chronic obstructive pulmonary disease research paper

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• Published: 05 May 2021

Characteristics of chronic obstructive pulmonary disease patients with robust progression of emphysematous change

• Akihiro Tsutsumi 1 ,
• Shotaro Chubachi 1 ,
• Hidehiro Irie 1 ,
• Mamoru Sasaki 1 ,
• Yoshitake Yamada 2 ,
• Hiroaki Sugiura 2 ,
• Masahiro Jinzaki 2 ,
• Hidetoshi Nakamura 3 ,
• Koichiro Asano 4 ,
• Tomoko Betsuyaku 1   na1 &
• Koichi Fukunaga 1  

Scientific Reports volume  11 , Article number:  9548 ( 2021 ) Cite this article

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• Epidemiology
• Outcomes research
• Translational research

Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P  = 0.04) and having osteoporosis (OR, 2.13; P  = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.

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Introduction.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation 1 . Emphysema is a major pathological change of COPD that is characterized by abnormal and permanent enlargement of distal airspaces as well as by alveolar wall destruction 2 . Airflow limitation is the main characteristic of COPD, but the severity of emphysema differs significantly among individuals who have similar forced expiratory volume in 1 s (FEV 1 ) 3 . Chest computed tomography (CT) has been the most accurate and minimally invasive technique used for the diagnosis of emphysema 4 , and CT-diagnosed emphysema is strongly associated with more rapid decline in FEV 1 5 , worse health status 6 , and increased mortality rates 7 .

Progression of emphysema was found to be more sensitive using chest CT than by using lung function parameters 8 and reported the utility as treatment outcome in COPD patients 9 . It has been reported that the progression of emphysema, as well as pulmonary function decline, varies between patients 10 . Thus, factors that could predict emphysematous progression are required. A recent study showed that sex, smoking status, plasma levels of surfactant protein D (SP-D), soluble receptor for advanced glycation endproducts (sRAGE) 10 , and the leptin/adiponectin ratio 11 were associated with changes in emphysematous progression. Several recent large-scale cohort studies evaluated the changes in emphysematous progression; however subjects underwent chest CT at baseline and 3- to 5-year follow-up in these studies 10 , 12 . Emphysema quantification is very sensitive to various conditions, including the level of inspiration. Thus, when assessing longitudinal changes by chest CT, the appropriate number of times, calibration of different CT scanners, and the scanning protocol used are important 13 . However, the annual changes in emphysematous progression on chest CT have not been assessed in COPD patients.

Systemic manifestations and comorbidities of COPD also contribute to the different clinical phenotypes and alterations in body weight and composition, from cachexia to obesity, demanding specific management 14 . Several previous reports have demonstrated the association among emphysema, low body mass index (BMI), and osteoporosis in COPD patients 15 , 16 , 17 . We hypothesized that low BMI and having osteoporosis could predict future changes in emphysematous progression and that the annual change in emphysema would correlate with the annual change in BMI and bone mineral density (BMD). Thus, the aims of this study were threefold: 1) to identify a subgroup of COPD patients who demonstrate rapid progression of emphysematous change during a 3-year follow-up period; 2) to identify possible baseline factors, including comorbidities, which could predict the rapid progression of emphysematous change; and 3) to assess factors that change synchronously with emphysematous progression in COPD patients.

Study population

The overall design of the Keio COPD Comorbidity Research (K-CCR) has been published previously 15 , 18 . This study was a 3-year, prospective, observational study that enrolled 572 men and women, aged 40–91 years, diagnosed with COPD (n = 440) or as being at risk of COPD (n = 132) by pulmonary physicians, from April 2010 to December 2012. Data of COPD patients who underwent CT at least two times over a 3-year period (n = 217) were analyzed (Supplemental Fig.  1 ). All patients were clinically stable at all assessments and had no exacerbations for at least 1-month pre-enrollment.

Distribution of annual changes in LAA% and time-dependency over 3 years. ( A ) Distribution of the annual changes in LAA% over the 3-year period. The mean ± SD of ΔLAA%/year was 0.47 ± 2.28. We had arbitrarily defined the cut-off value of ΔLAA%/year, based on the upper quartile value, as 1.48%/year. ( B ) Overall time-dependent LAA% in the rapid progression and non-progression groups. Data are shown as mean ± SD. LAA low attenuation area.

Written informed consent for the use of data was obtained from each patient, and the study (University Hospital Medical Information Network; UMIN000003470) was approved by the ethics committees of Keio University and its affiliated hospitals (20,090,008). All methods were performed in accordance with the relevant guidelines and regulations.

Assessment of clinical parameters

At enrollment and annually, a full medical and smoking history, and current pharmacological treatment information, were obtained 18 . Comorbid conditions were diagnosed based on clinical history and physical examination, supported by medical record review 18 , 19 . Spirometry was performed in all patients using an electronic spirometer (CHESTAC-9800; CHEST, Tokyo, Japan) according to the American Thoracic Society guidelines 20 . Body mass composition, i.e., fat-free mass (FFM) and muscle mass (MM), was assessed using a Tanita BC-308/BC-309 bioelectrical impedance analyzer (Tanita, Inc., Tokyo, Japan) 21 . The FFM index (FFMI) was calculated as FFM divided by height-squared 22 .

Blood samples were collected at baseline and annually thereafter. A pre-specified eosinophil cut-off of 300 cells/μl was used to determine association with the change in emphysematous progression 23 , 24 .

The Japanese version of the COPD assessment test (CAT) 25 and the St. George’s Respiratory Questionnaire (SGRQ) 26 , 27 , 28 was performed at baseline. Independent investigators retrospectively judged the number and severity of exacerbations based on reviews of physicians’ medical records 29 .

Assessment of low attenuation areas and airway wall thickness on chest CT

CT was performed using four multi-detector CT scanners, including 64-detector CT (LightSpeed VCT and Discovery CT 750 HD, General Electric Medical Systems, Milwaukee, WI, USA, or Aquilion 64, Toshiba Medical Systems, Otawara, Japan) or 256-detector CT (Revolution CT, General Electric Medical Systems, Milwaukee, WI, USA) scanners. All subjects underwent volumetric CT at full inspiration and at the end of a normal expiration. Scanning parameters for each scanner were as follows: the detector collimation was 0.5–0.625 mm; beam pitch, 0.813–0.984; reconstruction thickness, 1.0–1.25 mm; reconstruction interval, 1.0–1.5 mm; rotation time, 0.35–0.5 s; tube voltage, 120 kVp; tube current, Auto mAs (standard deviation [SD] = 12–15); and reconstruction kernel, chest for GE machine or FC 50 for Toshiba machine. For calibration among four CT scanners, a test object (Multipurpose Chest Phantom N1; Kyoto Kagaku, Kyoto, Japan) was scanned at the start of the study using each scanner 15 . (Supplemental Fig.  2 ). The emphysema extent was quantified as the ratio of the low attenuation area to the total lung volume (LAA%), with Hounsfield units < − 950 (AZE Ltd., Tokyo, Japan) 15 .

Comparison of BMI between the rapid progression group and non-progression group. ( A ) BMI at baseline. ( B ) Annual change in BMI over 3 years of follow-up. Data are shown as mean ± SD. BMI body mass index.

As shown in Supplemental Fig.  2 A below, the phantom was first scanned on one control CT scanner. The LAA% of this phantom varies depending on the cutoff HU value. When the cutoff LAA value was set at − 950 HU on the control CT scanner, LAA% was 76%. The same phantom was scanned on the other four scanners, and the cutoff HU level specific to each model by which LAA% became 76% was determined to allow adjustment (Supplemental Fig.  2 B).

Dual X-ray absorptiometry

Dual X-ray absorptiometry (DXA) measurements of bone mineral density (BMD) were performed at both hips and lumbar spine using a Hologic 4500A Discovery bone densitometer (HOLOGIC, Bedford, MA). Osteoporosis diagnosis was based on the lowest T-score of these locations, according to World Health Organization criteria 30 .

Statistical analysis

Data were compared between two groups using Student’s t - and χ 2 tests; three groups were compared by analysis of variance and χ 2 tests. LAA%, BMD, and BMI were compared by percent changes from baseline values. Excel (Microsoft Inc. Redmond, WA) was used to calculate the linear regression through data points, including data in the middle 31 . Univariate and multivariate logistic regression analyses were performed to assess factors affecting change in emphysematous progression. Correlations between continuous variables were evaluated using Pearson’s correlation coefficient. Multivariate logistic regression analysis was performed using related factors that either reached significance or trended towards an association on univariate analyses. The changes of LAA%, BMI or BMD at each visit were estimated by a linear mixed effect model with groups; non-progression and rapid progression groups, time point, and time-by- groups interaction as fixed effects, subject as a random effect, to obtain point estimates and 95% confidence interval. The correlation structure was assumed as compound-symmetry structure. For all tests, two-sided p-values < 0.05 were considered significant. Data were analyzed using JMP 14 software (SAS Institute, Cary, NC).

Clinical features of the study populations

Table 1 shows the baseline characteristics of the study participants. The average age of the COPD patients was 72.4 ± 8.4 years. The number of COPD patients in Global Initiative for Chronic Obstructive Lung Disease grades 1, 2, 3, and 4 were 30.8%, 47.0%, 17.5%, and 4.6%, respectively.

Distribution of annual changes in LAA% over a 3-year period

The annual changes in LAA% (ΔLAA%/year) is shown in Fig.  1 A. The mean ΔLAA%/year was 0.47. We had arbitrarily defined the cut-off value of ΔLAA%/year based on an upper quartile value of 1.48%/year (Rapid progression group; n = 54, Non-progression group; n = 163). Figure  1 B shows the longitudinal change in LAA% over the 3-year period in the two groups. The difference in the rate of LAA% change among the two groups was significant ( P  < 0.01). ΔLAA%/year significantly correlated with ΔLAA volume/year (r = 0.65, P  < 0.01), but not ΔTotal lung volume (TLV)/year (r = 0.03, P  = 0.77).

Baseline characteristics of COPD patients with emphysema and changes in emphysematous progression

The baseline characteristics of COPD patients, stratified by the baseline LAA% and annual change of LAA%, are shown in Table 2 and Supplemental Table 1 . Patients with mild (LAA% ≥ 10% to < 20%) and moderate/severe(LAA% ≥ 20%) emphysema had lower lung function, lower BMI, more osteoporosis, and worse quality of life (QOL) scores than those without emphysema (LAA% < 10%) (Supplemental Table 1 ). In contrast, there were no differences in lung function, BMI, and QOL scores between the rapid progression group and the non-progression group. Additionally, the baseline LAA% and prevalence of interstitial pneumonia did not differ between these two groups (LAA%: P  = 0.51; prevalence of interstitial pneumonia: P  = 0.25). Interestingly, the eosinophil count was lower in the rapid emphysema group than in the non-progression group (eosinophil count: 150.7 ± 89.5 cells/mm 3 vs. 226.9 ± 215.7 cells/mm 3 , P  = 0.01) (Table 2 ). These results imply that baseline LAA% does not predict the rate of future changes in emphysematous progression and the related factors differ between baseline advanced emphysema and changes in emphysematous progression.

