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(Chest. 2006;130:318-325.)
© 2006 American College of Chest Physicians

Can Global Initiative for Chronic Obstructive Lung Disease Stage 0 Provide Prognostic Information on Long-term Mortality in Men?

Knut Stavem, MD, MPH, PhD; Leiv Sandvik, PhD and Jan Erikssen, MD, PhD

* From the Medical Department (Dr. Erikssen), and Helse Ost Health Services Research Centre (Dr. Stavem), Akershus University Hospital, Lørenskog; and Centre for Clinical Research (Dr. Sandvik), Ullevaal University Hospital, Oslo, Norway.

Correspondence to: Knut Stavem, MD, MPH, PhD, Medical Department, Akershus University Hospital, NO-1478 Lørenskog, Norway; e-mail: knut.stavem{at}klinmed.uio.no

Abstract

Study objectives: To determine if the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 (subjects at risk for COPD) provides information about long-term mortality risk.

Design, setting, and participants: From 1972 to 1975, clinical, physiologic, and biochemical parameters including respiratory symptoms, spirometry, and physical fitness were measured in 1,999 healthy men aged 40 to 59 years in an occupational cohort, of whom 1,623 had acceptable spirometry findings. In a proportional hazards model with follow-up until 2000, we assessed all-cause mortality according to GOLD stage 0, I, II, and III compared with "normal" subjects, after adjusting for known risk factors and potential confounders.

Results: After 26 years (range, 25 to 27 years), 615 men (38%) had died. In multivariate proportional hazards models, GOLD stage 0 subjects had a nonsignificantly increased hazard of death (hazard ratio [HR], 1.19; p = 0.21) after adjustment for age, smoking, physical fitness, body mass index, systolic BP, and serum cholesterol. Similarly, subjects in GOLD stage I (HR, 1.30; p = 0.05) and stage II (HR, 1.77; p < 0.0001) had increased all-cause mortality. When expanding GOLD stage 0 to comprise patients with any respiratory symptom in a sensitivity analysis, the HR for all-cause mortality increased (HR, 1.35; p = 0.03).

Conclusion: There probably is an excess mortality among GOLD stage 0 subjects compared to symptom-free subjects; however, this should be interpreted cautiously and the results vary with the definition of the GOLD stage 0. Subjects in GOLD stage I or stage II had higher mortality than symptom-free subjects.

Key Words: COPD • epidemiology • prognosis • respiratory symptoms • risk factors

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has introduced a new staging system for COPD severity from mild (stage I) to very severe (stage IV).1 The GOLD guidelines introduced a new entity of subjects "at risk" for COPD (stage 0), characterized by having normal spirometry findings (FEV1/FVC ≥ 70%) but with chronic symptoms of cough or sputum production. This approach is pragmatic and meant to be an educational tool to support patient management. The FEV1 cut points are used for purposes of simplicity and have not been clinically validated. The GOLD guidelines recommend future research on evaluation of the clinical utility of the five-stage classification of severity used in the GOLD report.12

Previous studies have shown that reduced lung function345678910111213141516 and breathlessness391718192021 are strong and independent predictors of mortality. Less is known about the prognostic information conveyed in symptoms of cough and sputum production, as included in the GOLD stage 0 definition, although many earlier studies have investigated the predictive capacity of cough and phlegm, typically defined using questions from the British Medical Research Council (MRC) questionnaire.22 Cough/phlegm or mucus hypersecretion predict mortality in general populations and occupational cohorts after adjustment for age and smoking. However, this association frequently disappears when also adjusting for lung function.9 Only a few studies423 have shown that symptoms of cough/phlegm predict all-cause mortality after adjusting for lung function.

Little information is available whether a mixed classification system based on both respiratory symptoms and spirometry, as the GOLD staging system provides useful prognostic information. A previous study24 of a general population sample, assessing if subjects with respiratory symptoms classified as stage 0 would have subsequent airways obstruction, concluded that GOLD stage 0 was not constant over time and did not identify subsequent airways obstruction. In a cohort of 5,542 subjects in whom pulmonary function had been determined, there was a gradient of hazard ratios (HRs) for death across the strata of pulmonary disease, symptoms only (including cough, sputum or wheeze), and COPD severity level.25 However, this analysis was not adjusted for traditional cardiovascular risk factors such as systolic BP and serum cholesterol. In a well-defined cohort of apparently healthy men 40 to 60 years of age with follow-up over 26 years,26 we assessed whether subjects in the new GOLD stage 0 class had a different long-term mortality than subjects in GOLD stages I, II, and III after adjustment for traditional cardiovascular risk factors and potential confounders, including an objective measure of physical fitness.

