Association between underdiagnosed and overdiagnosed chronic obstructive pulmonary disease with all-cause mortality

Introduction

Chronic obstructive pulmonary disease (COPD) is caused by abnormalities of the airways and/or alveoli, such as chronic bronchitis or emphysema, leading to chronic respiratory symptoms and characterized by persistent and progressive airflow limitation (1). The global prevalence of COPD in adults aged 40 years and older is 10.3% (2). Given persistent exposure to risk factors and aging population, its prevalence will rise in the future (3). COPD diagnosis is based on risk factor exposure, respiratory symptoms, and airflow obstruction. A study revealed that approximately 70% of global COPD cases remained undetected, while 30–60% of previously diagnosed COPD cases were overdiagnosed, primarily due to limited access to spirometry and insufficient clinical consideration (4). Due to insufficient utilization of spirometry, absence of noticeable respiratory symptoms, and failure to seek medical care, individuals with underdiagnosed COPD may miss the opportunity for early detection, consequently delaying treatment (5,6). And overdiagnosed individuals may inappropriately use respiratory medications because of being misclassified as having COPD (7). Both scenarios contribute to increased respiratory symptom burden and healthcare utilization burden (7-10). Investigating the clinical characteristics and disease prognosis associated with COPD under- and overdiagnosis can provide valuable insights for improving screening and case identification strategies.

There are some researches about clinical characteristics and associated factors of under- and overdiagnosed COPD. The Canadian Longitudinal Study on Aging found that underdiagnosed COPD had higher risk for respiratory symptoms and lower physical performance than participants with normal spirometry and no self-reported COPD (10). Results from the National Health and Nutrition Examination Survey (NHANES) revealed that individuals with underdiagnosed COPD had a higher mortality risk than those without airflow limitation (11). Nevertheless, underdiagnosed COPD exhibited better health status, lower comorbidity burden, and superior lung function compared with correctly diagnosed COPD (11). In the Burden of Obstructive Lung Disease study, 569 of 919 (61.9%) previously diagnosed COPD showed no post-bronchodilator airflow limitation, indicating overdiagnosis. Overdiagnosed COPD was associated with higher smoking percentage, more respiratory symptoms, and increased rates of asthma and cardiovascular disease (7). Another study demonstrated that overdiagnosed COPD participants exhibited better health status and lung function than correctly diagnosed cases, with older age, higher body weight, and pollutant exposure being contributing factors (12).

However, current evidence remains limited regarding comorbidities and long-term survival outcomes in both underdiagnosed and overdiagnosed COPD. This study aims to fill the gap by investigating the associations of COPD underdiagnosis and overdiagnosis with comorbidities, chronic respiratory symptoms, and all-cause mortality. The analysis utilized data from the NHANES study, which is a population-based study with a nationally representative sample. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1334/rc).

Methods

Study design and population

The NHANES study was established and conducted by the Centers for Disease Control and Prevention of the United States to assess the health and nutritional status of the U.S. population (13,14). The NHANES study received approval from the National Centers for Health Statistics Institutional Review Board, with written informed consent obtained from all participants before data collection. To evaluate airflow limitation, this study utilized spirometry data from NHANES III [1988–1994] and the 2007–2012 cycles, as these were the only periods with available spirometry testing in NHANES. This study utilized data from NHANES III and 2007–2012 cycles, including demographics, spirometry, and mortality data, obtained from the website of NHANES study (www.cdc.gov/nchs/nhanes/). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Inclusion criteria for this study were: (I) aged 20 to 79 years old; (II) acceptable spirometry meeting quality control standards; (III) complete demographic data; (IV) smoking status assessment data; (V) complete data on chronic bronchitis and emphysema; (VI) available all-cause mortality assessment data.

Lung function assessment

Since most NHANES participants underwent prebronchodilator spirometry while only a subset completed postbronchodilator lung function testing, this study was conducted using prebronchodilator spirometry data. The spirometry measurements were performed using Ohio 822/827 dry-rolling seal volume spirometers in compliance with the recommended guidelines of American Thoracic Society (15,16). Participants were included if they had: (I) reproducible FEV₁ and FVC measurements with ≥2 acceptable maneuvers in NHANES III; or (II) FEV₁ and FVC quality grade A (exceeding American Thoracic Society data collection criteria) or grade B (meeting American Thoracic Society data collection criteria) in NHANES 2007–2012 (17,18). The study excluded participants whose spirometry failed to the quality criteria.