Relationships between nutritional status and changes in emphysematous progression in COPD patients

At baseline, there was no difference in BMI between the rapid progression group and the non-progression group (Fig.  2 A). In contrast, follow-up analysis indicated that the difference in the rate of BMI change among the two groups was significant ( P  = 0.01) (Fig.  2 B). As well as ΔBMI/year (r = − 0.21, P  < 0.01), ΔFFMI/year (r = − 0.20, P  < 0.01) and ΔMuscle mass/year (r = − 0.20, P  < 0.01) correlated weakly but significantly with ΔLAA%/year. (Table 3 ).

Relationships between BMD and changes in emphysematous progression in COPD patients

The ratio of patients with osteoporosis and osteopenia was higher in COPD patients in the rapid progression group than in those in the non-progression group (osteoporosis: 22.5% vs. 10.3%; osteopenia: 36.7% vs. 29.5%, P  = 0.03) (Fig.  3 A). Additionally, the baseline BMD at all three parts of the body were significantly lower in the rapid progression group than in the non-progression group (lumbar spine: P  = 0.03; right femur: P  = 0.02; left femur: P  = 0.03) (Fig.  3 B, Supplemental Fig.  3 A, B). Follow-up analysis over 3 years indicated that the difference in BMD between the two groups was statistically significant (lumbar spine: P  < 0.01; right femur: P  < 0.01; left femur: P  < 0.01), but there was no significant difference in the rate of BMD change between the two groups (lumbar spine: P  = 0.80; right femur: P  = 0.88; left femur: P  = 0.76) (Fig.  3 C, Supplemental Fig.  3 C, D).

Relationships between lumbar BMD and changes in emphysematous progression in COPD patients. ( A ) Frequency of osteopenia and osteoporosis in the non-progression group and rapid progression group. ( B ) Comparison of baseline T score in the lumbar spine between the two groups. ( C ) Annual change in BMD in the lumbar spine in the two groups over 3 years of follow-up. Data are shown as mean ± SD. BMD bone mineral density.

Predictors and factors showing synchronized progression with emphysematous change in COPD patients

We assessed the predictors of future changes in emphysematous progression using multivariate logistic analysis in which we included several factors that reached significance on univariate analysis (Tables 4 ). Low blood eosinophilia (< 300 cells/μl) (odds ratio [OR] 3.22, P  = 0.04), having osteoporosis or osteopenia (OR 2.13, P  = 0.03) independently predicted future changes in emphysematous progression. There was no difference in the incidence of moderate and severe exacerbations, change in smoking habits, or change in treatment between the rapid emphysema group and the non-progression group over the 3-year period (Supplemental Table 2 ). Also, there were no differences in the he annual ΔCAT score and ΔSGRQ total score between the two groups (Supplemental Fig.  4 ).

Ethics approval and consent to participate

Written informed consent for the use of data was obtained from each patient. This study was registered on the University Hospital Medical Information Network (UMIN000003470) and was approved by the ethics committees of Keio University and its affiliated hospitals (20,090,008).

In this longitudinal study in patients with COPD, we identified possible baseline factors, including comorbidities, that could predict the rapid progression of emphysematous change at three time points; this has not been reported previously. We demonstrated that having osteoporosis and low blood eosinophilia were predictors of future rapid changes in emphysematous progression; additionally, cachexia and health status deteriorated with changes in emphysematous progression.

Previous studies, including our own, have shown an association between emphysema and osteoporosis 15 , 16 . However, the influence of having osteoporosis on changes in emphysematous progression has remained unclear. The present study showed that having osteoporosis is an important predictor of not only baseline emphysema presence, but also of future changes in emphysematous progression in COPD patients. These results imply that osteoporosis is closely related to emphysema. Systemic inflammation is a plausible mechanistic link between emphysema and osteoporosis 32 , 33 . However, this concept had not been considered in detail to date. Future studies should focus on the development of targeted therapies designed to prevent the progression of both these disease processes.

Cachexia and muscle wasting are well-recognized comorbidities in COPD patients, and a number of studies have reported that these comorbidities contribute to decreased QOL 31 and increased mortality 35 , 36 . In a previous study, baseline BMI and FFMI were not related to baseline LAA%, but ΔBMI, ΔFFMI, and other nutrition indexes were correlated with changes in emphysematous progression. These results were in line with previous studies that demonstrated that lung volume reduction surgery (LVRS) significantly improved nutritional status 37 . Additionally, these results indicated that, even if nutritional status at enrollment is within the normal range, the nutritional status of COPD patients with changes in emphysematous progression deteriorates over time. An imbalance between protein synthesis and myogenesis has been proposed to underlie muscle wasting in COPD patients 38 , and nutritional supplementation promotes weight gain among COPD patients, especially if they are malnourished 39 . Patients who have related factors of changes in emphysematous progression might be requiring nutritional supplementation and targeted pharmacological interventions.

Recently, several studies have shown that the blood eosinophil count is predictive of exacerbations 40 and a good response to inhaled corticosteroids 41 , 42 . Interestingly, even if they are within the normal range, the blood eosinophil count was significantly higher in the non-progression group than in the rapid progression group in the present study. This result is in line with previous studies showing that high eosinophil counts were related to less emphysema 43 , better survival 22 , 44 , and a slower annual FEV 1 decline 23 . The specific cause and effect relationship between emphysema progression and low blood eosinophilia is unclear. Previous reports have demonstrated that T helper 1 and 17 cells are relatively abundant in lungs of patients with emphysema compared with those in lungs of former smokers without emphysema 12 . T helper 1-predominant inflammation appears to progress emphysema more rapidly compared to T helper 2-predominant inflammation, a difference that would be related to blood eosinophilia 45 . Blood eosinophil count is thus a simple and inexpensive biomarker predictive of future changes in emphysematous progression.

In COPD patients, the relative contributions of emphysema and small airway disease differ among patients 3 , 46 . Emphysema-predominance is reported to be associated with greater exercise limitation, reduced QOL 47 , and reduced mortality 48 .

Large clinical trials of COPD patients have shown that current pharmacological treatments have improved lung function 49 , 50 . Furthermore, Tanabe et al. reported the tiotropium-induced reduction of emphysema volume based on CT images 9 . However, the prognostic value thereof and appropriate therapy for progressive emphysema are unknown. These matters should be considered in future research.

Recent advance of CT metrics has improved phenotyping of COPD. For instance, parametric response mapping identified the extent of functional small airway disease and emphysema 51 . In addition, CT-derived pectoralis muscle area provides a relevant index of COPD morbidity 52 . Further studies that evaluate the relationship among changes in emphysematous progression and these new CT metrics are required.

This study has several strengths. First, the comprehensive assessment of comorbid factors in the K-CCR cohort study 18 , 19 . Second, assessment of changes in emphysematous progression was based on annual CT over 3 years. In this study, the ΔLAA%/year and not ΔTLV/year correlated with LAA volume. These results imply that the increase in ΔLAA%/year was due to the increase in ΔLAA volume/year, but not that of ΔTLV/year. Emphysema quantification is very sensitive to various conditions, including the level of inspiration, and this issue becomes more important when assessing longitudinal changes by chest CT 13 . Thus, we first carefully performed calibration using a lung phantom and annual CT. The distribution of ΔLAA% is diverse across the previous reports 10 , 53 , 54 . In this study, ΔLAA% was normally distributed and about 58.1% of participants were categorized in − 1 to 1 (ΔLAA%) / year. These results were consistent with the previous report 53 , but inconsistent with other report 10 . This discrepancy may be caused by differences in the inspiration levels or different machines.

There were several limitations to this study. First, Japanese COPD patients are reported to have a lower BMI and fewer exacerbations than COPD patients in other countries 29 , 55 . Thus, this study’s population may not reflect the general COPD population worldwide. Second, the number of females in this study was relatively small. It has been reported that male smokers are more likely to develop emphysema than female smokers 56 . Thus, the findings of our study may not be extrapolatable to female COPD patients. Third, we could not analyze the long-term follow-up outcome such as the rate of hospitalization or mortality. To date, the relationship between changes in of emphysematous progression and these outcomes are unknown. Further studies involving larger number of nested patients and longer follow-up are necessary. Fourth, we could not perform CT using a single CT scanner in this study. Although the calibration among four CT scanners was performed, the differences of CT values in the different scanners might have affected the results.

The rapid emphysema progression group exhibited a lower eosinophil count, and more often had osteoporosis than the non-progression group. Additionally, rapid progression of emphysema is associated with on-going deterioration of nutritional status in COPD patients. Future studies should focus on appropriate intervention for rapid changes in emphysematous progression and patients who are at risk of rapid emphysematous progression and might be requiring nutritional supplementation and targeted pharmacological interventions.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Low attenuation area

Annual changes in LAA%

Body mass index

Bone mineral density

Chronic obstructive pulmonary disease

Confidence interval

Computed tomography

COPD assessment test

C-reactive protein

Fat-free mass

Forced expiratory volume in 1 s

Forced expiratory volume in 1 s as a percentage of predicted forced expiratory volume in 1 s

Global Initiative for Chronic Obstructive Lung Disease

Inhaled corticosteroids

Keio COPD Comorbidity Research

Low attenuation area percentage

Lung volume reduction surgery

Muscle mass

Quality of life

Serum amyloid A

Soluble receptor for advanced glycation end products

St. George’s Respiratory Questionnaire

Surfactant protein D (SP-D)

ΔTotal lung volume

The percentage of airway wall area

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Acknowledgements

The authors would like to acknowledge Chiyomi Uemura for her contribution towards collecting data and all members of the Keio COPD Comorbidity Research (K-CCR) group for participation in this study. The authors would like to acknowledge Yasunori Sato for helping the statistical analysis.

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Tomoko Betsuyaku is deceased.

Authors and Affiliations

Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

Akihiro Tsutsumi, Shotaro Chubachi, Hidehiro Irie, Mamoru Sasaki, Tomoko Betsuyaku & Koichi Fukunaga

Department of Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

Yoshitake Yamada, Hiroaki Sugiura & Masahiro Jinzaki

Division of Pulmonary Medicine, Saitama Medical University Hospital, 38 Morohongo Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan

Hidetoshi Nakamura

Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa, 259-1193, Japan

Koichiro Asano

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A.T. participated in the design of the study, performed the statistical analyses, and was a major contributor in writing the manuscript. S.C. planned the study design and contributed to interpretation of results. T.B. conceived the study, participated in its design and coordination, and helped draft the manuscript.A. T., S. C., H. I., M. S., Y. Y., H. S., M. J., H. N., K. A., T. B., and K. F. collected the cohort datasets and revised the manuscripts critically for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Shotaro Chubachi .

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Tsutsumi, A., Chubachi, S., Irie, H. et al. Characteristics of chronic obstructive pulmonary disease patients with robust progression of emphysematous change. Sci Rep 11 , 9548 (2021). https://doi.org/10.1038/s41598-021-87724-8

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Association between common chronic pulmonary diseases and lung cancer: Mendelian randomization analysis

• Open access
• Published: 30 August 2024
• Volume 15 , article number  387 , ( 2024 )

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• Wenbin Zhang 1 ,
• Xinnan Song 1 ,
• Tianjun Song 2 &
• Dongyun Zeng 3 , 4  

Lung cancer is a leading public health concern worldwide. Previous evidence suggests that chronic obstructive pulmonary disease (COPD) and asthma may contribute to its development. However, whether these common chronic pulmonary diseases are causal factors of lung cancer remained unclear.

