- Email: [email protected]
Predicting loss of lung function in healthy people
Comment
It is almost 40 years since Fletcher and Peto1 reported their study of the natural history of airflow obstruction and its predictors. The data substantially improved understanding of how airflow obstruction develops and changes with age. Fletcher and Peto’s schematic of changes in forced expiratory volume in 1 s (FEV1) over time, standardised to age 25 years, has been reproduced in lectures and books ever since publication. It elegantly summarises many of the study’s messages: the striking effect of tobacco smoking in accelerating FEV1 loss, the stabilisation but not recovery of FEV1 with smoking cessation, and the age-related loss of FEV1 in healthy individuals and in those not susceptible to tobacco smoke. The association between pre-existing airflow obstruction and increased speed of decline in FEV1 has been confirmed in the Lung Health study,1,2 and replicated in the Framingham Offshoot Cohort,3 in people with a wide age range and over long follow-up periods. Despite that schematic being deservedly well known, another in the same report that illustrates differences in FEV1 trajectory over time in different individuals might be more relevant to the current situation. People with a low initial FEV1 can lose function at a normal rate, whereas others with better spirometry in early life might lose function more rapidly after airflow obstruction begins to develop. Either group of individuals might stay within the normal age-related range or might at any time progress to the point where airflow obstruction is recognised, despite very different natural histories of disease. Many other studies with longitudinal and crosssectional designs in healthy populations and in people with asthma or chronic obstructive pulmonary disease (COPD) have confirmed the variation in rate of change.4 Factors other than active tobacco smoking have been associated with rapid decline in FEV1, such as bronchial hyper-responsiveness, blood eosinophilia, childhood respiratory infections, and occupational exposures.5 Even in patients with severe COPD, variation in FEV1 decline has been reported, with smoking status and exacerbation history having the greatest effects on the rate of functional loss.6 Several potential biomarkers for decline were investigated, and one of these, CC16 (approved symbol SCGB1A1), was associated with increased rate of change, leading to an additional
decline of 4 (SD 2) mL/year with each 1 SD decrease in CC16 concentration.6 In The Lancet Respiratory Medicine, Stefano Guerra and colleagues7 report their findings on the relation between CC16 concentrations and lung function across the lifespan. They assessed longitudinal data on decline in FEV1 and incidence of airflow limitation for 960 participants from the US general population survey the Tucson Epidemiological Study of Airway Obstruction Disease (TESAOD) and 681 participants in two independent surveys done in Spain (European Community Respiratory Health Survey [ECRHS-Sp]) and Switzerland (Swiss Cohort Study on Air Pollution and Lung Diseases in Adults [SAPALDIA]). The authors found that low CC16 concentrations at baseline were independently associated with increased decline in lung function and the likelihood of developing stage 2 airway limitation (defined as FEV1 to forced expiratory volume [FEV1/FVC] ratio of less than 70% and FEV1 % predicted less than 80%) over time in TESAOD (adjusted hazard ratio 1·81, 95% CI 1·06–3·09, p=0·029). This finding was confirmed in ECRHS-Sp and SAPALDIA. Additionally, analysis of follow-up data for 601 individuals in TESAOD showed that persistently low CC16 concentrations were associated with the most rapid loss of FEV1 during follow-up, with an additional median loss of 9·0 mL/year (95% CI 4·3–13·7, p=0·0004). These findings, therefore, confirmed the predictive power of low FEV1/FVC ratio for decline in lung function, but also showed that CC16 concentration remained a predictor of this process after adjustment for sex, age, height, smoking status and intensity, packyears, asthma, and FEV1 at baseline, whether expressed as a fixed variable or by use of the lower limit of normal method of defining abnormality. In an elegant further analysis, Guerra and colleagues assessed the effect of CC16 concentrations on lung growth in three birth cohorts from the UK, the USA, and Sweden. They found that CC16 concentrations in the lowest tertile in children aged 4–6 years were predictive of an FEV1 deficit at age 16 years (p=0·0001). This effect was small in absolute terms, amounting to 2–3% of the expected FEV1 at age 16 years, but it was consistent across cohorts. By contrast the effect of being in the lowest tertile of CC16 concentrations in the US study
www.thelancet.com/respiratory Published online July 7, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00236-2
Philippe Plailly/Science Photo Library
Predicting loss of lung function in healthy people
Lancet Respir Med 2015 Published Online July 7, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00236-2 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(15)00196-4
1
Comment
