| EDITORIAL

COPD

Small airways and early origins of COPD:

pathobiological and epidemiological
considerations

Francesca Polverino1 and Joan B. Soriano 2,3

Affiliations: 1Asthma and Airway Disease Research Center, Dept of Medicine, University of Arizona, Tucson,
AZ, USA. 2Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain. 3Centro de
Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid,
Spain.

Correspondence: Francesca Polverino, Asthma and Airway Disease Research Center, Dept of Medicine,
University of Arizona, Tucson, AZ, USA. E-mail: [email protected]

@ERSpublications
The role of the small airways and the early origins of airflow limitation http://bit.ly/35Uaib3

Cite this article as: Polverino F, Soriano JB. Small airways and early origins of COPD: pathobiological and
epidemiological considerations. Eur Respir J 2020; 55: 1902457 [https://doi.org/10.1183/13993003.02457-
2019].

Until recently, the conceptual model of the natural history of COPD has been greatly focused on an
accelerated decline of lung function, which would occur in adult life in susceptible individuals when
chronically exposed to environmental noxious agents, such as cigarette smoke and other inhaled gases.
However, 25%–45% of all COPD patients worldwide have never smoked [1]. In addition, pre- and
peri-natal factors associated with diverse biological mechanisms can determine low lung function in young
adults [2–4]. Among these factors, asthma and active and/or passive smoking act synergistically to affect
early lung function deficits in young adulthood [5, 6]. The impact of smoke exposure in susceptible
smokers is detectable with exposures to as little as 8–10 pack-years, in their late 30 s to early 40 s [7].
Similarly, early onset asthma is observed in 26% of those diagnosed with COPD at a mean age of 37 years,
which represents a 20-fold increased risk of adult airway obstruction compared with those without asthma
diagnosis [8]. However, what the combined effects of current active smoking and asthma are in a
population of young adults is unknown.
The paper by ARSHAD et al. [9] in this issue of the European Respiratory Journal addresses this knowledge
gap. The authors examined the Isle of Wright Birth Cohort at ages 10, 18 and 26 years for lung function
and asthma, while information on environmental exposures, including active and passive smoking, were
obtained since birth. The presence of current asthma and/or current smoking at age 26 years was used as
rationale to divide the population into four groups (non-smokers without asthma; non-smokers with
asthma; smokers without asthma; and smokers with asthma), independently of their previous history of
smoking or asthma; further, they retrospectively assessed their previous lung function in order to assess
their risk of future COPD. These investigators should be praised for following up children from birth, with
extensive questionnaires, both pre- and post-bronchodilator spirometry, and with a decent retention
(>70% at age 26 years, as per their table S2), all following STROBE guidance for observational research.
And, last but not least, for successfully running a cohort for a quarter of a century, and counting [10].
Indeed, several limitations are inherent, such as the recall bias for previous smoke exposure in a
population which is classified solely according to their current smoking status. Nonetheless, this study