Summary statistics from genome-wide association studies (GWAS) were used for Mendelian randomization (MR) analysis. Genetic data for COPD were obtained from the Global Biobank Meta-Analysis Initiative, and asthma data were retrieved from the UK Biobank cohort. Suitable instrumental variables were selected based on quality control measures. GWAS summary data for lung cancer were obtained from a large study involved 85,716 participants. MR analysis was performed using various methods, and sensitivity analyses were conducted. Multivariable MR (MVMR) analysis was employed to account for potential confounding factors.

Our MR analysis revealed a significant causal association between COPD and lung cancer, including its subtypes such as lung squamous cell carcinoma, lung adenocarcinoma, and small cell lung carcinoma. Genetically predicted COPD was associated with a 64% increased risk of lung cancer and a 2.3 to 2.8-fold increased risk of the different subtypes. However, in the MVMR analysis adjusting for smoking, alcohol drinking, and body mass index, the association between COPD and lung cancer became non-significant. No significant association was observed between asthma (childhood-onset and adult-onset) and lung cancer and its histological subtypes.

Conclusions

Our study suggests a potential causal association between COPD and lung cancer. However, this association became non-significant after adjusting for smoking in the multivariable analysis.

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1 Introduction

Lung cancer is a global health burden and a leading cause of cancer-related mortality worldwide [ 1 ]. While smoking is widely recognized as the primary risk factor for lung cancer, recent evidence suggests that common chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and asthma may also contribute to its development [ 2 , 3 , 4 ]. Epidemiological studies have provided valuable insights into the associations between chronic pulmonary diseases and lung cancer. Understanding the potential causal relationship between these chronic pulmonary diseases and lung cancer is crucial for unraveling the complex etiology of this devastating disease.

COPD, characterized by persistent airflow limitation and frequently linked to long-term smoking, has been consistently associated with an increased risk of lung cancer [ 5 ]. However, these observational studies may be subject to confounders, such as smoking, which can complicate the interpretation of the results [ 6 ]. Similarly, the relationship between asthma and lung cancer has been the subject of investigation, but results from epidemiological studies have been conflicting. While some studies have reported an increased risk of lung cancer among individuals with asthma [ 7 , 8 , 9 ], others have found no significant association [ 10 , 11 ]. These inconsistencies could be attributed to over- or under-adjustment for confounding factors, including smoking and shared genetic predispositions.

To overcome the shortcomings of observational studies, in this study, we investigated the associations between common chronic pulmonary diseases (i.e., COPD and asthma) and the risk of lung cancer using Mendelian randomization (MR) methods [ 12 ]. Chronic bronchitis and emphysema, the two other common chronic lung diseases, were not considered in this study because no eligible genetic data were available. By employing genetic variants as instrumental variables, we can overcome confounding biases that may have affected previous epidemiological studies. These findings could provide valuable insights into the potential causal relationships between these chronic pulmonary diseases and lung cancer, ultimately leading to improved prevention strategies and targeted interventions for individuals at high risk.

In our research, we employed summary statistics from genome-wide association studies (GWAS) to implement MR analysis within a two-sample MR framework. MR has three fundamental assumptions: (1) instrumental variables (IVs) should demonstrate a strong association with the exposure, (2) IVs should not exhibit any association with potential confounding factors, and (3) IVs should not influence the outcome via pathways other than the exposure [ 13 ]. In the current study, we defined COPD and asthma as the exposures and lung cancer as the outcome.

2.1 GWAS of exposures and selection of instrumental variables

The genetic summary data for COPD were obtained from the Global Biobank Meta-Analysis Initiative (GBMI), which involved 18 biobanks comprising a total of 1.8 million participants with diverse ancestries [ 14 ]. For this study, we specifically collected the genetic data of participants with European ancestry. Among these individuals, 61,627 were diagnosed with COPD, while 980,360 were categorized as healthy controls (Additional file 1 : Tables S1-2). Each biobank independently conducted genotyping, imputation, and quality controls, as well as estimated sample ancestry. Inverse-variance weighted meta-analyses with fixed-effect were conducted for COPD, with the biobanks stratified by both ancestry and sex.

We retrieved the summary data of asthma from a GWAS based on the UK Biobank cohort [ 15 ]. In this GWAS, the asthma cases were identified by either self-reported or electronic health record and were classified as childhood-onset asthma (13,962 cases) and adult-onset asthma (26,582 cases) based on the age at first diagnosis. A total of 300,671 subjects free of any type of asthma were included as healthy controls. The GWAS was performed for childhood-onset asthma and adult-onset asthma, respectively, using BOLT-RELM software. Sex and an indicator of the array used for genotyping were incorporated as covariates.

To identify suitable IVs for COPD and asthma, we implemented a series of quality control measures. Firstly, we extracted single nucleotide polymorphisms (SNPs) that exhibited an association with exposures, meeting the conventional GWAS significance threshold (P < 5 × 10 –8 ). Secondly, we conducted a clumping procedure based on linkage disequilibrium (LD) estimates derived from the European samples within the 1000 genomes project. Specifically, we retained only one SNP from each pair of SNPs that displayed an LD estimate surpassing the specified threshold (0.01) within a window size of 10,000 kb, selecting the SNP with the lower P value. Thirdly, we excluded SNPs with a minor allele frequency below 1%. Additionally, we computed the F-statistics for the IVs [ 16 ]. A mean F-statistic exceeding 10 indicates a low likelihood of weak-instrument bias.

2.2 GWAS of outcomes

The largest GWAS conducted by McKay JD et al. [ 17 ] provided us with access to the GWAS summary data for lung cancer and its subtypes [i.e., lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung carcinoma (SCLC)]. The study comprised a total of 85,716 participants, including 29,266 cases of lung cancer (11,273 LUAD, 7,426 LUSC, and 2,664 SCLC). Within this European cohort, four independent GWASs focusing on lung cancer and its three subtypes were separately performed. From the lung cancer GWAS summary data, we obtained the relevant statistics, such as the beta coefficient and standard error, for the IVs. We then harmonized this data with that of the exposure GWAS. In cases where a requested SNP was not available in the cancer GWAS, we obtained data for a proxy SNP with a high linkage disequilibrium (LD) estimate (R 2  > 0.8) with the requested SNP. For subsequent two-sample MR analysis, we either corrected or excluded the effects of SNPs with inconsistent alleles or palindromic SNPs with ambiguous strands.

2.3 Mendelian randomization analysis

The univariable MR (UVMR) analysis was performed following the outlined procedure. Firstly, we examined horizontal pleiotropy using the MR-PRESSO global test [ 18 ] and excluded outliers (SNPs with P < 0.05) if evidence of horizontal pleiotropy was detected. Secondly, we assessed between-SNP heterogeneity using the inverse variance weighting (IVW) method based on the remaining SNPs after pleiotropy correction. Cochran's Q statistic was employed to evaluate heterogeneity, and SNPs with a significant P-value in the MR-PRESSO analysis (P-value of Cochran’s Q statistic < 0.05) were removed. Thirdly, MR analysis was conducted using the IVW method, which involved meta-analyzing the SNP-specific Wald estimates with multiplicative random effects to obtain the IVW estimate. To determine the statistical power for MR analysis, we utilized the mRnd website [ 19 ]. Additionally, we performed sensitivity analyses employing three different methods: MR-Egger regression, weighted median, and weighted mode methods. MR-Egger regression, based on the InSIDE assumption (Instrument Strength Independent of Direct Effect), consists of three components: (i) a test for directional pleiotropy, (ii) a test for a causal effect, and (iii) an estimation of the causal effect [ 13 ]. The weighted median and weighted mode methods are robust approaches utilized when more than 50% of the SNPs are considered invalid instruments [ 20 , 21 ]. Furthermore, an influential SNP analysis was conducted using the "leave-one-out" approach to identify any influential SNPs.

To address potential pleiotropy, we conducted multivariable MR (MVMR) analysis, which incorporated smoking, alcohol drinking, and body mass index (BMI) as covariates (Clinical variables present in the dataset). The genetic summary data for smoking and alcohol drinking were obtained from a GWAS of risk tolerance and risky behaviors involving over 1 million individuals [ 22 ]. Smoking status (ever vs. never smokers) and alcohol consumption measured in drinks per week were utilized as indicators. The genetic summary data for BMI were sourced from a GWAS on height and BMI involving approximately 700,000 individuals of European ancestry [ 23 ]. In cases where significant between-SNP heterogeneity was observed, we employed the multivariable weighted median method. Alternatively, if no significant heterogeneity was detected, we employed the multivariable IVW method.

To account for multiple testing, we utilized the false-discovery rate (FDR) adjustment, considering an FDR threshold of < 0.05 as statistically significant. Associations with a P-value < 0.05 but FDR > 0.05 were considered suggestive. All statistical analyses were conducted using R program (v 4.2.3). The MR analyses were performed using the TwoSampleMR, MendelianRandomization, and MRPRESSO packages.

In our MR analyses, we included nearly 100 IVs for childhood-onset asthma, all of which had a mean F-statistic greater than 400. This indicates that the IVs were suitable for further analysis (Table  1 ; Additional file Table S3-6). Similarly, for adult-onset asthma and COPD, we used 15–47 IVs, with mean F-statistics ranging from 38.6 to 285.6 (Table  1 ; Additional file Table S7-14). Most MR analyses showed significant between-SNP heterogeneity, as evidenced by a P-value for the Q-statistic of less than 0.05 (Table  1 ). However, our analysis did not detect any significant horizontal pleiotropy (all P-values for Egger-regression intercept were greater than 0.05). Based on the IVs used in our study, we had sufficient statistical power (greater than 80%) to detect odds ratios (ORs) between 0.8 and 1.2, as well as ORs below 0.8 or above 1.2 (Table  1 ).

In the UVMR analysis, we found no significant association between childhood-onset asthma and lung cancer or its histological subtypes. The OR for lung cancer was 1.00 (95% CI 1.00–1.00), for LUSC was 1.00 (95% CI 1.00–1.01), for LUAD was 1.00 (95% CI 1.00–1.01), and for SCLC was 1.00 (95% CI 1.00–1.01) (Fig.  1 A). Similarly, we did not detect any significant association between adult-onset asthma and lung cancer or its histological subtypes. The OR for lung cancer was 1.00 (95% CI 1.00–1.00), for LUSC was 1.00 (95% CI 1.00–1.01), for LUAD was 1.00 (95% CI 0.99–1.01), and for SCLC was 1.00 (95% CI 0.99–1.01) (Fig.  1 B). The sensitivity analyses yielded similar results.

Genetic association between asthma and chronic obstructive pulmonary disease (COPD) and lung cancers. A childhood-onset asthma, B adult-onset asthma, and C COPD. LUCA lung cancer, LUSC lung squamous cell carcinoma, LUAD lung adenocarcinoma, SCLC small cell lung carcinoma, IVW inverse variance weighted model

We found a significant association between COPD and lung cancer and its subtypes (Fig.  1 C). Genetically predicted COPD was associated with a 64% (95% CI 43–87%) increased risk of lung cancer and a 2.3–2.8-fold increased risk of the three other types of lung cancer (Fig.  1 C). This association remained statistically significant even after adjusting for multiple testing, and it was consistent across different MR approaches. Figure  2 displays the individual SNP effects on both exposure and outcome, as well as the regressed lines of different MR methods. To further validate the association between COPD and lung cancer, we conducted a leave-one-out analysis, which showed no significant outliers that influenced the observed association between these two diseases (Fig.  3 ).