Materials and Methods

In 1972, all healthy man aged 40 to 59 years from five companies in Oslo, Norway were invited to a cardiovascular screening survey (n = 2,341), and 2,014 men (86%) consented to participate. The companies included Siemens AS (Oslo, Norway), and four organizations from the public sector (Norwegian Postal Services, Norwegian Telecom, Norwegian Customs and Excise, and Norwegian State Railways). The participants had to be free from known or suspected heart disease, drug-treated hypertension, diabetes mellitus, malignancy, advanced pulmonary, renal and liver diseases, and locomotor activity limitation.27 In 1972, no institutional or regional review boards existed in Norway. Hence, a formal institutional review board could not approve the protocol. However, in the planning process, the protocol was circulated to prominent physicians in two hospitals in Oslo, who commented on the protocol in an ad hoc meeting.

Between August 1972 and March 1975, the participants underwent an examination program including assessment of cardiovascular risk factors, spirometry, a symptom-limited exercise test, and fasting blood tests.27 FVC and FEV1 were measured with a calibrated Bernstein spirometer without use of bronchodilator.27 After one trial test, FVC and FEV1 values were recorded from two successive maximum expiratory maneuvers,28 corrected to body temperature and ambient pressure and saturated with water vapor based on daily room temperature measurements and assumption of atmospheric pressure of 760 mm Hg. Originally, only the mean FEV1 and FVC values were recorded. To obtain the maximum of the two tests, in 2001 we retrieved the original spirograms and recorded values for both maneuvers. Among 1,999 patients with original spirometry recordings, 75 of the records (72 consecutively numbered) had disappeared in storage. Thus, 1,924 spirograms were available for review. In further analysis, we included only patients with ≤ 0.3 L difference between the two FVC tests (n = 1,623).2930 Reference values were derived in our total sample using multiple linear regression (n = 1,623):

Formula

Formula
The symptom-limited exercise test was performed on a calibrated electrically braked bicycle (Elema-Schönander; Solna, Sweden). The initial workload was 100 W (600 kilopond meters/min) with increments of 50 W (300 kilopond meters/min) every 6 min, continued until exhaustion unless stopped earlier for safety reasons.27 Physical fitness was defined as total work divided by body weight (in kilojoules per kilogram).

All participants were interviewed with questions from the MRC respiratory questionnaire22 at study start.2831 Productive cough was assessed using four questions about phlegm: (1) Do you usually bring up any phlegm from your chest first thing in the morning in the winter? (2) Do you usually bring up any phlegm from your chest during the day, or at night, in the winter? (accept twice or more); (3) Do you bring up phlegm like this on most days for as much as 3 months each year? (4) In the past 3 years have you had a period of (increased) cough and phlegm lasting for 3 weeks or more? For the purpose of defining GOLD stage 0 in the present study, we used an affirmative answer to item (3) above as indicative of productive cough, in line with a previous study.24

In addition, we used two questions from the MRC dyspnea questionnaire28 to assess breathlessness: (1) Are you troubled by shortness of breath when hurrying on level ground or walking up a slight hill? (2) Do you get short of breath walking with other people of your own age on level ground? We used the questions on breathlessness in combination with the items on phlegm to create an alternative definition of COPD stage 0.

Smoking status was categorized as never-smokers, former smokers, 1 to 10 cigarettes per day, and >10 cigarettes per day using standardized questions.28 Smoking status from follow-up after approximately 8 years was available for 1,423 of the 1,623 individuals (88%). Mortality until December 31, 1999, was obtained from Statistics Norway. Migration was minimal; only two participants were not available in the registry of Statistics Norway at the end of 1999. Underlying causes of death were coded according to the International Classification of Diseases, Eighth Revision and the International Classification of Diseases, Ninth Revision (ICD-9). Cardiovascular mortality consists of ischemic heart disease (ICD-9 codes 410–414), cerebrovascular disease (430–438), other cardiovascular disease (401–404, 420–429, 440–448), and sudden death (798.1). Sudden death was defined as unexpected or unwitnessed death within 24 h of being seen alive and well or, if witnessed, within 1 h of symptom onset. Respiratory mortality consists of lung cancer (ICD-9 code 162), pneumonia (480–487), obstructive lung disease (490–496), and other respiratory diseases (137,163).