was greater, with a faster rate of FEV1 decline than those with the highest concentrations. The associations were confirmed in children before exposure to any effects from active smoking. Clearly, Guerra and colleagues’ data have some limitations, as acknowledged by the authors. The cohorts were not designed to be combined in this way, and the sampling frames for observations differ. Differences in sample size and duration of follow-up might explain why not all the US findings were replicated in the European adult cohorts. As Guerra and colleagues note, however, the baseline characteristics of adults and children were sufficiently similar to justify pooling the data. Whether the patients with low CC16 concentrations reported other respiratory symptoms when first studied would be interesting to know, as symptomatic patients lose lung function with increasing rapidity over time.8 Further work is evidently needed to understand the mechanisms by which CC16 affects lung function. Experimental models of CC16 deficiency in knockout mice have suggested that it has an anti-inflammatory action, but how that might contribute during lung development remains to be clarified. Whether the effects of low CC16 concentrations are secondary to reduction in lung elastic recoil, which is the conventional explanation for age-related loss of lung function, or to changes in the structure or number of peripheral airways, perhaps reflecting differences in the way the lungs develop dependent on the availability of CC16, need to be explored. CC16 might simply be a
2
marker of other processes, genetic, environmental, or both, yet to be identified. Much work will be needed to interpret the emerging data properly, but comfort can be taken four decades on from Fletcher and Peto’s landmark report1 that why patterns of lung function decline differ between individuals is beginning to be understood. The continuing work could approach their goal of identifying obstructive lung disease before too much damage has been done to the lungs. Peter M A Calverley School of Ageing and Chronic Disease, University Hospital Aintree, Liverpool L97AL, UK [email protected] I declare no competing interests. 1 2
3
4 5 6 7
8
Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1: 1645–48. Drummond MB, Hansel NN, Connett JE, Scanlon PD, Tashkin DP, Wise RA. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1301–06. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009; 180: 3–10. Kohansal R, Soriano JB, Agusti A. Investigating the natural history of lung function: facts, pitfalls, and opportunities. Chest 2009; 135: 1330–41. Kerstjens HA, Rijcken B, Schouten JP, Postma DS. Decline of FEV1 by age and smoking status: facts, figures, and fallacies. Thorax 1997; 52: 820–27. Vestbo J, Edwards LD, Scanlon PD, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011; 365: 1184–92. Guerra S, Halonen M, Vasquez MM, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med 2015; published online July 7. http://dx.doi.org/10.1016/S22132600(15)00196-4. Probst-Hensch NM, Curjuric I, Pierre-Olivier B, et al. Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the SAPALDIA cohort. Thorax 2010; 65: 150–56.
www.thelancet.com/respiratory Published online July 7, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00236-2
It is almost 40 years since Fletcher and Peto1 reported their study of the natural history of airflow obstruction and its predictors. The data substantially improved understanding of how airflow obstruction develops and changes with age. Fletcher and Peto’s schematic of changes in forced expiratory volume in 1 s (FEV1) over time, standardised to age 25 years, has been reproduced in lectures and books ever since publication. It elegantly summarises many of the study’s messages: the striking effect of tobacco smoking in accelerating FEV1 loss, the stabilisation but not recovery of FEV1 with smoking cessation, and the age-related loss of FEV1 in healthy individuals and in those not susceptible to tobacco smoke. The association between pre-existing airflow obstruction and increased speed of decline in FEV1 has been confirmed in the Lung Health study,1,2 and replicated in the Framingham Offshoot Cohort,3 in people with a wide age range and over long follow-up periods. Despite that schematic being deservedly well known, another in the same report that illustrates differences in FEV1 trajectory over time in different individuals might be more relevant to the current situation. People with a low initial FEV1 can lose function at a normal rate, whereas others with better spirometry in early life might lose function more rapidly after airflow obstruction begins to develop. Either group of individuals might stay within the normal age-related range or might at any time progress to the point where airflow obstruction is recognised, despite very different natural histories of disease. Many other studies with longitudinal and crosssectional designs in healthy populations and in people with asthma or chronic obstructive pulmonary disease (COPD) have confirmed the variation in rate of change.4 Factors other than active tobacco smoking have been associated with rapid decline in FEV1, such as bronchial hyper-responsiveness, blood eosinophilia, childhood respiratory infections, and occupational exposures.5 Even in patients with severe COPD, variation in FEV1 decline has been reported, with smoking status and exacerbation history having the greatest effects on the rate of functional loss.6 Several potential biomarkers for decline were investigated, and one of these, CC16 (approved symbol SCGB1A1), was associated with increased rate of change, leading to an additional
