Chronic Obstructive Pulmonary Disease and Stroke

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the world and its incidence and prevalence is on the rise. It is evident that COPD is linked to cardiovascular disease. In the last years, several studies demonstrated that COPD may also be a risk factor for stroke, another major cause of death worldwide. Taking in consideration that COPD has multiple comorbidities it is hard to say whether COPD is an independent risk factor for stroke or it is due to confounding effect. This review is aimed to discuss current data on COPD and stroke, potential links, therapy, and prevention. Current data suggest that COPD may increase the risk of hemorrhagic stroke. The incidence of other stroke subtypes may also be increased in COPD or may be due to confounding effect. However, COPD patients who have stroke are at risk for pulmonary and extrapulmonary complications. We conclude that more studies are needed to further clarify the links between COPD and stroke. The management of COPD as well as the use of prevention therapy is essential to decrease the risk for stroke and should be at special attention in pulmonary medicine and neurology.

KEYWORDS:

• Airway obstruction
• COPD
• COPD exacerbation
• intracerebral hemorrhage
• ischemic stroke
• stroke
• subarachnoid hemorrhage

Abbreviations
ARDS	=	acute respiratory distress syndrome
AF	=	atrial fibrillation
CI	=	confidence interval
COPD	=	chronic obstructive pulmonary disease
FEV1	=	forced expiratory volume in 1 second
FVC	=	forced vital capacity
GERD	=	gastroesophageal reflux disease
HRs	=	hazard ratios
ICSs	=	inhaled corticosteroids
LABAs	=	long-acting β-agonists
LAMAs	=	long-acting muscarinic antagonists
OR	=	odds ratio
PEF	=	peak expiratory flow
SABAs	=	short-acting β-agonists
SAP	=	stroke-associated pneumonia

Introduction

Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the world (1,2), is currently defined by GOLD as a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases (3). Nevertheless, there is growing evidence that COPD represent the expression in the lungs, of a systemic inflammatory syndrome which affects every organ and system in the body (4). This assumption is based on the observation that COPD is linked to multisystemic comorbidities. Approximately 80% of the patients have at least one comorbidity, which greatly impacts their quality of life, physical and mental state, and complicates their management (5).

Stroke is another growing global health problem (1,6). In the last years, there is growing interest toward the links between these two leading causes of death and disability. It has been demonstrated that there is a tight interplay between COPD, acute, and chronic cardiovascular disease (7–9). But it has also been suggested that COPD is significantly more prevalent among patients with stroke and that the co-existence of both is associated with grim outcomes (10). These findings have been consistently observed in studies evaluating all different subtypes of stroke (ischemic, intracerebral, or subarachnoid hemorrhage) (11). There is growing interest towards neuropulmonology which underlines the complex interconnection between the central nervous and respiratory systems and aspires to optimize the management of patients where these pathologies co-exists, especially in the neurocritical care environment (12).

The purpose of this review is to summarize available data on the association between COPD and stroke and to describe their pathophysiological links.

Shared risk factors between COPD and stroke

COPD may be one of the risk factors associated with^{Figure 1} atherothrombotic stroke along with diabetes, hypertension, and transient ischemic attack (13). The major risk factors for stroke (which combined account for 88.1% of population-attributable risks) are history of hypertension, current smoking, waist-to-hip ratio, diet risk score, physical inactivity, diabetes mellitus, alcohol intake, psychosocial stress, cardiac causes, and ratio of apolipoproteins B to A1 (14). These risk factors can also be seen in COPD patients and thus the link between COPD and stroke can be to some degree due to confounding effect (Figure 1) (11).

Figure 1. Overlapping risk factors for COPD and stroke.

The prevalence of stroke among patients with versus without COPD was evaluated in a nationwide study from Sweden where COPD patients between 40 and 84 years of age, hospitalized for COPD between 1987 and 2003, were matched with one reference individual who was randomly selected from the general population matched for age, sex, and county of residence were included in the study. Hazard ratios (HRs) for stroke were estimated using Cox regression adjusting for demographics and comorbidities. Incidence of all-cause stroke was significantly increased among COPD patients compared to control individuals (HR 1.24, 95% confidence interval [95% CI]: 1.19–1.28), especially during the first 2 years after COPD diagnosis (HR 1.46, 95% CI: 1.37–1.55) (11). Similar results were found in the Rotterdam Study with a higher risk of both ischemic and hemorrhagic stroke in subjects with COPD (15). Paradoxically the greatest increase in the rate of stroke was found in the youngest age groups compared with the older age groups of COPD (16). Several studies suggest that the risk for all-cause strokes in COPD increases approximately by 20%, but there are data demonstrating that this risk may be even higher (16).

