Exercise intolerance in patients with COPD has significant implications for quality of life, hospitalization rates, and survival.

To assess functional capacity using the six-minute walk test (6MWT) by categorizing the distance walked in six minutes (6MWD) into tertiles and to assess the impact of this functional capacity on predictors of survival over a 24-month follow-up in patients with Chronic Obstructive Pulmonary Disease (COPD).

This prospective cohort study followed 118 patients with COPD for 24 months. Participants were stratified based on the 6MWD: Group 1 (mean distance 590–424 m); Group 2 (mean distance 423–337 m); and Group 3 (mean distance < 336 m). Symptoms and disease severity were assessed using CAT scores. Kaplan-Meier was used to determine the association between 6MWD and all-cause mortality.

The 6MWD, stratified by functional performance, was a significant predictor of survival in patients with COPD, despite heterogeneity in disease severity between groups. The 6MWD, stratified by functional performance, was a significant predictor of survival in patients with COPD, despite heterogeneity in disease severity between groups. Furthermore, in regression analysis for mortality, it was identified for 6MWD (CI 0.994; p = 0.043) and peripheral oxygen saturation (SpO₂) (CI 0.735; p < 0.001). Kaplan-Meier survival analysis revealed that patients who walked less than 336 m in the 6MWD had the lowest probability of survival at 24 months (log-rank p < 0.05).

The 6MWD is a robust predictor of mortality over a 2-year period in patients with COPD, reflecting a broad spectrum of disease severity. Poorer 6MWD performance is associated with increased desaturation, impaired heart rate recovery, and greater symptom burden during exercise, as indicated by CAT scores.

Not applicable.

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory condition characterized by persistent and progressive airway obstruction that is not fully reversible [1]. It is estimated that there are over 384 million cases of COPD globally, with the World Health Organization (WHO) projecting that COPD will become the third leading cause of death by 2030 [2, 3]. In Brazil, 61% of individuals with COPD report frequent emergency room visits and hospitalizations due to exacerbations of respiratory symptoms, increased pulmonary hyperinflation, reduced airflow, and dyspnea—factors that contribute to an elevated risk of mortality [4, 5].

While COPD primarily affects the lungs, it also has significant systemic manifestations. Systemic inflammation and oxidative stress contribute to the progressive loss of muscle mass, which in turn impacts physical capacity and overall health [6,7,8]. These manifestations result in clinical consequences such as increased fatigue and dyspnea during physical activity, further compounding the functional limitations experienced by patients [9, 10].

In this context, given the impact of COPD on both pulmonary and systemic health, assessing functional capacity early is crucial. Evaluation methods, including specific questionnaires that capture the individual’s perception of their disease, symptoms, quality of life, and functional capacity, are essential for effective COPD management [11]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends using the COPD Assessment Test (CAT), a straightforward and practical questionnaire that assesses health status and functional impairment, and serves as a valuable predictor of mortality [12,13,14].

Exercise intolerance in COPD patients has significant implications for quality of life, hospitalization rates, and survival [15]. Functional physical tests, such as the six-minute walk test (6MWT), are integral to clinical practice for differentiating submaximal exercise intolerance, monitoring disease progression, evaluating responses to various interventions, and predicting mortality [16]. The 6MWT is particularly advantageous due to its simplicity, ease of application, and cost-effectiveness, and it provides valuable prognostic information on both fatal and non-fatal outcomes [16,17,18].

However, diagnosing mild COPD can be challenging due to often subtle clinical manifestations. Thus, this study hypothesizes that performance in the 6MWT is associated with CAT scores and could serve as a potential predictor of functional capacity across a spectrum of COPD severity. Our objective was to evaluate functional capacity using the 6MWT, stratifying performance into three terciles of distance walked, and to assess the impact of this functional capacity as a predictor of survival over a 24-month follow-up period in COPD patients.