Scatter plots showing individual SNP effect on both exposure and outcome. A – D panels show the SNP effects on childhood-onset asthma and lung cancer ( A ), lung squamous cell carcinoma ( B ), lung adenocarcinoma ( C ), and small cell lung carcinoma ( D ). E – H panels show the SNP effects on adult-onset asthma and lung cancer ( E ), lung squamous cell carcinoma ( F ), lung adenocarcinoma ( G ), and small cell lung carcinoma ( H ). I – L panels show the SNP effects on COPD and lung cancer ( I ), lung squamous cell carcinoma ( J ), lung adenocarcinoma ( K ), and small cell lung carcinoma ( L )

Leave-one-out analysis for association between genetically predicted COPD and lung cancer. The blue line denotes the integrated effect size; A – D represents lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, and small cell lung carcinoma, respectively

In the MVMR analysis, using smoking, alcohol drinking, and BMI as covariates, we found that the significant association between COPD and lung cancer observed in the UVMR analysis disappeared (Fig.  4 ). In this analysis, genetically predicted COPD was not significantly associated with lung cancer or its three histological subtypes, with ORs of 0.98 (95% CI 0.92–1.04), 1.00 (95% CI 0.91–1.10), 1.01 (95% CI 0.92–1.09), and 1.02 (95% CI 0.88–1.19), respectively. However, we did find a significant association between genetically predicted smoking and lung cancer, LUAD, and SCLC, suggesting that smoking might confound the association between COPD and lung cancer.

Genetic association between COPD and lung cancers according to multivariable Mendelian randomization analysis. LUCA lung cancer, LUSC lung squamous cell carcinoma, LUAD lung adenocarcinoma, SCLC small cell lung carcinoma

4 Discussion

In the current study, we aimed to investigate the causal relationship between chronic obstructive pulmonary disease (COPD) and asthma (including child-onset and adult-onset asthma) and lung cancer using Mendelian randomization (MR) analysis. The findings of our study provide valuable insights into the associations between these chronic pulmonary diseases and lung cancer. We observed a significant causal association between COPD and lung cancer, including its histological subtypes such as lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and small cell lung carcinoma (SCLC). These results were consistent across different MR approaches and add to the existing body of evidence from previous observational studies and MR analyses. However, we did not identify any significant association between asthma and lung cancer.

Our findings of a causal association between COPD and lung cancer are in line with previous observational studies that have reported an increased risk of lung cancer among individuals with COPD [ 24 , 25 , 26 ]. These studies have consistently shown a higher prevalence of COPD history among lung cancer patients and have suggested that the underlying inflammation and tissue damage in COPD contribute to the development of lung cancer [ 27 , 28 ]. The present study strengthens this evidence by using MR analysis, which provides a more robust approach to infer causality and minimize biases [ 29 ].

The mechanism driving the causal relationship between COPD and lung cancer can be attributed to several factors. COPD is characterized by chronic inflammation, oxidative stress, and tissue remodeling in the lungs, which create an environment conducive to genetic and epigenetic alterations that promote lung cancer development [ 30 , 31 ]. Furthermore, the strong association between COPD and smoking, a well-established risk factor for lung cancer, likely contributes to the increased risk observed in individuals with COPD. The synergistic effects of lung inflammation and the carcinogenic components of tobacco smoke further potentiate the risk of lung cancer in this population [ 32 ].

In our multivariable MR analysis, which accounted for confounding variables such as smoking, alcohol drinking, and body mass index, the significant association between COPD and lung cancer disappeared, and only smoking remained significantly associated with lung cancer. This underscores the confounding role of smoking in the association between COPD and lung cancer. Smoking is a well-known risk factor for both COPD and lung cancer and is strongly associated with the development of both conditions [ 33 ]. The inclusion of smoking as a confounder in the multivariable analysis highlights its influence on the observed association between COPD and lung cancer. These findings emphasize the importance of considering smoking as a confounding factor in future studies investigating the relationship between COPD and lung cancer.

Contrary to most of previous epidemiological studies [ 34 , 35 ], our MR analysis did not find a significant causal association between asthma and lung cancer. This discrepancy may be explained by various factors. Observational studies have suggested a potential link between asthma and an increased risk of lung cancer, hypothesizing that chronic airway inflammation and immune dysregulation in asthma may contribute to lung carcinogenesis. However, our MR analysis, which addresses confounding biases and provides a stronger basis for causal inference, did not support a direct causal relationship between asthma and lung cancer. These discordant findings highlight the importance of considering the limitations of observational studies and the potential influence of confounding factors in establishing causal associations.

While our study contributes valuable insights into the causal relationships between chronic pulmonary diseases and lung cancer, it is important to acknowledge its limitations. First, MR analysis relies on certain assumptions, such as the validity of instrumental variables and the absence of horizontal pleiotropy. Although we employed rigorous methods to address these assumptions, residual bias may still be present. Additionally, our study focused on the general population, and the findings may not be applicable to specific subgroups or populations with distinct genetic backgrounds. Future studies with larger sample sizes and diverse populations are needed to validate our findings and explore potential heterogeneity in the associations. Moreover, our study focused on common chronic pulmonary diseases, and the associations with rare or specific subtypes of lung cancer were not investigated. Further research is warranted to examine these associations and provide a more comprehensive understanding of the etiology of lung cancer.

Although, our study confirms the above findings and provides some reference for the early prevention and treatment of lung cancer, however, it is worth noting that our data were derived from public datasets and lacked real-world data supplementation, and more datasets will be collected to validate the findings in future studies. In addition, the selection of confounding factors needs further evaluation to consider whether there are other potential confounding factors.

In conclusion, our MR analysis supports a significant causal association between COPD and lung cancer, highlighting the independent contribution of COPD to lung cancer risk. The observed association can be attributed to the chronic inflammation, tissue remodeling, and the synergistic effects of smoking. However, our study did not find a significant causal association between asthma and lung cancer. The confounding role of smoking in the association between COPD and lung cancer was evident in our multivariable MR analysis. These findings underscore the importance of early detection and intervention for individuals with COPD, particularly those with a history of smoking, in order to prevent or manage lung cancer. Further research is needed to elucidate the underlying biological mechanisms and explore associations with rare or specific subtypes of lung cancer, ultimately enhancing our understanding and clinical management of these diseases.

Data availability

The GWAS summary data of COPD were available at http://results.globalbiobankmeta.org/ . The GWAS summary data of asthma were available at https://genepi.qimr.edu.au/staff/manuelF/gwas_results/main.html . The GWAS summary data of lung cancer were available at GWAS-catalog (GCST004748, GCST004750, GCST004744, and GCST004746). All data are available from the corresponding author.

Code availability

All codes are available from the corresponding author.

Abbreviations

Chronic obstructive pulmonary disease

• Mendelian randomization

Lung squamous cell carcinoma

Lung adenocarcinoma

Small cell lung carcinoma

Inverse variance weighted model

Genome-wide association study

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Tianjun Song

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Zhang, W., Song, X., Song, T. et al. Association between common chronic pulmonary diseases and lung cancer: Mendelian randomization analysis. Discov Onc 15 , 387 (2024). https://doi.org/10.1007/s12672-024-01274-9

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Psychometric properties of computerized adaptive testing for chronic obstructive pulmonary disease patient-reported outcome measurement

• Jiajia Wang 1 , 2 , 3   na1 ,
• Yang Xie 1 , 2 , 3   na1 ,
• Zhenzhen Feng 1 , 2 , 3 &
• Jiansheng Li 1 , 2 , 3  

Health and Quality of Life Outcomes volume  22 , Article number:  73 ( 2024 ) Cite this article

Metrics details

Computerized adaptive testing (CAT) is an effective way to reduce time, repetitious redundancy, and respond burden, and has been used to measure outcomes in many diseases. This study aimed to develop and validate a comprehensive disease-specific CAT for chronic obstructive pulmonary disease (COPD) patient-reported outcome measurement.

The discrimination and difficulty of the items from the modified patient-reported outcome scale for COPD (mCOPD-PRO) were analyzed using item response theory. Then the initial item, item selection method, ability estimation method, and stopping criteria were further set based on Concerto platform to form the CAT. Finally, the reliability and validity were validated.

The item discrimination ranged from 1.05 to 2.71, and the item difficulty ranged from − 3.08 to 3.65. The measurement reliability of the CAT ranged from 0.910 to 0.922 using random method, while that ranged from 0.910 to 0.924 using maximum Fisher information (MFI) method. The content validity was good. The correlation coefficient between theta of the CAT and COPD assessment test and modified Medical Research Council dyspnea scale scores using random method was 0.628 and 0.540 ( P  < 0.001; P  < 0.001) respectively, while that using MFI method was 0.347 and 0.328 ( P  = 0.007; P  = 0.010) respectively. About 11 items (reducing by 59.3%) on average were tested using random method, while about seven items (reducing by 74.1%) on average using MFI method. The correlation coefficient between theta of the CAT and mCOPD-PRO total scores using random method was 0.919 ( P  < 0.001), while that using MFI method was 0.760 ( P  < 0.001).

Conclusions

The comprehensive disease-specific CAT for COPD patient-reported outcome measurement is well developed with good psychometric properties, which can provide an efficient, accurate, and user-friendly measurement for patient-reported outcome of COPD.

Chronic obstructive pulmonary disease (COPD), characterized by chronic respiratory symptoms and persistent (often progressive) airflow limitation, is a leading cause of morbidity and mortality worldwide inducing an economic and social burden that is both substantial and increasing [ 1 ]. The prevalence of COPD among people aged 40 years or older is 12.64% around the whole world, and 13.7% in China [ 2 , 3 ]. COPD is the third leading causes of death responsible for approximately 6% of the world’s total deaths in 2019 [ 4 ]. Health status in patients with COPD declines over time [ 5 ]. A patient-reported outcome (PRO) is any report of a patient’s health status derived directly from the patient [ 6 ]. It has been increasingly recognized that PRO instruments play an important role in assessing health status and treatment outcome of COPD [ 7 , 8 ]. Previously, our team has developed and validated a 27-item comprehensive disease-specific PRO measurement, the modified Patient-reported Outcome Scale for COPD (mCOPD-PRO), which is a 5-point Likert scale including physiological, psychological, and environmental domains, with lower scores indicating better health status [ 9 ]. In the stage of validation of the instrument, the measurement properties assessed referred to internal consistency reliability, content validity, construct validity, criterion validity, known groups validity, and feasibility [ 9 ]. It is showed that the mCOPD-PRO has good psychometric properties with the Cronbach’s alpha of 0.954 [ 9 ]. As a common chronic disease worldwide, patients with COPD usually require frequent outcome measures. In this case, the response burden of measurement tools can’t be ignored. Although the median completion time of the mCOPD-PRO is only 5 min, given the number of items, the response burden still needs to be considered [ 9 ].