The predicted FEV₁, the predicted FVC, and lower limit of normal (LLN) of FEV₁/FVC are calculated using race-neutral predicted value calculation formula (19). Airflow limitation was defined as prebronchodilator FEV₁/FVC less than LLN (20,21). Prior COPD diagnosis was defined as physician-confirmed chronic bronchitis and/or emphysema (22,23). Non-COPD was defined as neither airflow limitation nor prior COPD diagnosis. Underdiagnosed COPD was defined as airflow limitation without prior COPD diagnosis. Overdiagnosed COPD was defined as prior COPD diagnosis without airflow limitation. COPD was defined as both airflow limitation and prior COPD diagnosis.

Outcome

The primary outcome was all-cause mortality, with data obtained from the comprehensive death certificate records of the National Death Index maintained by the National Center for Health Statistics. All-cause mortality follow-up data were collected through December 31, 2019. Secondary outcomes included the risks of comorbidities and chronic respiratory symptoms, with data collected concurrently with spirometry measurement. Comorbidities information was ascertained by asking participants whether they had ever received physician-diagnosed comorbid conditions. Chronic respiratory symptoms were assessed through self-reported presence of chronic cough, chronic phlegm, wheezing, or shortness of breath.

Covariate definitions

Demographic and health-related factors, including age, sex, body mass index (BMI), race, smoking status, education, poverty income ratio (PIR), comorbidities, and respiratory symptoms, were collected during NHANES interviews near the time of spirometry testing. Race categories were Mexican American, non-Hispanic white, non-Hispanic black, or other. Education level categories were less than 9th grade, 9–12th grade, and more than 12th grade (24). PIR categories were low income (<1.3), middle income (1.30–3.49), and high income (≥3.50) (25). Smoking status was categorized as: never smokers (<100 cigarettes in lifetime), current smokers (≥100 cigarettes in lifetime and currently smoking), and former smokers (≥100 cigarettes in lifetime but not currently smoking) (26). Comorbidities and chronic respiratory symptoms were physician-diagnosed and self-reported, respectively.

Statistical analysis

Continuous variables were presented as mean ± standard deviation (SD), while categorical variables were presented as number (percentage). Intergroup comparisons were performed using one-way analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables. Post hoc multipleyin we comparisons were performed using Bonferroni correction (equal variance assumed) or Tamhane’s T2 correction (equal variance not assumed) following one-way ANOVA. For post hoc comparisons following chi-square test, the Bonferroni method was applied. The association of COPD underdiagnosis and overdiagnosis with comorbidities, chronic respiratory symptoms, and all-cause mortality risk were analyzed using the non-COPD group as the reference, and no additional post hoc multiple comparisons were conducted. Difference in the presence of comorbidities and chronic respiratory symptoms between groups was assessed using the multivariable logistic regression, adjusting for sex, age, BMI, race, smoking status, and PIR. Survival analysis was performed using Kaplan-Meier survival curves for visualization. Cox proportional hazards regression was used to quantify all-cause mortality risk between groups, adjusting for sex, age, BMI, race, smoking status, PIR, hypertension, diabetes, congestive heart failure, stroke, asthma, and cancer. The Cox proportional hazards regression met the proportional hazards assumption by the Schoenfeld residual test (27). We conducted subgroup analyses to examine differences in all-cause mortality between groups based on age (<40 vs. ≥40 years old), sex (male vs. female), smoking status (never smoker vs. former smoker vs. current smoker), and non-asthma status at baseline. To evaluate the robustness of the results, we used prebronchodilator FEV₁/FVC <0.70 to replace FEV₁/FVC < LLN as spirometry-defined airflow limitation to perform the sensitivity analysis (28). We used complete-case analysis to handle missing data. Two-sided P<0.05 was considered statistically significant. All analyses were performed using SPSS 28.0 and R 4.3.3 software. The writing of the article was improved using generative artificial intelligence (DeepSeek chat).

Results

Baseline characteristics

Among the 50,492 participants included in the NHANES III and 2007–2012 studies, we excluded 25,802 participants without qualified baseline data. Among 24,690 participants with qualified baseline data, 29 participants were excluded due to unavailable mortality follow-up data. Finally, there were 24,661 participants included in this study (Figure 1). According to airflow limitation and prior diagnosis of chronic bronchitis or emphysema, 20,856 (84.6%) participants had non-COPD, 2,338 (9.5%) participants had underdiagnosed COPD, 1,029 (4.2%) participants had overdiagnosed COPD, and 438 (1.8%) participants had COPD (Figure 1).

Figure 1 Study flow chart. BMI, body mass index; COPD, chronic obstructive pulmonary disease; NHANES, National Health and Nutrition Examination Survey.