Stroke subtypes and COPD

The nationwide study from Sweden demonstrated that the incidences of ischemic stroke (HR 1.20, 1.15–1.25), intracerebral hemorrhage (HR 1.29, 1.16–1.43), and subarachnoid hemorrhage (HR 1.46, 1.16–1.85) were all increased in COPD patients. Incidence of all stroke subtypes are increased in COPD, especially during the first years after COPD diagnosis (11).

COPD and stroke: Beyond smoking

It is well known that smoking increases the risk of stroke as well as the risk of fatal events (17). The Rotterdam Study demonstrated that after additional adjusting for smoking the risk of stroke among COPD patients versus controls was attenuated with HR, 1.09 (0.91–1.31) for all stroke; HR, 1.13 (0.91–1.42) for ischemic stroke; and HR 1.53 (0.91–2.59) for hemorrhagic stroke (15). These findings suggest that smoking history is only partly responsible for the increased incidence of stroke and, therefore, the presence of COPD may play an independent role in the pathogenesis of stroke, especially of hemorrhagic etiology.

Shared pathophysiological mechanisms

The pathophysiological links between COPD and stroke are still not fully understood and are likely to be interconnected (18). The key factors that promote pathophysiological changes in COPD are systemic inflammation, hypoxia, hypercapnia, and oxidative stress.

Systemic inflammation appears to play a major role in the development and outcomes of stroke. The mechanisms how systemic inflammation impacts stroke include increased neutrophil infiltration of cerebral cortex, disruption of the blood-brain barrier, brain edema, impaired tissue reperfusion, increased platelet activation, microvascular coagulation, and proinflammatory mediators contribution (19–21). It has been suggested that inhibition of the proinflammatory cascades may be a promising therapeutic option in stroke patients which underlines the impact of immune system during brain injury (22). Therefore, COPD, being characterized by chronic, low-grade systemic inflammation, could be a direct predisposing factor for the development of stroke.

Hypoxia is a major feature of COPD, the degree of which increases in the more advance stages of the disease. The role of hypoxia on the pathophysiology of stroke is debatable and recent studies found contradictory results. It seems reasonable to administer oxygen in stroke patients whose brain tissue is hypoperfused and hypoxic, due to the acute stroke (23). Several studies suggested that routine oxygen delivery is associated with a small improvement in neurological recovery and a decrease in the frequency of episodes of desaturation (24–27). On the other hand, recent studies suggested that hypoxia and hypercapnia, or hypercapnia alone, might provide neuroprotective effects (28,29).

Increased oxidative stress and decreased antioxidant enzymes activity may play a role in the pathogenesis of both ischemic stroke and hemorrhagic stroke (30,31). The management of oxidative stress also showed promising results with significant improvement of long-term neurological function (32).

Relationship between FEV1 and stroke risk

Interestingly decreased forced expiratory volume in 1 second (FEV1) is correlated with an increased risk of stroke. An extensive cohort study, with a study population of over 5600 participants demonstrated an inverse association between baseline FEV1 and risk of fatal stroke HR = 1.38 (95% CI: 1.11–1.71) and HR = 1.62 (95% CI: 1.22–2.15) for men and women, respectively (adjusted for age and height). The findings were not explained by smoking history, hypertension, diabetes, atherosclerosis, socioeconomic status, obstructive lung disease, physical inactivity, cholesterol or body mass index, and persisted in subgroups of never-smokers, subgroups without respiratory symptoms and survivors of the first 20 years of follow-up (33).

For each 10% decrease in FEV1 in percentage of predicted, the stroke risk increased by 5% (RR = 1.05, 95% CI: 1.00–1.09, p = 0.03). This represents an approximately 30% higher risk of stroke in the group of people with the lowest lung function as compared to the group with the highest lung function. The RR was 1.11 (95% CI: 1.03–1.19) for each 10% decrease in FEV1 in percentage of expected. This study shows that FEV1 is a predictor of first-time stroke and fatal stroke independent of smoking. The high risk of fatal first-ever stroke in the group of people with low lung function may be of significance in both the design and interpretation of clinical trials (34).

