Chronic obstructive pulmonary disease with mild airflow limitation: current knowledge and proposal for future research  a consensus document from six scientific societies

 [bib_ref] Epidemiology of chronic obstructive pulmonary disease: a literature review, Rycroft [/bib_ref] [bib_ref] Screening for and early detection of chronic obstructive pulmonary disease, Soriano [/bib_ref] [bib_ref] Interpretative strategies for lung function tests, Pellegrino [/bib_ref] [bib_ref] GOLD or lower limit of normal definition? A comparison with expert-based diagnosis..., Guder [/bib_ref] [bib_ref] Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global..., Quanjer [/bib_ref] [bib_ref] Phenotype of normal spirometry in an aging population, Vaz Fragoso [/bib_ref] [bib_ref] Phenotype of spirometric impairment in an aging population, Vaz Fragoso [/bib_ref] [bib_ref] Standardisation of spirometry, Miller [/bib_ref] [bib_ref] Grading the severity of airways obstruction: new wine in new bottles, Quanjer [/bib_ref] [bib_ref] Chronic obstructive pulmonary disease: clinical integrative physiology, O&apos;donnell [/bib_ref] [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] [bib_ref] An official European Respiratory Society statement on physical activity in COPD, Watz [/bib_ref] [bib_ref] Early chronic obstructive pulmonary disease: definition, assessment, and prevention, Rennard [/bib_ref] [bib_ref] Early-life origins of chronic obstructive pulmonary disease, Martinez [/bib_ref] [bib_ref] Susceptibility to exacerbation in chronic obstructive pulmonary disease, Hurst [/bib_ref] [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] [bib_ref] A two-year evaluation of the 'real life' impact of COPD on patients..., Kardos [/bib_ref] [bib_ref] Management of COPD in the UK primarycare setting: an analysis of real-life..., Price [/bib_ref] [bib_ref] Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity, Rodriguez-Roisin [/bib_ref] [bib_ref] Mild chronic obstructive pulmonary disease does existand affects gas exchange during exercise, Calverley [/bib_ref] [bib_ref] Site and nature of airway obstruction in chronic obstructive lung disease, Hogg [/bib_ref] [bib_ref] The nature of small-airway obstruction in chronic obstructive pulmonary disease, Hogg [/bib_ref] [bib_ref] The relations between structural changes in small airways and pulmonary-function tests, Cosio [/bib_ref] [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] [bib_ref] Quantitative analysis of the alveolar plateau in the diagnosis of early airway..., Buist [/bib_ref] [bib_ref] Small airway function improvement after smoking cessation in smokers without airway obstruction, Verbanck [/bib_ref] [bib_ref] Identification of smokers susceptible to development of chronic airflow limitation: a 13-year..., Stanescu [/bib_ref] [bib_ref] The contribution of small airway obstruction to the pathogenesis of chronic obstructive..., Hogg [/bib_ref] [bib_ref] Clinical significance of symptoms in smokers with preserved lung function, Woodruff [/bib_ref] [bib_ref] Clinical and radiologic disease in smokers with normal spirometry, Regan [/bib_ref] [bib_ref] The natural history of chronic airflow obstruction, Fletcher [/bib_ref] [bib_ref] Investigating the natural history of lung function: facts, pitfalls, and opportunities, Soriano [/bib_ref] [bib_ref] The natural history of chronic airflow obstruction revisited: an analysis of the..., Kohansal [/bib_ref] [bib_ref] Changes in forced expiratory volume in 1 second over time in COPD, Vestbo [/bib_ref] [bib_ref] Decline of FEV 1 by age and smoking status: facts, figures, and..., Kerstjens [/bib_ref] [bib_ref] Early chronic obstructive pulmonary disease: definition, assessment, and prevention, Rennard [/bib_ref] [bib_ref] Early chronic obstructive pulmonary disease: definition, assessment, and prevention, Rennard [/bib_ref] [bib_ref] Early-life origins of chronic obstructive pulmonary disease, Martinez [/bib_ref] [bib_ref] Decline of FEV 1 by age and smoking status: facts, figures, and..., Kerstjens [/bib_ref] [bib_ref] An international survey of chronic obstructive pulmonary disease in young adults according..., De Marco [/bib_ref] [bib_ref] Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease: the..., Scanlon [/bib_ref] [bib_ref] Long-term decline in lung function, utilisation of care and quality of life..., Bridevaux [/bib_ref] [bib_ref] Lower respiratory illnesses promote FEV 1 decline in current smokers but not..., Kanner [/bib_ref] [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] [bib_ref] Serum surfactant protein D is steroid sensitive and associated with exacerbations of..., Lomas [/bib_ref] [bib_ref] Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a..., Agusti [/bib_ref] 

## Epidemiology
Many epidemiological surveys have documented the high prevalence of COPD in the general adult population, in both men and women. In fact, the prevalence is consistently higher in men, and rises with age. Clearly, COPD is much more frequent in smokers and ex-smokers, but with a contribution also from never-smokers. Most publications report the data organized by age-groups and smoking habits, not by stages of severity. However, few studies have provided the classification of the COPD population according to the GOLD 2007 stages of airflow limitation. [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] The BOLD epidemiological research reports data on 9,425 men and women from 12 countries worldwide. The diagnosis of COPD was based on postbronchodilator FEV 1 :FVC ,0.7. [bib_ref] International variation in the prevalence of COPD (the BOLD study): a population-based..., Buist [/bib_ref] Overall, the prevalence of airflow limitation in the different countries ranged from 11.3% to 26%, increasing consistently through age-groups from 40 to .70 years. Grade 2 or more averaged 11.8% and 8.5% in men and women, respectively. The prevalence of grade 1 ranged from 1.4% to 15.5%, with an average of 8.1%, being 6.7% and 9.6% in women and men, respectively. A subsequent analysis focused on the difference between eversmokers (5,709) and never-smokers (4,291). Overall, 12.2% never-smokers fulfilled the criteria for GOLD COPD, 6.6% being classified as GOLD 1. Furthermore, never-smokers made up 27.7% of all COPD cases and 33% of GOLD 1. GOLD 1 amounted to 8.3% of cases in men and 5.7% in women. These data show that COPD with mild airflow limitation is a real issue in the COPD population, and in particular among never-smokers. [bib_ref] COPD in never smokers: results from the population-based burden of obstructive lung..., Lamprecht [/bib_ref] In the Spanish investigation on 4,274 adults aged 40-80 years, 3,802 subjects underwent good-quality