Computerized adaptive testing (CAT), based on item response theory (IRT), is a form of testing that uses a computer to automatically select appropriate items for the examinee [ 10 ]. Generally speaking, CAT selects an item from an item bank that is appropriate to the examinee’s theta, an index of the latent trait in IRT, here the health status, and then updates the examinee’s theta according to the responses to this item [ 10 ]. This process is repeated until the examinee’s theta is accurately estimated [ 10 ]. CAT is an effective way to reduce time, repetitious redundancy, and respond burden, and has been increasingly used for psychological and health measurement in an efficient, accurate, and user-friendly manner [ 11 , 12 , 13 ]. Recently, CAT has also been used for outcome measurement of COPD [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Norweg A et al. developed a modified and expanded item bank of Dyspnea Management Questionnaire measuring the dyspnea, one of the most prominent symptoms in COPD, to construct the CAT using an internally developed CAT program, and subsequently conducted CAT real data simulations to estimate the CAT’s accuracy, precision, and validity [ 14 ]. Choi SW et al. and Yount SE, et al. also focused on the dyspnea in COPD, and developed a measure of dyspnea and related functional limitations, where post-hoc CAT simulations were conducted to determine the number of items required to achieve high precision [ 15 , 16 ]. Additionally, Yount SE et al. administered the Patient-Reported Outcomes Measurement Information System (PROMIS ® ) measures using CAT, followed by administration of any remaining short form items that had not yet been administered by CAT, to examine their responsiveness to changes associated with COPD exacerbation recovery [ 17 ]. Paap MCS et al. performed simulations using empirical data from patients with COPD to assess the incremental value of multidimensional CAT compared with unidimensional CAT, and investigated the item usage for the multidimensional CAT drawing items from three PROMIS domains (fatigue, physical function, and ability to participate in social roles and activities) and a COPD-specific item bank [ 18 , 19 ]. O’Hoski S et al. estimated the test-retest reliability, construct validity, and responsiveness of the CAT version of Late Life Disability Instrument in patients with COPD, which was a participation measure not specifically developed for COPD [ 20 , 21 ]. Ho EH et al. used plausible values to account for measurement error and analyze the probability of true within-individual change in a sample of patients with COPD completing two PROMIS domains (physical function and fatigue), and indicated that CAT have better ability to detect change compared to short forms [ 22 ]. However, although two of the measures are designed for COPD, they are not comprehensive. By comparison, the others are multi-dimensional, but they are not designed for COPD or only include part of disease-specific items. The comprehensive disease-specific CAT for PRO measurement of COPD is urgently needed. Therefore, the current study aimed to develop and validate a comprehensive disease-specific CAT for PRO measurement of COPD based on the paper-and-pencil version of mCOPD-PRO.

Developing the CAT

The CAT was developed based on an open-source online adaptive testing platform Concerto developed and maintained by the University of Cambridge Psychometrics Centre (Available from: https://concertoplatform.com/about ) [ 23 ]. The essential elements of the CAT involved item parameters calibration, initial item, item selection method, ability estimation method, and stopping criteria [ 24 ].

Item parameters calibration

The item bank of the CAT was the same as the paper-and-pencil version of mCOPD-PRO. Item parameters including discrimination (a) and difficulty (b) were estimated using graded response model of IRT. Before modelling, the core assumptions (unidimensionality, local independence, and monotonicity) were evaluated. The unidimensionality assumption was assessed using both exploratory and confirmatory factor analysis. For the former, a ratio of the eigenvalue for the first factor to the second factor in excess of four was supportive of the unidimensionality assumption [ 25 ]. As for the latter, the recommended criteria for fit indices were as follows: (1) the comparative fit index and non-normed fit index were close to 0.90; (2) the incremental fit index was close to 0.95; and (3) the standardized root-mean-square residual and root-mean-square error of approximate (RMSEA) were close to 0.08 [ 26 , 27 ]. A Chen and Thissen’s index of > 0.30 implied possible local dependence [ 28 ]. The monotonicity was considered acceptable if the scalability coefficients (Hi) for the items were > 0.30 [ 29 ]. The data were from 366 patients with COPD in the phase of validation of the paper-and-pencil version of mCOPD-PRO [ 9 ]. The mean age was 66 years; 279 cases (76.2%) were males and 87 cases (23.8%) were females.

Initial item and item selection method

Item selection is dependent on the examinee’s responses to a given item. The random and maximum Fisher information (MFI) methods were adopted to select items. The former is simple and effective, and selects items randomly, while the latter selects items based on the information of items. Thus, the initial item selected by the random method is random, while that selected by the MFI method is the one with the maximum information.

Ability estimation method

As a key component of CAT, the ability estimation method not only affects the accuracy of ability estimation, but also affects the efficiency of item selection and the determination of stopping rule. In this study, the maximum likelihood estimation, one of the most widely used ability estimation method, was used to conduct ability estimation.

Stopping criteria

Generally speaking, the stopping criteria of CAT involves fixed length and standard error of measurement (SEM). The measurement accuracy may vary among subjects with different fixed lengths, and the fixed SEM can best reflect the core idea of CAT. In this study, the SEM of ≤ 0.30 was determined as our stopping criteria, which meant that the test was terminated if the pre-specified value of SEM was met or the item bank was exhausted [ 10 ].

Simulation test

The CAT simulation was performed to determine the appropriate sample size for the validation of the CAT based on the true participants’ responses data from the phase of validation of the paper-and-pencil version of mCOPD-PRO [ 9 ]. R commands for the simulated data of different sample sizes (60 cases, 100 cases, 300 cases, 500 cases, 1000 cases, 3000 cases, and 5000 cases, respectively) were generated using Firestar version 1.5.1, and then ran in R version 3.5.1. The CAT simulation settings for Firestar version 1.5.1 were as follows: (1) for the IRT model, graded response model was used; (2) for the item selection method, random and MFI methods were used respectively; (3) for the stopping criteria, the maximum SEM was 0.30; and (4) for the simulated data, the mean was specified as zero with the standard deviation of one.

Validating the CAT

There is no consensus regarding the validation of CAT for PRO instruments. In our study, the reliability was estimated based on IRT method, while the content and criterion validity were evaluated referring to classical test theory method. It was assumed that the response to each item of the CAT was consistent with that of the paper-and-pencil version of mCOPD-PRO in the phase of validation [ 9 ]. However, the number of items selected by the CAT might be less than that of the paper-and-pencil version of mCOPD-PRO.

• Reliability

The measurement reliability (r) was calculated through the SEM of the CAT. The relationship between SEM and measurement reliability (r) is inversely proportional function (assuming that the mean ability of the subjects is zero and the standard deviation is one). The formula: SEM = (1-r) 1/2 ; that is, the measurement reliability (r) = 1-SEM 2 [ 10 , 24 ].

Content validity

The content validity of the CAT was assessed based on the content validity of the paper-and-pencil version of mCOPD-PRO in the phase of validation [ 9 ].

Criterion validity

The COPD assessment test and modified Medical Research Council dyspnea scale (mMRC) recommended by the Global Strategy for the Diagnosis , Management , and Prevention of Chronic Obstructive Pulmonary Disease were both used as gold standard [ 1 , 30 , 31 ]. The criterion validity was evaluated using correlation coefficient between the test result theta of the CAT and COPD assessment test and mMRC scores. The correlation coefficient of ≥ 0.40 was considered acceptable [ 9 ].

Statistical analysis

Continuous data were expressed as the mean ± standard deviation or median (interquartile range), while categorical data were presented as frequencies (percentages). The confirmatory factor analysis was conducted using LISREL version 8.70 (Scientific Software International, Inc., Chicago, IL, USA). The local independence and monotonicity were tested using “TestAnaAPP” and “mokken” packages in R (The R Foundation, Vienna, Austria), respectively. The IRT analysis was performed using MULTILOG version 7.03 (Scientific Software International, Inc., Chicago, IL, USA), and the CAT simulation was conducted using Firestar version 1.5.1 (Northwestern University Feinberg School of Medicine, Chicago, IL, USA) and R version 3.5.1 (The R Foundation, Vienna, Austria). Additionally, descriptive statistics, exploratory factor analysis, calculation of measurement reliability (r), correlation analysis, and independent sample t -test were conducted using SPSS version 22.0 (IBM Corporation, Armonk, NY, USA).

Calibration of item parameters

The exploratory factor analysis showed that the ratio of the eigenvalues for the first factor (12.551) to the second factor (2.015) is 6.229 surpassing the thresholds of 4. Moreover, the confirmatory factor analysis showed that comparative fit index, incremental fit index, non-normed fit index, standardized root-means-quare residual, and RMSEA were 0.91, 0.91, 0.90, 0.11, and 0.16, respectively. The fit indices were close to the thresholds, except for the RMSEA which was less satisfactory. 32 of 351 item pairs (9.1%) showed a Chen and Thissen’s index of above threshold of 0.30 with a maximum of 0.526, and 25 of 32 item pairs (78.1%) ranged from 0.30 to 0.40. Most of the locally dependent items were found to be related to respiratory symptoms of COPD, such as cough, sputum, chest tightness, panting, and shortness of breath. Given the fact that multiple respiratory symptoms often coexist, and that one symptom may involve more than one item (for example, the items “Did you cough?“, “Was your cough aggravated by daily activities?“, and “Was your cough aggravated by mood swings?“), the test results of local independence are considered acceptable. The scalability coefficients (Hi) for all the items ranged from 0.36 to 0.54 exceeding the thresholds of 0.30. Overall, it can be considered that all three assumptions for IRT analysis are met. The item discrimination (a) of mCOPD-PRO ranged from 1.05 to 2.71, and the item difficulty (b) ranged from − 3.08 to 3.65 (Table  1 ). Moreover, the difficulty (b) of 24 items (88.9%) was between − 3.0 and 3.0. The first and fifth item characteristic curve showed monotonous changes, and the second, third and fourth item characteristic curve showed normal distribution except for individual items (Additional file 1 ). The maximum value of total information was 34.224 (Additional file 2 ).

Establishment of CAT model

The CAT model established based on Concerto platform included item bank, algorithm, test system, score report, and management system modules.

Formation of the CAT

The CAT was formed. At least five links ( Login , Run , Test , Feedback , and End ) were needed to complete the whole test. Taking a test with random item selection method as an example, a total of 11 items were tested. The test procedure was presented in Additional file 3 .

The results of CAT simulation using random and MFI methods were described in Table  2 , Figs.  1 and 2 , and Additional file 4 – 9 . Despite different sample sizes of simulated data (60 cases, 100 cases, 300 cases, 500 cases, 1000 cases, 3000 cases, and 5000 cases, respectively), the items administered in different simulation testes using random method were relatively discrete, and the average number was all ten. The correlation coefficient between simulated and true theta estimates ranged from 0.970 to 0.976, and the average SEM was 0.290 or 0.291. By comparison, the items administered in different simulation testes using MFI method were relatively centralized, and the average number was all seven. The correlation coefficient between simulated and true theta estimates ranged from 0.968 to 0.979, and the average SEM ranged from 0.289 to 0.292.

Number of items administered using random method in different simulation tests

Number of items administered using maximum Fisher information method in different simulation tests

Validation of the CAT

According to the results of CAT simulation above, the sample size for the validation of the CAT was determined as 60 cases. Therefore, the true participants’ responses data from 60 patients with COPD in the phase of validation of the paper-and-pencil version of mCOPD-PRO were used to evaluate the reliability and validity of the CAT. The mean age was 65 years; 41 cases (68.3%) were males and 19 cases (31.7%) were females.

The SEM ranged from 0.266 to 0.300 using random method, while that ranged from 0.276 to 0.300 using MFI method (Table  3 ). On this basis, the calculated measurement reliability (r) ranged from 0.910 to 0.929 using random method, while that ranged from 0.910 to 0.924 using MFI method (Table  3 ). The correlation coefficient of SEM and measurement reliability (r) between the two methods were both 0.267 ( P  = 0.040; P  = 0.040), and the independent sample t -test showed that there were no significant differences in SEM and measurement reliability (r) between the two methods ( t =-0.533, P  = 0.594; t =-0.472, P  = 0.637).

As was reported in our previous publication, the paper-and-pencil version of mCOPD-PRO had good content validity [ 9 ]. The CAT was developed based on the 27 items of the paper-and-pencil version of mCOPD-PRO, and therefore, was considered to have good content validity.

The theta ranged from − 2.331 to 1.226 using random method, while that ranged from − 2.336 to 1.102 using MFI method (Table  3 ). The correlation coefficient of theta between the two methods was 0.753 ( P  < 0.001), and the independent sample t -test showed that there were no significant differences in theta between the two methods ( t =-0.514, P  = 0.609). The correlation coefficient between theta and COPD assessment test and mMRC scores using random method was 0.628 and 0.540 ( P  < 0.001; P  < 0.001) respectively, while that using MFI method was 0.347 and 0.328 ( P  = 0.007; P  = 0.010) respectively.

Comparisons between the CAT and the paper-and-pencil version of mCOPD-PRO

The initial item of the paper-and-pencil version of mCOPD-PRO was all the same (“Did you cough?“), while that of the CAT was random using random method, and was all the same (“Was your chest tightness aggravated by daily activities?“) using MFI method. All (27 items) were tested for the paper-and-pencil version, while about 11 items (reducing by 59.3%) were tested on average for the CAT using random method with at least eight items (four cases) and at most 26 items (only one case), and about seven items (reducing by 74.1%) on average using MFI method with at least six items (36 cases) and at most 20 items (only one case) (Additional file 10 ). The correlation coefficient between theta of the CAT and the paper-and-pencil version of mCOPD-PRO total scores using random and MFI methods was 0.919 and 0.760 ( P  < 0.001; P  < 0.001) respectively. The correlation coefficient between theta and physiological, psychological and surrounding domain scores using random and MFI methods was presented in Table  4 .

To our knowledge, this was the first study to develop and validate a comprehensive disease-specific CAT for PRO measurement of COPD by using the Concerto platform. Our study showed that the CAT is efficient, accurate, and user-friendly with good reliability and validity. Compared with the paper-and-pencil version of mCOPD-PRO, the average number of items tested for the CAT reduced by more than 50%, which indicated a significant reduction of respond burden. Moreover, the measurement accuracy was quite high. These findings are believed to contribute to the field.

As an open-source online adaptive testing platform, the Concerto platform has been used for neuropsychological testing and PRO measurement, and has been considered capable of harnessing the power of CAT and machine learning for developing and administering advanced PRO measurement [ 23 , 32 , 33 , 34 ]. Therefore, our study chose this platform to establish the CAT. The item bank of high quality is the basis to ensure the scientificity and maximize the advantages of CAT. In the current study, the item discrimination (a) and difficulty (b) were calibrated using IRT analysis. Our results suggested that the item parameters were generally ideal, which ensured the robustness of the CAT. As is well known, the sample size for the validation of CAT is important. However, it is difficult to determine the appropriate sample size by repeated clinical tests. Therefore, the CAT simulation with different sample sizes was performed based on the true participants’ responses data of the paper-and-pencil version of mCOPD-PRO in the phase of validation. It was showed that the results of simulation tests were stable and reliable, and the sample size of 60 cases was enough. Therefore, the true participants’ responses data from 60 participants was used for analysis in this study.

At present, the researches on psychometric properties of CAT for PRO instruments are lacking. In our study, the reliability and validity were evaluated by referring to relevant researches in the field of psychological and educational measurements. The measurement reliability (r) was calculated through the SEM obtained from the CAT. As a result, the measurement reliability (r) using random and MFI methods were both greater than 0.9, which indicated a good reliability of the CAT. As for criterion validity, the selection of standard instruments is quite important. Both COPD assessment test and mMRC were selected as our gold standards, which were recommended by the Global Strategy for the Diagnosis , Management , and Prevention of Chronic Obstructive Pulmonary Disease [ 1 , 30 , 31 ]. The test results of the CAT showed moderate correlation with the two standard instruments using random method, and this indicated a good criterion validity. By comparison, the test results showed weak correlation with the two standard instruments using MFI method. This may be due to the concentration of items in psychological domain, and the results need to be further verified.

Although the item bank of the CAT and the paper-and-pencil version of mCOPD-PRO was the same, the order and number of items used were different. The initial item of the paper-and-pencil version was the first item “Did you cough?“, while that of the CAT was random or the same “Was your chest tightness aggravated by daily activities?“. A number of studies have assessed the effect of CAT on the length and accuracy of PRO measurement, robustly demonstrating that CAT can reduce the length of measurement by more than 50% while keeping excellent agreement between fixed-length measurement and CAT [ 34 ]. A CAT simulation study showed that when the stopping rule was matched to the reliability of published World Health Organization Quality of Life (WHOQOL) assessment instrument, the item bank produced a measurement that was as reliable as the paper-and-pencil version of WHOQOL-BREF and WHOQOL-100 with 43% and 75% fewer items, respectively [ 35 ]. Our study showed that the average number of items tested for the CAT was about 11 using random method and seven using MFI method, respectively, which were almost consistent with our simulation tests. More importantly, compared with the paper-and-pencil version mCOPD-PRO, the average number of items tested for the CAT reduced by 59.3% and 74.1%, respectively, and the findings are similar to the results of the CAT simulation study mentioned above [ 35 ]. Accordingly, it is obvious that the respond burden of the mCOPD-PRO was significantly reduced. That is, the CAT can improve the testing efficiency without reducing the measurement accuracy. In addition, the test results of the CAT showed strong correlation with the paper-and-pencil version of mCOPD-PRO, which supported the reliability of the CAT, and was in line with the published literature [ 34 ]. What’s more, the strong correlation of the test results between the two methods indicated the robustness of our CAT model.

There were limitations to our study. First of all, the CAT was developed and validated based on the Concerto platform, there may be limitation. Second, due to the different scoring rules and dimensions between the CAT and the paper-and-pencil version of mCOPD-PRO, this study did not directly compare the differences of test results between the two versions. Third, given no consensus regarding the psychometric properties of CAT for PRO instruments, further studies are needed to verify our discoveries. In addition, the tests based on different item selection methods, ability estimation methods, or stopping criteria remain to be explored. Furthermore, the accuracy of parameter estimation would benefit from the survey with larger sample sizes in the future.

In conclusion, the comprehensive disease-specific CAT for PRO measurement of COPD is well developed, and has good reliability, content validity, and criterion validity. Compared with the paper-and-pencil version of mCOPD-PRO, the CAT can provide an efficient, accurate, and user-friendly measurement for PRO of COPD. Further studies remain to be explored in the future.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Chronic Obstructive Pulmonary Disease

Patient-reported Outcome

Modified Patient-reported Outcome Scale for Chronic Obstructive Pulmonary Disease

Computered Adaptive Testing

Item Response Theory

Root-mean-square Error of Approximate

Maximum Fisher Information

Standard Error of Measurement

Modified Medical Research Council Dyspnea Scale

World Health Organization Quality of Life

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Acknowledgements

The authors thank all the experts and patients involved in this study for their kind help.

This study was supported by National Natural Science Foundation of China (81473648, 81830116), Qi-Huang Chief Scientist Project of National Administration of Traditional Chinese Medicine ([2020]219), and Central Plains Thousand People Program (ZYQR201810159).

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Jiajia Wang and Yang Xie have contributed equally to this work.

Authors and Affiliations

Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China

Jiajia Wang, Yang Xie, Zhenzhen Feng & Jiansheng Li

Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China

Department of Respiratory Diseases, the First Affiliated Hospital of Henan University of Chinese Medicine, 19 Renmin Road, Zhengzhou, 450003, China

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JJW was responsible for the modeling and analysis of data, and drafted the manuscript. YX and ZZF were responsible for the interpretation of data. YX and JSL conceived this study and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jiansheng Li .

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This study was approved by the Institution Review Board of the First Affiliated Hospital of Henan University of Chinese Medicine (2015HL-048). Written informed consent was obtained from all participants included in this study.

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12955_2024_2291_MOESM1_ESM.jpg

Supplementary Material 1: Additional file 1 The matrix plot of item characteristic curves of the modified patient-reported outcome scale for chronic obstructive pulmonary disease (mCOPD-PRO)

12955_2024_2291_MOESM2_ESM.jpg

Supplementary Material 2: Additional file 2 The test information and standard error of measurement of the modified patient-reported outcome scale for chronic obstructive pulmonary disease (mCOPD-PRO)

Supplementary Material 3: Additional file 3 The computerized adaptive testing procedure of an example

Supplementary Material 4: Additional file 4 The percent of item usage using random method in different simulation tests

12955_2024_2291_MOESM5_ESM.jpg

Supplementary Material 5: Additional file 5 The correlation between simulated and true theta estimates using random method in different simulation tests

12955_2024_2291_MOESM6_ESM.jpg

Supplementary Material 6: Additional file 6 The test information and standard error of measurement using random method in different simulation tests

12955_2024_2291_MOESM7_ESM.jpg

Supplementary Material 7: Additional file 7 The percent of item usage using maximum Fisher information method in different simulation tests

12955_2024_2291_MOESM8_ESM.jpg

Supplementary Material 8: Additional file 8 The correlation between simulated and true theta estimates using maximum Fisher information method in different simulation tests

12955_2024_2291_MOESM9_ESM.jpg

Supplementary Material 9: Additional file 9 The test information and standard error of measurement using maximum Fisher information method in different simulation tests

Supplementary Material 10: Additional file 10 The number of items tested for the computerized adaptive testing

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Wang, J., Xie, Y., Feng, Z. et al. Psychometric properties of computerized adaptive testing for chronic obstructive pulmonary disease patient-reported outcome measurement. Health Qual Life Outcomes 22 , 73 (2024). https://doi.org/10.1186/s12955-024-02291-6

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Health care of the disadvantaged: chronic obstructive pulmonary disease in later life

Affiliation.

• 1 Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
• PMID: 38026408
• PMCID: PMC10666629
• DOI: 10.3389/fpubh.2023.1304494

Introduction: Chronic diseases have emerged as the foremost causes of death and disability worldwide. This article employs an ethnographic approach to conduct a gerontological investigation of chronic obstructive pulmonary disease (COPD), the third leading cause of global mortality, trailing only cardiovascular diseases and cancers.

Methods: This study is rooted in an extensive amalgamation of biomedical literature and official epidemiological data. Additionally, it offers enriched insights through an extensive ethnographic research methodology, encompassing ethnographic fieldwork, participant observation, interviews, and focus groups.

Results: The findings expound that individuals grappling with chronic obstructive pulmonary disease often undergo intricate cognitive and emotional experiences, necessitating holistic solutions that consider psychological processes, contextual factors, and subjective age. These challenges extend beyond the purview of a purely medical perspective.