This study followed the Declaration of Helsinki and all ethics principles. The research was approved by the local ethics committee at the Federal University of São Carlos (protocol number: 91088318.7.1001.5504), and written informed consent was obtained from all participants. Figure 1 describes the experimental protocol used to develop our research. The study design was a 24-month cohort, cross-sectional in nature, guided by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [19]. Recruitment of participants occurred at the pulmonology outpatient clinics of the University Hospital of the Federal University of São Carlos (UFSCar) and the Medical Specialties Center (CEME) in São Carlos, from March 3, 2021, to December 10, 2022. After reviewing medical records of patients seen during this period, telephone contact was made to assess eligibility criteria for inclusion in the study.

Experimental protocol

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Eligibility Criteria were: (1) patients of either sex, aged ≥ 50 years; (2) diagnosed with COPD of any severity (mild, moderate, severe, very severe); (3) clinically stable for at least 3 months (no worsening of symptoms, no exacerbations, 4) no changes in medication dosage, no hospitalizations, and optimized disease treatment); (5) absence of conditions affecting exercise performance; and (6) not participating in a rehabilitation program for at least two months prior to the study. Exclusion Criteria were: (1) use of home oxygen therapy; and (2) presence of neurological or orthopedic conditions that contraindicate exercise testing.

All eligible patients were invited to the laboratory for initial evaluations, including pulmonary function testing and echocardiography. As demonstrated in Figs. 2 and 150 patients were contacted, but only 118 patients with confirmed COPD by spirometry and who met the study criteria were included. These patients were divided into three groups based on their performance in the 6MWT: Group 1 (distance covered: mean 590–424 m), Group 2 (mean 423–337 m), and Group 3 (mean < 336 m).

Study flowchart

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Six-minute walk test

Recruited individuals who met the inclusion criteria were invited to a second laboratory visit to perform the 6MWT. Participants were instructed to walk as far as possible within 6 min along a 30-meter-long flat corridor, marked with colored tape. Standardized verbal encouragement was provided to motivate participants to achieve their maximum distance. They were informed that they could interrupt the test at any time if necessary. The test was conducted twice with a 30-minute interval between tests, following the American Thoracic Society recommendations [20]. The best performance, defined as the greatest distance covered, was selected for analysis.

Prior to each test, participants rested for two 4-minute periods: one in a seated position and another in an orthostatic position. During the test, the distance covered, occurrence and duration of pauses, and desaturation greater than 4% were recorded at the peak of the exercise. A 6-minute rest period was observed post-exercise.

Physiological variables were measured during the 6MWT, including heart rate (HR) and heart rate delta (peak - rest) using a Polar S810i^® monitor (Kempele, Oulu, Finland), and systemic arterial pressure (SBP) using a BIC^® sphygmomanometer (Itupeva, São Paulo) with the auscultatory method (Littmann^® Classic II Stethoscope, USA). Peripheral oxygen saturation (SpO₂) was measured using a Nonin^® 2500 digital oximeter (Minneapolis, MN, USA). The modified BORG CR-10 Perceived Exertion Scale [21] was used to record perceived exertion at rest, at the peak of the exercise, and at 1, 3, and 6 min into recovery. The predicted distance was calculated using the formula [22]: 6MWDpred = 890.46-(6.11×age) + (0.0345×age ²) + (48.87× gender) - (4.87×BMI).

Based on the distribution of the data, we divided the results of the 6MWT into tertiles. This approach facilitated a more detailed analysis of performance across different levels.

Pulmonary function was assessed using spirometry (Masterscreen Body, Mijnhardt/Jäger, Würzburg, Germany). Testing was conducted by a trained researcher following the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines [23]. This involved performing at least three acceptable and reproducible maneuvers, with measurements repeated 20 min after inhalation of Salbutamol Sulfate (400 µg). COPD diagnosis was confirmed using the GOLD criteria, defined by a post-bronchodilator FEV1/forced vital capacity (FVC) ratio < 0.70. Participants were classified into GOLD stages based on the percentage of predicted FEV1: Stage I (mild) > 80%, Stage II (moderate) 50–79%, Stage III (severe) 30–49%, and Stage IV (very severe) < 30% [24].

