The lower respiratory tract: the hot spot for chronic fixed airflow limitation
- 1Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- 2Department of Medicine, University of Zaragoza, Zaragoza, Spain
- Corresponding author: Francesca Polverino (fpolverino{at}copdnet.org)
Abstract
The small airways are key for the childhood events that shape into chronic fixed airflow limitation later in life https://bit.ly/3OOBdeW
Persistent airflow limitation in children and young adults is emerging as an umbrella term encompassing various biological and clinical manifestations occurring during the lifespan and starting before birth [1, 2]. The previous model of an accelerated decline of lung function, that would become manifest in adult life in susceptible individuals when chronically exposed to environmental noxious agents, such as cigarette smoke and other inhaled gases, has made way for a more comprehensive model where events occurring during the first years of life are key in predicting the trend of one's lung function during the lifespan [3–6]. Asthma and lower respiratory tract infections (LRIs) are major factors determining low lung function early in life, can persist into young adulthood and become fixed airflow limitation [7, 8]. However, to which extent, and what kind of, respiratory infections in early life are associated with the risk of wheezing or asthma in later life remains unknown.
The interesting study by van Meel et al. [9] published in this issue of the European Respiratory Journal addresses this knowledge gap. The authors used data from 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper respiratory tract infections (URIs) and LRIs from age 6 months to 5 years with lung function and asthma at a median age of 7 (range 4–15) years. The authors show that mostly early-life LRIs, including bronchitis, bronchiolitis, pneumonia and chest infection, are associated with lower forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) and forced expiratory flow at 75% of FVC (FEF75), and an increased risk of asthma. Interestingly, the effect sizes for the associations of LRIs with asthma were much larger than those observed for URIs with asthma. These data add important information to the existing conflicting data on the development of asthma following LRIs in childhood. Previous longitudinal studies in which young children with confirmed severe respiratory syncytial virus (RSV, a major cause of LRIs in paediatric age groups) infection, were followed until adulthood showed increased risk of subsequent asthma-like symptoms; this risk decreased with age until adolescence, but increased again during early adult life [10]. The Tucson Children's Respiratory Study (CRS) has been pivotal in showing that the risk of asthma-like symptoms after confirmed RSV-LRI in early life was highest at age 6 years, and decreased thereafter, becoming statistically nonsignificant by the age of 13 years [11]. In the longest ongoing longitudinal study of young children hospitalised with LRIs in the first 2 years of life, 40% of whom were infected with RSV, prevalence of asthma decreased from 25% at age 4.5–6 years to 12–15% at ages 8–15, only to increase again to 30% at age 18–20 and up to 35% at age 30 years [12–15]. However, as the authors point out, most of these studies considered LRIs and URIs altogether, or only severe respiratory infections such as those requiring hospitalisation, or specific pathogens found in nasal lavage fluids or other biological samples were considered, thus neglecting the potential effect of less severe respiratory infections which might still have had an effect on the lung function and/or structure (figure 1).
Since chronic fixed airflow limitation can occur in young adults (“early COPD” [1, 2, 5, 16]) and has its roots in the first years of life, it is crucial to understand how the changes in lung function may shape into chronic airflow limitation. A first possibility is that early-life LRIs may play a direct role by altering immune responses and/or inducing airway injury, which would predispose the host to asthma, impaired lung function, and airway hyperreactivity on exposure to noxae, e.g. cigarette smoke, in adulthood. Alternatively, LRIs may simply identify a group of individuals susceptible to pulmonary infections, although it is not possible to determine whether lung structural damage is caused by the LRI itself or is attributable to pre-existing deficits in lung structure in young children in whom LRI develops. Studies of the heritability of RSV and asthma in twins have suggested that RSV infection does not cause asthma but is an indicator of the genetic predisposition to asthma [17]. Airway hyperresponsiveness early in life has been described in association with subsequent bronchiolitis in infancy [18, 19] and childhood asthma [20], suggesting that pre-existing airway hyperreactivity may be a shared predisposition to both viral LRIs and asthma. Lastly, several previous studies have suggested that active smoking is a risk factor for relapse or persistence of asthma symptoms into adulthood among subjects who had asthma or wheezing in early life. Active smoking has been associated with the persistence of airflow limitation early in life, being associated with increased risk of having asthma in young adults who had RSV-LRI in early life but not among subjects without these illnesses [8]. In the CAMP (Childhood Asthma Management Program) trial, the largest and longest asthma trial in children, factors in childhood that could predict the persistence of severe asthma were analysed. A low postbronchodilator FEV1/FVC ratio and maternal smoking during pregnancy were found to be significant childhood predictors of having severe asthma that persists from late adolescence to early adulthood, suggesting that early lung function decline likely drives severity [21]. 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. Importantly, the small conducting airways <2 mm in diameter are the major site of airflow obstruction in chronic obstructive pulmonary diseases, both asthma and, in particular, COPD. Interestingly, van Meel et al. [9] suggest that the persistence of asthma is primarily caused by involvement of the small airways, as suggested by the fact that LRIs had an adverse effect on FEV1, FEV1/FVC and FEF75, but not FVC. The authors suggest that LRIs might have a more direct effect on the lungs through disruption of the normal lung development and growth, specifically in the smaller airways. 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 [22–24]. 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 as small airway remodelling in asthma may lead to irreversible airflow obstruction and poor outcomes [4, 25, 26]. To develop effective treatments for chronic airway disease (both asthma and COPD) it is therefore vital to understand disease pathogenesis within these small airways (figure 1). What the contribution of the upper airways is to the onset and progression of fixed airflow limitation is unclear. A recent study showed that smaller airway calibre and airway-to-lung ratio are associated with airflow obstruction, whereas upper airway calibre and airway-to-lung ratio are not, suggesting that dysanapsis of the lower airway and its association with airflow obstruction does not extend to the upper airway [27].
These findings have important therapeutic implications. In fact, it is mandatory to assess how much asthma therapy can affect, whether negatively or positively, the pathologies occurring in the airways and thus the development of fixed airflow limitation. Although biological therapies targeting type 2 inflammation have shown promise in improving asthma outcomes, less is known about their effect on long-term airway remodelling. Some studies have hinted at a reversal of airway remodelling, particularly with omalizumab, which has been the most studied [28]. More research is needed to fully address whether, and to what extent, biological therapy of asthma can affect long-term airway remodelling.
To conclude, it appears evident that the definition of “asthma” and “COPD” is becoming too narrow to encompass a number of clinical and pathologic features that are too diverse to be still clustered under the same diagnostic label. Current diagnostic approaches do not allow for tracing subjects with chronic airflow limitation back to the vastly different origins of their disease. We have finally found the Ariadne's thread that connects chronic obstructive diseases back to their common origins. It is time to unroll the thread and find our way out of the maze of chronic airflow limitation.
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Footnotes
Conflict of interest: F. Polverino reports grants from NHLBI (HL149744); and the following leadership role: American Thoracic society RCMB assembly, executive committee member. J.M. Marin reports grants from Instituto Salud Carlos III (PI21/01954, PI18/01524, PM21/0090).
Support statement: F. Polverino is supported by the Baylor College of Medicine Funds, and the NIH/NHLBI HL149744 research grant. J.M. Marin is supported by grants from Instituto Salud Carlos III and European Regional Development Funds (PI18/01524, PI21/01954 and PM21/0090). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 14, 2022.
- Accepted June 21, 2022.
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