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Rossi et al postbronchodilator spirometry. [bib_ref] Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of..., Miravitlles [/bib_ref] The overall prevalence of airflow limitation was 10.2%, 15.1% in men, and 5.6% in women, and 7.1% and 2% in GOLD 2-4 respectively, increasing with age and smoking habits. COPD prevalence by GOLD classification of severity gave the following results: mild 56.4%, moderate 38.3%, severe 4.6%, and very severe 0.5%. The ECRHS study on more than 18,000 young adults (20-44 years) from 35 sites in 16 "high-income" countries showed stage 1 and stage 2-4 prevalence of 2.5% and 1.1%, respectively, [bib_ref] An international survey of chronic obstructive pulmonary disease in young adults according..., De Marco [/bib_ref] with an overall prevalence of COPD amounting to 3.6%. The diagnosis of airflow limitation was obtained with spirometric measurement of prebronchodilator FEV 1 :FVC ,0.7. Both the BOLD and the ECRHS surveys showed a remarkable difference in prevalence among countries. In the COPDGene cross-sectional observational study on 9,000 subjects, 9% were classified as GOLD 1, with a mean age of 61 years, slightly lower and higher than GOLD 2-4 and GOLD 0, with average mean ages of 63 and 56 years, respectively. [bib_ref] Clinical and radiologic disease in smokers with normal spirometry, Regan [/bib_ref] A crucial issue is whether COPD patients with mild airflow limitation sought contact with doctors. The Italian survey on COPD showed that 18.2% of the about 4,000 COPD patients referred to pulmonary clinics in Italy had mild airflow limitation and that 86% received some pharmacologic treatment (long-acting bronchodilators and/or inhaled corticosteroids). [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] However, the prevalence of reported exacerbations and comorbidities was 44.5% and 64%, respectively, the latter not far from the 81% of patients with very severe airflow limitation. This study suggests that COPD patients with mild airflow limitation are likely to seek doctors and even pulmonologists more for exacerbations and/or comorbidities, rather than common respiratory symptoms, such as dyspnea or cough. However, the ECLIPSE study [bib_ref] Susceptibility to exacerbation in chronic obstructive pulmonary disease, Hurst [/bib_ref] reported that the majority of COPD patients with moderate-severe airflow limitation were not frequent exacerbators. In fact, the 2-year follow-up data from the DACCORD study [bib_ref] A two-year evaluation of the 'real life' impact of COPD on patients..., Kardos [/bib_ref] showed that in a population of COPD patients with a low rate of exacerbation (,0.4 exacerbations/year), respiratory symptoms were a common cause for seeking medical help and should not be underestimated, as a significant improvement can be obtained with pharmacologic treatment. In the DACCORD population, almost 20% had mild airflow limitation. [bib_ref] A two-year evaluation of the 'real life' impact of COPD on patients..., Kardos [/bib_ref] In the longitudinal results from the COPDGene study [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] [bib_ref] Depression and health-related quality of life in chronic obstructive pulmonary disease, Omachi [/bib_ref] of 185 COPD patients classified as GOLD 1 were receiving pharmacologic treatment with long-acting bronchodilators and/or inhaled corticosteroids at the 5-year visit.
Lange et al 56 compared the mortality rate between the old (2007) [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] and the new (2011) 1,57 GOLD classifications on 6,628 individuals with COPD in the Copenhagen study. Among the 3,306 (50% of the total) patients with GOLD 1 airflow limitation, 90% were classified as A, whereas 10% were classified as B, C, and D, ie, patients with symptoms and exacerbation risk. In that study, women were 54%, and never-smokers 26% in GOLD stage 1. Mortality averaged 0.7% and 4% after 1 and 3 years, respectively, compared to 2.2% and 25.8% in GOLD 2007 stage IV patients.
In Slovenia, the National Institute of Public Health (NIJZ) is a state institution that reports prevalence of diseases on national level. In the Supplementary material, data from 2008 are presented for a small region of northern Slovenia (with high prevalence of smoking, above the average Slovenian level). The striking finding is the high prevalence of smoking in younger adults, which is increasing mostly in young women. Overall prevalence of COPD in that region is 5.7%, and in smokers 16.6%.

## Pathology
There is consensus on the notion that in COPD, inflammation in the small airways is related to cigarette smoking. However, the hypothesis of a central role of small-airway inflammation in the pathogenesis of COPD has been challenged by many recent studies. The role of premature lung aging has been proposed by many authors as central in the pathogenesis of COPD, [bib_ref] Does mechanical injury of the peripheral airways play a role in the..., Milic-Emili [/bib_ref] [bib_ref] Immunologic aspects of chronic obstructive pulmonary disease, Cosio [/bib_ref] [bib_ref] Small airway obstruction in COPD: new insights based on micro-CT imaging and..., Hogg [/bib_ref] where the critical balance between senescence and antisenescence factors is disrupted toward senescence in COPD lungs. [bib_ref] Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary..., Chilosi [/bib_ref] [bib_ref] Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, Faner [/bib_ref] [bib_ref] Accelerated lung aging: a novel pathogenic mechanism of chronic obstructive pulmonary disease..., Macnee [/bib_ref] [bib_ref] Early life origins of chronic obstructive pulmonary disease, Svanes [/bib_ref] [bib_ref] Genetic predisposition to accelerated decline of lung function in COPD, Molfino [/bib_ref] [bib_ref] Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease, Savale [/bib_ref] Telomere attrition is anticipated in COPD lungs, and this view is further supported by the occurrence of relevant comorbidities, such as weight loss, osteoporosis, cardiovascular diseases, and depression, all conditions where premature senescence and telomere-length abnormalities have been documented. [bib_ref] Genetic predisposition to accelerated decline of lung function in COPD, Molfino [/bib_ref] Experimental studies have demonstrated that telomere length is a susceptibility factor in emphysema. [bib_ref] Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease, Savale [/bib_ref] [bib_ref] Clusters of comorbidities based on validated objective measurements and systemic inflammation in..., Vanfleteren [/bib_ref] [bib_ref] Telomere length is a determinant of emphysema susceptibility, Alder [/bib_ref] The parenchymal remodeling and progressive dilation of alveolar spaces that is observed in emphysema is likely related to decreased and/or deregulated production of extracellularmatrix proteins, with eventual impaired capability to sustain connective and epithelial tissue repair. Several studies have evidenced connective tissue insufficiency leading to progressive decrease of matrix-protein production. [bib_ref] Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease, Savale [/bib_ref] Premature stem-cell exhaustion can represent the best candidate for this putative pathogenic mechanism. Senescence-related markers in COPD are mainly demonstrable in mesenchymal cells (fibroblasts and endothelial cells), [bib_ref] Telomere length is a determinant of emphysema susceptibility, Alder [/bib_ref] and a large variety of abnormalities have been described affecting pulmonary mesenchymal precursors, fibroblasts, and endothelial cells in

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Consensus document on mild COPD both human and experimental COPD. [bib_ref] Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are..., Togo [/bib_ref] [bib_ref] Endothelial cell death and decreased expression of vascular endothelial growth factor and..., Kasahara [/bib_ref] [bib_ref] Mesenchymal cell fate and phenotypes in the pathogenesis of emphysema, Horowitz [/bib_ref] [bib_ref] Endothelial colony forming cells (ECFC) are senescent and dysfunctional in COPD due..., Paschalaki [/bib_ref] [bib_ref] Targeted induction of lung endothelial cell apoptosis causes emphysema-like changes in the..., Giordano [/bib_ref] Notch and Wnt are signaling pathways involved in the correct differentiation of mesenchymal precursors. [bib_ref] Augmented Wnt signaling in a mammalian model of accelerated aging, Liu [/bib_ref] [bib_ref] Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging, Meshorer [/bib_ref] [bib_ref] Down-regulation of the canonical Wnt -catenin pathway in the airway epithelium of..., Wang [/bib_ref] [bib_ref] Activation of the WNT/ -catenin pathway attenuates experimental emphysema, Kneidinger [/bib_ref] Insufficient local immunoregulation might explain the autoimmune-like chronic inflammation and damage of small airways in COPD. [bib_ref] Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary..., Chilosi [/bib_ref] [bib_ref] Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease, Amsellem [/bib_ref] Pathophysiology Knowledge of the pathophysiology of COPD with mild airflow limitation is essential to understand the changes taking place in the lungs before the development of more severe spirometric abnormality, ie, GOLD $2. 1,53, [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Vestbo [/bib_ref] We can distinguish three levels: level 1, in which the biologic and physiologic abnormalities in the small airways of smokers coexist with spirometric values within normal limits; 14 level 2, COPD with mild airflow limitation (GOLD 2007 stage 1); [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] and level 3, COPD with moderate-severe and very severe airflow limitation (GOLD 2007 stage 2-4). [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] In level 1 (small-airway disease), pathobiological changes in the lungs can be detected by means of tests of small-airway function, which disclose abnormalities not present in healthy nonsmokers. [bib_ref] Correlation between the function and structure of the lung in smokers, Berend [/bib_ref] The single-breath nitrogen-washout test exhibits a high nitrogen slope of the alveolar plateau (N 2 slope, phase III), closing volume, and closing capacity. [bib_ref] Identification of smokers susceptible to development of chronic airflow limitation: a 13-year..., Stanescu [/bib_ref] [bib_ref] Identifying smokers at risk for developing airway obstruction, Hogg [/bib_ref] [bib_ref] Pathophysiology of evolution of small airways disease to overt COPD, Gennimata [/bib_ref] Among the tests that detect small-airway disease, [bib_ref] Ability of spirometry, flow-volume curves and the nitrogen closing volume test to..., Oxhoj [/bib_ref] [bib_ref] Does the singlebreath N 2 test identify the smoker who will develop..., Buist [/bib_ref] [bib_ref] Noninvasive assessment of airway alterations in smokers: the small airways revisited, Verbanck [/bib_ref] [bib_ref] Volume of isoflow: a new test in detection of mild abnormalities of..., Hutcheon [/bib_ref] one of the most sensitive (yet not in widespread use) appears to be low-density spirometry, [bib_ref] Volume of isoflow: a new test in detection of mild abnormalities of..., Hutcheon [/bib_ref] ie, assessing spirometric maximal expiratory flow volume before and after inhalation of heliox. The aforementioned tests are sufficiently sensitive indicators to allow detection of small-airway obstruction in smokers at a stage when the maximal expiratory flow-volume curve (while breathing air) is within normal limits. [bib_ref] Pathophysiology of evolution of small airways disease to overt COPD, Gennimata [/bib_ref] The majority of smokers (87%) who developed abnormal FEV 1 during a 9-to-11-year follow-up had an abnormal single-breath N 2 test at some time prior to their FEV 1 becoming abnormal. [bib_ref] Does the singlebreath N 2 test identify the smoker who will develop..., Buist [/bib_ref] However, the positive predictive value of an abnormal single-breath N 2 test is quite low, in that a large proportion of smokers with an abnormal single-breath N 2 test do not progress to abnormal FEV 1 . [bib_ref] Identification of smokers susceptible to development of chronic airflow limitation: a 13-year..., Stanescu [/bib_ref] [bib_ref] Does the singlebreath N 2 test identify the smoker who will develop..., Buist [/bib_ref] Recently, Elbehairy et al demonstrated that current symptomatic smokers who did not meet the spirometric criteria for an overt diagnosis of COPD had lower exercise tolerance, higher neuromuscular drive, and greater diaphragmatic effort than comparable healthy controls. [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] It has been shown that pathologic abnormalities in the small airways were found in COPD patients with mild airflow limitation. [bib_ref] The nature of small-airway obstruction in chronic obstructive pulmonary disease, Hogg [/bib_ref] [bib_ref] Small airway obstruction in COPD: new insights based on micro-CT imaging and..., Hogg [/bib_ref] Smokers with mean FEV 1 :FVC of 0.7170.038 but with small-airway disease detected by single-breath N 2 -washout test have reduced FEV 1 , and thus may be more susceptible to long-term smoking than smokers without small-airway disease to develop overt COPD. [bib_ref] Significance of small airway tests in middle-aged smokers, Nemery [/bib_ref] In smokers with airflow limitation (mean FEV 1 :FVC 0.5970.06), an abnormal single-breath N 2 -washout test predicted the development of low FEV 1 13 years later. [bib_ref] Identification of smokers susceptible to development of chronic airflow limitation: a 13-year..., Stanescu [/bib_ref] Patients with mild COPD may exhibit resting lung hyperinflation with increases in functional residual capacity (FRC; 119%-121% predicted) and RV (129%-135% predicted). [bib_ref] Lung hyperinflation and its reversibility in patients with airway obstruction of varying..., Deesomchok [/bib_ref] [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] Mid-volume expiratory-flow rates are also reduced (forced expiratory flow 25%-75% and 50%). [bib_ref] Lung hyperinflation and its reversibility in patients with airway obstruction of varying..., Deesomchok [/bib_ref] [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] Measurement of respiratory resistance and impedance with the oscillatory technique also has the potential to assess mild COPD. Frantz et al [bib_ref] Impulse oscillometry may be of value in detecting early manifestations of COPD, Frantz [/bib_ref] showed that pulmonary resistance measured by means of the impulse-oscillation system can be abnormal earlier than conventional spirometry.
The majority of COPD patients with mild airflow limitation have a reduction in lung-diffusing capacity for carbon monoxide (DL CO ), 91,92 though this reduction does not unanimously reach below 80% predicted. [bib_ref] Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity, Rodriguez-Roisin [/bib_ref] [bib_ref] Pathophysiology of evolution of small airways disease to overt COPD, Gennimata [/bib_ref] [bib_ref] Lung hyperinflation and its reversibility in patients with airway obstruction of varying..., Deesomchok [/bib_ref] [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] This reduction in diffusing capacity is a feature of both mild disease and early (and thus mild) disease. [bib_ref] Correlation between the function and structure of the lung in smokers, Berend [/bib_ref] In fact, Harvey et al followed a cohort of smokers with normal spirometry for up to 13 years, and found that among those with low DL CO (,80% predicted), ten (22%) of 46 developed spirometric obstruction (FEV 1 :FVC ,0.7), whereas among those with normal DL CO (~80%), only two (3%) of 59 developed spirometric obstruction. [bib_ref] Risk of COPD with obstruction in active smokers with normal spirometry and..., Harvey [/bib_ref] The result remained the same when either a fixed FEV 1 :FVC ratio (,0.7) or the LLN (of FEV 1 :FVC , LLN) was used. [bib_ref] Progression to COPD in smokers with normal spirometry/low DLCO using different methods..., Harvey [/bib_ref] Therefore, it stands to reason that diffusion impairment may occur before spirometric obstruction becomes manifest in the natural history of the disease.
On average, arterial blood gases are within the normal range in COPD patients with mild airflow limitation. [bib_ref] Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity, Rodriguez-Roisin [/bib_ref] [bib_ref] Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease: implications for..., Elbehairy [/bib_ref] However, the alveolar-arterial O 2 -tension gradient (D A-a O 2 ) is elevated (.15 mmHg) at rest and during exercise. [bib_ref] Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity, Rodriguez-Roisin [/bib_ref] [bib_ref] Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease: implications for..., Elbehairy [/bib_ref] [bib_ref] Gas exchange during exercise in mild chronic obstructive pulmonary disease: correlation with..., Barbera [/bib_ref] [bib_ref] Gas exchange abnormalities in mild bronchitis and asymptomatic asthma, Levine [/bib_ref] Ventilation-perfusion (V a :Q ) distribution, measured by means of the multiple inert-gas-elimination technique in patients with mild airflow limitation, unravels V a :Q mismatching, predominantly perfusion dispersion, [bib_ref] Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity, Rodriguez-Roisin [/bib_ref] [bib_ref] Gas exchange during exercise in mild chronic obstructive pulmonary disease: correlation with..., Barbera [/bib_ref] which is greater than predictable from the degree of airflow limitation, thus suggesting that COPD initially involves the periphery of the lungs, ie, small airways, parenchyma, and pulmonary vessels, with minimal or even negligible spirometric abnormalities. Recent data from the MESA study [bib_ref] Pulmonary microvascular blood flow in mild chronic obstructive pulmonary disease and emphysema:..., Hueper [/bib_ref] showed that pulmonary vascular blood flow was reduced in COPD patients with mild airflow limitation, and also in lung regions without obvious emphysema. In COPD patients with mild airflow limitation during exercise, minute ventilation is higher than in healthy control subjects at any given workload (in watts). Dyspnea, measured by means of the Borg scale, is greater at any level of minute ventilation, such that dyspnea is significantly greater at any given workload, and it is associated with a progressive decrease in inspiratory capacity, ie, dynamic hyperinflation, which does not occur in controls. [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] Furthermore, minute ventilation/CO 2 production, dead space to tidal volume ratio (V D :V T ), and arterial to end-tidal CO 2 difference are all higher than in healthy controls. [bib_ref] Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease: implications for..., Elbehairy [/bib_ref] Dynamic hyperinflation and tidal volume constraints result in a breathing pattern that becomes rapid and shallow. [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] [bib_ref] Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease: implications for..., Elbehairy [/bib_ref] In those patients, the high V D :V T leads to a compensatory rise in minute ventilation during exercise, thus maintaining effective alveolar ventilation and normal arterial blood gases, but at the expense of earlier dynamic mechanical abnormalities, greater dyspnea, and poor exercise tolerance.
Compared to healthy controls, subjects with mild airflow limitation at the highest equivalent work rate (60 W) have significantly higher total work of breathing, electromyographic activity of the diaphragm (EMG di ) and EMG di to transdiaphragmatic pressure (P di ) ratio. [bib_ref] Mechanisms of exercise intolerance in global initiative for chronic obstructive lung disease..., Guenette [/bib_ref] These findings indicate that greater neuromuscular drive (EMG di ) is needed at any given level of diaphragmatic effort (P di ). Furthermore, dyspnea-ventilation slopes are significantly higher in mild COPD than controls. Therefore, increased inspiratory effort and work in breathing and wider dissociation between diaphragmatic activation and pressure-generating capacity are observed at fixed work rates in subjects with mild COPD than in control subjects. In line with these mechanical and neuromuscular abnormalities, dyspnea is greater than in controls. Although significant dyspnea is experienced only at higher exercise work rates, overall exercise tolerance is reduced in COPD patients with mild airflow limitation compared to healthy controls.
Traditionally, the impairment of cardiac function is regarded as a late complication of severe COPD, affecting the right sections of the heart, a clinical picture known as cor pulmonale. However, in a cardiovascular disease-free study population, Barr et al [bib_ref] Percent emphysema, airflow obstruction, and impaired left ventricular filling, Barr [/bib_ref] showed that subclinical hemodynamic changes involving the left ventricle occur with mild emphysema and airflow limitation.
In summary, "mild" spirometric abnormality, or even normal spirometry in smokers, [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] is associated with important physiologic disturbances that may not manifest at rest and generate symptoms, ie, dyspnea, only during moderate-high levels of exercise. This may explain why this stage of COPD does not attract the attention of either the patient or the doctor until exercise intolerance reaches a level that interferes with daily life activities. [bib_ref] The contribution of small airway obstruction to the pathogenesis of chronic obstructive..., Hogg [/bib_ref] Imaging Chest X-ray is a standard part of the clinical evaluation of subjects with COPD, but it lacks sensitivity in detecting both airway disease and mild emphysema. The utility of chest X-ray is limited to exclude other conditions that may imitate COPD or complications, such as pneumonia. By contrast, techniques in chest imaging and quantitative image analysis have advanced to the point where they can provide novel in vivo insight into disease and potentially examine divergent responses to therapy. Computed tomography (CT) of the chest has become the standard method used for objective visualization of the lungs in COPD. It can provide useful measures of emphysema, airway-wall thickening, and air trapping associated with the disease. [bib_ref] Clinical and radiologic disease in smokers with normal spirometry, Regan [/bib_ref] [bib_ref] Association between functional small airway disease and FEV 1 decline in chronic..., Bhatt [/bib_ref] [bib_ref] Pulmonary function and sputum characteristics predict CT phenotype and severity of COPD, Camiciottoli [/bib_ref] [bib_ref] Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping,..., Schroeder [/bib_ref] Previous studies have shown that emphysema and airway-wall thickening on CT relate poorly to pulmonary function. The sensitivity of high-resolution CT in detecting early emphysema can be low, but its accuracy is greater than pulmonary function tests. [bib_ref] Pulmonary function and sputum characteristics predict CT phenotype and severity of COPD, Camiciottoli [/bib_ref] [bib_ref] Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping,..., Schroeder [/bib_ref] The population-based study of Barr et al showed that significant emphysema can be detected by means of the thoracic CT scan in subjects with preserved spirometric values. [bib_ref] Percent emphysema, airflow obstruction, and impaired left ventricular filling, Barr [/bib_ref] The COPDGene study showed that 81% of GOLD 1 and 42% of GOLD 0 patients had evidence of emphysema or airway disease by means of quantitative CT-scan analysis. [bib_ref] Clinical and radiologic disease in smokers with normal spirometry, Regan [/bib_ref] In GOLD 1 patients, 67% showed airway thickening and 68% predominant emphysema. In GOLD 2-4 patients, 100% had quantitative CT-scan abnormalities. Quantitative CT evidence of hyperinflation of the lungs predicts a rapid annual decline in FEV 1 in smokers with normal FEV 1 . [bib_ref] Prediction of the rate of decline in FEV 1 in smokers using..., Yuan [/bib_ref] The ECLIPSE study showed that the prevalence of all patterns of emphysema clearly increased across the GOLD grades, and emphysema was almost universally found in GOLD 4 patients.Bronchial wall thickening also increased in prevalence with GOLD grade, while centrilobular nodularity decreased in prevalence. CT lung-density measurements are used for the evaluation of the degree and the distribution of emphysema and air-wall dimensions. An elegant study from Jones et al [bib_ref] Emphysema on thoracic CT and exercise ventilatory inefficiency in mild-to-moderate COPD, Jones [/bib_ref] and emphysema severity. This in turn was related to reduced diffusing capacity, but not to airway-wall thickness, both assessed by means of CT.
Identification of the clinical, imaging, and genetic characteristics of GOLD 1 subjects with progressive disease could

## 2599
Consensus document on mild COPD provide opportunities for early treatment interventions. [bib_ref] Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene, Lee [/bib_ref] The COPDGene study has reported epidemiological and radiological characteristics (quantitative CT lung-density measurements) of GOLD 1 subjects. Clustering of GOLD 1 subjects identified "near-normal", "airway-predominant", "emphysema-predominant", and "lowest FEV 1 % predicted" subtypes. This study demonstrated substantial clinical heterogeneity of COPD patients with mild airflow limitation. [bib_ref] Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene, Lee [/bib_ref] The COPDGene study included 10% of GOLD 1 patients, who had clear abnormality of emphysema and/or small-airway disease at CT scan. Interestingly enough, these patients exhibited an FEV 1 decline over 5 years of observation, which was significantly greater than in GOLD 2+ patients. [bib_ref] Association between functional small airway disease and FEV 1 decline in chronic..., Bhatt [/bib_ref] Furthermore, GOLD 1 subjects with positive anamnesis of exacerbations exhibited thicker airway walls and greater prevalence of chronic bronchitis than patients without exacerbation in the previous year. [bib_ref] Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene, Lee [/bib_ref] Although thoracic CT is a very powerful tool for investigating the periphery of the lungs and has generated many expectations for a new subclassification of COPD, it has not yet achieved success comparable with that obtained by high-resolution CT for interstitial lung diseases. [bib_ref] Computed tomography-based subclassification of chronic obstructive pulmonary disease, Dirksen [/bib_ref] Other imaging modalities are interesting tools for ascertaining the mild stages of COPD, but are far from influencing clinical practice. [bib_ref] Early chronic obstructive pulmonary disease: definition, assessment, and prevention, Rennard [/bib_ref] 

