Overlap Between Asthma and COPD: Where the Two Diseases Converge

Asthma and chronic obstructive pulmonary disease (COPD) are traditionally recognized as distinct diseases, with some clearly separate characteristic. Asthma originates in childhood, is associated with allergies and eosinophils, and is best treated by targeting inflammation, whereas COPD occurs in adults who smoke, involves neutrophils, and is best treated with bronchodilators and the removal of risk factors. However, the distinction between the two is not always clear. Patients with severe asthma may present with fixed airway obstruction, and patients with COPD may have hyperresponsiveness and eosinophilia. Recognizing and understanding these overlapping features may offer new insight into the mechanisms and treatment of chronic airway inflammatory diseases.     

How Much Do We Know about Atopic Asthma： Where Are We Now？

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.     

Airway smooth muscle: a modulator of airway remodeling in asthma

Asthma is a disease characterized, in part, by airway hyperresponsiveness and inflammation. Although asthma typically induces reversible airway obstruction, in some patients with asthma, airflow obstruction can become irreversible. Such obstruction might be a consequence of persistent structural changes in the airway wall caused by the frequent stimulation of airway smooth muscle (ASM) by contractile agonists, inflammatory mediators, and growth factors. Traditional concepts concerning airway inflammation have focused on trafficking leukocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Recent studies suggest that ASM cells might modulate airway remodeling by secreting cytokines, growth factors, or matrix proteins and by expressing cell adhesion molecules and other potential costimulatory molecules. These ASM cell functions might directly or indirectly modulate submucosal airway inflammation and promote airway remodeling.     

Diagnostic problems in asthma

Asthma can be over-diagnosed, but is more often under-diagnosed. The diagnosis can be made by demonstrating the reversibility of airway obstruction or by a provocation test if the baseline spirometry is normal. The most frequent causes of missing the diagnosis are (1) atypical clinical presentation, (2) misconceptions about age of onset of childhood asthma, and (3) the coexistence of another chronic respiratory illness that may have a more dramatic clinical picture and constitute a "red herring." It is fascinating to speculate on the similarities and differences between classical asthma (which has a usually completely reversible obstruction) and the hyperreactivity and partial reversibility of chronic inflammatory diseases like COPD or CF. Unfortunately much remains to be investigated and little is known at present about these questions. Even in classical asthma, chronic or recurrent inflammation (even by late allergic reaction) could worsen the basic hyperreactivity and this could be amenable to treatment or prevention.     

Initiation, dose reduction, and duration of inhaled corticosteroid therapy

Asthma is characterized by persistent airway inflammation, which is associated with airway hyperresponsiveness and variable airflow obstruction, which accounts for the majority of symptoms experienced by asthmatic patients. Allergen sensitization and inhalation causes airway inflammation, and is likely important in the initiation and persistence of asthma in more than 50% of patients, and while allergen avoidance (or avoidance of other initiating factors, such as occupational sensitizers) can help some patients, it is often difficult to achieve. For this reason, pharmacologic treatment to reduce airway inflammation is currently the cornerstone of therapy for most individuals who have asthma.     

CD4(+) T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4(+) T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4(+) T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin-synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4(+) T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.     

Partitioned exhaled nitric oxide to non-invasively assess asthma

Asthma is a chronic inflammatory disease of the lungs, characterized by airway hyperresponsiveness. Chronic repetitive bouts of acute inflammation lead to airway wall remodeling and possibly the sequelae of fixed airflow obstruction. Nitric oxide (NO) is a reactive molecule synthesized by NO synthases (NOS). NOS are expressed by cells within the airway wall and functionally, two NOS isoforms exist: constitutive and inducible. In asthma, the inducible isoform is over expressed, leading to increased production of NO, which diffuses into the airway lumen, where it can be detected in the exhaled breath. The exhaled NO signal can be partitioned into airway and alveolar components by measuring exhaled NO at multiple flows and applying mathematical models of pulmonary NO dynamics. The airway NO flux and alveolar NO concentration can be elevated in adults and children with asthma and have been correlated with markers of airway inflammation and airflow obstruction in cross-sectional studies. Longitudinal studies which specifically address the clinical potential of partitioning exhaled NO for diagnosis, managing therapy, and predicting exacerbation are needed.     

