Asthma And Strokes: Understanding The Link And Risk Factors

Asthma is a chronic inflammatory disease that affects the airways and is characterised by symptoms such as shortness of breath, coughing, and wheezing. It is a severe condition that causes approximately half a million deaths every year worldwide.

Stroke is the second leading cause of death and a major cause of disability globally. It has multiple aetiologies, including embolism, artery occlusion, and atherosclerosis, a chronic inflammatory condition.

There is a complex relationship between asthma and stroke. Asthma patients have a higher risk of cardiovascular disease, which is a risk factor for stroke. Additionally, asthma is associated with increased inflammation and atherosclerotic vessel disorders, which can lead to plaque buildup in the carotid arteries, increasing the likelihood of stroke.

However, the link between asthma and stroke is not yet fully understood, and more research is needed to establish a causal relationship. Some studies suggest that the increased incidence of stroke in asthma patients may be due to confounding factors, such as smoking, cardiovascular risk factors, and other comorbidities.

While asthma may be a risk factor for stroke, the available evidence is inconclusive, and further investigations are warranted to clarify the nature of the association between these two conditions.

Asthma and stroke: a narrative review

Asthma is a heterogeneous disease, usually characterised by chronic airway inflammation, bronchial reversible obstruction, and hyperresponsiveness to direct or indirect stimuli. It is a severe disease causing approximately half a million deaths every year and thus possessing a significant public health burden. Stroke is the second leading cause of death and a major cause of disability worldwide. The purpose of this review is to analyse the complex relationship between asthma and stroke.

Asthma as a risk factor for stroke

Asthma may be categorised as an independent risk factor for stroke, irrespective of basal lung function. It can trigger cerebral hypoxemic episodes during asthma attacks or can indirectly increase stroke risk by inducing prothrombotic factors and endothelial dysfunction, thus initiating the development of atherothrombosis. The major risk factors for stroke include a history of hypertension, diabetes mellitus, cerebrovascular disease, tobacco exposure, older age, stress, depression, sleep disorders, and obesity. Some of these risk factors can also be seen in asthma patients, and thus the link between asthma and stroke can be attributed to a confounding effect.

Overlapping risk factors for asthma and stroke

A nationwide population-based cohort study was conducted in an Asian population to investigate the effects of asthma on the risk of stroke. The overall incidence of stroke was greater in the asthmatic cohort than in the non-asthmatic cohort (HR = 1.53, 95% CI = 1.47–1.60), with an adjusted HR of 1.37 (95% CI = 1.27–1.48) when controlling for age, sex, and comorbidities. Similar results were registered in the HUNT study in 2020, where participants with active asthma showed a modest increased risk for stroke (adjusted HR 1.17, 95% CI = 0.97–1.41). Conversely, a recent Korean study did not find an increased risk of ischemic stroke among asthma subjects (HR = 0.91, 95% CI = 0.86–0.95). However, there was a significantly higher risk of stroke among asthma patients who experienced more than three exacerbations per year (HR = 3.05, 95% CI = 2.75–3.38).

Stroke subtypes and asthma

A recent meta-analysis on stroke risk in asthma patients, including five articles comprising 524,637 participants and 6031 stroke cases, demonstrated that asthma was associated with a significantly increased risk of developing stroke. However, it is unclear whether this increased risk persists for all stroke subtypes. A nationwide study on the Asian population revealed that patients with asthma were 1.38 times more likely to develop ischemic stroke (95% CI = 1.27–1.49) and 1.31 times more likely to develop hemorrhagic stroke (95% CI = 1.09–1.65) than non-asthmatic controls after adjusting for age, sex, and comorbidities. Thus, the incidence of both subtypes of stroke is increased in asthma, especially in those with more than three annual exacerbations. However, data on subarachnoid haemorrhage (SAH) and asthma is limited, mostly presented as case reports. In a prospective cohort study of 20,534 men and 7237 women that lasted 26 years, baseline lung function, expressed as low FEV1 or FEV1/FVC, was found to be a risk factor for SAH, independent of smoking. These results suggest that asthma patients may also be at risk for SAH, depending on the degree of obstruction.

