Linking COPD epidemiology with pediatric asthma care; implications for the patient and the physician

Erik Melén1,2,3, Stefano Guerra4,5, Jenny Hallberg1,2,3, Deborah Jarvis6, Sanja Stanojevic7

1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

2Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

3Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden

4Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA

5ISGlobal, Barcelona, Spain

6National Heart and Lung Institute, Imperial College, London, United Kingdom

7Translational Medicine, Hospital for Sick Children, Toronto, Canada

Corresponding author:

Erik Melén, MD, PhD

Karolinska Institutet, Institute of Environmental Medicine

Nobels väg 13 Box 210, SE- 171 77, Stockholm, Sweden

E-mail: erik.melen@ki.se

Phone: +46-8-524 87508

Running title:

Childhood Asthma and future COPD risk

Key words:

Asthma, children, COPD, prevention, trajectories.

Introduction

A 10-year-old patient with asthma, diagnosed in early childhood, with a pre-bronchodilator forced expiratory volume in 1 second (FEV1) of 75% of predicted attends a routine follow-up visit. The patient and family perceive his asthma as ‘well controlled’, but should his physician be concerned about his reduced lung function? What are the implications of a lower than expected FEV1 in childhood on the respiratory health of this patient in adulthood? Lung function is known to track with age1, and there is a high likelihood that this patient will enter adulthood with a sub-optimal lung function. A FEV1 measurement less than 80% predicted would characterize this patient as a high-risk patient for later chronic airflow limitation, or even chronic obstructive pulmonary disease (COPD) according to recent studies.2 How does this apply to a young child, and how can we use the information to better understand whether early, targeted intervention is warranted?

COPD is estimated by the WHO to become the 3rd leading cause of death by 20303, which urges for preventive actions as early as possible. By the age of 50-60 years, low lung function trajectories that are associated with early life exposures and developmental processes, may contribute up to 75% of COPD burden.4 Can we translate findings from longitudinal epidemiologic studies to individual risk predictions and preventive guidelines in our pediatric care? Should we take action immediately to preserve lung function in this patient or should we hope for lung function catch-up with age? The evidence from longitudinal cohort studies around the world is clear – the lower the lung function in childhood and young adulthood, the higher the risk of COPD and the higher the risk of premature death.2,5 But how do you communicate long-term risks for chronic airflow limitation to a 10-year-old boy and his parents (Figure 1)? In this review, we discuss the clinical implementations of recent epidemiological respiratory studies and the importance of preserved lung health across the life course. Also, we evaluate available clinical tools, primarily lung function measures, and profiles of risk factors, including biomarkers, that may help identifying children at risk of chronic airway disease in adulthood.

Preserved lung health across the life course

To date, epidemiological studies that have examined risk factors for low lung function across the life course have usually reported on lung function measures from forced expiratory spirometric manoeuvres. Factors associated with lower forced vital capacity, FVC, which can be related to low total lung capacity, are not necessarily associated with airway obstruction (FEV1/FVC). Sometimes reports describe relationships with FEV1 without mention of its relationship with FVC, which means that the associations with FEV1 may be telling us about either airway obstruction or about ‘lung volume’. With this in mind, what information should we take from the available studies to inform clinical advice and management of patients with asthma and low lung function at the age of 10 years?

The ’double jeopardy’The clear signals emerging from studies that have examined lung function in pediatric cohorts is that children with low FEV1 and FEV1/FVC become young adults with low maximally attained lung function in their mid 20’s.4,6,7 While the childhood studies suggest that in young adulthood, those with asthma already have lower lung function, the adults studies show they go on to have more rapid decline.8 This ‘double jeopardy’ is of concern and one of the major interventions open to physicians is to ensure effective treatment of disease. There are no (and never will be) real long-term randomised controlled trials to test whether daily treatment with inhaled steroids (or other medications) prevents the excess decline in FEV1, but current observational evidence, some of which spans twenty years or more, of follow-up in adults suggest this may be the case particularly if there is evidence of underlying atopy.9

