Identification of Clinical Phenotypes Using Cluster Analyses in COPD Patients with Multiple Comorbidities

Table 1

Summary of studies exploring possible phenotypes using cluster analyses in stable COPD patients.

Reference	𝑛	Setting	Population characteristics	Data used to build clusters	Multiple comorbidities	Types of analyses	Main results	Outcome for validation
Altenburg et al. [33]	65	Single center, tertiary care, and pulmonary rehabilitation; (Groningen, The Netherlands)	Moderate to very severe airflow limitation; Referred for rehabilitation	Age, BMI, quadriceps force, body plethysmography, and exercise testing	Not assessed	K-means	2 phenotypes: (i) worse lung function and exercise capacity, worse quadriceps force, and better response to exercise training; (ii) better lung function and exercise capacity and less response to exercise training	High or low improvement in endurance exercise capacity rehabilitation
Burgel et al. [34, 35]	322	Multicenter cohort (Initiatives BPCO), and; tertiary care; (France)	Mild to very severe airflow limitation; Outpatients	Age, history, and symptoms, spirometry, BMI, exacerbations, health status, psychological status	Physician-diagnosed; Not included in the cluster analysis	PCA, HCA (Ward’s)	4 phenotypes: (i) young subjects with severe respiratory disease, cachexia; (ii) older subjects with mild; airflow limitation and mild; comorbidities; (iii) young subjects with moderate to severe airflow limitation, but few comorbidities; (iv) older subjects with moderate to severe airflow limitation and high rates of cardiovascular comorbidities	All-cause mortality
Burgel et al. [43]	527	Single center, tertiary care (Leuven, Belgium)	Mild to very severe airflow limitation; Outpatients and; COPD patients identified as part of a lung cancer screening study	Age, history and symptoms, health status, body plethysmography, DLCO, CT-scan, and physician-diagnosed comorbidities	Physician-diagnosed; Included in the cluster analysis	PCA, MCA, HCA (Ward’s)	3 phenotypes: (i) younger patients with severe respiratory disease, cachexia, and low rates of cardiovascular comorbidities.; (ii) older patients with less severe airflow limitation, but often obese and with high rates of cardiovascular comorbidities and diabetes.; (iii) mild to moderate airflow limitation, absent or mild emphysema, absent or mild dyspnoea, normal nutritional status, and limited comorbidities	All-cause mortality
Fens et al. [36]	157	Population-based survey; (Utrecht, The Netherlands)	Mild to moderate airflow limitation; COPD patients identified as part of a lung cancer screening study	History and symptoms, health status, comorbidities, spirometry, DLCO, CT-scan, and breathomics (electronic nose)	Self-reported; Included in the cluster analysis	PCA, HCA (Ward’s), K-means	4 possible phenotypes: (i) mild COPD; (ii) moderate airflow obstruction with chronic bronchitis and emphysema; (iii) asymptomatic emphysema with preserved lung function; (iv) high symptoms, preserved lung function	None
Garcia-Aymerich et al. [37]	342	Multicenter study, tertiary care; (Spain)	Mild to very severe airflow limitation; COPD patients recruited after a 1st hospitalization	History and symptoms, health status, body composition, body plethysmography, CT-scan, biology (sputum and serum), and exercise testing	Self-reported; Included in the cluster analysis	K-means	3 phenotypes: (i) severe respiratory COPD; (ii) moderate respiratory COPD; (iii) systemic COPD (high rates of cardiovascular comorbidities)	(i) Hospitalizations (COPD or cardiovascular); (ii) all-cause mortality
Paoletti et al. [38]	415	Single center, tertiary care; (Florence, Italy)	Mild to very severe airflow limitation; Outpatients	History and symptoms, body plethysmography, DLCO, and chest X-ray	Not assessed	MDS, PCA, MCA, K-means	2 phenotypes: (i) predominant airflow obstruction; (ii) predominant parenchymal destruction	None
Pistolesi et al. [39]	322	Single center, tertiary care; (Florence, Italy)	Mild to very severe airflow limitation; Outpatients	History and symptoms, body plethysmography, DLCO, and chest X-ray	Not assessed	MDS, PCA, cluster analysis*	2 phenotypes: (i) predominant airflow obstruction; (ii) predominant parenchymal destruction	None
Vanfleteren et al. [40]	213	Single center, tertiary care, pulmonary rehabilitation; (Horn, The Netherlands)	Moderate to very severe airflow limitation; Referred for rehabilitation	13 comorbidities	Systematically assessed; Cluster analysis performed exclusively on comorbidities	SOM, HCA (Ward’s)	5 possible comorbid phenotypes: (i) less comorbidity; (ii) cardiovascular; (iii) cachectic; (iv) metabolic; (v) psychological; with no difference in systemic inflammation	None

∗Type of cluster analysis not described; HCA: hierarchical cluster analysis; PCA: principal component analysis; MCA: multiple correspondence analysis; MDS: multidimensional scaling; SOM: self-organizing maps.