Pathophysiology of Asthma-Chronic Obstructive Pulmonary Disease Overlap

SUMMARY

Although there are many potential mechanisms at play in the development of ACO, we have not yet identified the exact pathways of inflammation and airway remodeling that result in the clinical phenotypes we see in patients with ACO (Table 1). Further investigations with a dedicated focus on this subgroup of patients is warranted to better elucidate the natural history of their disease course by defining the underlying pathophysiology of this clinically relevant syndrome. A better understanding of the pathophysiologic mechanisms that result in increased disease severity in patients with ACO will help us to better identify potential drug targets and improve symptom burden and overall quality of life for patients living with ACO.

INTRODUCTION

Asthma and chronic obstructive pulmonary disease (COPD) comprise 2 of the most common chronic respiratory diseases encountered globally. In 2019, it was estimated that there were approximately 262 million people worldwide living with asthma,¹ whereas the global prevalence of COPD was estimated at 13.1% and caused 3.23 million deaths.^2,3 Estimates of asthma-COPD overlap (ACO) can very due to differences in definitions of the disease, but worldwide prevalence is somewhere between 2% and 4% of the general population.^4,5

Asthma is a heterogenous disease characterized by chronic airway inflammation. It is associated with airway hyperresponsiveness and variable airflow limitation and is defined by the history of typical respiratory symptoms that vary over time and can be worsened by exposure to specific triggers.⁶ In contrast, COPD is characterized by fixed airflow limitation that is often progressive and associated with chronic, pathologic inflammatory responses to various noxious stimuli, such as tobacco smoke exposure.^7,8

Although asthma and COPD are considered distinct disease entities, there is increasing recognition that they are heterogeneous conditions with often overlapping features. For example, there is a subset of patients with COPD who exhibit markers of inflammation associated with type 2 immune responses that are classically exhibited by patients with asthma.⁹ ACO is a condition in which a person has clinical and biological features of both asthma and COPD.⁶ ACO is associated with high morbidity including increased respiratory symptoms, disease exacerbations, and hospitalizations as compared with those with asthma or COPD alone.⁴ Although epidemiologic studies suggest that ACO effects approximately 2.0% of the global population,¹⁰ definitions of the syndrome are highly variable across studies complicating the assessment of the true global health burden. ACO defines a subgroup of patients with asthma who have persistent airflow limitation or patients with COPD who may also exhibit variable airflow limitation with or without evidence of type 2–mediated inflammation. A better understanding of the pathophysiological mechanisms that underlie this clinical syndrome is essential to better understand the natural history and optimal treatment modalities for this patient population.

OVERVIEW OF THE PATHOPHYSIOLOGY OF ASTHMA

The pathophysiology of asthma is extremely complex, with multiple cell types and inflammatory pathways contributing to each patient’s disease process. There is considerable disease heterogeneity in asthma, with patients displaying varying levels of inflammation related to type 1 and type 2 immune responses. Type 1 inflammation is predominantly regulated by subpopulations of CD4+ T cells referred to as T helper 1 cells that stimulate phagocyte activity through the secretion of interleukin-2 (IL-2), interferon-gamma, and lymphotoxin-alpha.¹¹ Alternatively, type 2 inflammation is usually characterized by eosinophilia and high antibody titers through the effects of IL-4, IL-5, and IL-13.¹¹ It is regulated by a subpopulation of CD4+ T cells known as T helper 2 cells and also involves concerted effects through eosinophils, mast cells, basophils, group 2 innate lymphoid cells, and immunoglobulin E (IgE)-producing B cells.¹² These inflammatory indices are observed in patients with type 2 (T2) asthma, whereas patients with non-type 2 asthma do not exhibit increased levels of these inflammatory markers. This constellation of inflammatory signaling results in pathologic changes in the airways, including subepithelial fibrosis, smooth muscle hypertrophy/hyperplasia, increased volume of submucosal glands, and goblet cell hyperplasia.¹²