The benefits of healthy lifestyle across the life-course To date, there are few factors that appear likely to alter the persistent low lung function trajectory seen through the teenage years. As with all patients, it is important that physicians emphasise the role of healthy lifestyles on lung health in those showing evidence of low lung function in childhood. One major study has identified a group of children (8% of the population-based sample studied) who followed a trajectory suggestive of ‘catch-up’ growth from a low FEV1 at age 7 to a normal maximal FEV1.4 These children were more likely to be underweight at age 7 and to be female. The likely importance of body composition on lung function growth is supported by work showing that higher lean body mass during childhood and adolescence was associated with higher levels of growth in FEV1, FVC and FEF25-75% between 8 and 15 years while higher fat mass was associated with lower growth in FEV1/FVC.10 Such observations could be explained by positive effects of nutritional factors within a healthy diet and/or by levels of physical activity. Adolescents, particularly girls, have better FVC (not FEV1/FVC) if they are more physically active in the previous years.11

Taken as a whole, these observations emphasise the potential benefits of healthy lifestyles during adolescence to increase the chance that maximally attained lung function is at its greatest by adulthood. Such measures may impact on other physiological processes and will also be beneficial for prevention of other diseases. Poor diet, obesity and low physical activity may promote early puberty12 and children with early puberty have lower lung function as adults – but this association is largely seen with FVC rather than airway obstruction.13 This observation is interpreted as a failure to reach the expected maximal lung function and has been investigated and confirmed using sophisticated Mendelian Randomisation approaches.14

The impact of adult smoking on lung function decline remains the major cause of fixed airway obstruction in later life, but smoking during adolescence may equally impact on lung development through the teenage years.15 There is conflicting evidence whether the effect of smoking and asthma are additive or multiplicative risks for poor lung growth and excess lung function decline, but there is every reason to strongly advocate the complete avoidance of smoking in any child or adult with asthma and/or low lung function. One study from childhood to later adult life indicated the presence of a group of children (4% of the population-based sample studied) following a lung function trajectory characterised by failure to achieve maximal FEV1 followed by a rapid decline in FEV1. Within this group both smokers and those with childhood asthma were over-represented and almost half had developed fixed airway obstruction by their mid 50’s.4 In those who do smoke there is evidence that diets rich in anti-oxidants16 and remaining physically active17 may modify lung function decline - yet further evidence of the importance of healthy lifestyles on maintenance of lung function.

Patients and their families will be concerned over the potential effect of traffic related air pollution on their lung health. Traffic related pollution at the levels observed in most of Western Europe has yet to be shown to have major deleterious effect on lung function decline in adults.18 However, its impact on lung growth in children has been reported in numerous studies, which suggest that air pollution has an adverse effect on both FVC and FEV1.19,20

Relevance of occupational exposuresCross-sectional and longitudinal studies suggest that up to 15% of COPD in adult life could be related to exposures to vapours, gases, dust and fumes in the work place.21,22 Substances that have been linked to COPD include cadmium dust and fumes, mineral dusts, welding fumes, grain and flour dusts, organic dusts and silica dusts. Such exposures may add to risk of chronic air flow limitation and COPD in children with asthma and low lung function, but to date there is little evidence these children are particularly susceptible to such exposures. It is an employer’s duty to provide a safe working environment for all their workers through minimising harmful airborne agents, provision of respiratory protection equipment and appropriate health surveillance. However, anyone who as a child had low lung function and asthma should remain alert to the potential harms of their job. One of the occupational exposures that has gained particular attention more recently is increased lung function decline in those exposed to cleaning agents.23 The mechanism of action is unknown but the observation has wider implications for the use of cleaning products in the home where it would appear wise to minimise their use and avoid cleaning sprays where possible.

Lung function measures to identify children at risk

Spirometry: Population vs individual measures

One of the primary reasons that spirometry (and FEV1) is used to diagnose and monitor lung disease is that it tracks well with time in both healthy populations and those with respiratory disease, and most of the evidence linking early determinants of lung disease across the life course is based on spirometry findings. However, translation of epidemiological evidence to the individual patient is not straight forward. A single low measure of lung function may not represent an accurate estimate of an individual’s risk of later obstructive disease, whereas repeated measurements may indicate persistent reduction or rapid decline in lung function over time, which are more likely to be associated with an increased risk of COPD in early adulthood.24 In the case of the 10-year-old boy with asthma, the interpretation of his reduced lung function must consider the uncertainty of the measurement and prognosis, as well as the age-related changes observed in the healthy population. The spirometry result must be put in context of the clinical and family history of the patient, as well as the current symptoms, and the mental health implications of an early diagnosis for which treatment options carry their own burden and risk factors.