Asthma therapy and airway remodeling

Asthma is characterized by variable degrees of chronic inflammation and structural alterations in the airways. The most prominent abnormalities include epithelial denudation, goblet cell metaplasia, subepithelial thickening, increased airway smooth muscle mass, bronchial gland enlargement, angiogenesis, and alterations in extracellular matrix components, involving large and small airways. Chronic inflammation is thought to initiate and perpetuate cycles of tissue injury and repair in asthma, although remodeling may also occur in parallel with inflammation. In the absence of definite evidence on how different remodeling features affect lung function in asthma, the working hypothesis should be that structural alterations can lead to the development of persistent airway hyperresponsiveness and fixed airway obstruction. It is still unanswered whether and when to begin treating patients with asthma to prevent or reverse deleterious remodeling, which components of remodeling to target, and how to monitor remodeling. Consequently, efforts are being made to understand better the effects of conventional anti-inflammatory therapies, such as glucocorticosteroids, on airway structural changes. Animal models, in vitro studies, and some clinical studies have advanced present knowledge on the cellular and molecular pathways involved in airway remodeling. This has encouraged the development of biologicals aimed to target various components of airway remodeling. Progress in this area requires the explicit linking of modern structure-function analysis with innovative biopharmaceutical approaches.     

Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma

BACKGROUND: Asthma is a genetically complex disease characterized by respiratory symptoms, intermittent airway obstruction and airway hyper-responsiveness due to airway inflammation and remodelling. The ADAM33 gene is associated with asthma and airway hyper-responsiveness and is postulated as a gene for airway remodelling. OBJECTIVE: To investigate whether polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in patients with asthma. METHODS: In a cohort of 200 asthma patients followed over 20 years, eight single nucleotide polymorphisms of the ADAM33 gene were analysed to estimate their effect on annual FEV(1) decline. RESULTS: The rare allele of the S_2 polymorphism was significantly associated with excess decline in FEV(1) (P<0.05). CONCLUSION: These findings suggest that a variant in ADAM33 is not only important in the development of asthma but also in disease progression, possibly related to enhanced airway remodelling.     

Revisiting Type 2‐high and Type 2‐low airway inflammation in asthma: current knowledge and therapeutic implications

Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger‐related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2‐driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL‐4, IL‐5 and IL‐13 from cells of both the innate and adaptive immune systems. A number of well‐recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients’ needs.     

The sentinel role of the airway epithelium in asthma pathogenesis

The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation.     

Angiogenesis in asthma

Asthma is a chronic inflammatory disease of the airways characterized by infiltration and activation of inflammatory cells and by structural changes, including subepithelial fibrosis, smooth muscle cells hypertrophy/hyperplasia, epithelial cell metaplasia and angiogenesis. These structural changes are thought to correlate with asthma severity and to account for the development of progressive lung function deterioration. The mechanism underlying airway angiogenesis in asthma and its precise clinical relevance have not yet been completely elucidated. This review provides recent data showing the contribution of allergic inflammation in increased airway vascularity and potential therapeutical approaches in asthma treatment by acting on bronchial microvascular changes.     

The role of innate immunity in asthma development and protection: Lessons from the environment

Asthma, a complex, chronic disease characterized by airway inflammation, hyperresponsiveness and remodelling, affects over 300 million people worldwide. While the disease is typically associated with exaggerated allergen‐induced type 2 immune responses, these responses are strongly influenced by environmental exposures that stimulate innate immune pathways capable of promoting or protecting from asthma. The dual role played by innate immunity in asthma pathogenesis offers multiple opportunities for both research and clinical interventions and is the subject of this review.     

The allergic cascade: review of the most important molecules in the asthmatic lung

Asthma is the most common chronic inflammatory disorder of the airways among children. It is a complex clinical disease characterized by airway obstruction, airway inflammation and airway hyperresponsiveness to a variety of stimuli. The development of allergic asthma exists of three phases, namely the induction phase, the early-phase asthmatic reaction (EAR) and the late-phase asthmatic reaction (LAR). Each phase is characterized by the production and interplay of various cell-derived mediators. In the induction phase, T helper cytokines are important in the development of asthma. Most important mediators in the EAR are preformed mediators, newly synthesized lipid mediators and cytokines that are produced by mast cells. During the LAR, inflammatory molecules are produced by various cell types, such as eosinophils, neutrophils, T cells, macrophages, dendritic cells, and structural cells. Chronical inflammation leads to structural changes of the airway architecture. In this review, the most important mediators involved in the induction phase, the early-phase and late-phase asthmatic reaction are discussed.     

Impact of inhaled corticosteroids and leukotriene receptor antagonists on airway remodeling

Asthma is a chronic inflammatory disease of the airways that is characterized by the presence of inflammatory cells and remodeling, a term used to define complex morphological changes involving all the structures of the bronchial wall (e.g., goblet cell hyperplasia of the epithelium, thickening of reticular basement membrane, increases of airway smooth muscle[ASM], and blood vessels). An important factor in the pathophysiology of asthma is the recognition that airway inflammation and airway remodeling are linked, as they are in other chronic inflammatory diseases. First-line therapy of persistent asthma involves the use of inhaled corticosteroids to control the underlying inflammation of the airways. Because remodeling of the airway wall is thought to be a result of chronic inflammation within the bronchial wall, it follows that because steroids reduce or reverse inflammation, they may also prevent or modulate remodeling. It has been revealed that steroids improve the subepithelial fibrosis and also significantly reduce airway vascularity. The cysteinyl leukotrienes receptor antagonists may also be helpful regarding the targeting of the inflammation and remodeling in asthma. However,long-term studies were needed to appreciate the prevention and treatment of remodeling by drug therapies.     