Echocardiographic assessment was performed by a cardiologist specializing in echocardiography using a Phillips HD11 XE ultrasound device with a 3 MHz transducer. Measurements included left ventricular end-diastolic diameter and end-systolic diameter (mm). Color tissue Doppler imaging was used to determine early diastolic mitral filling velocities (E wave) and early diastolic mitral annulus velocity (E’ wave). Left ventricular ejection fraction (LVEF) was calculated using the Simpson method [25, 26].

The CAT score is designed to evaluate the impact of COPD on health status. The questionnaire includes eight items: cough, phlegm, chest tightness, shortness of breath, limitations in daily activities, confidence to leave the house, sleep quality, and energy levels. For each item, patients select one response option, with scores ranging from 0 to 5. The total score is derived by summing the scores for each item. Participants were categorized into groups based on their CAT scores as follows: CAT < 10 (mild impact), CAT 11–20 (moderate impact), and CAT > 20 (severe impact) [12].

The mMRC scale was used to assess patients’ self-reported perception of dyspnea and physical exertion. This scale classifies the intensity of breathlessness experienced during daily activities into five grades: Grade 0 indicates no breathlessness except during intense physical exertion; Grade 1, breathlessness when walking quickly or climbing a slight incline; Grade 2, breathlessness when walking at the same pace as other people of the same age on level ground; Grade 3, breathlessness when walking at a slower pace than usual speed; and Grade 4, breathlessness so severe that the patient has difficulty even leaving the house or performing light activities. The score is determined based on the patient’s selected response and was used to characterize the severity of dyspnea according to their subjective perception of exertion [27].

Patients were monitored over a 24-month period through routine medical consultations and telephone follow-ups conducted every three months. Mortality data were collected during these follow-up calls, where the date and cause of death were recorded. Family members provided information to confirm the date and cause of death when applicable.

The sample size was determined probabilistically. Data normality was assessed using the Shapiro-Wilk test. Descriptive statistics are presented as means, standard deviations, and percentages. To test the study hypotheses, the following statistical analyses were conducted: (1) Pearson Correlation Analysis: This two-tailed analysis was used to examine the correlations between measured variables. Correlation strengths were classified as follows: trivial (< 0.1), small (0.30–0.50), moderate (0.50–0.70), large (0.70–0.90), and almost perfect (> 0.90) [28]; (2) One-Way Analysis of Variance (ANOVA): ANOVA was performed to compare means among the three groups (Group 1, Group 2, and Group 3) based on 6MWT performance; (3) Survival Analysis: Kaplan-Meier survival curves were generated, and the log-rank test was used to assess differences in survival across groups, considering exposures such as 6MWD, number of deaths, and follow-up duration; (4) Cox proportional hazards regression models, adjusted for Age (years), Gender (M/F), Smoking, 6MWD, mMRC, FEV1 (L), SpO₂ (%), CAT, HTN, DM, and OSA, were performed. Associations are presented as hazard ratios (HRs) with 95% CIs. All data were analyzed using the Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM, Armonk, New York). Statistical significance was set at p < 0.05.

Table 1 presents the clinical characteristics and anthropometric data of the three groups evaluated. Most participants were male. Regarding comorbidities, stress was more prevalent in groups 2 and 3, which demonstrated a shorter distance walked in the 6MWT compared to Group 1 (p = 0.014). Patients in the most severe group (Group 3) presented worse performance in the 6MWT (p = < 0.0001). In addition, Group 3 presented significantly higher scores in the CAT questionnaire (p = 0.002), indicating greater severity of symptoms and functional limitations compared to the other groups. Regarding dyspnea, assessed by the modified mMRC scale, patients in Group 1 (distance walked: 590–424 m) demonstrated better scores, reflecting less severe dyspnea.

Figure 3 illustrates that Group 3 (distance covered < 336 m) demonstrated poorer performance, with this group predominantly consisting of individuals classified as having moderate to severe COPD according to the GOLD criteria (p < 0.007).