Standardization of spirometry equipment, protocols and quality control has meant that we can now obtain high quality objective measures of lung function across the life span.25,26 In many specialised research centres it is feasible to conduct high quality spirometry in children as young as 3 years.27,28 Translation of spirometry from a specialised test conducted in pulmonary function laboratories to the primary care setting has had mixed results29,30, especially for children for whom extra patience and a friendly environment are necessary to obtain reliable measurements. Early deficits in lung function may already be present by the time objective measurements of lung function are feasible to obtain, which represents yet another challenge.31 The critical window for intervention may also depend on the specific exposures and risk factors in an individual, in which case monitoring of lung function should begin shortly after birth for some children. At present, measurement of lung function during infancy is limited to a few specialised centres32 and interpretation of results remains challenging.

Another issue is the interpretation of spirometry results, particularly in children. The range of lung function values observed in healthy children is wide33, and an individual within the persistently low lung function trajectory of an epidemiological study can be well within the normal range. Indeed, children with well controlled asthma often have lung function values within the normal range. In addition, most populations used to define ‘normal’ lung function are based on cross-sectional samples of the population that are free of a history of respiratory disease at the time spirometry is measured, and may very well go on to have respiratory disease at some time in the future. Therefore, the normal range may be artificially wide and may miss early signs of lung disease. Spirometry is also more variable in young children, and it may be difficult to identify specific patients at risk of disease with a high degree of confidence.

Further, the most commonly used measure of spirometry defined COPD is an FEV1/FVC ratio of less than 70%; however, the definition varies by study and population with some studies including a post-bronchodilator reduction in FEV1/FVC, others using a combination of deficits in FEV1 and the FEV1/FVC ratio, while other studies use an age-specific lower limit of normal. Remarkably, while the prevalence of COPD differs based on the criteria, the risk factors for disease are similar regardless of the definition used (for a given disease phenotype). In young children, FEV1 and FVC are nearly equivalent, which further complicates interpretation of the ratio. Applying these adult based cut-points in children and young adults (like FEV1/FVC<70%) to identify a high risk group is problematic, and would inevitably miss a large proportion of patients at risk for COPD later in life. If low lung function in childhood persists, then the 10-year old boy may be at risk of COPD later in life. What remains challenging is how we determine who is at high risk based on childhood measures, and what if any intervention is appropriate to reduce the risk of later disease.

At present, children with lung function values outside the range observed in health, or in the lower range of healthy, may benefit from more comprehensive lung function tests to determine the underlying pathophysiology and best treatment options. For example, bronchodilator or bronchoprovocation testing can help distinguish fixed and reversible deficits and may help guide treatment decisions. Although fixed airflow limitation is rare in childhood, in children with asthma, poor bronchodilator response and increased airway hyper responsiveness are risk factors for irreversible airway obstruction in adulthood.24

Beyond spirometryThere are several sensitive physiological lung function tests that may indicate disease in the smaller airways, and therefore may be a more accurate way to identify early lung disease or potentially, to provide a predictive risk indicator for individuals likely to have poor lung function in the future. For example, lung function tests such the forced oscillation technique or the multiple breath washout (MBW) may provide complementary evidence to the spirometry outcomes.

There is evidence that ventilation inhomogeneity (measured by MBW), a marker of poor gas mixing efficiency, is worse in patients with COPD compared with healthy controls.34 In addition, MBW indices (lung clearing index, LCI) increased across the GOLD grading criteria for spirometry suggesting that it may provide complementary information to spirometry.34 Furthermore, lower values of LCI measured in men at age 55 were associated with future development of pulmonary obstruction and increased incidence of COPD hospitalization later in life.35 There is currently no evidence from longitudinal studies of ventilation inhomogeneity measurements in childhood with outcomes in early adulthood.