The baseline characteristics of participants are given in Table 1. Baseline age, BMI, and all prebronchodilator spirometry parameters did not meet the assumption of homogeneity of variances, Tamhane’s T2 correction was applied for multiple comparisons between groups. For baseline sex, race, smoking status, educational level, and PIR, Bonferroni correction was applied for all multiple group comparisons. Participants with underdiagnosed COPD were more likely to be older, male, white non-Hispanic, current smokers, less educated, and tended to have a lower BMI and worse lung function (all P<0.05) compared with non-COPD participants (Table 1). Participants with overdiagnosed COPD were more likely to be older, less male, white non-Hispanic, current smokers, less educated, and tended to have a higher BMI and worse lung function (all P<0.05) than those with non-COPD (Table 1).

Associations of diagnostic group with comorbidities and chronic respiratory symptoms

The associations between diagnostic group with comorbidities and chronic respiratory symptoms were observed in Table S1. Underdiagnosed COPD was associated with higher odds of asthma (adjusted P<0.001) than non-COPD after adjustment for sex, age, BMI, race, smoking status, and PIR (Table S1). Compared with non-COPD participants, participants with overdiagnosed COPD showed significantly increased odds of congestive heart failure, stroke, asthma, cancer, diabetes, and hypertension (all adjusted P<0.05) after adjustment for sex, age, BMI, race, smoking status, and PIR (Table S1).

Compared with non-COPD participants, participants with underdiagnosed COPD exhibited significantly higher rates of chronic cough, chronic phlegm, wheezing, and shortness of breath (all adjusted P<0.05) after adjusting for sex, age, BMI, race, smoking status, and PIR (Table S1). Similarly, participants with overdiagnosed COPD had higher odds of chronic cough, chronic phlegm, wheezing, and shortness of breath (all adjusted P<0.05) than non-COPD participants after adjusting for sex, age, BMI, race, smoking status, and PIR (Table S1).

Association between diagnostic group and all-cause mortality

Figure 2A demonstrates significant differences in all-cause mortality among different diagnostic groups over the follow-up period (log-rank P<0.05). During a median follow-up of 308 months, non-COPD participants had 4,262 (20.4%) deaths, participants with underdiagnosed COPD had 779 (33.3%) deaths, participants with overdiagnosed COPD had 320 (31.1%) deaths, and COPD participants had 261 (59.6%) deaths (Table 2). Underdiagnosed COPD individuals [unadjusted hazard ratio (HR) =1.91, 95% confidence interval (CI): 1.77–2.06, unadjusted P<0.001] and overdiagnosed COPD individuals (unadjusted HR =1.73, 95% CI: 1.55–1.94, unadjusted P<0.001) had a greater risk of all-cause mortality compared with non-COPD individuals. After adjustment for sex, age, BMI, race, smoking status, and PIR, hypertension, diabetes, congestive heart failure, stroke, asthma, and cancer, underdiagnosed COPD individuals (adjusted HR =1.25, 95% CI: 1.15–1.36, adjusted P<0.001) and overdiagnosed COPD individuals (adjusted HR =1.18, 95% CI: 1.04–1.33, adjusted P=0.01) still had a higher risk of all-cause mortality compared with non-COPD individuals.

Figure 2 Kaplan-Meier curves for all-cause mortality among the participants in this study. (A) Airflow obstruction defined by FEV₁/FVC < LLN. (B) Airflow obstruction defined by FEV₁/FVC <0.70. COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; LLN, lower limit of normal.

Subgroup analysis and sensitivity analysis

Table 3 shows all-cause mortality of the participants in subgroups stratified by age, sex, smoking status, and the absence of asthma. In the subgroup analysis of individuals aged 40 years or older, male, female, never smoker, current smoker, former smoker, and absence of asthma, individuals with underdiagnosed COPD were significantly associated with increased risk of all-cause mortality compared with non-COPD individuals after adjusting for covariates (all adjusted P<0.001) (Table 3). However, there was no significant difference in the risk of all-cause mortality between underdiagnosed COPD and non-COPD participants aged below 40 years. Participants with overdiagnosed COPD had greater risk of all-cause mortality than non-COPD participants after adjustment for covariates in the subgroups of individuals aged 40 years or older, female, current smoker, and absence of asthma (all adjusted P<0.05) (Table 3). But in the subgroups of individuals aged below 40 years, male, never smoker, and former smoker, there was no significant difference in the risk of all-cause mortality between overdiagnosed COPD and non-COPD participants after adjusting for covariates.

Table 2 also presents the all-cause mortality risk among the four groups classified as non-COPD, underdiagnosed COPD, overdiagnosed COPD, and correctly confirmed COPD, based on airflow limitation defined by prebronchodilator FEV₁/FVC <0.70 and prior physician-diagnosed chronic bronchitis or emphysema. Figure 2B demonstrates significant differences in all-cause mortality among four groups over the follow-up period (log-rank P<0.05). The mortality rates were 18.5% (3,777/20,431) in non-COPD participants, 45.7% (1,264/2,763) in underdiagnosed COPD participants, 27.5% (268/974) in overdiagnosed COPD participants, and 63.5% (313/493) in COPD participants (Table 2). Compared with non-COPD participants, there were higher risk of all-cause mortality in underdiagnosed COPD (adjusted HR =1.22, 95% CI: 1.13–1.31, adjusted P<0.001) and overdiagnosed COPD (adjusted HR =1.19, 95% CI: 1.04–1.36, adjusted P=0.01) before and after adjustment for covariates (Table 2).

Discussion

This analysis of NHANES III and 2007–2012 data demonstrated that both underdiagnosis and overdiagnosis of COPD were associated with higher odds of chronic respiratory symptoms, comorbidities, and elevated all-cause mortality risk compared to non-COPD individuals. These findings remained robust in subgroup and sensitivity analyses.

Based on prior research, this study systematically analyzed the associations of underdiagnosis and overdiagnosis of COPD with chronic respiratory symptoms, comorbidities, and all-cause mortality in a nationally representative sample of US adults. Approximately 70% of global COPD cases remain undiagnosed, while up to 60% of diagnosed cases may represent overdiagnosis (4). Several studies have demonstrated that individuals with underdiagnosed or overdiagnosed COPD exhibit more respiratory symptoms and higher risks of acute exacerbations compared to those without COPD (6,7,10,29). This study showed that underdiagnosed and overdiagnosed COPD were associated with higher all-cause mortality, providing further evidence to guide prognostic assessment and clinical management of affected individuals. For underdiagnosed COPD, individuals may appear healthy despite already having impaired lung function, underscoring the urgent need for spirometry-based screening, even in those without risk factors or respiratory symptoms. In resource-limited settings, where overdiagnosed cases lack spirometry-confirmed airflow limitation, early intervention remains critical. Such individuals should receive risk factor modification, disease management, treatment, and follow-up based on prior diagnoses of chronic bronchitis or emphysema to improve outcomes and reduce disease burden.

Underdiagnosed and overdiagnosed COPD were associated with higher all-cause mortality. We found that compared to non-COPD participants, overdiagnosed COPD was associated with significantly higher odds of congestive heart failure, stroke, and hypertension. In contrast, underdiagnosed COPD was not associated with higher risk of these cardiovascular conditions but was linked to a greater burden of chronic respiratory symptoms. A previous prospective study reported that undiagnosed symptomatic COPD participants had higher risk of acute exacerbations, pneumonia, and respiratory-related mortality than non-COPD individuals (6). Additionally, the hospitalization rate among overdiagnosed COPD participants was significantly higher than that in the non-COPD group, with circulatory system diseases being the primary reason for admission (8). We hypothesize that underdiagnosed COPD participants may experience higher mortality due to respiratory diseases, whereas overdiagnosed COPD participants may face increased risk of death due to undiagnosed and untreated conditions such as cardiovascular diseases or restrictive lung pathologies. Further analyses using cause-specific mortality data are warranted to validate these observations.

