American Journal of Respiratory and Critical Care Medicine

In 1961, Orie and colleagues from Groningen, the Netherlands, proposed that all airway diseases, including asthma, emphysema, and chronic bronchitis, should be considered a single disease with common genetic origins (1). This subsequently became known as the “Dutch hypothesis” and the term “chronic nonspecific lung disease” (CNSLD) was introduced to describe this single airway disease. The Dutch hypothesis was vigorously opposed by researchers in the United Kingdom and the United States, who argued that asthma and chronic bronchitis/emphysema (chronic obstructive pulmonary disease [COPD]) were distinct diseases with different causal mechanisms (2). Despite the intrinsic implausibility of the Dutch hypothesis, the debate has continued and new evidence from epidemiology and genetic studies, as well as experimental animal models, has been advanced to support the hypothesis. I believe that the evidence now argues strongly against the Dutch hypothesis as originally conceived, but I am inclined to think that there are some situations where it has merit.

Most clinicians can easily distinguish between asthma and COPD based on clinical history and simple lung function tests. Both asthma and COPD are characterized by airflow limitation. Asthma is usually episodic in nature, does not progress, usually begins in early childhood, and shows a good response to bronchodilators and corticosteroids. By contrast, COPD has a very slowly progressive onset and most patients are diagnosed in their 60s, there is little variability in symptoms, and patients show a poor response to bronchodilators and corticosteroids. The confusion is that some patients fall between these classical phenotypes, so that some patients with COPD have more reversibility, whereas some patients with asthma have a progressive course. This would be evidence in favor of the Dutch hypothesis, with a continuum from asthma to COPD and these atypical patients falling somewhere in between. However, it is more likely that both of these very common diseases may occur concurrently in some patients.

Both asthma and COPD involve inflammation of the respiratory mucosa, but the pattern and distribution of inflammation markedly differs between typical patients with asthma and COPD (3, 4). In asthma, infiltration of eosinophils into the airway wall, with increased numbers of T-helper 2 (Th2) lymphocytes, and activated mast cells are characteristic, whereas in COPD the predominant infiltrating inflammatory cells are neutrophils, macrophages, and cytotoxic T cells of the Tc1 subtype (5). The inflammatory mediator profile of asthma and COPD are different, with a predominance in asthma of bronchoconstrictor mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, as well as cytokines derived from Th2 cells, such as interleukin (IL)-5 and IL-13 (6). In COPD, neutrophil chemotactic mediators, such as leukotriene B4 (LTB4) and CXCL8 (IL-8), are prominent (7). Structural changes in the airway wall are different between asthma and COPD, with shedding of airway epithelial cells commonly seen on biopsies due to epithelial fragility and a characteristic deposition of collagen under the airway epithelia (subepithelial fibrosis) in asthma, whereas in COPD, the airway epithelium may show squamous metaplasia and subepithelial fibrosis is not a feature. Airway smooth muscle hypertrophy and hyperplasia and increased bronchial vascularity may be seen in asthma, but this is much less marked in COPD. The inflammation in asthma predominates in central airways, although inflammatory changes are also seen in small airways in patients with more severe disease; parenchymal involvement is not seen. By contrast, the inflammation in COPD predominantly involves small airways and lung parenchyma, with fibrosis of bronchioles and parenchymal destruction (8). The airway narrowing of asthma is predominantly due to contraction of airway smooth muscle as a result of multiple bronchoconstrictor mediators released from inflammatory cells, particularly mast cells. By contrast, the airflow limitation of COPD results from structural changes of small airways and closure of small airways as a result of disrupted alveolar attachments, resulting in air trapping and dyspnea. Emphysema also reduces gas exchange, with a reduction in transfer factor for carbon monoxide, whereas this value is normal or even high in patients with asthma. In an important study comparing inflammatory biomarkers in patients with asthma and COPD who had comparable airflow limitation and airway hyperresponsiveness (AHR), marked differences were seen between these two patient groups, with increased eosinophils in peripheral blood, sputum, bronchoalveolar lavage, and airway mucosa; fewer neutrophils in sputum and bronchoalveolar lavage fluid; a higher CD4+/CD8+ ratio of T cells; and thicker basement membrane in the patients with asthma than in the patients with COPD (9). Furthermore, they did not have emphysema on the computed tomography scan and had no defects in gas transfer, in contrast to the patients with COPD. Patients with asthma also had a higher level of exhaled nitric oxide (NO), a biomarker of eosinophilic inflammation. This study showed that, even when the degree of airflow obstruction is matched, patients with a history of asthma and COPD have very different inflammatory and clinical phenotypes.