In children, there is less convincing evidence that MBW distinguishes between patients with asthma and healthy controls, with some smaller studies demonstrating small differences on the population level,36-39 with others showing no differences. In a large Cohort study of 646 children, MBW was not able to distinguish children with persistent asthma symptoms from controls.40,41 However, in all of these studies, there were individual children with ventilation inhomogeneity values well outside the normal range. Many MBW studies also used the Scond index, a measure of gas mixing efficiency in the larger airways where convection is the primary mode of gas transport (as opposed to the small airways/diffusion) to distinguish between health and asthma.39,42-44 To date, the Scond outcome has yet to be fully integrated into all commercial devices, and is also not straight forward to explain to patients. To better understand the utility of MBW tests in children, longitudinal data are needed to define how these tests can be used to identify high risk individuals.

Impulse oscillometry (IOS) is a non‐invasive forced oscillation method that provides information on airway resistance and reactance. IOS has been evaluated both as an additional and alternative option to spirometry. Given its simplicity, the method is feasible in children as young as 2-3 years. IOS measures during preschool years has been associated with spirometric lung function in adolescence, albeit with a wide spread of data and uncertainty around the estimates.45 In cross-sectional studies, the IOS method was more sensitive than spirometry in differencing very young asthmatic from healthy children46-48, and has also been shown to correlate to disease severity and risk of exacerbation of both children and adults with asthma.49,50 Further, peripheral airway obstruction measured by IOS is suggested as a feature related to the eosinophilic inflammation in allergic asthma.51 In patients with COPD, IOS indices have been related to disease grading52, symptoms53 and health status54, indicating that the method may provide additional information to spirometry also on the physiopathology of fixed airway obstruction. However, the potential value of the method for finding individuals at risk for future airflow obstruction remains to be studied.

In summary, both MBW and IOS have been applied in numerous research studies, but have yet not been widely implemented in clinical practice. The utility of MBW and FOT at the individual level has yet to be defined, and both tests require expensive equipment, trained personnel and time to perform the test compared with spirometry.

Risk profiles

Lessons from birth cohorts and longitudinal studies

Given the established evidence of long term implications, it becomes critical to establish risk factors that can be used to identify children with asthma who, as adults, will go on to develop COPD-like phenotypes (first and foremost irreversible airflow limitation). Once this group of at-risk patients is identified, we can determine whether the trajectory towards early COPD can be modified.

Epidemiological evidence has consistently shown that the frequency and severity of asthma-like symptoms is one of the strongest predictors of the likelihood of developing lung function deficits in adult life. In the Dunedin Multidisciplinary Health and Development Study, participants with persistent wheezing had the lowest levels of the FEV1/FVC ratio from age 9 years well into their adult life55. Similarly, in the Melbourne study – a longitudinal cohort study enriched for cases of severe asthma – the group of participants who had severe asthma at age 10 was characterized by lower levels of FEV1 and FEV1/FVC and by a greater than 30-fold increased risk for COPD (defined as FEV1/FVC < 70% after bronchodilator) by age 507,56. Indeed, as shown repeatedly by birth cohort studies57-59, the link between recurrent asthma-like symptoms (mainly persistent wheezing) and lung function deficits begins at or even before school-age and tracks over time as patients transition from childhood into adult life. Consequently, among patients with asthma, low lung function in childhood strongly predicts not only the risk of developing chronic airflow limitation by adult life24 but also that of having persistent disease60,61, suggesting a profound and possibly bi-directional link between these two phenotypes.