Subgroup analyses revealed that the association between underdiagnosed COPD and higher all-cause mortality remained consistent across subgroups stratified by participants aged 40 years or older, sex (male/female), smoking status (never/former/current), and non-asthma patients. Similarly, the link between overdiagnosed COPD and increased all-cause mortality persisted in subgroups of participants aged 40 years or older, females, current smokers, and non-asthma participants. However, among participants aged below 40 years, neither underdiagnosed nor overdiagnosed COPD showed significantly elevated all-cause mortality risk compared to non-COPD individuals after covariates adjustment. This may reflect stronger physiological compensatory mechanisms or healthier lifestyles in younger populations, potentially delaying disease progression (30). Notably, global COPD mortality in individuals aged below 50 years remained low (≤2.5% in 2019), supporting this observation (31). Among never smokers and former smokers, individuals with overdiagnosed COPD showed no significantly elevated all-cause mortality risk compared to non-COPD individuals after covariates adjustment. Consistent with previous studies, chronic bronchitis or emphysema without airflow limitation in non-smokers was not significantly associated with mortality, suggesting these conditions alone are not independent risk factors for death in this population (32,33). Overdiagnosis of COPD among current smokers was associated with elevated mortality risk in our study. This suggested that smoking represented a significant risk factor for COPD overdiagnosis, highlighting the critical role of smoking cessation in mitigating adverse outcomes associated with overdiagnosis. Previous studies have documented diagnostic challenges between asthma and COPD due to overlapping clinical features and limited spirometry use (34,35). Some overdiagnosed COPD cases are possibly undiagnosed asthma, which includes all risks related to asthma and may bias this group. In this study, despite using prebronchodilator spirometry to define airflow limitation and excluding asthma patients, both underdiagnosed and overdiagnosed COPD remained associated with significantly higher all-cause mortality compared to non-COPD individuals. Underdiagnosed individuals required prompt intervention upon confirmation of airflow limitation by spirometry, as most subgroup analyses demonstrated consistent outcomes. Despite the exclusion of diagnosed asthma, if this diagnosis was not made, the overdiagnosed COPD group could contain some undiagnosed asthma cases. Overdiagnosed cases exhibited heterogeneous mortality risks influenced by age, sex, and smoking status, necessitating targeted prevention and management strategies. Their elevated mortality risk may be driven by alternative underlying etiologies.

The primary causes of COPD underdiagnosis and overdiagnosis are insufficient spirometry utilization, followed by: (I) limited expertise in spirometry performance/interpretation; (II) variable primary care physician competency; (III) limited patient health literacy; and (IV) comorbidities with COPD-like symptoms (22,36). These findings underscore the necessity of implementing widespread spirometry-based COPD screening in primary care settings. Recent nationwide Belgian data demonstrated that timely spirometry not only enabled accurate COPD identification but also significantly reduced future mortality risk (37). For both underdiagnosed and overdiagnosed COPD, spirometry improves diagnostic precision while facilitating standardized management and treatment, thereby potentially improving outcomes.

There are several limitations in this study. First, only a subset of NHANES III and 2007–2012 cycles underwent postbronchodilator spirometry, necessitating airflow limitation assessment using prebronchodilator test. Although existing evidence suggested postbronchodilator spirometry had marginally superior mortality predictive value than prebronchodilator spirometry, the clinical difference was minimal (38-40). Second, the definition of prior COPD diagnosis relied on previous diagnosis of chronic bronchitis and/or emphysema, as NHANES III and 2007–2012 cycles only recorded these conditions without data on previous COPD diagnosis. Therefore, the observed association between underdiagnosed and overdiagnosed COPD with all-cause mortality may be affected by this factor. Third, cause-specific mortality data were unavailable, precluding evaluation of respiratory-specific mortality risks associated with COPD under/overdiagnosis. Fourth, while this study adjusted for common COPD-related confounders, unmeasured confounding factors may remain. However, the minimal differences between unadjusted and adjusted models for associations of under/overdiagnosed COPD with comorbidities, chronic respiratory symptoms, and all-cause mortality risk suggested limited influence from unknown confounders. Finally, as our analysis was restricted to U.S. adults, the findings may not generalize to other populations (e.g., Asian).

Conclusions

Underdiagnosed and overdiagnosed COPD were associated with increased all-cause mortality risk, comorbidities, and chronic respiratory symptoms. Future efforts should prioritize spirometry implementation to standardize COPD diagnosis, thereby facilitating precision interventions and minimizing delays in diagnosis and treatment caused by underdiagnosis and misdiagnosis. When spirometry is unavailable in resource-limited settings, early intervention targeting underlying etiologies should be initiated.

Acknowledgments

We thank all the study participants and their families in NHANES cohort study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1334/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1334/prf

Funding: This work was supported by the Foundation of Guangzhou National Laboratory (Nos. SRPG22-016 and SRPG22-018, to Y.Z.), the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (No. SKLRD-L-202402, to Y.Z.), the Plan on Enhancing Scientific Research in Guangzhou Medical University (No. GMUCR2024-01012, to Y.Z.), and the Guangzhou Science and Technology Plans (No. 202201020372, to Y.Z.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1334/coif). Y.Z. declared receiving funding from the Foundation of Guangzhou National Laboratory (Nos. SRPG22-016 and SRPG22-018), the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (No. SKLRD-L-202402), the Plan on Enhancing Scientific Research in Guangzhou Medical University (No. GMUCR2024-01012), and the Guangzhou Science and Technology Plans (No. 202201020372). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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