 _{These findings suggest}

that lung function growth is amendable to change after childhood as well.

The use of inhaled corticosteroids (ICS) has not shown to

im-prove lung function growth in subjects with asthma 65 _{; however,}

a sparsity of information exists on the topic. Use of ICS amongst

subjects with asthma has furthermore been associated with a lower lung function level during development in several stud-ies.4,23,52 _{However, interpretation of the association between ICS}

and lung function growth in a non- randomized setting is compli-cated as ICS use suggests a more severe asthma phenotype. There was a paucity of studies investigating the association between blood eosinophils and lung function growth. Recently published research has shown that blood eosinophils in adolescent subjects

with asthma are associated with a lower lung function growth.66

Therefore, further research should investigate the role of ICS and anti- eosinophilic treatments in the preservation of lung function development in subjects with asthma.

Allergic sensitization 45 _{and allergic rhinitis} 47 _{are associated with}

lower- than- normal lung function trajectories, yet results varied be-tween studies. In some studies, children sensitized to common al-lergens were more likely to have a lower- than- normal lung function

trajectory until childhood,45,48 _adolescence 45,46,48 _{and early}

adult-hood 3,48 _{compared to children without sensitization. The timing of}

allergic sensitization (preschool age) and the level of sensitization (polysensitization) appeared to be strong predictors of low lung

function growth.3,34,38 _{The association of early onset of}

sensitiza-tion or polysensitizasensitiza-tion with lower lung growth may be the result of a more atopic constitution leading to a more severe and chronic course of asthma.

Next to sensitization, allergic rhinitis was associated with a

lower- than- normal lung function trajectory until adulthood.47 _The

association between allergic rhinitis and adverse lung function is supported by the Norwegian ECA cohort in which lung

func-tion growth in FEV₁ and FEF_{25%- 75%} until adolescence was

signifi-cantly lower in children with allergic rhinitis, atopic dermatitis

and asthma compared to children with only asthma or rhinitis,12

findings also supported by the PARIS cohort.49 _{These findings}

suggest that there is an additive effect of allergic comorbidity on lung function deficits in children with asthma and that the con-tribution to airway inflammation is also present in the small air-ways. Consequently, allergic rhinitis should be seen as a risk factor for lower lung function growth, primarily in children with asthma. Allergic rhinitis, in addition to sharing many of the same immuno-logic traits of the lower airway, may also impact lung inflammation by not properly performing air humification and filtration during periods of rhinorrhoea. Given the association with lung function growth, it may be speculated that accurate recognition and treat-ment of allergic rhinitis in children with asthma may potentially impact long- term lung function development.

4.5  |  Small airway disease

In this systematic review, we found that asthma and/or wheez-ing,17,21,53 _{allergic sensitization} 28,48,56 _{and allergic rhinitis} 49

were associated with both large and small airway parameters. Furthermore, two studies reported lower lung function growth