Results
Selection of studies
Of 4418 studies (in 4419 papers) initially identified, 1335 were deemed unsuitable for review at initial screening and 3053 were excluded at later assessment stages (figure 1). Therefore, 29 studies were deemed to be relevant to this report.
Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. COPD, chronic obstructive pulmonary disease.
Multimorbidity prevalence and characteristics
Shen et al19 performed a cluster analysis to investigate disease combinations in 91 453 US patients with COPD. They reviewed electronic health records and identified four distinct profiles: low morbidity (based on CCI; 61%; mean CCI score 1.9 SD±1.4), metabolic–renal (21%; 4.7±1.8), cardiovascular (12%; 4.6±1.9) and multimorbidity (7%; 7.5±1.7).
A cluster analysis study in Lithuania assessed records of 321 297 patients for 32 chronic diseases.20 In this cohort, 4834 had COPD, which was associated with significantly increased prevalence of cardiovascular diseases, arrhythmia, heart failure, kidney diseases and lung cancer (all p<0.0001). They further assessed the 19 conditions seen in at least 5% of patients (n=3338) and revealed six disease clusters in men with COPD: cardiovascular diseases (99% had at least one), asthma–musculoskeletal (49%), stroke–cancer–sensory (44%), endocrine–metabolic (42%), gout–renal (12%) and mental disorders (8%). Five clusters were identified in women with COPD. Again, the most common contained cardiovascular diseases (100%), followed by glaucoma–mental disorders–osteoarthritis–back pain–asthma–obesity–dyslipidaemia–diabetes (87%), cancer–osteoporosis–hypothyroidism–hearing loss–cancer (38%), dementia–stroke (14%) and anaemia (5%).
Using network visualisation software, Divo et al21 compared comorbidity networks for 79 disorders in 1969 patients with COPD and 316 individuals without COPD. From the 79 disease nodes, the COPD network showed 428 links with significance of p≤0.01. By comparison, the non-COPD network contained only 56 of the disease nodes and had 149 links. Thus, the prevalence, diversity and degrees of association of comorbidities seem much greater in people with COPD. Nevertheless, the sample size for people without COPD was much smaller. The authors further identified four distinct clusters of anthropometric and clinical characteristics in which nodes were highly interlinked with COPD. One cluster that included 50% of patients had a cardiovascular disease ‘theme’. Although cardiovascular disease clustering was also seen in the non-COPD group, the prevalence was 30% and the number of links was considerably fewer. Another node with 50% prevalence in the COPD group centred around individuals with less obstruction, higher body mass index (BMI) and comorbidities mainly associated with metabolic syndrome. Metabolic syndrome components were present in the non-COPD controls but they were seen mostly in older individuals. Two clusters had 30% prevalence in the COPD group. The first included mainly younger current smokers with psychiatric disorders and diseases associated with high-risk bevaviours (eg, schizophrenia, anxiety, hepatitis, liver cirrhosis, pancreatitis and HIV), whereas for individuals without COPD, the cluster contained only anxiety, asthma and depression and had prevalence of 5%. The theme of the second was gastrointestinal diseases, musculoskeletal diseases and cancer. While the prevalence in the non-COPD group was also 30%, the cluster contained fewer nodes and links. The authors concluded that patients with COPD are affected by larger numbers of interlinked morbidities, the clustering patterns of which may suggest common pathobiological processes that might be useful for screening and/or therapeutic interventions. In another study, Divo et al 5 also showed that COPD affects the timing of multimorbidity. They extracted data from the EpiChron Cohort in Aragón, Spain, for 27 617 people with COPD and 27 617 controls without COPD matched for age, sex and site. Patients were separated into incremental age groups (40–55, 56–65, 66–75, 76–85 and ≥85 years) and the prevalence of chronic disorders seen mainly in elderly people was compared between the two groups. The number of comorbidities increased with age in both but occurred earlier in the COPD group. For instance, in the youngest age group of 40‒55 years, 50% of controls had any disease of interest compared with 82% of people with COPD (p<0.001). Furthermore, multimorbidity with two or more disorders were seen 10–15 years earlier among patients with COPD at baseline than among controls.