If persistent childhood asthma is a strong risk factor for the development of chronic lung function deficits into adult life, then factors that increase the risk for the persistence of asthma may, in turn, help identifying patients at risk for its long-term sequela of COPD development. Atopy – as defined by specific IgE in circulation or skin test sensitization – has emerged as a consistent risk factor for forms of childhood asthma that persist into adulthood. This is particularly true for atopic sensitization that is already present early in life and directed towards multiple allergens57,62. Consistent with this scenario, by using latent class analysis on multiple dimensions of atopy, a recent study identified a class of children with “severe atopy” that was strongly associated with asthma and lung function deficits and found the intensity of specific IgE production early in life to be its main feature affecting asthma risk63. Children with asthma who present simultaneously with rhinitis and/or eczema have been also shown to be at increased risk of persistent disease. Among participants with childhood asthma in the Tasmanian Longitudinal Health Study, the co-existence of eczema and rhinitis increased their risk of having persistent asthma in adult life by nearly 12 times64. Bronchial hyper-responsiveness is another characteristic of children with asthma that is predictive of persistent disease. In the Tucson Children’s Respiratory Study (TCRS), bronchial hyper-responsiveness to cold dry air at age 6 years increased the risk for chronic asthma (i.e., asthma that was active both in childhood and adulthood) by 4.5-fold, whereas this effect was much weaker and non-significant for inactive asthma (i.e., asthma that remitted in adult life)65. In the same birth cohort, among participants with childhood asthma, being overweight or obese at age 11 was also associated with a nearly 9-fold increased risk of having persistent disease after the onset of puberty66. In addition to these factors, when predicting persistence of asthma, attention should be given to possible influences by sex (increased risk in females has been described in multiple but not all population-based studies55,56,67), race/ethnicity68, and socio-economic status (particularly low parental education69), as well as to events that may have occurred in early life. Among the latter, of particular interest are early lower respiratory illnesses70 (LRIs). In TCRS, participants who had radiologically ascertained pneumonia by age 3 had increased risk for active asthma and deficits in FEV1, FEV1/FVC, and FEF25-25% that tracked from age 11 to 26 years71. Other types of early LRIs were associated with similar, though milder, trajectories of lung function deficits.

Molecular biomarkersDespite the tremendous progress made in determining these and other early risk factors for lung function deficits1, to what extent these characteristics can be used in an effective and reproducible way to identify ahead of time children with asthma who will go on to develop COPD-like phenotypes remains elusive. While multiple prediction models (reviewed by Smit et al72) have been developed to identify pre-school children with wheezing who will have asthma in childhood, there is a paucity of population-based studies that have systematically attempted a similar approach to predict persistence and long-term sequelae of childhood asthma into adult life. One of the reasons is that this type of studies require large numbers of participants followed for many years with repeated assessments of lung outcomes from childhood well into their adult life. As of today, only a small number of epidemiological studies have this type of data available.

In this context, there has been growing interest by the scientific community in exploring the contribution that molecular biomarkers73 may provide not only to improve the performance of the above risk factors in predicting children with asthma who will progress into COPD, but also to identify possible endotypes and, in turn, possible therapeutic targets for such progression. Apart from IgE and skin test sensitization as discussed above, eosinophils in circulation have been one of the biomarkers most extensively studied in the context of the natural history of asthma and multiple studies have found them positively associated with persistent disease. In the TESAOD cohort, blood eosinophilia was the strongest risk factor for developing persistent airflow limitation among asthmatics with disease onset before age 2574 and in the CAMP study eosinophil count in childhood was inversely associated with remission of asthma in adult life60. In the latter study, by combining information on better lung function, decreased airway responsiveness, and lower eosinophil count in childhood, the authors identified a group of patients with asthma who had a greater than 80% probability of disease remission in adult life. Related to these observations, the fraction of exhaled nitric oxide (FeNO, a possible marker of eosinophilic airway inflammation), when assessed among symptomatic pre-school children, was also found to improve the prediction of subsequent active asthma at school age75,76.

Additional potential biomarkers are emerging from omics-based discovery studies. Although in asthma (as for most other complex diseases) genetic variants that have been identified by GWAS studies carry relatively small increases in disease risk77, the strategy to combine information from multiple variants into genetic scores has shown promising results. Interestingly, in the Dunedin cohort a genetic risk score generated from 15 asthma-related single nucleotide polymorphisms (SNPs) predicted life-course persistent asthma and development of irreversible airflow limitation by adult age among participants with childhood asthma, suggesting that this polygenic approach may provide helpful information to predict the natural history of the disease78. In the same cohort, life-course persistent asthma was also associated with shorter leukocyte telomere length in mid-adult life79, although it is unknown whether this association would hold true earlier in life. Genetic scores based on SNPs linked to adult lung function have been also associated with lung function levels in childhood80 and lung function trajectories from childhood into adult life6, but the extent to which they may be involved in the development of chronic lung function deficits among patients with asthma remains to be determined. Contributions from other omics fields (from epigenomics, transcriptomics down to proteomics and metabolomics) are growing exponentially81, but these biomarkers have been rarely evaluated in the context of prediction for asthma progression and at the present time there are no validated molecular tools for early risk stratification of development of chronic airflow limitation and long-term sequelae of childhood asthma. In this context, molecules that have been associated with both asthma persistence and lung function deficits from childhood into adult life, such as low levels of the pneumoprotein Club cell secretory protein 16 (CC16)82,83, represent select candidates for further investigation.