Lower levels of FEV1 are associated with a further increased risk of stroke in those already at high risk, for example, those with ischemic heart disease or hypertension. However, inclusion of FEV1 in a risk score for stroke conferred only a small increase in the absolute risk or the yield of cases in the top fifth of the score distribution during the follow-up period (35).

Impact of stroke on lung function

Complications and disturbances of the respiratory system function are common after stroke (36). Compared to healthy controls patient who suffered from stroke have significantly lower FEV1, forced vital capacity (FVC), peak expiratory flow (PEF) values, and chest excursion. This lung function deterioration may be due to the weakness of respiratory muscles (37). In patients with hemiplegia FEV1 values are lower in the group with right-side hemiplegia. Forced expiratory flow at 25–75% of the pulmonary volume and PEF values were also lower in right hemiplegic group when compared to the control group (p = 0.01 and p = 0.009, respectively) (38). Patients with hemiplegia have a greater degree of hypoxia, hypercapnia and decreased serum bicarbonate level compared to the control group (39). In left-hemiplegic patients diaphragmatic excursion is reduced on the left side and increased on the right side compared to that in control subjects. Left diaphragmatic motion during deep breathing correlates positively with FVC (r = 0.86, p = 0.007) and FEV1 (r = 0.79, p = 0.021) (40). All in all, there is a reduction in diaphragm mobility in patients with COPD, which is associated with a decline in pulmonary function. More specifically, diaphragmatic mobility correlated with airway obstruction, limited ventilatory capacity, and pulmonary hyperinflation (41). Thus, stroke consequences may have a further impact on the lung function of COPD patients who already have severe defects.

Relationship between COPD comorbidities and stroke risk

Well known comorbidities of COPD represent strong predisposing factors for stroke, particularly cardiovascular and metabolic disorders (Table 1) (4,42–50).

Table 1. COPD comorbidities as risk factors for stroke.

Comorbidity	Prevalence
Hypertension	28.5%–64.7%
Diabetes	25.63%–28.5%
Atrial fibrillation	23.3%–68%
Dyslipidemia	36%–52%
Metabolic syndrome	20%–55.2%

The exact mechanism of vascular dysfunction in COPD is still under investigation, but systemic inflammation, oxidative stress, hypoxia, and sympathetic activation driven by the pathological state of the lung are likely to contribute (51,52). Atherosclerosis frequently coexists with COPD and affects arteries of all calibers starting with aorta and its major branches (53,54). COPD is associated with increased arterial stiffness independently of cigarette smoke exposure and this abnormality is not explained by systemic endothelial dysfunction (55). The severity of emphysema is strongly associated with arterial stiffness and calcification in patients with COPD (53,56). Atherosclerosis, assessed by aortic calcification can also be associated with small pulmonary vascular alteration in COPD (57).

Patients with COPD are at higher risk of cardiovascular complications. COPD is highly prevalent in patients with atrial fibrillation, and is associated with higher rates of cardiovascular death, all-cause death, and the composite outcome of any thromboembolic death (58). Patients with atrial fibrillation (AF) and COPD had ischemic cerebrovascular accident 2.05 (95% CI: 1.203–3.94; p = 0.007) times more frequently compared to those with either COPD or AF. Logistic regression showed AF plus COPD was a stronger predictor of ischemic cerebrovascular accident (p = 0.001) than AF alone (p = 0.07) or COPD alone (p = 0.8, nonsignificant). Odds ratio (OR) of ischemic cerebrovascular accident was 2.85 (CI, 1.57–5.16; p = 0.001) for AF plus COPD versus 1.81 (CI, 0.94–3.47; p = 0.71) for AF only and 1.08 (CI: 0.58–2.10; p = 0.8) for COPD only (59).

Arterial and venous thromboembolism is a frequent complication in COPD patients (60). Fibrin clots in COPD patients have an altered network that is resistant to lysis and patients are in a constant prothrombogenic status due to the proinflammatory state (61–63). They also have significantly increased platelet count, along with a reduced mean platelet volume when compared to healthy controls (64). The mean platelet volume also tends to decrease during acute exacerbation of COPD and increases during the stable phase (65). Thus, COPD comorbidities may also contribute to the increased risk for stroke.