Impact of smoking on stroke risk among asthma patients

Smoking is one of the main risk factors for death after a stroke. However, the impact of tobacco smoking is not limited to those who smoke; it also affects those exposed to secondhand smoke. One of the largest numbers of deaths attributable to secondhand smoke in adults is caused by coronary artery disease and stroke. Current smoking is linked to poorer outcomes of asthma treatment and, therefore, more frequent exacerbations and medication use, representing a major additional risk factor for stroke. In addition, a cohort study on the Copenhagen general population emphasises the substantial role of tobacco smoking in the development of asthma's cardiovascular comorbidities. Adjusted hazard ratios for ischemic heart disease were 1.2 (0.9–1.6) in never smokers, 1.5 (1.2–2.0) in former smokers, and 2.0 (1.4–2.9) in current smokers. Similar results were found for ischemic stroke: 1.4 (0.9–2.1) in never smokers, 1.2 (0.8–1.9) in former smokers, and 3.0 (1.7–5.3) in current smokers.

Pathogenesis and pathophysiology

Atherosclerosis is the main pathophysiological mechanism of stroke development in asthma. Asthma has a systemic impact associated with the development of atherosclerosis, and several studies have revealed measurable modifications in the structure and function of blood vessels. Asthma, as a chronic inflammation, also has a systemic impact by correlating with increased atherosclerotic vessel disorders. A recent study found that people with persistent asthma had higher levels of inflammation and more artery plaque than those without asthma.

Relationship between FEV1 and stroke risk

The relationship between pulmonary function, expressed by forced expiratory volume in 1 second (FEV1) and asthma comorbidities such as CVD or stroke, has been established by several cohort studies. FEV1 at rest and after response to bronchodilation are the generally accepted surrogate markers of asthma severity. In an extensive study on 5617 participants, an association was observed between baseline FEV1 and the risk of fatal stroke (HR = 1.38, 95% CI = 1.11–1.71 for men, and HR = 1.62, 95% CI = 1.22–2.15 for women, adjusted for age and height). The findings could not be explained by smoking, hypertension, diabetes, atherosclerosis, socioeconomic status, obstructive lung disease, physical inactivity, cholesterol, or body mass index, and they persisted in non-smokers, subgroups without respiratory symptoms, and survivors of the first 20 years of follow-up. Similarly, the Atherosclerosis Risk in Communities study, which followed 13,842 middle-aged adults initially free of stroke and CVD for 13 years, demonstrated that white subjects with impaired lung function had a modestly higher risk of ischemic stroke, even if they had never smoked or had respiratory symptoms.

Impaired lung function and CVD risk and stroke

The chronic inflammation present in asthma mediates the initiation and progression of atherosclerosis and is intricately involved in plaque rupture and acute CVD events. A large contemporary, multiethnic, long-term, prospective cohort study was conducted to analyse the association of asthma and CVD. The study found that persistent asthmatics had a greater risk of CVD events than non-asthmatics (HR = 1.6, 95% CI = 1.01–2.5), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Furthermore, a cohort study comprising 446,346 Taiwanese adults showed similar results: an increase of 27% in the risk of dying from CVD in individuals with active asthma (adjusted HR = 1.32, 95% CI = 1.08–1.62). Additionally, they established that the risk of death from CVD or stroke was increased in a similar manner (HR = 1.16, 95% CI = 0.77–1.73, and HR = 1.23, 95% CI = 0.86–1.74, respectively). Moreover, deaths from CVD and stroke were more strongly associated with active asthma in men than in women.

Asthma phenotypes, severity, and comorbidities

Early-onset asthma and late-onset asthma are two substantially different disease phenotypes, differing in risk factors, pathophysiology, response to treatment, and incidence of comorbidities, such as CVD and stroke. Certain cohort studies have shown that late-onset asthmatics had a higher adjusted risk of CVD than non-asthmatics (HR = 1.57, 95% CI = 1.01–2.45). Furthermore, adult asthma was associated with a 1.40-fold (95% CI = 1.35–1.45) increased hazard of CVD, a 1.20-fold (95% CI = 1.15–1.25) hazard of cerebrovascular disease, and a 1.46-fold (95% CI = 1.25–1.71) increased prevalence of ischemic heart disease, especially in older patients and/or those with untreated asthma.