Staging was done according to GOLD based on spirometry and responses to the MRC questionnaire: stage 0 (FEV1/FVC ≥ 70%; cough or sputum production), operationalized by the response to item (3) of the MRC questionnaire above; stage I (FEV1/FVC < 70%; FEV1 ≥ 80% of predicted); stage II (FEV1/FVC < 70%; FEV1 ≥ 50 to < 80% of predicted); stage III (FEV1/FVC < 70%; FEV1 ≥ 30 to < 50% of predicted); stage IV (FEV1/FVC < 70%; FEV1 < 30% of predicted), and "normal" (FEV1/FVC ≥ 70%; no cough or sputum production).

Four subjects corresponded to GOLD stage IV and were excluded from further analysis. For each GOLD stage, we estimated risk ratios (RRs) for death compared with the normal group, adjusted across strata for age (above/below the median) and smoking status (current vs previous/never-smoker) using the Mantel-Haenszel method. Cox proportional hazards regression models32 were used to assess the association of GOLD stage with mortality after adjustment for well-known risk factors: relative FEV1, age, serum cholesterol, systolic BP, smoking habits, physical fitness, and body mass index (BMI). Smoking status was included in the Cox model as a time-dependent covariate, assuming that changes in smoking status appeared at the midpoint of time between the two assessments. We assumed unchanged smoking status for participants without follow-up data.

In a sensitivity analysis, we assessed the impact on the HRs of the following: (1) removing individuals with FEV1/FVC ≥ 0.7 and FEV1<80% of predicted or FVC < 70% of predicted from the normal reference category; (2) including all subjects with FEV1/FVC ≥ 0.7 and any of the respiratory symptoms (any breathlessness, any phlegm, or recent increased cough and phlegm); and (3) limiting the analysis to baseline smokers and ex-smokers because the GOLD guidelines definition on diagnosing COPD specifically refers to a history of exposure to risk factors, especially cigarette smoking. COPD might be a different entity in smokers and never-smokers. In these analyses, we repeated the multivariable Cox regression analysis using the same covariates and method as described above.

The proportional hazards assumption for the Cox models was checked graphically and with a test for proportional hazard.33 Mortality curves were created plotting a Cox model, adjusted to the mean population age of 50 years. A 5% significance level was chosen using two-tailed tests.

Results

Acceptable spirometric recordings according to our criteria were available in 1,623 of the 2,014 apparently healthy men, 84% of the 1,924 spirograms reviewed. The sample mean (SD) age was 49.8 ± 5.5 years, mean unadjusted FEV1 was 3.50 ± 0.75 L, and 43.4% were current smokers (Table 1 ). Advanced GOLD stages were associated with high rates of current smoking (Table 1). At the follow-up examination after on average 8 years (n = 1,423, 88% of the cohort), 6% of never-smokers had started smoking (21 of 356 never-smokers), 10% of ex-smokers had started smoking again (47 of 484 ex-smokers), and 32% of the baseline smokers reported that they had quit smoking (185 of 583 baseline smokers).


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  		Table 1. Baseline Characteristics of 1,619 Subjects Included in the Analysis*

 
After an average of 26 years of follow-up (range, 25 to 27 years; 42,262 total man-years), 615 men (38%) had died, of whom 308 men (50%) died from cardiovascular diseases and 96 men (16%) from respiratory diseases. The principal causes of death were: ischemic heart disease (n = 151; 9.3%), sudden death (n = 85; 5.2%), cerebrovascular disease (n = 42; 2.6%), other cardiovascular (n = 30; 1.9%), lung cancer (n = 42; 2.6%), pneumonia (n = 32; 2.0%), obstructive lung disease (n = 20; 1.2%), other respiratory (n = 2; 0.1%), GI cancer (n = 64; 3.9%), other cancer (n = 66; 4.1%), miscellaneous (n = 64; 3.9%), and unknown (n = 17; 1.1%).

Age and smoking-adjusted mortality rate ratios according to GOLD stage are shown in Table 2 . A survival curve according to GOLD stage after adjusting only for age shows that survival of individuals in GOLD stage 0 lies between stages I and II, whereas the symptom-free (normal) clearly has the highest survival rate (Fig 1 ).


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  		Table 2. Adjusted RRs for All-Cause Mortality According to GOLD Stage in 1,619 Subjects With 611 Deaths

 

Figure 1
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  		Figure 1. Cumulative age-adjusted mortality according to GOLD stages 0 to II or normal.