The therapeutic response of patients with COPD differs in several respects to that of the typical patient with asthma. Patients with asthma typically show a large bronchodilator response to β2-agonists, reflecting the reversal of bronchoconstriction induced by mediators such as LTD4, a modest response to anticholinergic drugs, indicating that cholinergic mechanisms are a minor component of the bronchoconstriction, and most strikingly, a good response to corticosteroids, which effectively suppress the inflammation in asthmatic airways. By contrast, patients with COPD usually have a poor bronchodilator response and respond to anticholinergics to a similar extent as β2-agonists, indicating that the only reversible component is cholinergic tone. Strikingly, corticosteroids, even in high doses, do not have significant antiinflammatory effects in patients with COPD (1013). Steroid insensitivity is also seen at the level of single cells, such as macrophages from patients with COPD (14), and appears, at least in part, to be due to an active steroid resistance mechanism due to a reduction in histone deacetylase, which is required for corticosteroids to switch off activated inflammatory genes (15, 16). Some patients with COPD appear to show a greater response to bronchodilators and corticosteroids, which may seem to support the Dutch hypothesis. These patients also have a greater number of eosinophils and higher levels of exhaled NO, indicating that they probably have concomitant asthma (9, 17). A recent study showing an impressive antiinflammatory effect of a combination therapy with a corticosteroid and long-acting β2-agonist in bronchial biopsies of patients with COPD is difficult to interpret because there is no comparison with corticosteroids or long-acting β2-agonist alone (18) and it is possible that the antiinflammatory effect is due to the β2-agonist.

Both asthma and COPD have important genetic predispositions, but the prediction of the Dutch hypothesis is that the genes should be the same and that environmental factors then shape the differences in clinical manifestation. There has been an explosion of interest in susceptibility genes that predispose to asthma and AHR and to COPD (19, 20). Few gene polymorphisms have been replicated and each has a small effect, but there is no good concordance between the genes associated with asthma and those associated with COPD. In patients with asthma, many single nucleotide polymorphisms (SNPs) have been described in genes encoding cytokines and their receptors as well as several novel genes. The most consistent genetic associations have been with genes encoding Th2 cytokines, such as IL-4 and IL-13, and their receptors, which is plausible because these genes may determine the development of atopy, which has long been recognized to be genetically determined. However, these genes are not associated with COPD; this is not surprising since COPD is not associated with Th2 cytokines. Approximately 15% of smokers develop symptomatic COPD, strongly suggesting a genetic predisposition. It has been difficult so far to identify susceptibility genes in COPD, but there is increasing evidence that SNPs in genes encoding various proteases and antiproteases, antioxidants, and detoxifying enzymes may be involved. The classical genetic predisposition is α1-antitrypsin deficiency, but this affects less than 1% of patients with COPD and α1-antitrypsin polymorphisms have not been associated with atopy or asthma. Cystic fibrosis is associated with an inflammatory airway disease and therefore comes within the definition of CNSLD, but it is due to a single gene disorder that is unrelated to asthma or COPD.

However, although most SNPs associated with asthma or COPD differ, some appear to be common to both diseases. These may be related to genes that determine disease severity through amplification of the inflammatory response. For example, polymorphisms in the promoter region of tumor necrosis factor-α have been associated in some studies with COPD and asthma and may determine the severity of the inflammatory process. Similar polymorphisms have also been described in other inflammatory and immune diseases, such as Crohn's disease, rheumatoid arthritis, and systemic lupus erythematosis, so these are more related to the inflammatory process than airway diseases per se (21). Some novel asthma genes, including ADAM33 and DPP10, have been associated with COPD as well as asthma and may be genes determining disease severity (22, 23).

The Dutch hypothesis predicts that atopy and AHR, which are important determinants of asthma, should also be linked to the development of COPD. There is no evidence that patients with COPD have a higher prevalence of atopy or atopic diseases, such as rhinitis or eczema (24). Specific and nonspecific IgE levels are not elevated in patients with COPD.

The relationship between AHR and COPD progression has been a key area of debate. The Dutch hypothesis predicts that AHR predisposes to an accelerated decline in lung function, but this is difficult to interpret because AHR is seen in patients with COPD as a result of the geometric effect of airway narrowing, which increases responsiveness to inhaled methacholine (25). Even a small increase in the thickness of an airway as a result of any inflammatory process may markedly augment the increase in airway resistance induced by a bronchoconstrictor without affecting the baseline measurement (26). This makes it impossible to determine whether AHR is the cause or the consequence of COPD. However, patients with asthma are characteristically responsive to indirect bronchoconstrictors, such as allergen, adenosine, exercise, hyperventilation, and hypertonic saline, most of which release bronchoconstrictor mediators from mast cells (27). Patients with COPD do not typically respond in such an exaggerated way, if at all, to these challenges. Some patients with COPD respond to inhaled adenosine monophosphate, but this is associated with increased eosinophils in the airways, indicating likely concomitant asthma (28).