Asthma control, severity, and stroke risk

According to the GINA report, asthma symptom control represents an important predictor of asthma outcomes. Thus, uncontrolled asthma is the ultimate step towards severe asthma and an important risk factor for exacerbations. As stated in the HUNT study, patients with uncontrolled asthma had an increased risk of stroke (HR = 1.34, 95% CI = 1.03–1.73) compared to controlled asthma. Moreover, severe asthma was related to a statistically significant difference in CIMT and FIMT (p = 0.002 and p < 0.001, respectively) and the highest risk for AF (adjusted HR = 1.74, 95% CI = 1.26–2.42). Likewise, patients with severe asthma had increased baPWV and CRP compared to patients with stable asthma and control subjects.

Asthma exacerbations and stroke risk

Asthma exacerbations are highly related to further complications, especially myocardial infarction and stroke. During the reference period, the incidence rate of CVD events was 25.0/100 person-years. In the subsequent risk period of one to seven days after asthma exacerbations, the incidence rate significantly increased to 129.1/100 person-years, with a corresponding adjusted incidence rate ratio of 5.04 (95% CI = 4.29–5.88). Compared with the non-asthmatic cohort, patients in the asthmatic cohort who visited the emergency room more than three times per year were associated with a significantly higher risk of stroke (adjusted HR = 3.05, 95% CI = 2.75–3.38). Moreover, patients who experience wheeze attacks with shortness of breath have a greater risk for stroke.

Asthma comorbidities and stroke

Chronic respiratory diseases are associated with a number of comorbidities due to their proinflammatory state. Asthma is no exception, and its list of commonly encountered comorbidities includes chronic rhinitis, chronic sinusitis/rhinosinusitis, gastroesophageal reflux disease, obstructive sleep apnea/sleep-disordered breathing, psychological disturbances (particularly depression and anxiety disorders), chronic/recurrent respiratory infections, hyperventilation syndrome, hormonal disturbances, and others. Some of these comorbidities lead to an increased risk of stroke and are highly prevalent in asthma patients. This raises the question of whether the increased risk of stroke in asthma patients may be due to a confounding effect. Nevertheless, the important point is that proper screening and diagnosis of comorbidities in asthmatics are essential for preventing serious complications, including stroke.

Impact of asthma treatment on stroke

Asthma treatment, including bronchodilators and oral or systemic corticosteroids, has been identified as a risk factor for CVD events and stroke. Compared with asthmatic patients who received inhaled corticosteroids, those who received inhaled SABA or LABA had a significantly increased risk of stroke (aHR = 1.93, 95% CI = 1.63–2.27), followed by those who had received both inhaled corticosteroids and inhaled SABA or LABA treatment (aHR = 1.33, CI = 1.13–1.56). Carotid atherosclerosis is reduced in asthmatic patients treated with ICS compared with matched controls, suggesting that ICS may have protective effects against atherosclerosis.

Impact of stroke treatment on asthma

Several medications are used in the treatment and prophylaxis of stroke, and some of them can have positive and negative effects on asthma patients. Tissue plasminogen activator (TPA) is the main drug that has revolutionised the management of ischemic stroke. While it has been lifesaving, there have been cases of anaphylactic reaction that require emergency treatment. Asthma patients are generally more likely to have allergic events due to the atopic nature of their disease. Mild allergic reactions involving skin and subcutaneous tissue generally respond well to steroids and antihistamine drugs, but they should not be confused with acute anaphylaxis, which requires epinephrine. In cases of orolingual angioedema, the general steps in management include stopping the TPA infusion, administering diphenhydramine, ranitidine/famotidine, methylprednisolone, epinephrine, and consulting otolaryngology or anaesthesia.

Aspirin and non-steroidal anti-inflammatory medications are well-known drugs that can trigger allergies, particularly in asthma patients (Samter's triad). This limits their use as an antithrombotic drug in clinical practice. In this group of patients, aspirin desensitisation therapy can be used to overcome this problem and has proven effective in cardiovascular and cerebrovascular disease. Clopidogrel and ticlopidine allergies can be managed in a similar fashion.

