To identify relevant studies, two investigators (JO and HF) independently searched the Embase, Web of Science, and PubMed databases for studies published from inception to 1 March 2023 with no language restrictions. The search terms and related variants used included “GOLD 1”, “GOLD I”, “GOLD”, “mild COPD”, “mild airflow obstruction”, “mild airflow limitation”, “COPD”, and “mortality”. Further details of the search strategy are shown in Supplement. The terms were chosen by two investigators (JO and HF) and by checking keywords in other articles and reviews on similar topics. References from other related articles and the selected articles were manually reviewed to identify potential studies of interest.

Two investigators (JO and HF) independently reviewed all potentially relevant articles. Disagreements or uncertainties were resolved by a third investigator (FW). The initial investigation included reviews of article titles and abstracts. Articles were mainly excluded because they did not include COPD and mortality. The secondary investigation included a full-text review and selection of articles based on the inclusion and exclusion criteria. The studies included in this systematic review and meta-analysis met the following inclusion criteria: (1) data were available to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality, respiratory-related mortality, cardiovascular disease-related mortality, or cancer-related mortality associated with individuals with mild COPD compared with those with normal spirometry; (2) the studies were independent, and studies with the same data set as published studies were not considered independent; and (3) they were cohort studies. We considered that studies were eligible if they were cohort studies that enrolled adults and reported an association between mild COPD and all-cause mortality. Mild COPD was defined as a pre-bronchodilator FEV1/FVC <0.70 and FEV1 ≥80% of the predicted value.1 Other accepted definitions of mild COPD included a post-bronchodilator FEV1/FVC <0.70 and FEV1 ≥80% of the predicted value. The definitions of normal spirometry included pre-bronchodilator or post-bronchodilator FEV1/FVC ≥0.70 and FEV1 ≥80% of the predicted value. When two studies referred to the same population in the same period and showed overlapping data,19,23 we chose to include articles containing our primary outcome that compared all-cause mortality in patients with mild COPD with that in participants with normal spirometry.19

Two investigators (JO and HF) independently evaluated the quality of all identified studies and extracted and entered the data. These authors then independently verified the quality of the identified studies and the validity of the extracted data. Any disagreements were settled by a third investigator (FW). The following extracted data were recorded: first author, year of publication, location, characteristics of the subjects (sample size, age, diagnostic criteria of mild COPD, and definition of normal spirometry), study design type, and follow-up time.

Two investigators (JO and HF) used the Newcastle–Ottawa quality assessment scale for the quality assessment of cohort studies. In this scale, a study is judged based on selection (four items, one star each), comparability (one item, up to two stars), and exposure/outcome (three items, three stars each).24 The quality of the studies was graded as poor (<4 points), fair (4–6 points), and good (≥7 points).

The primary outcome of this systematic review and meta-analysis was all-cause mortality in patients with mild COPD compared with individuals with normal spirometry. Cardiovascular disease-related mortality, cancer-related mortality, and respiratory disease-related mortality were examined as secondary outcomes. The random-effects model was used to calculate the pooled effect sizes and 95% CI because the studies were conducted over a wide range of settings in different populations. Specific subgroups (sex, different smoking statuses, follow-up time, and different definitions of mild COPD) were examined. We used data on the adjusted outcome in every included study. The I2 statistic was used to evaluate the heterogeneity of the studies. An I2 value of 0%–24% was considered as having no heterogeneity. Greater I2 values represented greater heterogeneity, where I2 values of 25%–49% represented low heterogeneity, 50%–74% represented moderate heterogeneity, and ≥75% represented high heterogeneity.25 The publication bias was evaluated using a funnel plot, Begg's test, and Egger's test.26 All statistical tests were two-sided, and a P value of <0.05 was considered statistically significant. Stata/SE 15.1 (Statacorp LP, College Station, TX, USA) software was used for the meta-analysis.

Fig. 1 shows a flow chart of the literature screening, including the key words used in the search strategies, the number of articles identified in the databases, the number of excluded studies, and the reason for exclusion. Of 5,242 abstracts identified during the search, 105 were selected for full-text review and 5,137 were excluded because the topic of this review was not evaluated. After reading the full text, an additional 93 articles were excluded for the following reasons: no mention of mild COPD and mortality, no comparison of mortality in patients with mild COPD versus that in normal subjects, duplicate publications, no cohort study, no independent study, and subjects were in a specific group. Finally, 12 studies were included in the qualitative synthesis (meta-analysis).13-22,27,28

Fig. 1.

Preferred reporting items for systematic reviews and meta-analyses flow diagram of systematic search and selection.