Classification of patients using the GOLD. GOLD: Global Initiative for Chronic Obstructive Lung Disease; Distance covered in the six-minute walk test (6MWT). GROUPS: G1: 6MWT (590–424 m); G2: 6MWT (423–337 m); G3 6MWT (< 336 m)

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Figure 4 shows that individuals in Group 3, who had the lowest functional performance, also had higher CAT questionnaire scores, reflecting a greater clinical impact of COPD (p < 0.01).

Classification of patients using the CAT criteria. CAT: COPD assessment test; Distance covered in the six-minute walk test (6MWT). GROUPS: G1: 6MWT (590–424 m); G2: 6MWT (423–337 m); G3 6MWT (< 336 m)

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Figure 5 displays various physiological parameters at the end of the 6MWT. The dyspnea was significantly higher in Group 3 compared to Group 1 (p < 0.001). Group 3 had lower SpO₂ compared to the other groups (p < 0.05). Group 3 exhibited a lower HR during the 6MWT compared to the other groups (p < 0.05). Additionally, the nadir of SpO₂ was lower in Group 3 compared to Group 1 (p < 0.05).

Physiological variables in 6MWT. A: Dyspnea post 6MWT peak; B: saturation (SpO2) post 6MWT peak; C: Heart rate delta (HR) after the 6MWT; D: Nadir (minimum oxygen saturation) SpO2 post 6MWT

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Figure 6 shows the Kaplan-Meier survival analysis, indicating that patients who walked less than 336 m on the 6MWD over a 24-month period had the lowest probability of survival (log-rank p < 0.05), with censoring marks indicated along the curves. Panel A presents an overview of the survival probabilities, ranging from 0 to 100%, while the Panel B magnifies of the range from 70 to 100%, providing a more detailed observation of the curves.

Kaplan-Meier curve for assessing the mortality risk of COPD patients based on the distance covered in the six-minute walk test. A: %: percentage; G1: 6MWT (590–424 m); G2: 6MWT (423–337 m); G3 6MWT (< 336 m); < less than; statistically significant difference for Log-rank; B: %: percentage; G1: 6MWT (590–424 m); G2: 6MWT (423–337 m); G3 6MWT (< 336 m); < less than; statistically significant difference for Log-rank

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The Cox regression model (Table 2) identified 6MWD (95% CI 0.994; p < 0.043) and SpO₂ (%) (95% CI 0.735; p < 0.001) as significant predictors of mortality.

Our study offers valuable insights into the prognostic value of functional performance assessments in patients with COPD. The key findings of our research are as follows: (1) 6MWT distance is a significant predictor of survival in COPD patients; and (2) lower SpO₂ (%) values are associated with an increased risk of mortality.

Assessing functional capacity through exercise tolerance is pivotal in managing COPD. It aids in differential diagnosis. tracking disease progression. evaluating response to interventions. and predicting mortality [29]. The 6MWT and the COPD Assessment Test (CAT) score are essential tools in this regard. Our results underscore that the 6MWT [30] serves as a robust predictor of survival. with patients demonstrating better functional performance (greater 6MWT distance) showing improved survival probabilities. Conversely, those walking less than 336 m exhibited significantly reduced survival rates. as evidenced by Kaplan-Meier survival analysis (Fig. 5).

These findings align with existing literature which highlights the predictive value of exercise capacity for survival in COPD [16, 31]. Celli et al. [31] identified exercise capacity as a crucial predictor of mortality in COPD. and Pinto-Plata et al. [16] found that a 6MWT distance of less than 100 m is associated with a high one-year mortality rate (92%). Dajczman et al. [32] evaluated the relationship between the distance covered in the 6MWD and mortality in patients with severe COPD and a 4-year follow-up. Theuy found that distances shorter than 200 m were associated with a higher risk of mortality. Analyzing different patient profiles, such as those in early and advanced stages of COPD, Provides a more comprehensive understanding of the impact of functional capacity on disease progression. In our investigation, we included individuals classified between GOLD 1 and GOLD 4, allowing for a broader analysis of the applicability of the 6MWD across different stages of the disease. Although longer follow-up periods may offer additional insights into the evolution of COPD, our findings emphasize that even over shorter intervals, the 6MWD remains aa relevant prognostic indicator.