Conclusions

In this report, we have discussed the clinical implications of recent longitudinal cohort studies on lung function and respiratory health, also captured in the early origins of chronic airway disease concept.84 The importance of preserved lung health across the life course is reinforced, but translating population level results to the individual patient in the pediatric care setting is not straight forward (see Facts box). Any clinician would agree that a single low lung function value in childhood may not be sufficient to warrant pharmacotherapy, but a series of pulmonary function tests that indicate airway obstruction would provide a constellation of evidence to support early intervention. Treatment plans that go beyond medication, including investigation of risk factors in the household and environment, as well as encouragement of a healthy lifestyle in general, will likely have a more profound impact on the overall risk of lung disease in adulthood. Yet, we acknowledge the difficulties to make correct diagnosis of chronic airway disease in children and adolescents beyond asthma.

We conclude that there is a need for studies specifically designed to evaluate performance of prediction of risk profiles taking lung function indices, clinical data and molecular markers into account for long-term sequelae of childhood asthma. MBW and FOT techniques are promising as a supplement to spirometry in order to capture disease in more detail. However, the prognostic value of these methods needs to be assessed in longitudinal studies. Emerging data suggest very early epigenetic changes in relation to asthma85, some of which may be detected already at birth86,87, but the long-term disease risk and outcomes remain to be elucidated. Ideally, biomarkers should be analytically robust, easy to measure, and non-invasive, the latter particularly important in pediatric care settings. Promising early biomarkers for chronic airway disease are now under study (e.g. CC1682,83), but we encourage large-scale efforts in this research field in order to find the most informative and clinically useful candidates.

Acknowledgements

This article was initiated during the three-day workshop “Respiratory and allergic diseases from childhood to adulthood” held in Stockholm, Sweden, August 23-25 2019. The workshop was funded by the Swedish Heart-Lung Foundation, the Swedish Asthma and Allergy Foundation, the Aii (allergy, immunology and inflammation) doctoral programme at Karolinska Institutet and the BAMSE Study (https://ki.se/en/imm/bamse-project). EM is supported by a grant from the European Research Council (n° 757919). This article also incorporates results and emerging evidence from the Ageing Lungs in European Cohorts study (www.alecstudy.org) funded through the European Union’s Horizon 2020 research and innovation programme (Grant agreement No 633212).

Author Contributions

EM conceived and designed the study. SG, JH, DJ and SS contributed expertise knowledge in the field. All co-authors contributed equally in writing and finalizing the manuscript.

Conflict of interest

The authors have no conflict of interest in relation to this work.

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From childhood to adulthood; clinical implications [in a Facts box]

· Impaired lung function in childhood is associated with chronic airway obstruction in adulthood. This risk is particularly strong in persistent and severe forms of childhood asthma.

· In numbers, one to two in ten children with low lung function will develop chronic airway obstruction in adulthood.

· Complete avoidance of smoking in any child or adult with asthma and/or low lung function is recommended. Benefits of healthy lifestyles are underscored.

· Translating population level results to the individual patient in the pediatric care setting is, however, not straight forward.

· Asthma control remains a clinical priority, despite its effects to prevent long-term lung function deficits need to be better understood.

· Repeated spirometry measures supplemented with assessment of small airway involvement give insights about underlying pathophysiology.

· Risk prediction models for long-term sequelae of childhood asthma taking lung function indices, clinical data and molecular markers into account are warranted.

Legend to Figure 1 [final figure in preparation; draft as uploaded]:

Although we know that impaired lung function in childhood is associated with chronic airway obstruction in adulthood, translating population level results to the individual patient in the pediatric care setting is not straight forward. Risk prediction models for long-term sequelae of childhood asthma taking lung function indices, clinical data and molecular markers into account are warranted.