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The characteristics of the included studies are shown in Table 1. In total, 9,973 participants with mild COPD and 255,527 participants with normal spirometry were included in the 12 studies.13-22,27,28 All data included in our study were adjusted for confounding factors, such as age and body mass index. The average follow-up time of seven studies was ≥10 years,13-15,18-20,27 and the average follow-up time of five studies was <10 years.16,17,21,22,28 Nine studies used pre-bronchodilator FEV1/FVC <0.70 and FEV1 ≥80% predicted as the main definition of mild COPD.13-16,18,20-22,27 Two studies used a post-bronchodilator FEV1/FVC <0.70 and FEV1 ≥80% predicted as the main definition of mild COPD.17,28 One study used both of these definitions for mild COPD.19 All studies were published between 2003 and 2022. The methodological quality of the included studies was satisfactory, with Newcastle-Ottawa Scale 9-point quality assessment scores between 7 and 9. All studies were graded as good quality. The details of the quality assessment are shown in eTable 1 in the Supplementary material.

Fig. 2 shows the pooled results for all-cause mortality. Eleven studies examined the association between mild COPD and all-cause mortality.13-22,27 Patients with mild COPD had a higher risk of all-cause mortality than individuals with normal spirometry (pre-bronchodilator: HR = 1.21, 95% CI: 1.11–1.32; post-bronchodilator: HR = 1.19, 95% CI: 1.02–1.39). There was low between-study heterogeneity (pre-bronchodilator: I2 = 47.1%, P = 0.023; post-bronchodilator: I2 = 0.0%, P = 0.365). In jackknife sensitivity analyses, the increased risk of all-cause mortality remained consistent for mild COPD. When the meta-analysis was repeated and one study was omitted each time, the HR and corresponding 95% CI were >1 (Supplementary eFig. 1). Funnel plots showed a symmetrical distribution of the studies and did not show evidence of publication bias (Supplementary eFig. 1). Egger's linear regression (t = −1.13, P = 0.279) showed no obvious publication bias (Supplementary eFig. 1).

Fig. 2.

Forest plot of the risk of all-cause mortality in individuals with GOLD stage I COPD compared with individuals with normal spirometry.

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Fig. 3 shows the pooled results of respiratory disease-related mortality, cardiovascular disease-related mortality, and cancer-related disease mortality. Patients with mild COPD had a higher risk of respiratory disease-related mortality than participants with normal spirometry (HR = 1.71, 95% CI: 1.03–2.82, I2 = 0.0%). However, patients with mild COPD did not have a higher risk of cardiovascular disease-related mortality (HR = 1.22, 95% CI: 0.87–1.71, I2 = 27.1%) or cancer-related mortality (HR = 1.19, 95% CI: 0.93–1.51, I2 = 0.0%).

Fig. 3.

Forest plot of the risk of cardiovascular death, cancer death, and respiratory disease death in individuals with GOLD stage I COPD compared with individuals with normal spirometry.

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Supplementary eTable 2 shows the predefined subgroup analysis of all-cause mortality events for mild COPD. The number of studies in each subgroup was too small to obtain clear research results. The risk of all-cause mortality was higher in patients with mild COPD than in individuals with normal spirometry in current smokers (HR = 1.31, 95% CI: 1.04–1.64, P = 0.021; I² = 62.0%, Tau²=0.0246, P = 0.072) and never smokers (HR = 1.25, 95% CI: 1.08–1.43, P = 0.002; I²=0.0%, Tau²=0.00, P = 0.761). However, the risk of all-cause mortality in patients with mild COPD associated with former smoking was not significant (HR = 0.84, 95% CI: 0.64–1.10, P = 0.205; I² = 15.1%, Tau²=0.0098, P = 0.308). In the follow-up period of ≥10 years, mild COPD was associated with increased mortality (HR = 1.21, 95% CI: 1.10–1.33) and moderate heterogeneity was found (I²=50.8%, Tau²=0.0118, P = 0.022). In the follow-up period of <10 years, mild COPD was not a significant risk factor for all-cause mortality (HR = 1.25, 95% CI: 1.00–1.55; I² = 32.0%, Tau²=0.0158). We also analyzed the HR of all-cause mortality in the two subgroups of male (HR = 1.20, 95% CI: 0.97–1.48, P = 0.094; I² = 75.8%, Tau²=0.0433, P = 0.002) and female sex (HR = 1.17, 95% CI: 0.86–1.57, P = 0.316; I² = 52.4%, Tau²=0.0524, P = 0.078). The subgroup analysis showed no effect of sex on all-cause mortality.

Our study has several limitations. First, GOLD guidelines recommend the use of post-bronchodilator spirometry to diagnose mild COPD, but most of our included studies used pre-bronchodilator spirometry, and the different diagnostic methods of spirometry may have affected the final assessment of the results. However, previous studies have indicated consistent results in the use of pre- and post-bronchodilator spirometry to diagnose COPD.19 The post-bronchodilator and pre-bronchodilator findings obtained in this study are consistent, supporting the robustness of our results. Second, not all of our pre-defined subgroup analyses on the association of mild COPD with the risk of all-cause mortality showed a positive association. The fact that the number of studies in each subgroup was too small to obtain clear results needs to be taken into consideration. Therefore, further studies on mild COPD and all-cause mortality are still required to assess these subgroups in the future. Third, our analysis was based on pooled data (studies) and not individual data. We had no access to individual participants’ data, and potential confounders could not be ruled out.