Furthermore. our study reveals that dyspnea. measured by the BORG scale. was notably higher in patients with poorer 6MWT performance (Group 3. <336 m) (Fig. 4A). This increased dyspnea contributes to a progressive decline in physical conditioning. exercise intolerance. and overall functional capacity [33]. Similarly. post-6MWT SpO2 was lower in Group 3 (Fig. 4B). indicating that exercise-induced desaturation is prevalent among patients with more severe disease. The lower heart rate (HR) observed in Group 3 during recovery (Fig. 4C) is particularly noteworthy. Rodríguez et al. [34] found that a slower HR recovery is associated with increased susceptibility to exacerbations. suggesting that impaired autonomic balance in COPD patients may contribute to these findings. Our data corroborate these observations. emphasizing the significance of recovery HR as an indicator of disease severity and prognosis [35, 36].

According to our cox regression analysis model (Table 2), both 6MWT and SpO₂ r were significant predictors of mortality in COPD patients (p = 0.043 for 6MWT and p < 0.001 for SpO₂). This aligns with findings from Moreira et al. who noted a correlation between desaturation and 6MWT performance while Waatevik et al. [37] did not find a direct association with mortality. Our results reinforce the notion that desaturation during the 6MWT is a critical mortality risk factor. particularly in long-term follow-ups.

The 6MWT remains well-established. standardized assessment tool in clinical settings for evaluating functional capacity across various chronic conditions. including COPD. Its practical application and reliability make it a valuable method for capturing the severity of symptoms and functional status during physical exertion [33]. Although our study indicates a negative correlation between 6MWT performance and the CAT score. the 6MWT provides a more comprehensive evaluation of physical intolerance [20] due to its direct measurement of functional capacity and physiological responses.

Our study’s two-year follow-up duration offers a unique perspective on long-term trends in 6MWT performance. which is critical for understanding the progressive nature of COPD. This extended follow-up period reveals trends not evident in shorter studies. highlighting the impact of additional comorbidities and functional decline on mortality. Integrating objective measures from the 6MWT allied with simple psychophysiological responses during exercise and subjective assessments from the CAT score provides a holistic view of patient health. enhancing clinical practice by enabling more accurate monitoring of disease progression and informing clinical decision-making. This combined approach has the potential to improve patient outcomes and quality of life by facilitating timely interventions and reducing mortality. especially in low-income countries. where more robust tests are not used in a broader assessment of exercise tolerance. such as the cardiopulmonary exercise test. In this sense, the walking test can broaden the perspectives of assessment in the context of secondary health care. as a powerful screening indicator.

Additionally. 6MWT is a valuable tool for objectively assessing the efficacy of both pharmacological and non-pharmacological interventions in COPD. It serves as a robust indicator of disease severity and provides critical information that can guide specific evaluations and optimize treatment strategies in clinical practice. Our study underscores the importance of combining the 6MWT with the COPD Assessment Test (CAT) score. Patients with poorer 6MWT performance consistently had higher CAT scores. despite a broaden heterogeneity of severity disease. The CAT is an easily administered tool that can be utilized across all cardiorespiratory rehabilitation settings. offering an accessible method for healthcare professionals to assess symptom severity and functional capacity. This integration of the 6MWT and CAT score not only supports the accurate prescription of exercises by physiotherapists but also enhances the overall management of COPD by tailoring interventions to individual patient needs and improving clinical outcomes.

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Correspondence to Audrey Borghi-Silva.

Approval by the Research Ethics Committee of the Universidade Federal de São Carlos (protocol number: 5.188.654). All individuals who voluntarily agreed to participate signed a consent form.

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The authors declare no competing interests.

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