Received: 20 Dec 2019 | Accepted after revision: 6 Jan 2020

Copyright ©ERS 2020

https://doi.org/10.1183/13993003.02457-2019 Eur Respir J 2020; 55: 1902457

 COPD | F. POLVERINO AND J.B. SORIANO

delivered important outcomes. Predictably, subjects with both asthma and smoking at the age of 26 years
had the poorest lung function, but had already low lung function very early in life (age of 10 years). This
suggests that asthma in early adulthood is preceded by changes in lung function which can be tracked
back to many years previously, and which need to be identified early, as they might lead to future early
development and (mis)diagnosis of COPD.
A novel aspect of this study is the longitudinal assessment of the mean forced expiratory flow between
25% and 75% of the forced vital capacity (FEF25–75), an indicator of small airway disease which is affected
early in smoking-related lung disease. For years, the FEF25–75 has been underused in clinical cohort studies
due to its high rate of variation among subjects. However, others have shown that the FEF25–75 is highly
sensitive to early lung changes leading to airflow limitation [5]. In the current study, FEF25–75 and forced
expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio were more sensitive than
FEV1 alone in detecting early lung function impairment in young adult smokers. This aspect calls for an
important consideration: the decline in indices of lung function reflecting airway diameter occurs early in
adult life and should be evaluated more frequently within the assessment of lung volumes in cohort
studies of young adults at risk for early COPD.
The early changes in FEF25–75 and FEV1/FVC mirror the contribution of the small airways in the
pathogenesis of early lung function limitation, and might therefore be a link between childhood asthma
and early COPD. Regrettably, many knowledge gaps in the pathogenesis of early airflow limitation still
exist, mainly because COPD has always been considered a disease of the elderly, and little attention has
been paid to the pathological changes occurring in the lungs of individuals at risk before they develop
clinically evident COPD [2]. COPD is still considered as a clinical disorder associated with large airway
disease (chronic bronchitis) and alveolar loss (emphysema). However, it later became apparent that the
small conducting airways of less than 2 mm in internal diameter (terminal bronchioles) are the major site
of airflow obstruction in susceptible smokers, leading to accelerated loss of lung function in the early
stages of COPD (figure 1) [11]. Given the intrinsic limitations of obtaining biopsies, the introduction of
micro computed tomography (micro-CT) has made it possible to show that a reduction in both terminal
and transitional bronchioles is well established before emphysematous destruction is evident (figure 2) [12],
and even before the subjects meet the spirometric criteria for COPD. Interestingly, small airway
remodelling may also be a primary event in asthma pathogenesis if it is the result of disturbed lung
development. The small airway wall structure can be altered very early in life, and can indeed precede
airway wall inflammation and thus may present as a primary event in asthmatic lungs [13, 14].
Understanding how early life, or even prenatal, risk factor exposures may be mechanistically linked to
Expiratory flow rate L·s–1

Remodelling and loss of

Normal small airways small airways
Obstructive

Volume L

FEV25–75 FEV1
Normal Early COPD Late COPD

FIGURE 1 Pathology samples of respiratory biopsies. The small airways are the major site of airflow
obstruction in susceptible smokers, leading to accelerated loss of lung function in the early stages of COPD.
Representative pictures of a) a small airway in a 43-year-old never smoker (female); and b) a small airway
with severe remodelling in a 45-year-old smoker without COPD (male). Trichrome staining of formalin-fixed
paraffine embedded sections. Magnification 40×. The blue staining represents areas of remodelling around
the airways. FEF25–75: forced expiratory flow between 25% and 75% of forced vital capacity; FEV1: forced
expiratory volume in the first second.

https://doi.org/10.1183/13993003.02457-2019 2
 COPD | F. POLVERINO AND J.B. SORIANO

Donor control COPD

V
V

FIGURE 2 Micro computed tomography (micro-CT) scans of lungs. Representative cross-sectional images
from age and sex matched subjects (control: 52-year-old female; COPD: 47-year-old female). Scale bar
1 mm. White arrows indicate terminal bronchiole; v: blood vessel (in controls, blood is flushed out); yellow
arrow: ice crystal. Credit to Dragoş M. Vasilescu and Tillie-Louise Hackett from the Centre for Heart Lung
Innovation, The University of British Columbia, Canada.

small airway structural and functional changes later in life will be both highly interesting from a scientific
perspective as well as highly important for understanding how bronchial asthma evolves into fixed airflow
limitation and early COPD.
Future clinical cohorts and therapeutic trials might target younger subjects with low lung function before
they meet the spirometric criteria for COPD [3], as trials on older, more severe COPD may have failed
because they were initiated in patients with COPD who already had “irreversible disease”, characterised by
established small airway remodelling. A clear understanding of the cause of early airflow limitation leading
to COPD could lead to more personalised strategies for subclinical disease [15], and preventive therapies
that ameliorate the underlying pathological process rather than the symptoms alone.

Support statement: This work was supported by the Flight Attendant Medical Research Institute (grant: YFAC14004),
by the Parker B. Francis Foundation, and by the Asthma and Airway Disease Research Center at University of Arizona.
Funding information for this article has been deposited with the Crossref Funder Registry.

Conflict of interest: None declared.

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