 
In Cox regression models, after adjusting for age, smoking habits, systolic BP, BMI, cholesterol, and physical fitness, there was a gradient of hazard rates for all-cause mortality across the GOLD stages, with increased mortality risk with the more advanced stages (Table 2). Subjects in stage 0 had a HR of 1.19 (95% confidence interval [CI], 0.91 to 1.57; p = 0.21) that was not significantly different from the symptom-free subjects, while subjects in stage I and stage II had higher all-cause mortality (Table 2). When removing physical fitness from the multivariate model, the HR for GOLD stage 0 was 1.25 (95% CI, 0.95 to 1.64; p = 0.12) [n = 1,619].

When repeating the analysis in a larger sample, also including 322 subjects with > 0.3 L between two measurements of FVC (n = 1,995), the HR for GOLD stage 0 was 1.23 (95% CI, 0.95 to 1.58; p = 0.12) compared with the symptom-free subjects in multivariate analysis after adjusting for the same variables as above including physical fitness. Finally, when removing physical fitness from this model, the HR for GOLD stage 0 was 1.26 (95% CI, 0.98 to 1.63; p = 0.07).

When we excluded individuals with FEV1/FVC ≥ 0.7 and reduced FEV1 (< 80% of predicted) or reduced FVC (< 70% of predicted) [n = 71] from the normal group, the HRs were essentially unchanged from our initial analysis (Table 3 ). Transfer of normal subjects with any respiratory symptom (n = 225) to the initial GOLD stage 0 COPD group caused an increase in all the HRs, and all became statistically significant (Table 3). Among the 225 subjects who changed group (n = 172 with any phlegm, n = 53 with any breathlessness), there were 106 deaths, of which 47% were cardiovascular and 15% were pulmonary, compared with 46% and 24%, respectively, in the GOLD stage 0 group as defined in the initial analysis (n = 131). Finally, excluding never-smokers (n = 398) from the analysis caused little change from the initial analysis (Table 3).


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  		Table 3. Adjusted HRs for All-Cause Mortality for Each GOLD Stage According to Variations in Populations and Operationalization of GOLD Stage 0 by Multivariable Cox Regression Analysis*

 
Discussion

In this study of working apparently healthy, middle-aged men, multivariate models show that GOLD stage 0 represents subjects with a better long-term prognosis than subjects in stages I, II, and III, with no significant excess long-term mortality than those without cough or phlegm. The relative prognosis between the stages depends on the number of covariates in the models. The novelty of this article is that the outcome is mortality, rather than a proxy such as transfer from GOLD stage 0 to another GOLD stage, ie, subsequent airways obstruction.24 The present study also differs from studies assessing the mortality impact of respiratory symptoms because the current GOLD classification is a hybrid classification based on FEV1/FVC, FEV1, and symptoms of cough/sputum production. Another characteristic of the present study is the adjustment for physical fitness that is rarely done in similar studies.

When widening the operationalization of GOLD stage 0 to include other respiratory symptoms than those typical for chronic bronchitis, such as breathlessness, subjects in GOLD stage 0 had significantly higher mortality than in the remaining normal referent group. This is important and gives support to having more respiratory symptoms in GOLD stage 0 than purely those of chronic bronchitis. This also is in line with previous studies202134 reporting an association between dyspnea and mortality.

There are few previous studies in occupational cohorts, general populations, or COPD populations with which we can compare our findings. A similar general population study25 used a modification of the GOLD staging system, however, with a group with "symptoms only" (presence of respiratory symptoms in the absence of any lung function abnormality) comprising individuals with cough, phlegm, or wheeze. The study25 also reported no excess mortality in the symptoms-only group, with a HR of 1.1 (95% CI, 0.8 to 1.5) in multivariate analysis, as for GOLD 0 in the present study. However, that study did not adjust for systolic BP, serum cholesterol, or physical fitness,25 in contrast to the present study.

Another recent study35 reported that symptoms fulfilling the definitions of chronic bronchitis were associated with an increased mortality risk in smoking individuals with mild-to-moderate COPD (stage I and stage II), in line with the findings in the present study. Moreover, they35 reported an increased mortality risk among male smokers with normal pulmonary function (GOLD stage 0) in contrast to the findings in the present study, which might be explained by some of the methodologic differences between the studies. The Swedish study35 was a general population study with a larger sample than the present study, performed analyses separately for men and women, and presented separate analyses according to baseline smoking status; however, they only adjusted for age, inhalation habits, and baseline tobacco consumption. In contrast, the present study was based on an occupational cohort, included only men, also adjusted for well-known cardiovascular risk factors including an estimate of physical fitness, and included follow-up data on smoking status after approximately 8 years in the analysis. There were also slight differences in the composition of the reference groups used.