Beta-blockers are frequently used to manage arrhythmias, hypertension, and other cardiovascular diseases. Traditionally, they are contraindicated in patients with asthma as they may lead to bronchoconstriction and exacerbate the condition. However, there is more data on the use of beta-blockers in fundamental and clinical practice, and the debate continues between the use of selective versus non-selective beta-blockers, as some studies indicate that selective beta-blockers possess less risk for asthma patients. Therefore, it seems that beta-blockers can be used more widely when the cardiovascular risks outweigh the risk for pulmonary complications. Another group of drugs frequently used to manage hypertension are angiotensin-converting enzyme inhibitors. Although they do not cause changes in pulmonary function, they can cause cough and wheezing, which can be interpreted as asthma manifestations. Therefore, angiotensin-receptor blockers are a better alternative for asthma patients. Hypertension can also be managed with calcium channel blockers, which are not contraindicated in asthma and, in some types of asthma, can even be beneficial for lung function improvement.

Seizures are a frequent complication in stroke patients, and asthma patients have a higher risk of epilepsy. This makes them particularly at risk of stroke-associated seizures. Some antiepileptic drugs might play a role in preventing or reducing the frequency of asthma attacks, particularly phenytoin, valproic acid, and carbamazepine. Interestingly, lidocaine, which works primarily by blocking sodium channels and decreasing membrane excitability, is effective in a form of nebuliser for treating asthma patients. Although this group of medications is not the standard of care in asthma, reports of antiepileptic drug efficiency raise several important questions about some patients having a neurogenic component to their disease.

Disease progression, relationship, and prevention

Overall pathophysiological mechanisms from asthma to stroke suggest that atherosclerosis could be the main pathophysiological mechanism in the development of stroke in asthma patients. This concept is sustained by other studies that try to explain in detail the pathways that potentially explain how lung inflammation can trigger acute vascular events such as heart attacks and stroke. Lung inflammation due to COPD, asthma, infection, or exposure to air pollution results in a systemic inflammatory response with increased levels of circulating leukocytes, platelets, cytokines, and acute-phase proteins. These mediators activate the vascular endothelium, causing endothelial dysfunction characterised by reduced vasodilation, decreased nitric oxide (NO), increased endothelin (ET) expression, and increased vascular permeability and uptake of oxidised low-density lipoproteins (LDLs) into atherosclerotic plaques. Collectively, these events destabilise plaques by up-regulating adhesion molecules, increasing foam cell formation, recruiting smooth muscle cells, and releasing and activating proteases that degrade the extracellular matrix and destabilise plaques, making them vulnerable to rupture. Indeed, a cohort study demonstrated the close interplay between systemic endothelial dysfunction and lung dysfunction, suggesting that even individuals with mild impairment of lung function may have vascular damage that increases the risk for cardiovascular disease. Therefore, patients with asthma may induce an inflammatory environment that favours atherosclerosis progression.

The burden of cardiovascular comorbidity in obstructive airway disease is increasingly acknowledged, and there is a need to identify which patients are at an increased risk to facilitate optimal treatment and prevention.

Impact of stroke on lung function

Pulmonary complications, such as respiratory failure, pneumonia, pleural effusion, acute respiratory distress syndrome, pulmonary edema, and pulmonary embolism from venous thromboembolism, are common in stroke and are among the major causes of death in stroke patients. A cohort study assessed the lung function of stroke survivors and found that lung function was significantly lower in stroke patients compared with healthy participants, with lower values for FEV1 (81% of predicted value vs. 95% predicted), FVC (82% vs 92% of predicted values), and PEF (52% vs 70%). Additionally, chest excursion was markedly lower for stroke survivors when compared to the control group (3.0 ± 0.71 cm vs. 3.5 ± 0.91 cm), which may result from weakened respiratory muscles.

Impact of stroke on asthma outcomes

Stroke is associated with major complications, such as dysphagia, GERD, aspiration, immunodepression, and pneumonia. Obstructive airway disease, such as asthma, is the most common extraesophageal manifestation of GERD

Asthma as a risk factor for stroke

Asthma is a severe disease that affects the airways and causes inflammation and narrowing of the small airways. It is characterised by chronic airway inflammation, bronchial reversible obstruction, and hyperresponsiveness to direct or indirect stimuli. It is a significant public health burden, causing approximately half a million deaths every year.

Stroke is the second leading cause of death and a major cause of disability worldwide. It has multiple etiologies, including embolism, artery occlusion, and atherosclerosis, and can be divided into two main subtypes: ischemic and hemorrhagic stroke.

There is a complex relationship between asthma and stroke, and asthma may be a risk factor for stroke. However, the increased incidence of stroke in asthma patients could be due to confounding factors, as asthma is associated with various comorbidities such as cardiovascular, metabolic, and respiratory conditions.

Several studies have investigated the link between asthma and stroke, with conflicting results. Some studies have suggested an elevated risk of stroke in asthma patients, while others have found no significant association or even a limited association. The relationship between asthma and stroke may be influenced by age, sex, medication history, asthma phenotype, and other factors.

Asthma as an Independent Risk Factor for Stroke

Asthma may be considered an independent risk factor for stroke, triggering cerebral hypoxemic episodes during asthma attacks or indirectly increasing stroke risk by inducing prothrombotic factors and endothelial dysfunction, which can lead to the development of atherothrombosis. The risk of stroke is also influenced by shared risk factors between asthma and stroke, such as hypertension, diabetes mellitus, cerebrovascular disease, tobacco exposure, older age, stress, depression, sleep disorders, and obesity.

Impact of Asthma Treatment on Stroke Risk

The impact of asthma treatment on stroke risk is important to consider. Inhaled corticosteroids (ICS) have been shown to have a protective effect, reducing the risk of carotid atherosclerosis in asthmatic patients. On the other hand, oral or systemic corticosteroids have been associated with an increased risk of cerebrovascular disease and other adverse effects.

Subgroup Analyses

Subgroup analyses based on age, sex, and medication history provide further insights into the relationship between asthma and stroke. Most subgroup analyses did not show a higher risk of stroke in asthma patients, except for a lower adjusted hazard ratio for ischemic stroke in middle-aged men with asthma compared to the control group.

Limitations and Future Directions

It is essential to consider the limitations of the studies and the need for further research. The studies had varying definitions of asthma and stroke, and some studies did not match or adjust for socioeconomic factors or comorbidities, which could influence the results. Future studies should focus on differentiating between asthma phenotypes and stroke subtypes, considering the impact of lifestyle factors, and evaluating the effectiveness of different asthma treatments in reducing stroke risk.

In conclusion, while asthma may be a risk factor for stroke, the relationship is complex and influenced by various factors. Further research is needed to fully understand the interplay between asthma and stroke and to develop effective strategies for stroke prevention in asthma patients.

The impact of asthma treatment on stroke

Inhaled Corticosteroids (ICS)

ICS are often used to manage asthma and are known to have anti-inflammatory properties. Some studies have found that ICS can reduce the risk of stroke in asthmatic patients. Otsuki et al. observed that ICS treatment was associated with reduced carotid atherosclerosis in asthmatic patients compared to those who did not receive ICS. This suggests that ICS may have a protective effect against atherosclerosis, a major risk factor for stroke.

Oral or Systemic Corticosteroids

Oral or systemic corticosteroids are another type of asthma treatment that has been associated with an increased risk of stroke. In a study by Corlateanu et al., they found that the use of oral or systemic corticosteroids was linked to a greater risk of cerebrovascular disease and heart failure. However, it is important to note that these medications are often used in more severe cases of asthma, and the increased risk may be related to the severity of the disease rather than the treatment itself.

Bronchodilators

Bronchodilators, including short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA), are commonly used to manage asthma symptoms. Some studies have suggested that bronchodilators may increase the risk of stroke, particularly when used without ICS. However, other studies, such as one by Lee et al., found no significant association between bronchodilator use and the risk of stroke.

Combination Therapies

The impact of combination therapies on stroke risk is less clear. Some studies have shown that the use of ICS in combination with LABA or SABA may increase the risk of stroke, while other studies have not found a significant association. More research is needed to understand the complex interactions between different asthma treatments and their impact on stroke risk.

Other Treatments

Other asthma treatments, such as antimuscarinic agents, have not shown a significant impact on stroke risk in asthmatic patients. Additionally, emerging drug groups are being investigated for their potential in reducing stroke risk and improving asthma management.

The impact of stroke treatment on asthma

Tissue plasminogen activator (TPA) is a drug used to treat ischemic stroke, and is considered a life-saving medication. However, it can cause anaphylactic reactions, which require emergency treatment. Asthma patients are more likely to experience allergic events due to the nature of their disease, and so general awareness of the possible side effects is important. Mild allergic reactions that involve the skin and subcutaneous tissue generally respond well to steroids and antihistamine drugs, but acute anaphylaxis requires epinephrine.

Aspirin is a well-known drug that can trigger allergies, particularly in asthma patients. This limits its use as an antithrombotic drug in clinical practice. In such cases, aspirin desensitisation therapy can be used to overcome this problem.

Beta-blockers are frequently used to manage hypertension, arrhythmias and other cardiovascular diseases. Traditionally, they are contraindicated in patients with asthma as they may lead to bronchoconstriction and exacerbate the condition. However, there is more data to support the use of beta-blockers in fundamental and clinical practice, and it seems that they can be used more widely when the cardiovascular risks outweigh the risk of pulmonary complications.

Angiotensin-converting enzyme inhibitors do not cause changes in pulmonary function, but can cause coughing and wheezing which can be interpreted as an asthma manifestation. Therefore, angiotensin-receptor blockers are a better alternative for asthma patients.

Hypertension can also be managed with calcium channel blockers, which are not contraindicated in asthma and can even be beneficial for lung function improvement in some types of asthma.

Antiepileptic drugs may play a role in preventing or reducing the frequency of asthma attacks, particularly phenytoin, valproic acid and carbamazepine. Interestingly, lidocaine, which works by blocking sodium channels and decreasing membrane excitability, is effective in treating asthma patients in the form of a nebulizer.

In summary, the impact of stroke treatment on asthma depends on the type of medication used, and the possible side effects and interactions that may occur.

The prevention of stroke in asthma patients

Asthma is a severe disease that affects the airways and causes approximately half a million deaths every year. It is characterised by chronic inflammation and reversible obstruction of the bronchial tubes, which can lead to hyperresponsiveness to direct or indirect stimuli. Stroke is the second leading cause of death and a major cause of disability worldwide.

There is a complex relationship between asthma and stroke. Asthma and asthma medications may be risk factors for developing a stroke. However, asthma is often associated with a variety of comorbidities, such as cardiovascular, metabolic, and respiratory issues, which could also increase the risk of stroke.

Several previous studies have demonstrated an increased risk of stroke in asthma patients. However, a recent Korean study found no increased risk of ischemic stroke among asthma patients. This discrepancy may be due to differences in study design, sample size, and the definition of asthma and stroke used.

To prevent stroke in asthma patients, it is important to focus on modifiable risk factors such as obesity and tobacco use, which can impact both asthma outcomes and stroke prevention. Weight loss in obese asthma patients has been shown to significantly improve health status. Additionally, obesity has been linked to bronchodilator unresponsiveness in children and adolescents with asthma.

Another important aspect of stroke prevention in asthma patients is the monitoring of subclinical atherosclerosis through standard clinical and laboratory tests. This can help identify early signs of cardiovascular disease, a major risk factor for stroke. Asthma patients have a prothrombotic state, which can be counteracted by heparin or enoxaparin therapy.

Furthermore, the treatment of asthma should be customised according to its severity, phenotype, and endotype. Targeted therapy can minimise the risk of complications, including stroke. Inhaled statins, for example, have been shown to reduce airway inflammation and oxidation, as well as regulate nitric oxide synthase and attenuate airway remodelling. Vitamin D supplementation has also been found to improve lung function and reduce airway hyperresponsiveness in asthma patients, which may indirectly lower the risk of stroke.

In conclusion, while the relationship between asthma and stroke is complex and not yet fully understood, preventing and managing asthma, as well as addressing modifiable risk factors, can play a crucial role in reducing the risk of stroke in asthma patients.

Frequently asked questions