From GOLD 0 to Pre-COPD

Abstract

The diagnosis of chronic obstructive pulmonary disease (COPD) currently requires the demonstration of poorly reversible airflow limitation, defined as a post-bronchodilator FEV1/FVC <0.7 (1–3). Although some have argued that the lower limit of normal rather than a fixed value to define obstruction may be more accurate and theoretically more appropriate, recent pooled data from multiple NIH cohorts demonstrate that the fixed FEV1/FVC ratio <0.70 provides discrimination of COPD-related hospitalization and mortality that is equal to or better than other thresholds and the lower limit of normal (4). At present, FEV1/FVC remains the most robust and widely available marker of airflow limitation (5), although it may be less sensitive than some other measures (e.g., forced oscillometry). Likewise, FEV1 is one of the most powerful predictors of clinically relevant outcomes, including symptoms, exacerbations, and mortality (6, 7). Spirometry is inexpensive and widely available, even in many developing countries. Yet, at the same time, at an individual level, FEV1 may not fully indicate the extent of disease severity and progression, which may instead be manifest by symptoms, exacerbations, and increased risk of death. Furthermore, significant lung damage may have already occurred before abnormalities in FEV1 are evident. Identifying individuals who will eventually develop airflow obstruction consistent with a diagnosis of COPD may enable therapeutic interventions with the potential to modify the course of disease. In 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease, proposed an “at-risk” stage (GOLD stage 0). It was defined by the presence of risk factors (smoking) and symptoms (chronic cough and sputum production) in the absence of spirometric abnormalities that cross the diagnostic threshold for COPD (3). This category was later abandoned because not all these individuals progressed to COPD (8). In retrospect, this may not have been the best decision, as many other medical disciplines have adopted the concept of “predisease” status (e.g., prediabetes, prehypertension, precancer, or preeclampsia). In those disciplines, predisease does not imply that all will develop the disease, but rather, the classification identifies an especially at-risk population for closer follow-up and risk management. Here, we propose to adopt a similar concept in the field of COPD. As has been highlighted in the recent perspective by Martinez and colleagues (9, 10), more is becoming understood about the pathogenesis of early COPD and the importance of identifying such individuals, in particular, for the development of disease-modifying therapies. In this perspective, our goal is to review the evidence available today that supports the need for the recognition of individuals at risk for COPD and discuss whether it is time to consider the evolution of the GOLD stage 0 concept to that of “pre-COPD” from a clinically relevant perspective (11). Although not an official GOLD document, this manuscript was generated on the basis of discussions within the GOLD Science Committee for the purposes of engaging the scientific community around the concept of pre-COPD. Symptomatic individuals with “normal” spirometric results are a heterogeneous group with a variety of abnormalities, including cough, sputum production, dyspnea, exacerbation-like events, and radiographic features that in some cases are similar to the clinical and radiographic presentation of patients with spirometrically confirmed COPD (12, 13). In the COPDGene (Genetic Epidemiology of COPD) cohort, roughly 43% of smokers with a normal FEV1/FVC ratio had emphysema, gas trapping, or airway wall thickening on computed tomography (CT). Twenty-three percent of these individuals had a modified Medical Research Council (MRC) dyspnea score ≥2 compared with 4% of never-smokers and 22% of individuals with GOLD stage 1 COPD (12). Furthermore, chronic bronchitis symptoms among unobstructed participants are also associated with impaired quality of life, reduced walk distance, and increased exacerbation-like events (14). In SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), another NIH-funded cohort of smokers, roughly half of the smokers without airflow obstruction had a COPD Assessment Test score ≥10 and exacerbation rates similar to those of symptomatic subjects at GOLD stages 1–2 (15). These symptomatic individuals without spirometrically defined obstruction also displayed airway wall thickening on CT and elevated airway mucin concentrations, pointing to a pathologic basis for their symptoms (16). Similar findings were also observed in the Canadian population-based CanCOLD (Canadian Cohort Obstructive Lung Disease) cohort in whom exacerbation-like events were again seen among individuals without airflow obstruction. These subjects also had worse health-related quality of life and were more likely to miss social activities and work (13). Individuals with symptoms but without spirometrically defined obstruction compose a heterogeneous group, with some having dyspnea and others having chronic bronchitis. CT may show no abnormality or may demonstrate airway wall thickness, gas trapping, and even emphysema (12, 15). Of note, some of these individuals may never develop spirometrically defined airflow obstruction, whereas others will experience rapid lung function decline and develop full-blown disease (17–21). In SPIROMICS, 42% of symptomatic smokers without spirometrically defined obstruction were prescribed bronchodilators, and 23% were prescribed inhaled corticosteroids, suggesting physicians believed the symptoms warranted treatment (15). However, very few therapeutic clinical trials have been conducted in these individuals, and clear evidence on the effects of treatment with either bronchodilators or inhaled corticosteroids does not exist. To address this knowledge gap, the NHLBI has funded the currently enrolling RETHINC (Redefining Therapy in Early COPD) trial (NCT 02867761) to examine whether symptomatic smokers without spirometrically defined obstruction derive benefit from inhaled bronchodilator therapy. Several studies have examined the relationship between respiratory symptoms in unobstructed individuals and the subsequent development of COPD (Table 1). In a Swedish cohort of over 6,000 middle-aged and older subjects, the 10-year cumulative incidence of COPD was 13.5% (17). Cough, sputum production, and chronic productive cough were significantly associated with incident COPD in women, whereas dyspnea and wheeze were significantly associated with incident COPD in men. SAPALDIA (Swiss Study on Air Pollution and Lung Disease in Adults), with a cohort of over 5,000 individuals, also found that chronic bronchitis was associated with incident COPD, as defined by prebronchodilator spirometric results (rate ratio, 1.23; 95% confidence interval, 1.00–1.51) (22). Association between Symptoms and Lung Function Decline among Individuals at GOLD Stage 0 Definition of abbreviations: adjHR = adjusted HR; ARIC = Atherosclerosis Risk in Communities; CARDIA = Coronary Artery Risk Development in Young Adults; CB = chronic bronchitis; CI = confidence interval; COPD = chronic obstructive pulmonary disease; CT = computed tomography; ECRHS = European Community Respiratory Health Survey; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HR = hazard ratio; MRC = Medical Research Council; OR = odds ratio; SAPALDIA = Swiss Study on Air Pollution and Lung Disease in Adults; TESAOD = Tucson Epidemiological Study of Airway Obstructive Disease; UK = United Kingdom. In the ARIC (Atherosclerosis Risk in Communities) cohort, both smokers and nonsmokers with any chronic respiratory symptom but prebronchodilator FEV1 in the normal range had an increased risk of mortality (hazard ratio [HR], 1.5) (23), although whether this related to the subsequent development of COPD in some of these subjects is unknown. Among another Norwegian cohort of men aged 40–59, subjects at GOLD stage 0 had an increased risk of death (HR, 1.35) (24). The CARDIA (Coronary Artery Risk Development in Young Adults) study reported that any respiratory symptom, including cough or phlegm, episodes of bronchitis, wheeze, shortness of breath, and chest illness, was associated with a 2.71-ml/yr excess decline in FEV1 (P < 0.001), a 2.18-ml/yr excess decline in FVC (P < 0.001), and a 1.63 odds ratio (OR) for development of incident obstruction (18). Cough-related symptoms specifically were associated with a 1.56 OR for development of visually assessed emphysema on Year 25 CT scans. Other studies have examined chronic bronchitis symptoms more specifically. In the Copenhagen City Heart study, chronic bronchitis symptoms were associated with an excess loss of 19 ml/yr, with a stronger association noted in men (25). However, although 20.5% of smokers with chronic bronchitis at baseline had developed COPD at 15 years, 18.5% of smokers without symptoms at baseline had also developed COPD. Furthermore, smokers without symptoms represented the majority of individuals who developed COPD (8). The ECRHS (European Community Respiratory Health Survey) cross-sectional study of over 18,000 adults aged 20–44 years in 16 countries (26) demonstrated the prevalence of chronic cough and phlegm to be 11.8% (27). Compared with those without respiratory symptoms, symptomatic subjects were more likely to be current smokers, report respiratory infections before the age of 5 years, and report the presence of occupational exposures to vapors, dust, or fumes. Longitudinal follow-up of this cohort identified chronic cough and phlegm as an independent predictor of incident COPD (incident rate ratio, 1.85). Probably because of its multidimensionality and the variety of its causes, dyspnea alone was not associated with incident disease (incident rate ratio, 0.98), even after adjusting for smoking habits. The MRC National Survey of Health and Development was a prospective cohort of over 5,000 individuals within the United Kingdom (19). Chronic bronchitis symptoms at the ages of 36 and 43 years were associated with subsequent risk for incident airflow obstruction, with ORs of 3.70 and 4.11, respectively. Among smokers, symptoms before age 36 were not associated with incident airflow limitation. However, among nonsmokers, symptoms at most ages were associated with incident airflow limitation by ages of 60–64 years. The longer individuals had symptoms, the greater the rate of FEV1 decline. Reporting of chronic bronchitis on at least one occasion between 43 and 60–64 was associated with an additional 4.5-ml/yr decline in FEV1. TESAOD (Tucson Epidemiological Study of Airway Obstructive Disease) examined over 1,400 participants aged 21–80 in the southwestern United States. Among adults <50 years of age with over 24 years of follow-up, 42% of those with chronic bronchitis developed airflow obstruction, versus 23% of those without chronic bronchitis (20). The presence of chronic bronchitis was also associated with increased mortality (HR, 1.31) among subjects less than 50 years of age but not among subjects 50 years of age or older. Taken together, these studies provide compelling evidence for a relationship between chronic cough and phlegm, in particular, and the subsequent development of airflow limitation. However, there is only a subset of individuals who experience disease progression, and this subset does not even include the majority (8, 25). Some of the variability in the data with respect to respiratory symptoms, particularly dyspnea alone, may relate to greater variation in their etiology from comorbid conditions such as cardiac disease and obesity. The contribution and potential confounding effect of such factors as comorbidities to the relationship between respiratory symptoms and the development of COPD has not been fully addressed by most studies to date. The measurement of lung function as a tool to determine the presence or absence of respiratory health has been central to diagnosis, prognosis, and response to interventions in the field of COPD. Recent evidence from cohorts of children followed over time with sequential spirometry show that those who belong to the lower quartiles of predicted FEV1, even if the values are still within the normal range for their age, are more likely to meet spirometric criteria for a diagnosis of COPD during early adulthood (28, 29). In the Lovelace prospective study of ever-smokers, low-normal FEV1 without obstruction at baseline combined with “rapid” decline as defined by a loss of FEV1 greater than 40 ml/yr (normal rate of loss after the third decade of life is <25 ml/yr) over 18 months was associated with a 36-fold risk of developing COPD over the time of observation, as compared with those with high baseline lung function without rapid decline (30). The single-breath DlCO test is another measurement that identifies individuals at increased risk for COPD. In one small New York City study, follow-up of active smokers over 45 months found that among those with normal spirometric findings/normal DlCO, 3% developed GOLD-defined COPD, whereas in those with normal spirometric findings/low DlCO, the incidence was 22% (31). These studies support the use of lung function as a useful, practical tool to identify subjects at risk for incident COPD development (Table 2). Other physiologic measures besides FEV1/FVC that may also prove helpful in this regard include the forced oscillation technique, the multiple-breath nitrogen washout, and new spirometry-derived indices (32–34). Association between Lung Function and Incident COPD in Smokers without Airflow Limitation Definition of abbreviations: COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; mMRC = modified Medical Research Council; SGRQ = St. George’s Respiratory Questionnaire. Imaging is another way to identify patients with pathology who may be at risk for developing spirometrically defined airflow obstruction (Table 3). Although not currently the standard of for COPD, CT is widely available in many countries and is in lung of CT cohort studies provides a of abnormalities and their relationship to disease Association between Imaging and among Individuals at GOLD Stage 0 Definition of abbreviations: CanCOLD = Canadian Cohort Obstructive Lung Disease; CI = confidence interval; COPD = chronic obstructive pulmonary disease; COPDGene = Epidemiology of CT = computed tomography; = = of COPD to GOLD = Global Initiative for Chronic Obstructive Lung Disease; HR = hazard ratio; = = Study of = Lung OR = odds ratio; = = pulmonary function = the of the wall of a airway with a of = response SPIROMICS = and Intermediate Outcome Measures in COPD is identified on CT either on the basis of the of lung with and have both been as or by the that the lung value the lower the the lower the of lung for an individual Although small studies to a relationship between emphysema as demonstrated by emphysema and FEV1 decline among unobstructed individuals results from studies are more In the trial Lung a population-based CT for in smokers without baseline airflow obstruction who developed spirometrically defined obstruction at follow-up had significantly lower at baseline < with emphysema also had greater loss in lung function at follow-up than those with emphysema independent of extent of emphysema Individuals with a lower at baseline had an OR of (P < for the development of airflow obstruction. In a study CT visually emphysema was also associated with incident airflow obstruction (HR, In the Study of Lung Study population of subjects had an lung the limit of normal In adjusted the lung greater than the limit of normal was associated with an increased odds of incident airflow limitation with similar results seen the lung as a or a fixed threshold of The and also be CT and may also provide COPD. In of airway wall was also significantly from associated with development of airflow obstruction greater with an OR of (P < In a greater was associated with a FEV1 decline (P = and incident COPD < at follow-up was also associated with a risk of hospitalization or mortality related to chronic lower respiratory disease. The small with an are believed to a at the early stages of disease progression, in which pathologic abnormalities may before the development of spirometrically airflow obstruction response data from and to emphysema from gas trapping, to be a abnormality studies in lung with disease have confirmed significant abnormalities in these in a range of abnormalities were seen among at-risk current and smokers and was associated with subsequent excess FEV1 decline. Individuals within the of demonstrated an FEV1 decline of ml/yr as compared with those in the who demonstrated a decline of CT that over time, with among at-risk smokers to with emphysema abnormalities with in to COPD suggesting to early emphysema, with impaired gas in an of the and SPIROMICS cohort the ratio the of at standard by the of lung was associated with COPD and COPD suggesting that lung development early in life conditions the risk of developing COPD and to In abnormalities, airway wall and emphysema may all be helpful in identifying patients at increased risk for disease to COPD, but the and for thresholds of CT abnormalities in have not been in CT as as and likely also to in study findings and the of clinical The of to airflow limitation is Some individuals have lung function in the normal range in early adulthood but decline more whereas whether because of early life never lung function and develop COPD normal rates of lung function decline are also individuals who may have lung function but significant lung damage and still have normal spirometric findings at the age of because of their high Furthermore, although we have that most patients from normal spirometric results to GOLD stages 1 and data from COPDGene that some patients with defined as Spirometry an FEV1/FVC and predicted < also to defined GOLD COPD In among subjects with at to normal spirometric whereas progressed to GOLD stages at the Year 5 with at baseline also had rates of mortality than those with normal spirometric although these rates were lower than that those of participants at GOLD stages It has been by COPDGene that those who the may have more disease and that those who from normal spirometric results have more of an disease, although these are In the study, of subjects to normal spirometric whereas developed airflow obstruction after years in of is highlighted by a recent of COPDGene data on CT at baseline and at 5 years. identified of disease progression, one in which of subjects developed abnormalities and emphysema before developing abnormalities and one in which of the cohort demonstrated a with abnormalities these data to airway wall excess mucin production, and symptoms of chronic bronchitis to relate to COPD development but not identify the majority of those who one be to symptoms, lung and CT to to stage with respect to risk for COPD recent from the COPDGene group this and a new proposed for COPD to this individuals be a of symptoms, spirometric and CT features as and COPD. It be noted that this both some individuals without spirometrically defined obstruction as having or COPD others with spirometrically defined obstruction COPD. At this the clinical of patients in this is unknown. prospective data will be to disease evolution from these as as response to therapies. It is clear that some with risk factors for COPD experience respiratory but have an FEV1/FVC ratio in the normal COPD, this population is as is their risk of developing airflow limitation. Yet, we the “pre-COPD” be to identify individuals in whom spirometry is to airflow limitation but in whom the disease is likely to in airflow obstruction without the studies such individuals are likely to demonstrate respiratory symptoms, including cough with sputum physiologic abnormalities, including low-normal FEV1, DlCO, FEV1 radiographic abnormalities, including airway abnormalities and the GOLD stage 0 concept that identified at-risk individuals on the basis of symptoms alone, we be to identify a majority of individuals who will develop COPD. In particular, patients with chronic cough and phlegm as having a clear of for these symptoms are the most associated with to COPD, an has been identified increased mucin production) and this abnormalities airway wall thickening on the has been rather to identify these However, to and the clinical importance of this we propose to to the classification proposed by the MRC over years and these individuals as having chronic This group is of for the purposes of risk and that be developed and even if spirometrically defined obstruction never (14). it is clear that patients with only a subset of those at risk for disease also there may be other of individuals, to be who may or may not develop airflow obstruction but clinically relevant because of significant symptoms, exacerbations, or increased that the of the concept of provide greater within the medical community and of the that by the time spirometrically defined obstruction significant airway damage has already occurred 1). that a for is and and but evidence does not of the However, we that to a population include disease status on a of individuals who current are not to have a respiratory disease diagnosis, who may never and for whom there is no treatment from However, risk is the current for other conditions with predisease such as and of such individuals also of of the among symptoms, and function with respect to pre-COPD. COPD = chronic obstructive pulmonary disease; CT = computed In about COPD we that airway abnormalities without spirometrically identified abnormalities and that this be In the proposed that disease be defined by including clinical of of and in about versus COPD, symptoms, abnormalities, and are with the in this is defined by the presence or absence of spirometrically defined airflow obstruction. The at is developing a of clinically thresholds to identify at risk of developing fully spirometric COPD. Here, we the GOLD stage 0 that on symptoms of the with GOLD stage 0 is that it only identified a of individuals who progressed to COPD. in a range of physiologic and radiographic abnormalities, we have the potential to identify the majority of individuals who will we that at the time, is to fully from a clinical currently have data on the or for any individual or of to identify those Furthermore, as highlighted by the recent perspective by Martinez and colleagues on the pathogenesis of early COPD, it is also likely that age and the among symptoms, CT abnormalities, and lung function which fully be additional data are in individuals also have significantly data on COPD that among we also that even among patients who meet spirometric criteria for COPD, studies for to such individuals, most health not have robust or measures in to identify these more on of such will be to to disease. The a of physiologic and current of COPD on the FEV1/FVC ratio is for the disease we COPD, but as the data we show it is not sensitive to the of abnormalities we may in the disease only are such patients at increased risk for disease progression, in some such patients also experience significant in the absence of a reduced FEV1/FVC we propose that the be to to individuals in whom spirometry is to airflow obstruction but who are at risk of developing COPD with a reduced FEV1/FVC of is symptoms in this population with are associated with of whether individuals with develop spirometrically defined obstruction. are of recognition by such as the and and European particularly data to support a pathologic that more data on disease in individuals are to develop and a clinically of that has and and that be clinically with by NIH and all to the and of this in as on are available with the of this

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