Conclusion: This article concludes that the lens of gerontology is invaluable in comprehending chronic obstructive pulmonary disease, particularly due to its association with old age and increased longevity. Among older individuals, diagnosing the condition presents a formidable challenge. Breathlessness, a cardinal symptom, often overlaps with normal age-related declines in pulmonary function, rendering COPD's insidious onset misconstrued as a consequence of aging-related changes.

Keywords: United Kingdom; breathlessness; chronic disease; ethnography; respiratory disease; stigma; support groups.

Copyright © 2023 Nyman.

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The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Epidemiology of chronic obstructive pulmonary disease: a literature review

Catherine e rycroft.

1 Market Access and Outcomes Strategy, RTI Health Solutions, Manchester, United Kingdom;

2 Epidemiology, RTI Health Solutions, Waltham, MA, USA;

Karin Becker

3 Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim, Germany

Associated Data

Search strategy used for literature search

Abbreviations: COPD, chronic obstructive pulmonary disease; MeSH, Medical Subject Headings.

Summary of articles included in literature review

Abbreviation: NA, not applicable.

Articles reporting prevalence included in literature review

Abbreviations: ATS, American Thoracic Society; ATS/ERS-LLN 5 , ATS/ERS-defined LLN at the 5th percentile; BDT, bronchodilator test; BTS, British Thoracic Society; CBE, chronic bronchitis or emphysema; CCHS, Canadian Community Health Survey; COPD, chronic obstructive pulmonary disease; ECRHS, European Community Respiratory Health Survey; ERS, European Respiratory Society; F, female; FEV 1 , forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GP, general practitioner; GPRD, General Practice Research Database; HCPCS, Healthcare Common Procedure Coding System; HIS6, a population-based survey; HSD, a computerized general-practice database; HSE, Health Survey for England; ICD-9, International Classification of Diseases, 9th Revision; ICD-10, International Classification of Diseases, 10th Revision; LLN, lower limit of normal; LMS-LLN 5 , lambda-mu-sigma-defined LLN at the 5th percentile; M, male; MOH, Ministry of Health; NA, not applicable; NHANES, National Health and Nutrition Examination Survey; NHIS, National Health Interview Survey; NR, not reported; OLIN, obstructive lung disease in Northern Sweden; SD, standard deviation; UK, United Kingdom; USA, United States of America.

The aim of this study is to quantify the burden of chronic obstructive pulmonary disease (COPD) – incidence, prevalence, and mortality – and identify trends in Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America. A structured literature search was performed (January 2000 to September 2010) of PubMed and EMBASE, identifying English-language articles reporting COPD prevalence, incidence, or mortality. Of 2838 articles identified, 299 full-text articles were reviewed, and data were extracted from 133 publications. Prevalence data were extracted from 80 articles, incidence data from 15 articles, and mortality data from 58 articles. Prevalence ranged from 0.2%–37%, but varied widely across countries and populations, and by COPD diagnosis and classification methods. Prevalence and incidence were greatest in men and those aged 75 years and older. Mortality ranged from 3–111 deaths per 100,000 population. Mortality increased in the last 30–40 years; more recently, mortality decreased in men in several countries, while increasing or stabilizing in women. Although COPD mortality increased over time, rates declined more recently, likely indicating improvements in COPD management. In many countries, COPD mortality has increased in women but decreased in men. This may be explained by differences in smoking patterns and a greater vulnerability in women to the adverse effects of smoking.

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Introduction

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by a decline in lung function over time and accompanied by respiratory symptoms, primarily dyspnea, cough, and sputum production. 1 Consequently, COPD is associated with a significant economic burden, including hospitalization, work absence, and disability. 1 Current data suggest that COPD mortality is increasing, and by 2020, COPD is predicted to be the third-leading cause of death worldwide. 2

The severity of COPD can be determined and classified by different methods. Incidence and prevalence estimates differ greatly, depending on the methods used for diagnosis and classification. It is important to understand the true epidemiology of COPD to monitor trends over time and to determine the effectiveness of potential treatments or preventive measures.

The objectives of this study were to conduct a structured, comprehensive literature review to identify articles on the epidemiology of COPD in eleven developed countries (Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States of America [USA]); quantify the burden of illness of COPD in terms of incidence, prevalence, and mortality; identify trends in these data over time; and identify any trends regarding age, sex, and/or disease severity.

A structured and comprehensive search of medical literature indexed in the electronic PubMed ( http://www.ncbi.nlm.nih.gov/sites/entrez ) and EMBASE ( http://www.embase.com/info/accessing-embase ) databases was conducted using a detailed search strategy with a combination of free-text search terms and medical subject headings. Search terms included terms related to COPD, chronic bronchitis, and pulmonary emphysema, and terms for epidemiology including incidence, prevalence, rate of mortality, and risk of dying (see Table S1 ). The search was restricted to articles in English published between January 2000 and September 2010.

Articles identified from each literature search were screened in two phases by one reviewer using predefined inclusion and exclusion criteria. Phase 1 involved reviewing all titles and abstracts to determine whether to include or exclude them, and Phase 2 involved reviewing the full text of the articles identified in Phase 1 to determine their inclusion or exclusion for data extraction.

Articles were included if they reported incidence, prevalence, and/or mortality in COPD, or trends in such data for at least one of the countries of interest (Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the UK, or the USA). Articles were excluded if they met at least one of the following exclusion criteria; that is, if the article:

• was a comment, an editorial, a letter, a case report, or a clinical trial;
• did not report data specifically for COPD;
• did not report data on incidence, prevalence, and/or mortality, or trends in such data;
• was not concerned with any of the countries of interest;
• focused on a limited population, including studies in small numbers of patients, patients in very limited sub-populations, such as patients who were hospitalized, and patients with an existing condition that increased their risk for COPD, or studies that investigated risk factors for COPD;
• reported a study conducted in a single site, clinic, hospital, or city;
• focused on comorbidities in patients with COPD; or reported incidence, prevalence, or mortality associated specifically with exacerbations of COPD, not COPD overall;
• reported incidence or prevalence estimates from a model (ie, the article was not the primary data source);
• reported on design of a study but did not report results;
• was a duplicate of an article that had been previously identified.

Inclusion and exclusion processes were documented fully, and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart was completed. 3

Relevant data were extracted from the included articles into evidence tables for each country. Quality-control checks verifying the summarized data against the source articles to confirm correct extraction were performed by an independent quality-control specialist on all extracted data.

Summary of identified studies

The PRISMA flow chart ( Figure 1 ) presents the two-phase screening approach, and the number of articles included, and excluded at each phase. From the initial database searches, 2838 unique articles were identified of which 299 articles were retrieved for full-text evaluation. Of those, 133 were included for data extraction.

PRISMA flow diagram of the literature review.

Notes: a Includes studies in small numbers of patients, patients in very specific populations, patients who are hospitalized, patients with an existing condition that increases risk for COPD, and studies investigating risk factors for COPD.

Abbreviations: COPD, chronic obstructive pulmonary disease; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Overall, the greatest number of relevant articles was identified for the USA (n = 49), Sweden (n = 19), and Canada (n = 12) (see Table S2 ). A total of 19 articles were identified that reported data for more than one country (“multicountry” studies). Most articles (80) focused on prevalence of COPD; another 15 articles reported incidence, and 58 reported mortality associated with COPD ( Table S2 ). Twelve articles reported trends in incidence and/or prevalence, whereas 25 articles reported trends in mortality.

The reported prevalence of COPD ranged from 0.2% in Japan to 37% in the USA, but this varied widely across countries and populations, by diagnosis method, and by age group analyzed. Table 1 presents those studies that measured COPD by multiple methods within the same population to compare prevalence estimates resulting from different methods. Prevalence estimates varied according to the method of diagnosis and classification of COPD. 4 – 7 When individuals were identified by spirometry, and classified using the 2001 Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD (forced expiratory volume in 1 second/forced vital capacity [FEV 1 /FVC] < 0.70), a greater COPD prevalence was reported than when using other classification methods such as the British Thoracic Society (BTS), European Respiratory Society (ERS), American Thoracic Society (ATS) spirometric, or ATS clinical criteria. 4 – 6 , 8 , 9

COPD prevalence studies comparing multiple methods

Abbreviations: ATS, American Thoracic Society; ATS/ERS-LLN 5 , ATS/ERS defined LLN at the 5th percentile; BTS, British Thoracic Society; CB, chronic bronchitis; CBE, chronic bronchitis or emphysema; COPD, chronic obstructive pulmonary disease; ECRHS, European Community Respiratory Health Survey; ERS, European Respiratory Society; F, female; FEV 1 , forced expiratory volume in one second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GPRD, General Practice Research Database; HSE, Health Survey for England; LLN, lower limit of normal; LMS, Lambda-mu-sigma; LMS-LLN 5 , LMS defined LLN at the 5th percentile; M, male; NHANES, National Health and Nutrition Examination Survey; NR, not reported; OLD, obstructive lung disease; OLIN, obstructive lung disease in Northern Sweden; OXMIS, Oxford Medical Information Systems; UK, United Kingdom; US(A), United States (of America).

This was supported by information from other studies that found that prevalence estimates by spirometry were higher than those estimated using methods based on symptoms ( Table 1 ). 5 , 6 , 10 – 16 Some multicountry studies reported similar findings when looking at data from several countries, reporting a greater prevalence of COPD diagnosed by spirometry compared with self-reporting (see Table 1 ).

COPD was more commonly reported in older populations and was most prevalent in adults aged 75 years and older. Overall, the studies showed that the prevalence of COPD has increased over time, although the rate of increase has declined in recent years, particularly among men.

Details of all studies providing prevalence data are given in Table S3 in the supplementary material.

Table 2 presents a summary of the population-incidence data reported in the identified articles. The incidence of COPD varied greatly between countries, but it is difficult to compare estimates because they are reported in different units and over different lengths of time. In most of the studies, the incidence of COPD was greater in men than in women. 17 – 21 The incidence of COPD was also greater in older individuals, particularly in those aged 75 years and older. 15 , 21 Six articles reported trends in incidence over time for Australia, Canada, Sweden, and the USA. 15 , 18 , 22 – 25 Although COPD incidence has increased over the last 20 years, within the last 10 years, there has been an overall decrease. Studies in Canada 18 and the USA 25 reported that trends in incidence over time were similar between men and women; however, in Australia, COPD incidence decreased in men between 1998 and 2003 but increased in women. 22 Two articles, both conducted in Sweden as part of the Obstructive Lung Disease in Northern Sweden (OLIN) study, reported incidence rates in smokers ( Table 2 ). 20 , 26 These studies reported a two- to three-times greater incidence in smokers than nonsmokers when measured by spirometry, and assessed by GOLD or BTS criteria. 20 , 26 One study also reported that COPD incidence in former smokers was more than double that in nonsmokers. 26

Identified studies presenting data on incidence of COPD

Abbreviations: BTS, British Thoracic Society; CBE, chronic bronchitis and emphysema; CDC, Centers for Disease Control and Prevention; COPD, chronic obstructive pulmonary disease; ECRHS, European Community Respiratory Health Survey; F, female; FEV 1 , forced expiratory volume in one second; FVC, forced vital capacity; GOLD, global obstructive lung disease initiative; GPRD, General Practice Research Database; ICD-9, International Classification of Diseases, 9th Revision; ICD-10, International Classification of Diseases, 10th Revision; M, male; NA, not applicable; NAMCS, National Ambulatory Medical Care Survey; NCHS, National Center for Health Statistics; NHAMCS, National Hospital Ambulatory Medical Care Survey; NR, not reported; OLIN, Obstructive Lung Disease in Northern Sweden; OXMIS, Oxford Medical Information Systems; UK, United Kingdom; USA, United States of America.