Carmona-Pírez et al22 also performed a network analysis based on data from the EpiChron Cohort to assess multimorbidity in 28 608 patients with COPD. The findings revealed several clusters of diseases that were specifically associated with COPD, such as behavioural risk disorders. These clusters featured psychiatric multimorbidity in women and cancer multimorbidity in men with COPD. Risks of gastro-oesophageal reflux disease and obstructive sleep apnoea were also raised in men.
In an exploration of multimorbidity patterns in a population of 12 032 men aged over 50 years, Zacarías-Pons et al23 identified that the strongest risk factors for multimorbidy among men with COPD were social deprivation (OR 3.3, 95% CI 2.3 to 4.7), current smoking (OR 3.2, 95% CI 2.4 to 4.3), former smoking (OR 1.9, 95% CI 1.4 to 2.4), obesity (OR 1.7, 95% CI 1.3 to 2.4), being separated or single (OR 1.7, 95% CI 1.3 to 2.4) and age (OR 1.16, 95% CI 1.15 to 1.18). They found also that COPD was clustered with osteoarthritis, rheumatoid arthritis, ulcer and cataracts.
Knorst et al24 assessed multimorbidity in 470 patients with COPD for whom they could obtain Global Initiative for Chronic Obstructive Lung Disease stage and BMI data. The mean number of comorbidities per patient was 3.1 (SD 1.9), rising to 4.1 in patients with obesity, indicating a significant correlation with BMI (r=0.32, p<0.001). Five or more multimorbid disorders were present in 105 (22%). No correlation was found between the number of comorbidities and severity of COPD. The most common comorbidities were hypertension (45%), cardiac disease (20%), diabetes (15%), osteoporosis (14%) and dyslipidaemia (13%).
In an observational longitudinal study of Medicaid data for 37 151 people with COPD in the USA, Ajmera et al25 investigated multimorbidity with inflammatory diseases (arthritis, cardiovascular diseases, diabetes, hypertension, hyperlipidaemia and osteoporosis) and psychiatric disorders (anxiety, bipolar disorder, depression and schizophrenia). The overall prevalence of multimorbidity was 79%. Multinomial logistic regression revealed that the risk of coexisting disorders was increased in women versus men (adjusted OR 1.88, 95% CI 1.75 to 2.01) and older adults (age 55‒64 years) versus younger adults (age 18‒24 years; adjusted OR 6.14, 95% CI 5.05 to 7.04).
Cardiovascular and metabolic diseases
Heart diseases are seen in a substantial proportion of people with COPD. In an analysis by Hansen et al26 of 70 274 people with a diagnosis of COPD in Danish health registries, hypertension was reported in 48% and heart disease in 16%. In an investigation of disease combinations in 11 734 long-term residents in 1174 nursing homes in the USA, COPD was seen in combination with hypertension in 7% of residents (7% of women and >10% of men).27 COPD was noted in a three-disease combination with hypertension and composite vascular diseases in 4% of residents (3.5% of women and 5.5% of men). Jurevičienė et al20 found that among 4834 patients with COPD, rates of cardiovascular diseases, arrhythmia and heart failure were significantly increased (all p<0.0001). At least one cardiovascular disease was seen in nearly all men (98.7% of 3338) and women (99.5% of 1496) with COPD.
Nesterovska et al28 investigated whether risk of atrial fibrillation was increased by the presence of COPD. The study included 86 patients with coexisting asthma and COPD but no cardiovascular disease or thyroid dysfunction. Around half (42 (49%)) had paroxysmal atrial fibrillation.
Asker et al29 found that among 95 people with COPD and pulmonary hypertension, 68 (72%) had coronary artery disease. The presence of coronary artery disease correlated positively with male sex (rs=0.224, p=0.029) and hypertension (rs=0.227, p=0.07) but negatively with the ration of forced expiratory volume in 1 s forced vital capacity (FEV1:FVC) (rs=‒0.253, p=0.013) and systolic pulmonary artery pressure (rs=‒0.215, p=0.037). No correlation was found between the severity of coronary artery disease and pulmonary hypertension. In a large population study in Copenhagen, Denmark, Ingebrigtsen et al30 compared the risks of coronary heart disease and heart failure in people with varying phenotypes of COPD and/or coexisting asthma and COPD (n=11 988) or no respiratory disease (n=42 058). Risks of coronary heart disease and heart failure were greatest in the presence of COPD with FEV1 <50% of predicted (HRs 1.8, 95% CI 1.4 to 2.3 p<0.001 and 2.9, 2.2 to 3.9, p<0.001, respectively) and COPD with late-onset asthma with FEV1 <50% of predicted (HRs 2.2, 95% CI 1.6 to 3.0, p<0.001 and 2.9, 2.0 to 4.3, p<0.001, respectively).
Miller et al31 found that heart disease in people with COPD increases the risk of further disorders. They used US household survey data for 968 people with self-reported COPD and heart disease and 767 with COPD and no heart disease. Those with heart disease were most likely to be men and were nearly five times as likely to have diabetes (OR 4.8, 95% CI 3.5 to 6.5; p<0.001) and more than twice as likely to have arthritis (OR 2.2, 95% CI 1.7 to 2.8; p<0.001) as people without heart disease. Risks of other conditions (arthritis, sleep apnoea, chronic pain, depression, gastro-oesophageal reflux disease, osteoporosis and overactive bladder) were also significantly increased, with ORs ranging from 1.5 to 1.8.
Triest et al32 identified a cachetic disease cluster in 39 (19%) of 208 patients with COPD that was characterised particularly by low muscle mass and underweight (both 80%), hyperglycaemia (54%), arterial stiffness (29%) and hypertension (28%). This cluster of disorders was not relevant in the control group without COPD. A metabolic diseases cluster was also identified among patients with COPD, which featured obesity, hyperglycaemia, insulin resistance, dyslipidaemia and cardiovascular disorders. However, it was also present in the control group and did not have specificity for COPD.
Respiratory disease
O’Kelly et al33 performed a multivariable analysis to assess risk of multimorbidity in patients with chronic respiratory conditions in Dublin, Ireland. The authors separated respiratory disease into asthma (n=432), COPD (n=206) or other (n=15). Among all 653 patients, 393 (60%) had multimorbidity. While asthma was the most frequently reported disease, the rate of multimorbidity was lower than that for COPD (213 (54%) of 432 vs 169 (82%) of 206). In multivariable analysis, only a diagnosis of COPD was associated with increased rates of multimorbidity. The most common comorbidities in the whole cohort were depression or anxiety, hypertension and cardiovascular diseases (all 28%), musculoskeletal disorders (23%) and endocrine disorders (20%).
Nesterovska et al28 assessed 86 patients with asthma and COPD overlap syndrome (ACOS). The respiratory effects of this condition in people who developed paroxysmal atrial fibrillation were a reduction in FEV1 by 36.5% and an increase in hypoxaemia by 12.3%. These changes correlated significantly with the development of atrial fibrillation when seen alongside increased blood pressure and systemic inflammation.
Ganga et al34 performed a single-centre study to investigate new-onset atrial fibrillation in 2873 patients older than 65 years with obstructive sleep apnoea alone (n=60), COPD alone (n=416), both (n=28) or neither (n=2369). Non-adjusted incidence of atrial fibrillation was 7%, 11%, 21% and 5%, respectively. The risk of multimorbid atrial fibrillation was significantly increased in the COPD subgroup (OR 1.79, 95% CI 0.190 to 0.962, p=0.003) and notably more so in the subgroup of patients with both obstructive sleep apnoea and COPD (3.66, 95% CI 1.06 to 6.9, p=0.007). By contrast, obstructive sleep apnoea alone and neither disease were not predictive.
Spicuzza et al35 reported a retrospective observational study of people with obstructive sleep apnoea with and without COPD. The risk of cardiovascular diseases, metabolic disorders and gastro-oesophageal reflux disease was substantially increased by COPD (OR 7.8, 95% CI 4.86 to 11.39; p<0.001). Lacedonia et al36 found similar trends in a retrospective analysis where they compared people with coexisting asthma and COPD or obstructive sleep apnoea alone.
Psychological disorders
Anxiety and depression are common comorbidities in COPD. Phan et al37 reported in a cross-sectional study that among 242 people with COPD, 124 (51%) had symptoms of depression and/or anxiety, and 81 (34%) had symptoms of both. Multiple regression revealed associations with younger age, having a carer, psychological medical history, comorbidities and reduced quality of life. Silva Júnior et al38 hypothesised that the presence of COPD would increase the risk of major depression even in people with mild hypoxaemia. They assessed 30 patients with major depression and 30 controls without depression. A significant association was seen between COPD Assessment Test scores greater than 20 and major depression (OR 7.88; 95% CI 1.96 to 31.7; p=0.004), making COPD a predictive factor.
A UK study used questionnaires in 44 patients with COPD and lung cancer who were attending an outpatient clinic to assess the risk of depression.39 The relative risk and ORs of patients with COPD developing depression were 1.4 and 1.6, respectively. The number of coexisting comorbidities significantly raised the OR to 2.13 (95% CI 1.02 to 4.49).
Triest et al32 performed a validation study of comorbidity clusters previously identified in patients with COPD. They compared the clusters in 208 patients with COPD and a control group of 200 elderly patients without COPD. The psychological cluster included 40 patients with COPD, of whom 95% had anxiety and 59% had depression. By contrast, very few controls had anxiety and/or depression and, therefore, this cluster was deemed relevant only to COPD.
Physical activity
Associations between COPD and 31 comorbidities and how these were affected by level of physical activity were assessed in 601 adults in Spain.40 94% of participants had comorbidities. Low levels of physical activity were significantly associated with increased risk of urinary incontinence (OR 2.12, 95% CI 1.21 to 3.69), chronic constipation (OR 1.97, 95% CI 1.12 to 3.46), cataracts (OR 1.84, 95% CI 1.07 to 3.15), chronic anxiety (OR 1.51, 95% CI 1.00 to 2.27) and chronic lumbar back pain (OR 1.49, 95% CI 1.04 to 2.13). The authors concluded that recommending increased physical activity could improve the quality of life for patients with COPD.
Yu et al41 performed a longitudinal study to assess the relationship between physical activity and multimorbidity risk in 409 patients with COPD selected from primary care in the Netherlands and Switzerland. Patients were followed up for 5 years and self-reported physical activity, occurrences of cardiovascular, neurological, endocrine, musculoskeletal, malignant and infectious diseases and mental health. Physical activity showed significant associations with reduced anxiety (adjusted HR 0.89, 95% CI 0.79 to 1.00; p=0.045) and depression (adjusted HR 0.85, 0.75 to 0.95; p=0.005). For other disorders, likelihood of occurrence was reduced with physical activity, but not significantly so.
Polypharmacy
One study addressed polypharmacy (defined by the authors as taking five or more drugs per day) along with multimorbidity. Among 245 patients with COPD in Crete, Greece, Ierodiakonou et al42 found that 77% of patients had multimorbidity, which increased to 84% in those with age 65 years or older. More than half (55%) of patients were receiving multiple drugs, but 10% of medications were found to be inappropriate. Polypharmacy was associated with COPD Assessment Test scores of 10 or greater, multimorbidity, several cardiometabolic diseases, cancer, depression and anxiety and prostate disorders. Co-administration of medications increased the cumulative risk of falls in 22%, constipation in 17% and cardiovascular events in 13% of patients. The authors concluded that polypharmacy increases the risk of worse health outcomes in patients with COPD.
Smoking
Garneau-Picard et al43 investigated the influence of smoking on multimorbidity in people with ACOS. In a group of 154 patients with irreversible airway obstruction (47% men, 53% women; 100 smokers with ACOS and 54 with irreversible airway obstruction not related to smoking), a sex-specific symptom pattern was found that suggested greater susceptibility of women to smoke. Woman had lower prevalence of severe asthma (44.9% vs 64.7%, p=0.0264) but had higher FEV1:FVC values (67.2, 95% CI 66.7 to 67.7 vs 65.5, 95% CI 64.8 to 66.2, p=0.0002) and more comorbidities (4.6, 95% CI 3.9 to 5.4 vs 3.2, 95% CI 2.7 to 3.7, p=0.0012) than men, despite having lower tobacco exposure (36.0 pack-years, 95% CI 32.5 to 39.5 vs 41.9 pack-years, 95% CI 38.1 to 45.7, p=0.0278). Furthermore, compared with female non-smokers with airway obstruction, more women with ACOS had severe asthma, used more medication and had a worse FEV1:FVC, whereas men showed no significant differences from other men with ACOS or men or women with non-smoking-related disease.
Cunningham et al44 explored the relationships between smoking, COPD and 10 other conditions (arthritis, asthma, cancer, coronary heart disease, depression, diabetes, high blood pressure, high cholesterol, kidney disease and stroke). In a cross-sectional study of 405 856 adults in the US general population who had responded to surveys from the national Behavioral Risk Factor Surveillance System, 33 088 (7%) had COPD. The prevalence of COPD was 14% among current smokers, 7% among former smokers and 3% among never smokers. Only a quarter of people with COPD (24%) were never smokers, compared with 57% of those without COPD (39% vs 27% were former smokers and 37% vs 16% were current smokers). 95% of those with COPD had any of the 10 comorbidities of interest, compared with 69% of those without COPD, and the prevalence of all conditions was higher in the COPD group than in the non-COPD group. Significant interactions (p<0.001) were seen between smoking status and COPD and each of the other chronic conditions. Zacarías-Pons et al23 calculated ORs of 3.2 (95% CI 2.4 to 4.3) for current smoking and 1.92 (95% CI 1.4 to 2.4) for former smoking in a disease cluster that included COPD.
In a retrospective study, Le et al45 investigated the multimorbidity burden in 739 118 Medicare beneficiaries with COPD in the USA, aged 65 years or older. The authors calculated the prevalence of multimorbidity at COPD diagnosis and 1 year after diagnosis and estimated the rates of onset per 100 person-years 1 year before versus 1 year after diagnosis. The findings were compared with the same number of Medicare beneficiaries without COPD, matched for age, sex and race. In the COPD group, the average number of comorbidities was 10 (SD 4.7) compared with only 1 (SD 3.3) in the non-COPD group. The most frequent comorbidities seen at COPD diagnosis had all increased in prevalence 1 year later: hypertension changed from 70.8% to 80.2%; hyperlipidaemia from 52.2% to 64.8%; anaemia from 42.1% to 52.0%; arthritis from 39.8% to 47.7%; and congestive heart failure from 31.3% to 38.8%. The rates of new onset 1 year before and after COPD diagnosis were hyperlipidaemia (22.8 and 27.6 cases per 100 person-years, respectively), anaemia (17.8 and 20.3), arthritis (12.9 and 13.2), hypertension (39.8 and 32.3) and congestive heart failure (16.2 and 13.2). The ORs for all diseases assessed were increased in the COPD group compared with those in the non-COPD group.