OVERVIEW OF THE PATHOPHYSIOLOGY OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Similar to asthma, the pathophysiology of COPD is complicated with many routes of inflammation contributing to the pathologic changes observed on a cellular level. For most cases, the pathogenesis of COPD is thought to be due to an abnormal inflammatory response to the inhalation of noxious stimuli such as tobacco smoke or biomass fuel. Prior studies have shown that the airways of patients with COPD exhibit increased levels of inflammatory cell infiltration, predominantly driven by macrophages (CD68+) and CD8+ lymphocytes.^13,14

Patients with COPD also exhibit increased neutrophils in sputum and bronchoalveolar lavage (BAL) samples.¹⁵ Although the exact role of neutrophils in the pathogenesis of COPD is not entirely clear, it is thought that alveolar destruction may be due in part to secretion of serum proteinases by neutrophils, as prior studies have shown a relationship between circulating neutrophil count and disease severity.¹⁶ As the disease process progresses, patients with COPD also exhibit an increased level of B lymphocytes and bronchial-associated lymphoid tissue, which suggests a role of the adaptive immune response in the pathogenesis of the permanent airway damage seen in patients with COPD.^8,17

The abnormal concentration of inflammatory cells found in patients with COPD results in abnormal levels of cytokines and chemokines within the airways of patients with COPD. Increased levels of IL-8, IL-6, tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein, metalloproteinases, transforming growth factor-beta (TGF-β), and epidermal growth factor have all been shown to be present in patients with COPD.¹⁸ These extracellular signaling proteins can then go on to enhance inflammation and damage through a variety of processes, including chemotaxis of inflammatory cells, proliferation of fibroblasts, and increased levels of mucin production within the airways.¹⁸ In addition, prior studies have demonstrated increased levels of reactive oxygen species within the airways of patients with COPD, which result in tissue damage and carbonyl stress that causes a variety of pathologic processes, including mitochondrial dysfunction and increased proinflammatory signaling.¹⁹ The constellation of pathologic inflammatory processes seen in COPD results in increased levels of fibrosis, alveolar wall destruction, loss of lung elastic recoil, and mucous hypersecretion.⁸

PATHOPHYSIOLOGY OF ASTHMA-CHRONIC OBSTRUCTIVE PULMONARY DISEASE OVERLAP

Although much is known about the pathophysiology of asthma and COPD as distinct disease entities, ACO is a disease process for which the underlying pathophysiology is not entirely clear. The Global Initiative for Asthma and Global Initiative for Chronic Obstructive Lung Disease describe ACO as a disease process characterized by persistent airflow limitation with multiple features of asthma and COPD present, including symptom patterns, lung function, age of onset, and time course of illness.²⁰ Although it is evident that patients with ACO exhibit overlapping clinical characteristics of both asthma and COPD, the underlying pathophysiology for this subset of patients with airway disease has not been entirely elucidated at this point in time. In addition, there are likely multiple phenotypes present within the broad category of patients with ACO, as patients with ACO may have varying clinical manifestations depending on the underlying pathophysiologic mechanisms present. This article focuses on the cellular and molecular mechanisms that may underlie the development of ACO with the understanding that further investigation is required to better understand the undoubtedly complex mechanisms at play in the development of this disease process.

DISCUSSION

Eosinophilic Versus Noneosinophilic Disease

In patients with overlapping features of asthma and COPD, it is difficult to determine which disease process determines a patient’s clinical course. Some patients with asthma go on to develop irreversible, permanent airflow limitation associated with permanent structural airway remodeling changes. This process is often associated with a decrease in bronchodilator responsiveness and an increase in symptoms.⁹ Conversely, there can be patients with established COPD who have concomitant features that resemble asthma with features of increased T2-mediated inflammation and clinical evidence of airway hyperresponsiveness, atopy, and significant reversibility of airflow limitation with administration of bronchodilators.⁹

Patients with asthma and COPD exist along a phenotypic continuum with marked heterogeneity due to clinical, symptom, and pathophysiologic variability among subjects; this is also likely true for patients with ACO, but further investigation is warranted to determine how eosinophilic versus neutrophilic/macrophage predominant inflammation early versus late in the disease process relates to the development of ACO as well as the phenotypic heterogeneity seen in clinical manifestations of the disease.

Role of Environmental Triggers

Environmental triggers including tobacco smoke, air pollution, and environmental allergens play a large role in the development of COPD and asthma and are likely significant contributors to the development of ACO.

Tobacco smoke

In patients with asthma, exposure to tobacco smoke has been shown to increase neutrophilic inflammation and create a mixed neutrophilic/eosinophilic picture in lieu of the eosinophil predominance typically seen.^21,22 This effect has also been shown to occur in mouse models of asthma in which attenuated eosinophilic responses to known allergic triggers were seen in subjects that were exposed to tobacco smoke.²³ Although the pathophysiological mechanisms that explain increased disease severity in subjects with ACO are unclear, the development of ACO may be due in part to the shift toward more neutrophil-predominant inflammatory mechanisms. In addition, this transition to a more neutrophil-predominant infiltration of the airways has been shown to result in airway remodeling, which can lead to fixed airflow limitation that characterizes ACO.^4,24

Exposure to tobacco smoke has also been shown to increase the concentration of CD8+ T cells within the airway epithelium of patients with asthma in a similar fashion to that seen in patients with COPD.^25,26 This increase in CD8+ T cells results in abnormal inflammatory indices, which can result in chronic inflammation, airway remodeling, and persistent airflow limitation characteristic of ACO. For further discussion on this topic, please see the full paper on smoking and ACO by Thomson within this series.

Air pollution

Air pollutants are contaminants that enter the atmosphere at concentrations high enough to result in detrimental effects, including negative effects on human health.²⁷ Prior studies have evaluated the link between increased levels of air pollution with the development of asthma²⁸ and COPD.²⁹ Air pollution contributes to worsening lung disease through a complex cascade of inflammation, oxidative stress, and immunomodulatory effects.³⁰ In addition, prior studies have shown that patients with asthma may have enhanced susceptibility to air pollution, as they have increased permeability of airway epithelium, which may place them at increased risk for continued inflammation and damage from inhaled irritants in air pollution.³¹ Thus, this chronic inflammation may play a role in continued damage to the airways of patients with asthma, resulting in irreversible airflow limitation characteristic of ACO.

Indoor air pollutants also influence the development of airways disease. Biomass fuel exposure, including the burning of wood, garbage, charcoal, and crops, is a known risk factor for the development of COPD. Additional studies have shown that exposure to biomass fuels used for cooking is associated with increased rates of asthma in children.³² Exposure to biomass fuel has also been shown to be a risk factor for the development of ACO in low- and middle-income countries and may represent an overlooked risk factor for the development of the disease in these populations.⁵ Long-term ozone exposure has been associated with a more rapid decline in forced expiratory volume in 1 second (FEV1), whereas nitrogen dioxide, fine particulate matter, and black carbon have been linked to having greater percentage of emphysema.³³ Further investigation is warranted to better elucidate the mechanisms behind how air pollution may contribute to the development of ACO, as this represents a potentially modifiable risk factor for development of the disease. This is a topic of great interest in the field, particularly in the setting of the current global climate crisis resulting in continually increasing concentrations of various air pollutants around the world.

Environmental allergens

There is an association between exposure to certain allergens with increased risk for development of asthma. Prior studies have shown that pediatric patients with increased exposure to specific molds, dust mites, cockroaches, and mice exhibit increased rates of asthma and worse asthma control.³⁴ Recurrent exposure to known allergens may contribute to the development of ACO in patients with asthma due to chronic inflammation within the airways resulting in permanent remodeling and subsequent fixed airflow limitation. Alternatively, patients with COPD may become sensitized to allergens following repeated exposure, and this may cause an imbalance in the adaptive immune response, with subsequent development of hypersensitivity and airway hyperreactivity, consistent with ACO.

Role of Inflammatory Cells

The inflammatory response in both asthma and COPD involves a concerted effort between innate and adaptive immunity. Unfortunately, the body of literature looking at inflammatory endotypes observed in patients with asthma or COPD has traditionally excluded patients with features of ACO. Although inferences can be made by looking at inflammatory profiles noted in patients with asthma or COPD, dedicated research investigating the inflammatory endotypes seen in patients with ACO is required to better classify the underlying pathophysiology in this patient population.

Macrophages

Macrophages are key players in the coordination of the chronic inflammatory state that results in airway remodeling and irreversible damage in the airways of patients with COPD. As previously discussed, patients with COPD have been shown to have increased levels of macrophage infiltration in the airways and lung parenchyma as well as increased concentrations in sputum and BAL samples. It is likely that proinflammatory macrophages predominate in COPD and contribute to the defective airway remodeling seen in this disease process.^35,36 Macrophages isolated from patients with COPD have also been shown to release increased levels of inflammatory mediators, including TNF-alpha, IL-1β, and IL-6.^37,38

The role of macrophages in the pathophysiology of asthma is less clear, as they may have proinflammatory or antiinflammatory effects depending on their surrounding environment and activation state.³⁷ However, it can be hypothesized that patients with asthma with increased levels of macrophages present in airway epithelium may be at increased risk for developing irreversible airflow limitation resulting from an imbalance of proinflammatory and antiinflammatory macrophage activation similar to what is observed in patients with COPD.

Lymphocytes

Lymphocytes likely play a key role in the pathophysiology of the development of ACO, as they mediate the inflammatory states seen in both asthma and COPD. In asthma, the T2 endotype of inflammation is driven by the coordination of CD4+ T2 lymphocytes that release IL-5 to drive eosinophilic inflammation and IL-4 and IL-13 that result in increased IgE production.^12,37 Conversely, patients with COPD have an increased concentration of CD8+ lymphocytes with increased T-cell infiltration correlating with higher levels of alveolar damage and more severe airflow limitation.^15,37 Prior studies have shown that patients with asthma who have a smoking history display a distinct pattern of airway pathology including high concentrations of CD8+ T cells.²⁵ This transition from predominantly CD4+ to CD8+ T-cell infiltration can result in alveolar destruction and the irreversible airflow limitation characteristic of patients with ACO.

In addition, patients with asthma and COPD have been shown to have increased levels of Th17 lymphocytes, which have been shown to be instrumental in the orchestration of airway hyperresponsiveness and tissue destruction seen in asthma and COPD, respectively.³⁹ This common pathway of inflammation may be key in understanding the role of lymphocytes in the pathogenesis of ACO, but dedicated research into the topic is required to better elucidate the effects of this subpopulation of lymphocytes in this particular disease process.

Eosinophils

Eosinophils were previously thought of as differentiated cytotoxic effector cells but have since been shown to have a more robust role in the orchestration of function of other immune cells.⁴⁰ Eosinophilic inflammation is characteristic of the T2 inflammation seen in patients with asthma. Increased levels of sputum eosinophils have been shown to correlate with increased frequency of airway mucous plugs and lower FEV1 in patients with asthma, which is one proposed mechanism of chronic airflow limitation in this population.⁴¹ Some patients with COPD exhibit increased numbers of eosinophils within the airways, which may place them at increased risk for airway hyperresponsiveness consistent with ACO⁴; this is further supported by studies that have shown that (1) there is more beneficial therapeutic outcome to corticosteroids and bronchodilators in patients with COPD who have elevated eosinophils in comparison to patients with COPD without eosinophilia³⁷ and (2) reducing peripheral eosinophils with mepolizumab, an anti-IL-5 monoclonal antibody, is associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype.⁴²

Neutrophils

Some patients with asthma display a neutrophil-predominant inflammatory phenotype within the airways, and the inflammation seen in COPD is classically characterized as being neutrophilic.⁴³ Neutrophils secrete serine proteases, which may contribute to alveolar destruction, and have also been shown to be linked with mucous hypersecretion via stimulation of submucosal glands and goblet cells.^37,44 At this time, there are not any studies looking at the role of neutrophils resulting in irreversible airflow limitation in patients with asthma with a neutrophil-predominant inflammatory endotype, but this mechanism could certainly contribute to the development of ACO.

Role of Cytokines and Chemokines

Patients with COPD and asthma have been shown to have abnormal levels of cytokines that orchestrate the chronic inflammatory states seen in each disease process by recruiting, activating, or promoting the survival of various inflammatory cells and pathways within airway epithelium.^37,45 Patients with asthma often exhibit increased markers of Th2-mediated inflammation with elevated levels of IL-4, IL-5, IL-9, and IL-13 as well as proinflammatory cytokines including TNF-α and IL-1β that help to intensify the inflammatory response.³⁷ Patients with COPD have been shown to have increased levels of IL-6, IL-β, TNF-α, and IL-8 in sputum.⁴⁶

Th17 cells release IL-17A and IL-22, both of which have been found to be elevated in patients with asthma and COPD and are believed to play a role in increasing neutrophilic inflammation in the airways.³⁹ Airway epithelial cells in patients with asthma and COPD have also been found to release increased levels of thymic stromal lymphopoietin (TSLP), an upstream cytokine that has been shown to selectively attract Th2 cells in asthma and orchestrate the function of innate lymphoid cells in COPD.^47,48 These shared inflammatory pathways may play a role in the underlying pathophysiology of ACO by causing neutrophilic airway infiltration, resulting in remodeling and permanent airflow limitation in patients with asthma. Increased levels of TSLP in patients with COPD can cause increased recruitment of Th2 cells, resulting in upregulation of allergy-mediated inflammation and bronchial hyperreactivity characteristic of ACO.⁴⁷

Chemokines have been shown to increase inflammation in the airways of patients with asthma and COPD through their role in attracting inflammatory cells from the circulation into the lungs by activation of G-protein–coupled receptors.³⁷ This recruitment of inflammatory cells into the airways likely contributes to ongoing damage and may be in an important mechanism by which patients develop ACO.

The body of scientific literature looking at cytokine and chemokine balance in patients with ACO is sparse at this time, as patients with features of ACO have traditionally been excluded from studies looking at the inflammatory profiles present in patients with COPD or asthma. Dedicated work looking at this subject may be of benefit to better classify the inflammatory endotypes seen in patients with ACO.

Role of Genetics and the Microbiome

Asthma and COPD are complex diseases with contributions from both genetics and environmental exposures. Substantial previous work has demonstrated a genetic predisposition to asthma^49,50 and COPD.^51,52 Investigating the role of genetic variation to the development of ACO is a growing field, but genetic studies in well-characterized cohorts of ACO remain limited. With the advent of more widely available genome-wide association techniques, the literature on this topic is expanding. One recent study looking at more than 8000 patients with ACO found 8 novel signals for ACO that suggest a shared genetic influence that may predispose individuals to the development of the disease.⁵³ Further research is warranted to look at the interplay between each of these genetic predispositions and their role in the development of ACO as well as their influence on the phenotypic heterogeneity of the disease process.

The human microbiome affects the development of airways disease. Prior studies have looked at the effects of the microbiome on development of asthma and chronic wheeze in children and have found that colonization with certain organisms, including Streptococcus pneumoniae, Haemophilus Influenzae, or Moraxella catarrhalis, increases the risk of developing asthma.^54,55 One study looking at the microbiome of patients with exacerbations of asthma or COPD revealed biological clusters with distinct inflammatory mediator and microbiome profiles despite having similar clinical presentations.⁵⁶ Additional investigation is required to better elucidate how the lung microbiome affects the development of ACO, as this may reveal novel treatment or prevention strategies for patients.

Architectural Destruction and Airway Remodeling

Prior studies looking at patients with COPD and asthma have shown elevated levels of cytokines that not only result in the differentiation and promotion of inflammatory cells but also act to promote and activate various structural cells that result in airway remodeling.⁴⁵ Biopsies from patients with asthma have been shown to demonstrate increased collagen type III deposition, larger mucous glands and airway smooth muscle (ASM) areas, augmented ASM size, and increased myosin light chain expression in patients with severe asthma, which has then been correlated with lower FEV1 values.^57,58 Two mechanisms of particular importance may be mucous hypersecretion and airway fibrosis, as these are shared between patients with asthma and COPD at differing degrees of severity.

The effect of tobacco smoke also influences airway remodeling and progression from the reversible bronchoconstriction seen in asthma to the fixed airway limitation characteristic of ACO. Prior studies looking at mouse models of allergen-induced asthma have shown exposure to tobacco smoke along with a pathogenic allergen resulted in increased collagen deposition in comparison to subjects only exposed to the allergen itself.²³ In addition, when looking at epithelial changes in patients with asthma who smoke versus those who do not smoke, it was shown that patients with asthma who smoke had increased numbers of goblet cells and mucous-positive epithelium, increased epithelial thickness, and an increased proliferation rate of basal epithelium.²⁴

Table 1.

Pathophysiologic features of asthma, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap

	Asthma	COPD	ACO
Macrophage infiltration within the airways	-	+	+
CD8+ T lymphocyte predominance	-	++	+/−
CD4+ T lymphocyte predominance	++	-	+/−
Eosinophilic inflammation predominates	+	-	+/−
Neutrophilic inflammation predominates	+	++	+/−
Elevated IL-5, IL-4, IL-13	+	-	+
Elevated IL-6, IL-8	-	+	+

“+”, typically present in the disease process; “−”, not typically observed in the disease process; “+/−”, can be present or absent in the disease process.

Table represents the phenotypic traits classically recognized in each disease process with the knowledge that there are cases that will not fit into the classic pattern typically observed.

KEY POINTS.

• Patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) exhibit overlapping clinical characteristics of both asthma and COPD but the underlying pathophysiology for this subset of patients with airway disease has not been entirely explained.

• The development of ACO involves the innate and adaptive immune responses with contributions from various inflammatory cells, cytokines, chemokines, and architectural distortion/remodeling of the airways.

• Further investigations into the biological mechanisms behind the development of ACO is warranted to better elucidate the natural history of the disease course by defining the underlying pathophysiology of this clinically relevant syndrome.

CLINICS CARE POINTS.

• The development of ACO involves the innate and adaptive immune responses with contributions from environmental and genetic influences.

• Further research into the pathophysiology of ACO is warranted to help better elucidate the mechanisms underlying this disease to provide treatments to improve the lives of patients living with this condition.

• There is likely considerable phenotypic heterogeneity within the disease process, but additional research focused on the evaluation of this is needed to better classify the inflammatory and clinical characteristics of patients with ACO.

• When evaluating for ACO, it may be helpful to characterize the inflammatory profile present within the airways, but further research is warranted to better classify the inflammatory phenotypes seen in patients with ACO.

• The interaction between airway inflammation and environmental triggers, such as tobacco smoke and air pollution, can play a pivotal role in the development of ACO, so a thorough history is key when making the diagnosis.

• Exposure to tobacco smoke may be of particular importance in regard to the architectural destruction and airway remodeling in patients with ACO, so emphasis on smoking cessation remains of utmost importance.