Unfortunately, animal models of asthma and COPD do not closely mimic chronic airway diseases, but they have provided evidence for and against the Dutch hypothesis. Various animal models have been sensitized to allergen, usually ovalbumin, then exposed to aerosolized allergen, which induces an eosinophilic inflammatory response in the airways and lungs, mucus hypersecretion, and a small degree of AHR. However, these models do not demonstrate the development of emphysema and therefore appear to be models of pure allergic asthma. Transgenic and knockout mice have been valuable in elucidating the roles of specific genes but may give misleading results in terms of disease models. For example, transgenic mice overexpressing IL-13 develop an eosinophilic inflammation, mucus secretion, and AHR but also alveolar wall destruction similar to emphysema through induction of various proteases (29). This has been taken as support for the Dutch hypothesis (29), but IL-13, which is a Th2 cytokine expressed in asthma, if anything shows a reduced expression in patients with emphysema (30). Transgenic overexpression of IFN-γ in transgenic mice induces emphysema consistent with a Th1/Tc1 inflammation of COPD, but does not cause an allergic pattern of inflammation, and indeed, IFN-γ suppresses allergic inflammation in mice (31).

The Dutch hypothesis proposed that there was a common host mechanism but the phenotype of airway disease was determined by environmental factors. This is best demonstrated by cigarette smoking, which is by far the most important risk factor for the development of COPD. However, only about 20% of smokers develop clinically important COPD, indicating the importance of innate susceptibility factors that are presumably genetically determined. The Dutch hypothesis implies that patients with asthma who smoke would be at greater risk of developing COPD than patients without asthma due to the common host factors of CNSLD. The prevalence of smoking among patients with asthma is surprisingly similar to that in the general population and there is evidence that asthma is more severe, patients are more frequently admitted to hospital, and they show a reduced responsiveness to corticosteroids (32). The rate of decline in lung function is increased in patients with asthma and in normal smokers, but in smokers with asthma, the decline in lung function is additive rather than multiplicative as might be implied by the Dutch hypothesis (33).

Although the nature of pro/con articles is to emphasize the extreme views on a topic, reality is usually less clear-cut. This appears now to be the case with the Dutch hypothesis. Although it is clear that asthma and COPD usually have distinct mechanisms, pathologies, and clinical presentations, there are circumstances where these distinctions are less clear. In patients with severe asthma, the inflammation in the airways becomes more similar to the pattern seen in COPD, with an increase in the number of neutrophils and IL-8, increased proteases, increased oxidative stress, and a reduced responsiveness to corticosteroids (Table 1). This might reflect common mechanisms between COPD and asthma that are related to the intrinsic determinants of disease severity.




Severe Asthma
CellsNeutrophils ++ Macrophages +++ CD8+ cells (Tc1)Eosinophils ++ Macrophages + CD4+ cells (Th2)Neutrophils + Macrophages ++ CD4+ cells (Th2), +CD8+ cells
Key mediatorsIL-8 TNF-α, IL-1β, IL-6 NO +Eotaxin IL-4, IL-5, IL-13 NO +++IL-8 IL-5, IL-13 NO ++
Oxidative stress+++++++
Site of diseasePeripheral airways Lung parenchymaMainly proximal airwaysAlso peripheral airways
 Pulmonary vessels
ConsequencesSquamous metaplasia Mucous metaplasiaFragile epithelium Mucous metaplasia ↑↑ Basement membrane Airway obstruction not fully reversible
 Small airways fibrosis Parenchymal destruction Pulmonary vascular remodeling Basement membrane
Response to therapy
Small b/d response Poor response to steroids
Large b/d response Good response to steroids
Smaller b/d response Reduced response to steroids

Definition of abbreviations: b/d = bronchodilatation; COPD = chronic obstructive pulmonary disease; IL = interleukin; TNF = tumor necrosis factor.

Most evidence now contradicts the Dutch hypothesis, because asthma and COPD are seen to be distinct clinical entities, with different inflammatory cells and mediators, different causal mechanisms, and different responses to therapy. There is little or inconclusive evidence that AHR predicts the progression of COPD or that atopy, the genetic substrate of asthma, has any influence on COPD. However, there is emerging evidence that patients with severe asthma behave more like patients with COPD, with similar inflammatory mechanisms and similar poor responsiveness to corticosteroid therapy. It is possible that these similarities may be explained by common genetic predispositions that determine both asthma severity and disease progression in COPD. Although the Dutch hypothesis appears to be largely incorrect, it still provides a basis for important future research. Politically, there is some advantage to lumping asthma and COPD because together they would become one of the commonest single disease worldwide, and this may highlight the importance of this clinical problem.

The author thanks Neil Pride for his very helpful comments and advice during the preparation of this manuscript.

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