The 58 articles that presented mortality associated with COPD varied in the way they reported the data. Twenty-four articles reported the mortality rate within a group of patients with COPD, 14 reported the proportion of all deaths that could be attributed to COPD, and 21 articles reported overall mortality from COPD within the whole population.

Of the studies that reported mortality rates within patients with COPD, length of follow-up differed, which resulted in difficulties comparing studies. However, the one-year mortality rate of COPD (all severity stages) was reported in four studies and varied from 4.1% in patients aged 45 years and older, to 27.7% in patients aged 65–100 years in Canada, 18 , 27 , 28 and to 5.1% in patients aged 41–83 years in Sweden. 29

Between 2.3% and 8.4% of all deaths were caused by COPD, and this proportion was greater in men than women, 30 – 32 and greatest in subjects aged 65–74 years. 33

Measuring the number of COPD deaths per whole population provides a true picture of the burden of COPD mortality within the population. The overall mortality rate varied between countries, ranging from 3–9 deaths per 100,000 population in Japan to 7–111 deaths per 100,000 population in the USA. In almost all these studies, COPD mortality was greater within the male population than within the female population 15 , 34 – 45 and was greatest in elderly adults aged 75 years and older. 15 , 35 – 38 , 43

Two studies were identified that reported deaths due to COPD as a proportion of deaths attributable to smoking: numbers ranged from 12.8% across several industrialized countries 46 to 20.9% in the USA. 47 One study also reported that 19%–24% of all smoking-related deaths in women and 52%–54% of all smoking-related deaths in men resulted from COPD. 48 One US study reported that mortality in a population of those who quit smoking was almost half of that in a population of individuals who switched from cigarette smoking to spit tobacco (49 versus 89 per 100,000 population). 49

Trends in mortality

A total of 25 articles reported COPD mortality over different years to allow trends to be observed, 14 of which reported the changes in COPD mortality within the overall population. These included studies conducted in Australia (2), Canada (1), France (1), and the USA (10) ( Table 3 ). Our literature review did not identify any articles reporting trends in mortality in Germany, Italy, Japan, The Netherlands, Spain, Sweden, or the UK. In general, the studies reported an overall increase in COPD mortality rates within the last 30–40 years, with a much greater increase in mortality in women compared with men. 15 , 34 , 35 , 38 , 40 , 42 , 45 Some studies have indicated that more recently (within the last 10 years) mortality rates have increased at a slower rate or have decreased, particularly in men. 22 , 34 , 35 , 42 , 43 , 45 Some remarkable differences in COPD mortality exist between countries, particularly regarding the differences between men and women. In Australia, one study 34 reported a decrease in COPD mortality in men between 1979 and 1997, whereas an increase was seen in women over the same period. In France, COPD mortality has increased in women over time, whereas a decrease has been reported in men. 35 Data from several US studies show more heterogeneity. Data from two studies showed a clear increase in COPD mortality in women and only a slight increase in men between 1980 and 2000. 15 , 45 Data from a later study 43 suggested that COPD mortality decreased between 2000 and 2005 in men, with little change in women.

Articles providing data allowing calculation of trends in COPD mortality in the overall population

Abbreviations: ABS, Australian Bureau of Statistics; AIHW, Australian Institute of Health and Welfare; CCHS, Canadian Community Health Survey; CDC, Centers for Disease Control and Prevention; COPD, chronic obstructive pulmonary disease; F, female; ICD-9, International Classification of Diseases, 9th Revision; ICD-10, International Classification of Diseases, 10th Revision; M, male; NCI, National Cancer Institute; NCHS, National Center for Health Statistics; NHIS, National Health Interview Survey; NR, not reported; SEER, Surveillance Epidemiology and End Results; USA, United States of America; WONDER, Wide-ranging Online Data for Epidemiologic Research.

We conducted a structured and comprehensive literature review to identify published data on the prevalence, incidence, and mortality in COPD, and/or trends in those data. The review identified a wealth of data on the prevalence of COPD in the eleven countries studied (Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the UK, and the USA). However, data on mortality and incidence were sparser. Only 15 articles reported incidence data, and six reported trends in incidence; 21 articles reported mortality from COPD within the whole population, and 14 of those reported trends in those data.

Several other literature reviews have previously been conducted to identify prevalence and/or mortality data. 50 – 53 One of these reported data only for the Asia-Pacific region and, of those countries investigated here, included only Japan. 53 Results from the other three literature reviews can be compared with findings from our review. One review included articles published between 1962 and 2001 that were indexed on MEDLINE, 51 one review included articles published between 1990 and 2004 that were indexed on PubMed, and also provided pooled estimates of prevalence by means of a meta-analysis, 52 and the third review included articles reporting prevalence, and/or mortality in Europe published between 1991 and 2009 in the Science Citation Index database via the Web of Science. 50

As with our study, all three published reviews reported substantial heterogeneity between studies, particularly in terms of the definition of COPD used, methods used (eg, self-report, spirometry), diagnostic criteria (eg, GOLD, ATS), populations studied, and year(s) of study. 50 – 53 The estimates obtained from the multicountry studies in our review ranged from 3.6%–10.1%, which is in line with the estimates reported in two of the previous reviews (4%–10%, 51 9%–10% 52 ). When all studies in our review were taken into account, prevalence estimates ranged from 0.2%–37%, which was in line with the most recent published review (2.1%–26.1% 50 ). Differences can be accounted for by the wider scope of our study, which identified 80 studies reporting prevalence estimates in Europe, the USA, Canada, Australia, and Japan compared with 32 studies reporting estimates for Europe only, as identified by Atsou et al. 50

Our findings with respect to mortality were also similar to those reported in a recent literature review regarding both mortality within the overall population (3–111 per 100,000 [current review] versus 7.2–36.1 per 100,000 [review by Atsou et al 50 ]) and the greater mortality rate in men compared with women. 50 The slightly higher mortality rates identified in our studies again relate to the scope of the two reviews. The lowest and highest mortality estimates in our review were from Japan and the USA, respectively, 38 , 54 which were not captured in the European-focused literature review. 50 Therefore, it is likely that the inclusion of countries outside Europe led to the greater heterogeneity in estimates that were identified in our review.

The current review also reported that, although COPD mortality rates have increased over time, rates have declined in more recent years, which suggests improvements in COPD management. However, several studies identified within the review also reported that the mortality rate in women with COPD has increased or stabilized, whereas it has decreased in men.

The difference in these trends may be explained by trends in smoking prevalence in the countries of interest. A relationship between smoking and COPD mortality can be investigated by examining trends in smoking prevalence such as using data from the Organisation for Economic Co-operation and Development (OECD). 55 We were specifically interested in those countries where a difference in COPD mortality trends was observed between men and women (ie, Australia, France, and the USA). These countries all showed an overall decline in smoking rates with the greatest prevalence in men. 55 Recently, the discrepancy in smoking rate between men and women has reduced because the rate in men has declined at a much greater rate than in women.

In Australia, 34 COPD mortality between 1979 and 1997 followed a pattern similar to that observed in smoking prevalence between 1965 and 1980, with a decrease in men and an increase in women. The mortality data mirrored the smoking patterns with a delay of 15–20 years in women and 20–25 years in men. This “lag time” between smoking and COPD onset has been reported in previous literature. 46 In France, both smoking prevalence and COPD mortality have increased over time, whereas a decrease in smoking prevalence and COPD mortality has been reported in men. 35 Smoking prevalence data in France were not available from the OECD before 1981, which made it difficult to determine whether a lag time between smoking and COPD onset occurred. However, COPD mortality data from US studies show more heterogeneity; smoking prevalence substantially decreased over time in both men and women, whereas COPD mortality increased to a greater extent in women than men between 1980 and 2000, after which a decrease was observed in men, and a plateau in women between 2000 and 2005.

Although smoking prevalence might explain some of the discrepancy between men and women in COPD mortality, other reasons must be considered as well. Recent evidence suggests that women younger than 55 years are significantly more susceptible to severe COPD than men. 56 Furthermore, women tend to have smaller airways and lung volumes than men, 57 and previous studies have shown that females are consequently more vulnerable to the adverse effects of smoking than men. 58 – 60

As with all literature reviews, both the current review and the data identified had certain limitations. First, this review focused on only eleven countries of interest (Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the UK, and the USA). Although the literature search itself was not restricted to certain countries, articles related only to countries outside those of interest were excluded from the review during the screening process. Second, the search was limited to articles published in English, so we may not have identified relevant articles published in other languages, particularly those relating to the non–English-speaking countries of interest. Third, several articles did not report true population-based estimates of prevalence or incidence, but instead reported prevalence or incidence of COPD within a population at increased risk for the condition. Fourth, and as with similar reviews involving searches of literature databases, any articles that were not indexed in PubMed or EMBASE would not have been initially identified. Fifth, the studies varied widely in the ages of populations studied, so they were difficult to compare and to draw conclusions from overall. Finally, differences between countries in terms of COPD diagnosis and management will also lead to discrepancies and hinder meaningful comparisons across countries.

However, our review has certain strengths when compared with other similar literature reviews in the epidemiology of COPD. Our review was a comprehensive literature review that identified literature from the MEDLINE and EMBASE databases. Furthermore, we investigated data on prevalence, incidence, and mortality as well as trends in prevalence, incidence, and mortality. Our review included more recent data (published from January 2000 to September 2010) compared with the previous reviews. 51 , 52 Also, compared with the most recent review, which only reviewed data from countries in Europe, 50 our review considered data from Australia, Canada, Japan, and the USA as well as from European countries. Consequently, we anticipate that our review contains more complete epidemiology data that present a current picture of the burden of COPD in major developed countries.

Although our review reported an overall decrease in the burden of COPD, in incidence, prevalence, and mortality in certain countries in recent years, 18 , 22 , 25 , 26 , 31 , 61 , 62 COPD remains a substantial health problem throughout the world. We found that several data gaps exist within the current literature on the epidemiology of COPD, particularly regarding studies reporting the incidence of COPD or trends in mortality data. Also, no studies were identified that reported incidence or trends in incidence in France, Germany, Italy, Spain, and The Netherlands, or trends in overall mortality in Germany, Italy, Japan, The Netherlands, Spain, Sweden, or the UK. A need exists for studies in these countries to examine trends in COPD incidence and mortality to fully understand the true burden of COPD in the population. There is also a need to continue to improve uniformity in definitions and methods of diagnosis to improve understanding of the burden of disease and aid in clearer evaluation of the patient response to treatment.

Acknowledgments

This study was sponsored by Boehringer Ingelheim GmbH. Dr Rycroft, Ms Heyes, and Dr Lanza are full-time employees of RTI Health Solutions. Dr Becker is a full-time employee of Boehringer Ingelheim GmbH.

The authors report no conflicts of interest in this work.

Supplementary materials