## Clinical
Dyspnea is the most common symptom for which COPD patients seek medical advice. However, in patients with mild airflow limitation, dyspnea is perceived mainly with moderate-high levels of exercise, rather than at rest. [bib_ref] Chronic obstructive pulmonary disease: clinical integrative physiology, O&apos;donnell [/bib_ref] [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] Most COPD patients are smokers or aged ex-smokers, and hence they accept symptoms as direct consequences of both smoking and aging. Most often, patients choose to limit their physical activities to avoid the gradually emerging dyspnea on exertion. They often do not ask for medical care until the symptoms interfere with their daily life activity, which typically occurs in more severe disease. However, there is also a group of patients with slightly abnormal spirometry who are otherwise asymptomatic. Exerciseinduced shortness of breath is one of the earliest COPD symptoms, progressing over the course of the disease and often determining a significant reduction in activity levels, which in turn may cause deconditioning, skeletal muscle dysfunction, and further functional limitations. [bib_ref] COPD as a lung disease with systemic consequences: clinical impact, mechanisms, and..., Decramer [/bib_ref] Recent studies have demonstrated muscle weakness of arms and legs in GOLD 1 patients, documenting that physical deconditioning is present in COPD patients with mild airflow limitation. [bib_ref] COPD as a lung disease with systemic consequences: clinical impact, mechanisms, and..., Decramer [/bib_ref] [bib_ref] COPD: early diagnosis and treatment to slow disease progression, Welte [/bib_ref] Chronic bronchitis, ie, cough and sputum on most days for 3 consecutive months in 2 consecutive years, is frequent in smokers, and can be present with mild airflow limitation and even without airflow limitation, but it is associated with poorer health status and worse prognosis. [bib_ref] Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the..., Probst-Hensch [/bib_ref] [bib_ref] The impact of COPD on health status: findings from the BOLD study, Janson [/bib_ref] The traditional physical examination is often negative in most COPD patients with mild airflow limitation.
Patients with mild airflow limitation are not a homogeneous group. Symptomatic patients have a faster rate of decline of lung function, lower health-related quality of life, and increased health utilization compared with asymptomatic individuals. [bib_ref] COPD as a lung disease with systemic consequences: clinical impact, mechanisms, and..., Decramer [/bib_ref] Recent research has indicated that health care utilization and health-related quality of life are similar in asymptomatic patients with mild airflow limitation and in those with normal lung function. [bib_ref] Defining COPD exacerbation in chronic obstructive pulmonary disease, O&apos;reilly [/bib_ref] On the other hand, some patients have significant symptoms with near-normal lung function. 14 This could be attributed to excessive ventilatory demand with decreased inspiratory muscle pressuregenerating capacity due to dynamic hyperinflation, and ventilation-perfusion mismatching during exercise. [bib_ref] COPD as a lung disease with systemic consequences: clinical impact, mechanisms, and..., Decramer [/bib_ref] Although COPD exacerbations are usually associated with more severe disease, they can occur in patients with GOLD 1 stage. In a 1-year prospective study, 70% of patients with mild and moderate airflow limitation (FEV 1 $50% predicted) reported at least one exacerbation. [bib_ref] Defining COPD exacerbation in chronic obstructive pulmonary disease, O&apos;reilly [/bib_ref] In the COPDGene study, [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] 27.4% of GOLD 1 patients experienced one or more exacerbations during the 5 years of observations with a mean rate/year of 0.18 compared to 0.13 of GOLD 0 and 0.89 of GOLD 4 patients, respectively. In an Italian observational study on about 4,000 COPD patients, 745 were classified as GOLD 1; only 55% reported being exacerbation-free, and 20% reported two or more exacerbations in the previous year, with 9.6% reporting one or more hospitalizations. [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] A survey of 3,306 COPD patients classified as GOLD 1 showed that about 10% were in categories B, C, and D of the 2011 GOLD classification, suggesting that they had symptoms. About 1% were classified as C and D, also indicating a high risk of exacerbation. [bib_ref] International variation in the prevalence of COPD (the BOLD study): a population-based..., Buist [/bib_ref] In the GOLD 1 group, 2.5% of the mild group had exacerbations in the previous year. In the 3 years of observation, the average number of exacerbations per year was 0.1, with 27 hospital admissions due to COPD and two respiratory deaths, while deaths from any causes increased from 4% to 5.9%, 14.3%, and 25.8% from stage 1 to 4.
In fact, the actual incidence of exacerbations in COPD with mild airflow limitation may be higher than expected, since many are likely to be unreported. [bib_ref] COPD as a lung disease with systemic consequences: clinical impact, mechanisms, and..., Decramer [/bib_ref] In a study of patients with GOLD 1, the incidence of acute events was [bib_ref] Respiratory viral infection in adults with and without chronic obstructive pulmonary disease, Greenberg [/bib_ref] It has been documented that the occurrence of exacerbations is associated with faster loss of lung function in GOLD 1 and 2. [bib_ref] The natural history of chronic airflow obstruction, Fletcher [/bib_ref] The overall burden of COPD is aggravated by comorbidities, which are often observed early in the disease progression. These include diabetes, cardiovascular disease, osteoporosis, gastroesophageal reflux, and depression. In the Italian survey, the presence of at least one comorbidity was reported by 64% of GOLD 1 patients compared to 81% of patients classified as GOLD 4. [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] Patients with COPD are at greater risk of developing depression than demographically matched healthy controls, even at the mild stages of the disease. The ECLIPSE study reported that comorbidities were independent of severity of airflow limitation. [bib_ref] Characterisation of COPD heterogeneity in the ECLIPSE cohort, Agusti [/bib_ref] However, in the German observational study, including almost 70% grades 1 and 2 COPD, the exacerbation rate was low, and such symptoms as dyspnea had a major impact on patients' lives. [bib_ref] A two-year evaluation of the 'real life' impact of COPD on patients..., Kardos [/bib_ref] In conclusion, COPD patients with mild airflow limitation are likely to seek medical help more for different reasons, such as exacerbations, dyspnea, and comorbidities. In particular, however, episodes of mild exacerbation should draw the attention of the attending physician to a more complete evaluation of the patient's condition and to plan a follow-up program.

## Physical activity
Particular attention should be devoted to the issue of physical activity in COPD patients with mild airflow limitation. Although specific studies on this subgroup of patients are lacking, several lines of evidence have shown that physical activity is consistently low in COPD patients at any stage, [bib_ref] Daily physical activity in subjects with newly diagnosed COPD, Van Remoortel [/bib_ref] with deleterious consequences on decline in lung function, 115 extrapulmonary effects, 116 quality of life, and even survival. [bib_ref] Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary..., Garcia-Aymerich [/bib_ref] [bib_ref] Physical activity is the strongest predictor of all-cause mortality in patients with..., Waschki [/bib_ref] The mechanisms of interaction between physical (in)activity and the pathophysiology of chronic disorders is poorly understood, and certainly deserves future research. [bib_ref] An official European Respiratory Society statement on physical activity in COPD, Watz [/bib_ref] Rehabilitation programs give inconsistent results on physical activity, although sometimes the effect of rehabilitation is statistically significant. [bib_ref] Does exercise training change physical activity in people with COPD? A systematic..., Ng [/bib_ref] However, due to the beneficial effects, including the increased survival 120 , of physical activity in human beings, behavioral changes to a more active life, in addition to smoking-cessation programs, should be encouraged at any stage of airflow limitation. 15

## Therapy
The treatment of COPD patients cannot be "one size fits all". The overall assessment of the disease must include measurements of lung function and symptoms, as well as estimation of exacerbations and comorbidities. It has been suggested that it might be possible to link the therapy to the patient's phenotype, [bib_ref] Daily activity energy expenditure and mortality among older adults, Manini [/bib_ref] [bib_ref] Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice, Miravitlles [/bib_ref] [bib_ref] Spanish Guideline for COPD (GesEPOC): update 2014, Miravitlles [/bib_ref] and this concept deserves further investigation. [bib_ref] Susceptibility to exacerbation in chronic obstructive pulmonary disease, Hurst [/bib_ref] [bib_ref] Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a..., Agusti [/bib_ref] [bib_ref] Pulmonary function and sputum characteristics predict CT phenotype and severity of COPD, Camiciottoli [/bib_ref] [bib_ref] Emphysema-and airwaydominant COPD phenotypes defined by standardized quantitative computed tomography, Subramanian [/bib_ref] [bib_ref] CT-definable subtypes of chronic obstructive pulmonary disease: a statement of the Fleischner..., Lynch [/bib_ref] However, although it does not reflect either the severity of the overall disease [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Vestbo [/bib_ref] or the total impairment in lung function, [bib_ref] Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD, Rossi [/bib_ref] the measurement of the FEV 1 % predicted remains a milestone variable in all clinical trials in COPD.
Traditionally, clinical trials on COPD therapy have recruited patients with postbronchodilator FEV 1 :FVC ,0.7 and FEV 1 ,80%, thus excluding patients with mild airflow limitation. [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] [bib_ref] Activation of the WNT/ -catenin pathway attenuates experimental emphysema, Kneidinger [/bib_ref] However, real-life studies have shown than not only patients with mild airflow limitation are treated [bib_ref] A two-year evaluation of the 'real life' impact of COPD on patients..., Kardos [/bib_ref] and even over-treated [bib_ref] How far is real life from COPD therapy guidelines? An Italian observational..., Corrado [/bib_ref] [bib_ref] Management of COPD in the UK primarycare setting: an analysis of real-life..., Price [/bib_ref] but also that symptomatic subjects with normal spirometry receive prescriptions of bronchodilators and inhaled corticosteroids. [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] [bib_ref] Clinical significance of symptoms in smokers with preserved lung function, Woodruff [/bib_ref] [bib_ref] Clinical and radiologic disease in smokers with normal spirometry, Regan [/bib_ref] The only study specifically addressing GOLD 1 patients was that done by O'Donnell et al, [bib_ref] Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage..., O&apos;donnell [/bib_ref] who performed a short-term, randomized, double-blind, placebo-controlled, crossover clinical trial in COPD patients with mild airflow limitation, measuring lung function and exercise tests after either placebo or the nebulizer ipratropium bromide 500 g. Interestingly, the mean baseline modified Medical Research Council dyspneascale score was .1, suggesting the presence of symptoms even with postbronchodilator FEV 1 averaging 90% predicted. Mean postbronchodilator FEV 1 :FVC was ,0.6, and lung volumes showed a slight degree of lung hyperinflation, while DL CO and maximum pressures were well within the normal limits, while airway resistance increased. Symptom-limited  V O 2 averaged 1.8 L/min, ie, 79% predicted. O'Donnell et al 128 found that treatment with a short-acting bronchodilator, ie, ipratropium bromide, was associated with a significant improvement in FEV 1 , airway resistance, and RV. During exercise, there was a significant increase in dynamic inspiratory capacity, though there was no improvement in endurance time. The reduction in dynamic hyperinflation was linked to a reduction in ratings of exertional dyspnea intensity at higher levels of ventilation. The authors suggested that this study provided a physiologic rationale for considering a trial of bronchodilating therapy in COPD patients with mild airflow limitation who experience activity-related dyspnea. Casaburi et al 129 investigated the effect of tiotropium on pulmonary hyperinflation and exercise tolerance in symptomatic patients with mild-moderate airflow limitation (GOLD 1 and 2). [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] In that 22-week, randomized, crossover study, they found that tiotropium improved inspiratory capacity in both groups of GOLD 1 and 2 patients, whereas exercise duration was enhanced only in group 2 (moderate airflow limitation). The lack of effect of tiotropium on exercise tolerance, despite the significant reduction in dynamic lung hyperinflation in GOLD 1, was only partially explained by a limitation of the study protocol. Additional research on GOLD 1 patients was encouraged.
A few studies in the 90s recruited COPD patients with mild-moderate airflow limitation in prospective trials. The longest period of observation, 11 years, was obtained in the Lung Health Study on smoking cessation, [bib_ref] Smoking and lung function of Lung Health Study participants after 11 years, Anthonisen [/bib_ref] which showed that smoking cessation was effective to slow FEV 1 decline significantly and quite substantially in sustained quitters compared to intermittent quitters and continuous smokers, particularly in COPD with mild airflow limitation. [bib_ref] Lower respiratory illnesses promote FEV 1 decline in current smokers but not..., Kanner [/bib_ref] By contrast, three prospective clinical trials, lasting 4 131 and 3 [bib_ref] Long term effect of inhaled budesonide in mild and moderate chronic obstructive..., Vestbo [/bib_ref] [bib_ref] Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary..., Pauwels [/bib_ref] years, failed to show any effect of inhaled corticosteroids in the rate of FEV 1 decline in patients with mild-moderate COPD. In the Copenhagen study, 132 mean FEV 1 was .80% predicted, suggesting a high proportion of patients with mild rather than moderate COPD. That study failed to find any effect of budesonide on symptoms and exacerbations. An interesting observation in EUROSCOPE [bib_ref] Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary..., Pauwels [/bib_ref] was the FEV 1 improvement in the budesonide group (+17 mL on average) and not in the placebo group (-81 mL on average) in the first 6 months of the study. Afterward, the decline progressed at a similar rate from the 9th month to the end of treatment. A 5-year follow-up clinical trial compared the effect of inhaled ipratropium with placebo, and an aggressive smoking-intervention program, in COPD patients with mild-moderate airflow limitation: the use of the bronchodilator did not influence the long-term decline in FEV 1 . [bib_ref] Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator..., Anthonisen [/bib_ref] On the basis of the available evidence, it may be concluded that in COPD patients with mild airflow limitation: - smoking cessation is the most effective measure to decrease the rate of FEV 1 decline; - changes in lifestyle toward more active physical activity must be encouraged; - a short-acting muscarinic antagonist can improve lung function, at least in the short run, but influences the rate of FEV 1 decline; - regular monotherapy with inhaled corticosteroids does not reduce either the rate of decline of FEV 1 or the rate of exacerbations; however, a rich body of data in a recent publication suggests that a substantial proportion of patients with COPD may not have rapid FEV 1 decline, which for decades has been regarded as the hallmark of COPD. [bib_ref] A 4-year trial of tiotropium in chronic obstructive pulmonary disease, Tashkin [/bib_ref] The last point has important implications for future research on mild COPD. In fact, it suggests that different end points should be considered to assess the effect of treatments on the progression of the disease, eg, other tests of lung function, exacerbations, quality of life, and symptoms. [bib_ref] Clinical significance of symptoms in smokers with preserved lung function, Woodruff [/bib_ref] [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] 

## Pulmonary function tests
In this document, we are not addressing the investigation of lung function in smokers, either with or without symptoms, with spirometry within normal limits and possibly smallairway disease. 14,31 Furthermore, we are not addressing the longstanding question of whether a fixed FEV 1 :FVC ,0.7 or ,LLN ratio should be preferred; 1 nor are we debating whether FVC or VC should be the denominator.However, the GLI approach 8,12 is discussed in this article because it may be a major topic of future research. For this article, we accept the operational definition adopted in most articles on patients with a diagnosis of COPD and mild airflow limitation. [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Rabe [/bib_ref] [bib_ref] Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage..., Ofir [/bib_ref] However, on the basis of the available evidence, we recommend some additional physiologic measurements, which may provide a better understanding of lung abnormalities, in particular in patients with such symptoms as dyspnea [bib_ref] Mechanisms of exertional dyspnoea in symptomatic smokers without COPD, Elbehairy [/bib_ref] [bib_ref] Clinical significance of symptoms in smokers with preserved lung function, Woodruff [/bib_ref] and/or chronic cough and sputum. [bib_ref] The presence of chronic mucus hyper secretion across adult life in relation..., Allison [/bib_ref] Lung volume TLC is needed to distinguish between a true obstructive pattern (TLC within normal limits or above LLN) or a mixed obstructive/restrictive pattern (TLC , LLN). 6 FRC may be increased above normal limits, due to static pulmonary hyperinflation. [bib_ref] Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD, Rossi [/bib_ref] RV is likely to be above normal limits, due to premature airway closure during forced expiration. [bib_ref] Does mechanical injury of the peripheral airways play a role in the..., Milic-Emili [/bib_ref] [bib_ref] Closing volume: a reappraisal (1967-2007), Milic-Emili [/bib_ref] TLC, FRC, and RV are expected to increase progressively with advancement of the disease. [bib_ref] The therapeutic implications of the pathophysiology of COPD, Macklem [/bib_ref] Diffusing capacity (DL CO or TL CO )
The transfer factor of carbon monoxide (TL CO ) or diffusing capacity (DL CO ) [bib_ref] In defence of the carbon monoxide transfer coefficient KCO (TL/V'A), Hughes [/bib_ref] can be abnormal in smokers with otherwise-preserved lung function; [bib_ref] Correlation between the function and structure of the lung in smokers, Berend [/bib_ref] in particular the carbon monoxide transfer coefficient 140 is significantly correlated with the amount of emphysema in smokers. A low baseline carbon monoxide transfer coefficient is independently associated with more rapid progression of emphysema and airflow limitation in heavy smokers. [bib_ref] Association of the transfer coefficient of the lung carbon monoxide with emphysema..., Hoesein [/bib_ref] TL CO measurement can provide additional prognostic information in COPD patients on follow-up. [bib_ref] Lung function indices for predicting mortality in COPD, Boutou [/bib_ref] Low DL CO is a predictor of future airflow obstruction in smokers with normal spirometry. [bib_ref] Risk of COPD with obstruction in active smokers with normal spirometry and..., Harvey [/bib_ref] Cardiopulmonary exercise test

## Respiratory impedance
It has been shown that the impulse-oscillation system allows determination of respiratory impedance and frequency dependence of resistance and has the potential to detect lung pathology in patients with COPD earlier than spirometry. [bib_ref] Impulse oscillometry may be of value in detecting early manifestations of COPD, Frantz [/bib_ref] Therefore, smokers with a diagnosis of COPD and mild airflow obstruction should be carefully studied to explain symptoms, when present, and to establish a time 0 (baseline) for follow-up. [bib_ref] Examination of the carbon monoxide diffusing capacity (DLCO) in relation to its..., Hughes [/bib_ref] [bib_ref] Association of the transfer coefficient of the lung carbon monoxide with emphysema..., Hoesein [/bib_ref] 

## Follow-up
After the seminal study by Fletcher and Peto, 33 the rate of FEV 1 decline over time has been suggested as the milestone variable to assess the progressive loss of lung function in COPD. However, the most recent GOLD document suggests that symptoms and exacerbations are the crucial variables for follow-up, whereas lung function may not be needed. This concept, which makes the life of the busy clinician easier, might be appropriate for patients with the overt disease, but should not be applied to patients with mild airflow limitation whose symptoms are highly dependent on an active lifestyle, where exacerbations may be interpreted as common viral infections, as in the general population. The physiologic drop in lung function found in otherwisehealthy nonsmokers has been reported as up to 30 mL/ year, and is accelerated in smokers up to a mean 80 mL/ year. [bib_ref] The natural history of chronic airflow obstruction, Fletcher [/bib_ref] However, the trajectories leading to COPD include not only rapid FEV 1 decline but also normal rate of decay with lower starting value, eg, due to childhood respiratory illness. [bib_ref] The relationship of childhood respiratory illness to adult obstructive airway disease, Burrows [/bib_ref] [bib_ref] Lung-function trajectories leading to chronic obstructive pulmonary disease, Lange [/bib_ref] A population-based study reported data over 11 years of observation in subjects with respiratory symptoms and normal lung function and GOLD 1 or more. [bib_ref] Long-term decline in lung function, utilisation of care and quality of life..., Bridevaux [/bib_ref] Overall, FEV 1 decline was greater in GOLD 1 patients than in normal subjects, and within stage 1 it was greater in those with respiratory symptoms than without. [bib_ref] Long-term decline in lung function, utilisation of care and quality of life..., Bridevaux [/bib_ref] This was associated with increased utilization of respiratory care resources and lower health-related quality of life; 45 the asymptomatic GOLD 1 patients being similar to the reference group of normal subjects. This is consistent with the observation that symptoms of chronic bronchitis without airflow obstruction are a risk factor for the development of COPD. [bib_ref] Incidence of chronic obstructive pulmonary disease in a cohort of young adults..., De Marco [/bib_ref] Thoracic CT has been used to investigate the small airways and the periphery of the lungs. Recent publications have shown that CT-assessed functional small-airway disease and emphysema are associated with FEV 1 decline, but the association with functional airway disease has greatest importance in mild-moderate COPD, where the rate of FEV 1 decline is greatest. [bib_ref] Lung function decline in COPD, Tantucci [/bib_ref] [bib_ref] Association between functional small airway disease and FEV 1 decline in chronic..., Bhatt [/bib_ref] The COPDGene study showed that the rate of FEV 1 decline was higher in GOLD 1 than GOLD 2 and above, and that it was fostered by severe exacerbations. [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] All these data support the idea that repeated measurements of FEV 1 should be performed in the follow-up of patients with GOLD 1 COPD, particularly in subjects with respiratory symptoms and exacerbations. Clearly, CT is an excellent tool for research, but it cannot be proposed for clinical practice, at least at present. [bib_ref] Acute exacerbations and lung function loss in smokers with and without COPD, Dransfield [/bib_ref] [bib_ref] Association between functional small airway disease and FEV 1 decline in chronic..., Bhatt [/bib_ref] [bib_ref] CT-definable subtypes of chronic obstructive pulmonary disease: a statement of the Fleischner..., Lynch [/bib_ref] A few years ago, Macklem suggested a different perspective to look at the natural history of COPD. [bib_ref] The therapeutic implications of the pathophysiology of COPD, Macklem [/bib_ref] Rather than focusing on FEV 1 decline, he pointed attention to the progressive rise in static lung volume, ie, lung hyperinflation. [bib_ref] Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD, Rossi [/bib_ref] Due to the loss of lung elastic recoil and small-airway closure at higher volumes, RV, FRC, and TLC increase, while VC, FVC, and FEV 1 decrease. The fall in VC (or FVC) brings to the drop in FEV 1 , according to the formula FEV 1 = (FEV 1 :VC)/VC. Although specific research on the natural history of COPD patients with mild airflow limitation is lacking, the analysis from Macklem suggests that the measurement of changes in lung volume might be convenient for assessing the evolution of COPD. In this respect, the Swedish study (SCAPIS), [bib_ref] Vital capacity and COPD: the Swedish Cardiopulmonary Bioimage Study (SCAPIS), Toren [/bib_ref] which showed that the FEV 1 :VC ratio is more sensitive than the FEV 1 :FVC ratio in detecting the spirometric abnormalities of COPD, has to be mentioned. That study concluded that the use of only FVC when assessing airflow limitation may result in a considerable underdiagnosis of patients with mild airflow limitation. [bib_ref] Vital capacity and COPD: the Swedish Cardiopulmonary Bioimage Study (SCAPIS), Toren [/bib_ref] Therefore, once a diagnosis of COPD with mild airflow limitation is obtained, periodic spirometry can provide a simple and reliable parameter for follow-up of patients. In this connection, there are two factors to be considered. First, the history of either childhood or maternal asthma [bib_ref] Early-life origins of chronic obstructive pulmonary disease, Martinez [/bib_ref] [bib_ref] Risk factors for growth and decline of lung function in asthmatic individuals..., Grol [/bib_ref] [bib_ref] A distinct low lung function trajectory from childhood to the fourth decade..., Berry [/bib_ref] and early-life lower respiratory illness 147 should be investigated carefully, particularly in never-or former-smoking subjects with mild but irreversible airflow limitation, as a risk factor for faster FEV 1 decline in adulthood. Second, low FEV 1 in early adulthood may lead to COPD without an accelerated decline in FEV 1 . [bib_ref] Lung-function trajectories leading to chronic obstructive pulmonary disease, Lange [/bib_ref] This emphasizes the need for more extensive use of spirometry early in life to disclose susceptible smokers, rapid FEV 1 decliners (about 50 mL/year), or normal FEV 1 decliners (,30 mL/year) starting from low FEV 1 .
Therefore, we support the idea that lung function should be measured for the follow-up of patients with GOLD 1 COPD. At present, the decision on the timing of measurement remains completely discretionary. It may depend upon the intensity of symptoms and exacerbations, age, and history of smoking, for example. Spirometry might be scheduled from 6 months to 2 years, according to the individual evaluation.

# Future research
Many patients who meet the spirometric criteria of GOLD 1 COPD are asymptomatic at rest and at moderate levels of exercise. The immediate consequence of this fact is that it is not known to a great extent what the natural history of this COPD subtype and its specific treatment are. In our opinion, there is a need for future research in the following areas in COPD patients with mild airflow limitation.

## Diagnosis
Undiagnosed COPD is associated with increased health care costs and more cardiovascular risk factors. [bib_ref] Economic burden prior to COPD diagnosis: a matched case-control study in the..., Akazawa [/bib_ref] [bib_ref] The direct medical costs of undiagnosed chronic obstructive pulmonary disease, Mapel [/bib_ref] Although undiagnosed subjects appeared healthier than those with a diagnosis, their risk of death was increased compared with subjects without obstruction.At present, we do not know the prevalence or outcomes of COPD with mild airflow limitation based on the LLN. Neither do we know if a change in the diagnosis of mild airflow limitation based on such criteria as the LLN and/or GLI Z-scores could be associated with a different clinical presentation. We propose the following initiatives:
- studies to compare prevalence, clinical presentation, and outcomes among individuals diagnosed with mild airflow limitation on the basis of FEV 1 :FVC ,0.70 with those among individuals diagnosed on the basis of FEV 1 : FVC , LLN or even FEV 1 :VC , LLN; - longitudinal studies addressing the GLI approach, using GLI prediction equations and FEV 1 Z-scores to delineate severity grades; - studies to investigate whether measurements of lung volume add valuable information for the diagnosis of COPD when airflow limitation is classified as mild; - studies to evaluate the impact of the diagnosis of COPD with mild airflow limitation among younger versus older individuals (ie, is it more important to general health to diagnose asymptomatic or paucisymptomatic GOLD 1 COPD in a 50-year-old than an 80-year-old?).

## Clinical assessment
Most but not all COPD patients with mild airflow limitation are either current or ex-smokers with at least 10 pack-years of smoking history. At a primary care office, over a third of ex-and current smokers who were diagnosed with GOLD stage 1 COPD based on screening spirometry were asymptomatic at the time of testing. [bib_ref] Prevalence, severity and underdiagnosis of COPD in the primary care setting, Bednarek [/bib_ref] As such, any current or ex-smokers should be tested with spirometry, regardless of the presence of respiratory symptoms. [bib_ref] COPD in 2016: some answers, more questions, Labaki [/bib_ref] The question remains as to what else to perform after COPD with mild airflow limitation has been diagnosed. Of course, a minimum of anthropometric measurements and chest X-ray must be obtained. However, further research is needed to determine:
- the role of DL CO and/or oscillatory resistance, and CT to identify subgroups of patients (phenotypes) with different clinical presentation and differential responses to treatment; - whether different available indices of symptoms (eg, CAT), disease severity (ie, BODE index), coexistence comorbidities (ie, asthma, COTE index) or other measures (eg, lung function, CT findings, biomarkers) are useful surrogate markers of short-, medium-, or long-term patient-centered outcomes.

## Treatment
It is believed that hospitalizations and deaths are relatively infrequent in COPD patients with mild airflow limitation. However, the information available is old and scarce. [bib_ref] Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator..., Anthonisen [/bib_ref] As in the rest of COPD patients, treatment goals should be focused on: 1) relieving patient symptoms, 2) slowing the progression of disease, and 3) mitigating the risk of the leading causes of hospitalization and mortality (cardiovascular disease and lung cancer). There is a need for:
- studies to clarify the appropriate approach and strategy to achieve abstinence from smoking (value to spirometry results, ie, effectiveness of pharmacological agents); - pharmacological trials to analyze outcomes among GOLD stage 1 COPD subtypes (ie, current vs ex-smokers with or without coexistent asthma); it might be of interest to investigate whether long-acting bronchodilators, in particular antimuscarinic agents, anti-inflammatory drugs, or the combination of inhaled corticosteroids/long-acting  2 -agonists can provide more benefits in the early stage of the disease, rather than in the most advanced ones; - different end points might be considered to assess the effectiveness of pharmacologic treatment, such as lung-function tests more closely related to the periphery of the lungs (RV, diffusion capacity, exercise tolerance) than FEV 1 decline, and relevant clinical outcomes, such as exacerbations; - nonpharmacological trials (ie, rehabilitation and encouragement of active lifestyle plus smoking-cessation intervention);

# Conclusion
It has been known for many years that significant pathophysiologic abnormalities can be detected in smokers with normal spirometry. Furthermore, recent data show that smokers can report respiratory symptoms and seek medication with spirometric values still within normal limits. These two pieces of information suggest that "mild" airflow limitation, in smokers at least, can reflect well-established disease and not just a negligible insult of an otherwise-sufficient health status. These patients should be encouraged to pursue an active life style, which is not only healthy but also unravels the reduced exercise tolerance and may support any smokingcessation program.
A diagnosis of COPD with mild airflow limitation helps in recognizing and adequately treating exacerbations that might otherwise be interpreted differently and underestimated. Finally, a follow-up program should be planned, both to understand whether "mild" is really "early" and to take any measurement (nonpharmacologic and pharmacologic) to prevent the progressive deterioration of health status. On one hand, any smoker or ex-smoker should undergo spirometry early in her/his health file; on the other hand, acute episodes should be regarded as possible exacerbations of undiagnosed COPD. submit your manuscript | www.dovepress.com

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## Rossi et al

# Supplementary materials
In Slovenia, the National Institute of Public Health (NIJZ) is a state institution that reports on the prevalence of diseases at a national level. In Tables S1-S3, the data from year 2008 are presented in a small region of northern Slovenia (with prevalence of smoking, above average Slovenian level). The striking finding is the high prevalence of smoking in younger adults, which is increasing mostly in young women. The overall prevalence of COPD in that region is 5.7% and in smokers 16.6%.

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Consensus document on mild COPD [fig_ref] Table S4: Prevalence of the disease Do you have or have you ever had [/fig_ref] describes the trend of self-reported diagnosis of either asthma or chronic bronchitis (including COPD) in 2014 compared to 2007 in Slovenia. All answers of yes were supplemented by a doctor's confirmation of diagnosis.
Ten-year groups were created in the report of prevalence. The decrease in prevalence of both conditions is seen in the 7-year period.
[table] Table SI: Smoking exposure and COPD prevalence from the year 2008 Smoking exposure in the general population Current smokers by age groups and gender, year 2008 (estimation on sample size 7,706) Past smokers by age groups and gender, year 2008 (estimation on sample size 7,706) Notes: Sourced from Cindi health monitor survey, 2008. University Clinic Respiratory and Allergic Diseases, Golnik, Slovenia. 2 [/table]
[table] Table S2: Hospital admissions in the year 2007 Prevalence of COPD in current smokers is 16.6% Note: Sourced from Institute for Public Health of Slovenia, Ljublijana, In-patient Statistics Database University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia, Estimation based on a survey focused on COPD Epidemiology within Pomurje Region, year 2006, sample size 2000, author Simona Slacek, General Hospital Murska Sobota. 3 International Journal of COPD 2017:12 submit your manuscript | www.dovepress.com [/table]
[table] Table S4: Prevalence of the disease Do you have or have you ever had...Comment: Those who answered positive for any of the above diagnoses were additionally asked whether the diagnosis had been confirmed by a doctor [/table]