decline of 4 (SD 2) mL/year with each 1 SD decrease in CC16 concentration.6 In The Lancet Respiratory Medicine, Stefano Guerra and colleagues7 report their findings on the relation between CC16 concentrations and lung function across the lifespan. They assessed longitudinal data on decline in FEV1 and incidence of airflow limitation for 960 participants from the US general population survey the Tucson Epidemiological Study of Airway Obstruction Disease (TESAOD) and 681 participants in two independent surveys done in Spain (European Community Respiratory Health Survey [ECRHS-Sp]) and Switzerland (Swiss Cohort Study on Air Pollution and Lung Diseases in Adults [SAPALDIA]). The authors found that low CC16 concentrations at baseline were independently associated with increased decline in lung function and the likelihood of developing stage 2 airway limitation (defined as FEV1 to forced expiratory volume [FEV1/FVC] ratio of less than 70% and FEV1 % predicted less than 80%) over time in TESAOD (adjusted hazard ratio 1·81, 95% CI 1·06–3·09, p=0·029). This finding was confirmed in ECRHS-Sp and SAPALDIA. Additionally, analysis of follow-up data for 601 individuals in TESAOD showed that persistently low CC16 concentrations were associated with the most rapid loss of FEV1 during follow-up, with an additional median loss of 9·0 mL/year (95% CI 4·3–13·7, p=0·0004). These findings, therefore, confirmed the predictive power of low FEV1/FVC ratio for decline in lung function, but also showed that CC16 concentration remained a predictor of this process after adjustment for sex, age, height, smoking status and intensity, packyears, asthma, and FEV1 at baseline, whether expressed as a fixed variable or by use of the lower limit of normal method of defining abnormality. In an elegant further analysis, Guerra and colleagues assessed the effect of CC16 concentrations on lung growth in three birth cohorts from the UK, the USA, and Sweden. They found that CC16 concentrations in the lowest tertile in children aged 4–6 years were predictive of an FEV1 deficit at age 16 years (p=0·0001). This effect was small in absolute terms, amounting to 2–3% of the expected FEV1 at age 16 years, but it was consistent across cohorts. By contrast the effect of being in the lowest tertile of CC16 concentrations in the US study
www.thelancet.com/respiratory Published online July 7, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00236-2
Philippe Plailly/Science Photo Library
Predicting loss of lung function in healthy people
Lancet Respir Med 2015 Published Online July 7, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00236-2 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(15)00196-4
1
Comment
was greater, with a faster rate of FEV1 decline than those with the highest concentrations. The associations were confirmed in children before exposure to any effects from active smoking. Clearly, Guerra and colleagues’ data have some limitations, as acknowledged by the authors. The cohorts were not designed to be combined in this way, and the sampling frames for observations differ. Differences in sample size and duration of follow-up might explain why not all the US findings were replicated in the European adult cohorts. As Guerra and colleagues note, however, the baseline characteristics of adults and children were sufficiently similar to justify pooling the data. Whether the patients with low CC16 concentrations reported other respiratory symptoms when first studied would be interesting to know, as symptomatic patients lose lung function with increasing rapidity over time.8 Further work is evidently needed to understand the mechanisms by which CC16 affects lung function. Experimental models of CC16 deficiency in knockout mice have suggested that it has an anti-inflammatory action, but how that might contribute during lung development remains to be clarified. Whether the effects of low CC16 concentrations are secondary to reduction in lung elastic recoil, which is the conventional explanation for age-related loss of lung function, or to changes in the structure or number of peripheral airways, perhaps reflecting differences in the way the lungs develop dependent on the availability of CC16, need to be explored. CC16 might simply be a
2
marker of other processes, genetic, environmental, or both, yet to be identified. Much work will be needed to interpret the emerging data properly, but comfort can be taken four decades on from Fletcher and Peto’s landmark report1 that why patterns of lung function decline differ between individuals is beginning to be understood. The continuing work could approach their goal of identifying obstructive lung disease before too much damage has been done to the lungs. Peter M A Calverley School of Ageing and Chronic Disease, University Hospital Aintree, Liverpool L97AL, UK [email protected] I declare no competing interests. 1 2
3
4 5 6 7
8
Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1: 1645–48. Drummond MB, Hansel NN, Connett JE, Scanlon PD, Tashkin DP, Wise RA. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1301–06. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009; 180: 3–10. Kohansal R, Soriano JB, Agusti A. Investigating the natural history of lung function: facts, pitfalls, and opportunities. Chest 2009; 135: 1330–41. Kerstjens HA, Rijcken B, Schouten JP, Postma DS. Decline of FEV1 by age and smoking status: facts, figures, and fallacies. Thorax 1997; 52: 820–27. Vestbo J, Edwards LD, Scanlon PD, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011; 365: 1184–92. Guerra S, Halonen M, Vasquez MM, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med 2015; published online July 7. http://dx.doi.org/10.1016/S22132600(15)00196-4. Probst-Hensch NM, Curjuric I, Pierre-Olivier B, et al. Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the SAPALDIA cohort. Thorax 2010; 65: 150–56.
www.thelancet.com/respiratory Published online July 7, 2015 http://dx.doi.org/10.1016/S2213-2600(15)00236-2