Natural history of asthma: persistence versus progression-does the beginning predict the end?

Environmental exposures during the early years and airway obstruction that develops during this time, in conjunction with genetic susceptibility, are important factors in the development of persistent asthma in childhood. Established risk factors for childhood asthma include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia, as well as allergic sensitization to aeroallergens and certain foods. Risk factors for the development of asthma in adulthood remain ill defined. Moreover, reasons for variability in the clinical course of asthma--persistence in some individuals and progression in others--remain an enigma. The distinction between disease persistence and disease progression suggests that these are different entities or phenotypes. There is currently no consensus on whether disease progression requires either airway inflammation or airway remodeling or the combination of the two. For patients with irreversible airway obstruction, inflammation might, in part, be necessary but perhaps not entirely sufficient to induce the irreversible component, some of which could be attributed to alterations in the structure of the bronchial wall. Intervening with intermittent or daily inhaled corticosteroids in high-risk infants and children does not prevent disease progression or impaired lung growth. These findings, however, might not apply to adults, and further study in adults is needed to determine the effect of inhaled corticosteroid therapy on disease progression.     

Clinical approaches towards asthma and chronic obstructive pulmonary disease based on the heterogeneity of disease pathogenesis

Asthma and chronic obstructive pulmonary disease (COPD) are each heterogeneous disease classifications that include several clinical and pathophysiological phenotypes. This heterogeneity complicates characterization of each disease and, in some cases, hinders the selection of appropriate treatment. Therefore, in recent years, emphasis has been placed on improving our understanding of the various phenotypes of asthma and of COPD and identifying biomarkers for each phenotype. Likewise, the concept of the endotype has been gaining acceptance; an endotype is a disease subtype that is defined by unique or distinctive functional or pathophysiological mechanisms. Endotypes of asthma or COPD may be primarily characterized by increased susceptibility to type 2 inflammation, increased susceptibility to viral infections, bacterial colonization or impaired lung development. The ‘Dutch hypothesis’ is as follows: gene variants underlying particular endotypes interact with detrimental environmental stimuli (e.g. smoking, viral infection and air pollution) and contribute to the ultimate development of asthma, COPD or both. Novel approaches that involve multidimensional assessment should facilitate identification and management of the components that generate this heterogeneity. Ultimately, patients with chronic inflammatory lung diseases may be treated based on these endotypes as determined by the respective biomarkers that correspond to individual endotypes instead of on disease labels such as asthma, COPD or even asthma–COPD overlap syndrome (ACOS).     

Asthma, asthma medication and autonomic nervous system dysfunction.

Asthma is associated with autonomic nervous imbalance: an increased bronchial sensitivity to cholinergic constrictors and possibly a decreased sensitivity to beta2-adrenergic dilators have been reported in this disease. Also, non-adrenergic and non-cholinergic (NANC) mediators have a small regulatory effect on airway function. These mediators contribute to the pathogenesis of asthma not only by regulating smooth muscle tone in the airways but also by affecting pulmonary blood flow, endothelial permeability and airway secretions. In many studies increased parasympathetic responsiveness has been associated with clinical asthma or the worsening of asthma in adults. However, most of the studies in children have not found association between autonomic dysfunction and asthma. Therefore, the autonomic dysfunction in asthma may be related to more advanced disease or long-term asthma medication in adults. This article briefly reviews the relationships between airway inflammation, beta2-agonist, anticholinergic and glucocorticoid medication as well as autonomic nervous function in asthma.     

Phenotyping airways disease: an A to E approach

The airway diseases asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous conditions with overlapping pathophysiological and clinical features. It has previously been proposed that this heterogeneity may be characterized in terms of five relatively independent domains labelled from A to E, namely airway hyperresponsiveness (AHR), bronchitis, cough reflex hypersensitivity, damage to the airways and surrounding lung parenchyma, and extrapulmonary factors. Airway hyperresponsiveness occurs in both asthma and COPD, accounting for variable day to day symptoms, although the mechanisms most likely differ between the two conditions. Bronchitis, or airway inflammation, may be predominantly eosinophilic or neutrophilic, with different treatments required for each. Cough reflex hypersensitivity is thought to underlie the chronic dry cough out of proportion to other symptoms that can occur in association with airways disease. Structural changes associated with airway disease (damage) include bronchial wall thickening, airway smooth muscle hypertrophy, bronchiectasis and emphysema. Finally, a variety of extrapulmonary factors may impact upon airway disease, including rhinosinusitis, gastroesophageal reflux disease, obesity and dysfunctional breathing. This article discusses the A to E concept in detail and describes how this framework may be used to assess and treat patients with airway diseases in the clinic.