The prevalence of GOLD stage 0 in our population ranged from 8.5 to 10.0% for three of the scenarios and was 22.0% when using the widest range of respiratory symptoms to define the GOLD stage 0. This compares with a reported prevalence of GOLD stage 0 of 2 to 13% in other studies,242535 depending on the selection criteria as shown in the present study.

Some earlier studies have shown an association between respiratory symptoms and death from respiratory causes, lung cancer, or other cancer in most9363738 but not all.18 An association with respiratory death could explain some of the reported excess mortality. Phlegm, which is one of the symptoms qualifying for the GOLD stage 0, is a known predictor of mortality among workers in the Paris area23 and in a general population study in Crakow, Poland4 after adjustment for lung function. Various mechanisms for the association between phlegm production and mortality have been suggested, such as through recurrent lower respiratory tract infection and COPD, although this hypothesis has not yet been confirmed.39404142

The present study adjusted for an objective measure of physical fitness, and it should be noted that none of the above studies have adjusted for an objective measure of physical fitness, known to be associated with various coronary risk factors43 and reduced mortality.444546 That the more advanced GOLD stages predicted all-cause mortality was no surprise, as the definition of these groups are based on the FEV1, a well-known predictor of mortality.345678910111213141516

The major limitation of this study is the limited number of individuals in GOLD stage 0 reducing the power of the study. Additionally, the reliability of the questionnaire was not assessed in this study; however, the questions in the original MRC questionnaire have been subjected to extensive assessments and the repeatability is reported to be approximately 80%.31 Our cohort consisted of only men and was an occupational cohort that might experience favorable survival rates compared with a general population sample because of a possible healthy worker effect, and would be different from a general population cohort or subjects with COPD. In addition, the smoking prevalence in Norway has been reduced since the 1970s. We also lacked specific data on occupational exposures (although this would be very heterogeneous) and moreover lacked information about socioeconomic status known to be associated with smoking, lung function, and mortality.474849 These issues could limit the generalizability of our findings. The limited sample size also precluded further analysis on subgroups of the populations, such as according to baseline smoking status.

In this study, we adjusted for smoking using four strata, although we also adjusted our analysis for reported changes in smoking history after 8 years of observation. Some respiratory symptoms, such as productive cough, are closely associated with smoking and there might be a possibility of residual confounding. There is no consensus on how to model different aspects of smoking history, including definitions of current and ex-smokers and how to accommodate the duration and intensity of smoking in statistical models.50 Moreover, it is difficult to separate the effects of age at initiation, duration of smoking, and time since cessation among ex-smokers because of problems with multicolinearity.50

The approach to COPD is greatly facilitated by a staging system that would allow standardized categorization of the heterogeneous populations of patients. Such a staging system is useful for epidemiologic and clinical studies, health resource planning, prognostication, and application of clinical recommendations.51 However, the current GOLD stage 0 does not predict development of bronchial obstruction24 and does not imply a different level of health status than stages I to III (current classification).52 The findings in the present study indicate a higher long-term mortality in GOLD stage 0 than among symptom-free subjects with normal spirometry findings, although this clearly depends on which symptoms are included in the definition of COPD stage 0. Whether this additional mortality risk is significant we think is a matter of sample size.

In conclusion, the present study suggests that the GOLD stage 0 probably provides prognostic information with respect to long-term mortality when using symptoms compatible with chronic bronchitis to define GOLD stage 0, although the HR for death was not significantly higher than for symptom-free subjects in this cohort, in which approximately 8% of the population was classified as stage 0. Inclusions of a wider range of respiratory symptoms such as breathlessness or productive cough increased the predictive capacity and hence the validity and usefulness of the entity GOLD stage 0. However, our sample size was limited, and the results should be interpreted cautiously and should be confirmed in larger samples.

Footnotes

Abbreviations: BMI = body mass index; CI = confidence interval; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HR = hazard ratio; ICD-9 = International Classification of Disease, Ninth Revision; MRC = Medical Research Council; RR = risk ratio

All authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication August 16, 2005. Accepted for publication March 10, 2006.

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