Exacerbation of COPD and stroke

After an acute severe exacerbation, subjects with COPD had a 6.66-fold (2.42–18.20) increased risk of stroke (15). COPD exacerbation are also associated with poststroke mortality (OR, 1.34, 95% CI: 1.20–1.52), epilepsy (OR, 1.43; 95% CI: 1.22–1.67), and pneumonia (OR, 1.50; 95% CI: 1.39–1.62) (66). Another study demonstrates that the risk of stroke (1.26-fold [95% CI: 1.0–1.6; p = 0.05]) is maintained 1 to 49 days after the exacerbation (67).

On the other hand, a study from the UK compared frequent exacerbators (≥2 exacerbations in the year prior to their stroke) and infrequent exacerbators (≤1 exacerbation in the year prior to their stroke) who had a first stroke (6441 cases) and they were matched on age, sex, and general practice to controls with COPD but without a stroke (19,323 controls). There was no evidence that frequent exacerbators had increased odds of stroke compared to infrequent exacerbators (OR = 0.95, 95% CI: 0.89–1.01). Although in the subgroup analysis investigating stroke subtype, frequent exacerbators had 33% lower odds of hemorrhagic stroke than infrequent exacerbators (OR = 0.67, 95% CI: 0.51–0.88, p = 0.003), no association was found with other stroke types (68).

Impact of COPD on stroke outcomes

The crude and age-adjusted in-hospital mortality rates for stroke patients with COPD and without COPD in the US are 6.33% (95% CI: 6.14–6.53) and 5.99% (95% CI: 4.05–7.94), respectively. On multivariable analyses, COPD is modestly associated with overall stroke mortality (OR 1.06; 95% CI: 1.02–1.08; p = 0.018) but it is strongly associated with higher mortality among patients with intracerebral hemorrhage (OR 1.12; 95% CI: 1.03–1.20; p = 0.005) and ischemic stroke (OR 1.08; 95% CI: 1.03–1.13, p = 0.001). However, no excess mortality was observed among COPD patients when the analysis was restricted to ischemic stroke patients who received recombinant tissue plasminogen factor (10).

Another study demonstrates using logistic regression that COPD is an independent risk factor for the development of seizures after stroke (p < 0.001). The occurrence of seizures was not related to the severity of the COPD or to its treatment and the most plausible explanatory mechanism was frequent nocturnal oxygen desaturation (27). This can be supported by other studies that involved patients with epilepsy and demonstrated that the degree of desaturation is significantly correlated with the seizure duration (p = 0.001). Epilepsy can also cause central apneas in 50% of cases and mixed or obstructive apneas in 9% of cases (69). Furthermore, an overlap between COPD and sleep apnea further complicates the prognosis and management of stroke patients (70).

Impact of stroke on COPD outcomes

Dysphagia, gastroesophageal reflux disease (GERD), aspiration, and pneumonia are major complications in stroke patients (71,72). GERD is considered to be a risk factor for COPD exacerbations and this can further increase the mortality in this group of patients (73). The use of acid suppressing agents (histamine-2 receptor antagonists and proton pump inhibitors) which are commonly used in GERD are associated with an increased risk of stroke-associated pneumonia (SAP) (74,75). The compromised immune state and the use of corticosteroids already puts COPD patients at higher risk for pneumonia (76). Seizures are another risk factor for pneumonia and stroke patients with COPD have a higher risk for their development (27,77). SAP and stroke-induced immunosuppression are two other major problems in neurocritical care associated with poor outcomes (78). Dysphagia, stroke-induced immunosuppression syndrome and GERD are risk factors for SAP (72,78). A healthcare professional already faces these problems in a COPD patient thus stroke has several complications which overlap with the already existing pathological state (Fig. 2). This is further supported by Park and coworkers which demonstrate stroke patients with COPD had higher risk of aspiration than stroke patients without COPD (79).

Figure. 2. Risk factors for pneumonia and ARDS in patients with stroke and COPD.

Finally smoking is risk factor for acute respiratory distress syndrome (ARDS) (80,81). Lungs as a source of infection and stroke are also major risk factors for ARDS (82,83).

Impact of COPD treatment on stroke

There is currently limited data on whether COPD treatment reduces the risk of stroke (84). CRP levels are raised in COPD patients and reduced in patients with COPD using inhaled corticosteroids (ICS) (85). It seems logical since there are studies which show that local inflammation in COPD occurs earlier than systemic (86). Still other studies demonstrate that ICS reduce lung-specific but not systemic inflammation in COPD (87).

New use of short- (SABA) and long-acting β-agonists (LABA) and muscarinic antagonists (LAMA) in patients with COPD may slightly increase the risk of cardiac arrhythmia which is a potential risk factor for stroke (88,89). The rate of cardiac arrhythmias was elevated with the new use of short-acting (RR, 1.27; 95% CI: 1.03–1.57) and long-acting (RR, 1.47; 95% CI: 1.01–2.15) β-agonists. This should be taken into consideration particularly in patients who receive the treatment for the first time (90). The rate of arrhythmia is also raised with the new use of ipratropium (RR, 2.4; 95% CI: 1.4–4.0). The same study demonstrated that a higher risk for arrhythmias with the use of LABAs (RR, 4.5; 95% CI: 1.4–14.4) but no risk elevation with new use of short-acting β-agonists or methylxanthines (91).

Lin and co-workers, in a nationwide, population-based study with a follow up duration of three years and a matched cohort design demonstrated that among COPD patients, the use of SABA is associated with an increased risk of stroke (adjusted HR = 1.67, 95% CI: 1.45–1.91; p <0.001), and combination treatment with LABA and ICS relates to a risk reduction (adjusted HR 0.75, 95% CI: 0.60–0.94; p = 0.014) (92). Inhaled ipratropium bromide was also associated with stroke risk in COPD patients and this effect depended on the duration of treatment and combination with SABA or theophylline (93). Tiotropium use in COPD showed proischemic and proarrhythmic effects (94). However other studies demonstrated no increase in mortality (95), stroke, and transient ischemic attack risk with the use of tiotropium Handihaler (96).

Oxygen therapy may be another beneficial intervention in COPD patients with stroke. Routine controlled oxygen supplementation started within 24 h of hospital admission with acute stroke may lead to a small improvement in neurological recovery (24,25). It also decreases the number of nocturnal desaturations which may be one of the risk factor for seizures in stroke patients (26,27). But there are also data suggesting that hypoxia and hypercapnia, or hypercapnia alone, provides neuroprotective effects (28,29).

The data on the use of noninvasive ventilation are limited, but show an improvement in cerebral hemodynamics in COPD patients and thus may be useful in stroke patients (97,98).

Finally major studies that evaluated COPD treatment such as TORCH (99), SUMMIT (100), UPLIFT (101), FLAME (100), TRILOGY (102), did not find an increased risk of stroke.

Prevention of stroke in COPD patients

Since stroke is an acute, burdensome, and preventable condition several preventive options may be useful in COPD patients. Hematological changes often occur in patients with COPD. Thrombocytosis is of particular interest for stroke prevention. Administration of antiplatelet treatment correlated with a reduction in 1-year mortality in COPD patients (103). The absolute risk of death due to circulatory disease is raised among COPD patients receiving long-term oxygen and antiplatelet therapy can be of potential use in this case (104,105).

Statins appear to have beneficial effects in COPD, as it has been suggested that they may reduce the risk of exacerbation by up to 30% and the risk of mortality by 21–78% (106,107). However, data are still conflicting and while a recent meta-analysis confirmed that statins are associated with a significant reduction of the risk for a myocardial infection, they failed to demonstrate any benefit for stroke prevention (108).

Future points

It is important to clarify whether COPD increases the risk of all stroke types and to elaborate safe and effective methods for stroke prevention. More studies are required to evaluate whether oxygen therapy or permissive hypoxia and/or hypercapnia may be used in stroke patients with COPD. More studies that show the effectiveness of preventive therapy may also help us to understand what drugs should be added to the current management of COPD.

Moreover, basic research is required to explore the inflammatory interplay between the two diseases.

Conclusions

COPD is a complex disease with several key pathophysiological mechanisms that impact the whole body. Taking this into consideration there are enough data to suspect that it may also cause stroke. Current data suggests that COPD may increase the risk of hemorrhagic stroke. The incidence of other stroke subtypes may also be increased in COPD or may be due to confounding effect. The management of COPD as well as the use of prevention therapy is essential to decrease the risk for stroke and improve its outcomes and both respiratory clinicians and neurologists should be aware.

Declaration of interest statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript.