American Journal of Respiratory and Critical Care Medicine

In 1961, during the first Bronchitis Symposium held in Groningen, the Netherlands, Orie and colleagues hypothesized that the various forms of airway obstruction, such as asthma, chronic bronchitis, and emphysema, should be considered not as separate diseases but as different expressions of one disease entity, chronic nonspecific lung disease (1). They proposed that endogenous (host) and exogeneous (environmental) factors play roles in pathogenesis. A hereditary predisposition to develop atopy and airway hyperresponsiveness (AHR) was considered an important factor in disease susceptibility, and airway obstruction was the pathophysiologic characteristic. At the Third International Bronchitis Symposium in the Netherlands in 1969, C. Fletcher and colleagues suggested the term “Dutch hypothesis” (2); it has been used to suggest that all obstructive diseases are manifestations of the same basic disease process.

British Hypothesis

The Dutch hypothesis is in contrast to the “British hypothesis,” where asthma and chronic obstructive pulmonary disease (COPD) are seen as distinct entities generated by different mechanisms. Yet, in every country, patients frequently ask their physicians, “Do I have asthma or COPD?” Whether it actually matters or not can be a difficult question to answer because significant physiologic and pathologic overlap exists between obstructive diseases. I assert that asthma and COPD are indeed phenotypes of the same obstructive disease process.

This begs the question as to which physiologic tests can best distinguish between asthma and COPD as obstructive phenotypes? Reversibility of airflow obstruction by an inhaled bronchodilator is one reasonable possibility. The problem is that even those with the diagnosis of asthma can demonstrate a component of fixed obstruction, particularly those with more severe asthma. Indeed, fixed obstruction has been reported to occur in 30% of a large population of patients with the diagnosis of asthma (3). Likewise, considerable reversibility of lung function exists in patients with the diagnosis of COPD. Using 15% improvement in FEV1 as the threshold to distinguish between asthma and COPD, Mannino and colleagues found it afforded only 44% sensitivity for detecting asthma, and a quite modest 72% specificity in distinguishing asthma from COPD (4).

So, if reversibility is not helpful, then how about measurement of lung volumes? It well accepted that patients with the diagnosis of COPD exhibit resting and dynamic hyperinflation, and the inspiratory capacity does correlate better than the FEV1 with steady-state exercise bicycle endurance (5). Yet, these characteristics are also seen in asthma, as demonstrated by Pare and colleagues (6). Although 58% of their subjects were “flow responders,” characterized by an FEV1/FVC > 1 consistent with an improvement in large airway resistance, the other 42% were “volume responders,” reflecting dilation of the peripheral airways, the latter a pattern associated with COPD (6). Diffusing capacity (DlCO), thought to be the single best physiologic discriminator between asthma and COPD, is inadequate in an individual patient; a DlCO of 80% was merely 77% sensitive and 71% specific in discriminating COPD from asthma (7).

If our standard physiologic tests of reversibility, lung volume, and DlCO cannot reliably distinguish between obstructive phenotypes, what about more exotic measures associated with COPD, such as loss of elastic recoil? Unfortunately for the “British” side, two recent reports have described decreases in elastic recoil, particularly in moderate to severe asthma (8, 9). In fact, 34% of the decrease in expiratory flow in these subjects with asthma was due to loss of recoil rather than airway disease. We have recently shown that reduced elastic recoil exists in mild asthma, and is not reversed by antiinflammatory agents (10). I conclude that none of the physiologic tests can definitely distinguish between obstructive phenotypes of asthma and COPD.

Perhaps physiology is not the best way to distinguish the obstructive airway phenotypes, and pathologic examination of airway tissues could be more definitive. Classically, asthma is characterized by a predominance of CD4+ lymphocytes, eosinophils, and a Th2 cytokine profile, including interleukin (IL)-13. COPD is characterized by a predominance of CD8+ cells and macrophages and enhanced expression of IFN-γ and tumor necrosis factor-α (11). In the modern world, the lines distinguishing asthma and COPD are blurred; mucous metaplasia, goblet cell hyperplasia, and neutrophils have been well documented in asthma (12), whereas eosinophilia and Th2 cytokines can be readily found in COPD (13). Furthermore, studies in transgenic mice have shown that overexpression of IL-13, a Th2 cytokine, induces airway and parenchymal changes similar to those seen in both asthma and COPD phenotypes (14).

Further reinforcing this view is that the phenotype of chronic bronchitis is characterized by mucous metaplasia, goblet cell hyperplasia, and mucous gland enlargement, remarkably similar to those changes noted in asthma (12). Although airway fibrosis has not been classically highlighted in COPD, recent work suggests that total airway smooth muscle is increased in COPD, most prominently in the small bronchi and bronchioles (12). Certainly, dysregulated repair with peribronchiolar fibrosis and mural wall edema has been recognized in COPD (12). In the distal lung, the emphysema phenotype of COPD is classically associated with alveolar destruction, and proteolytic responses have been considered to be minimal in asthma. However, recent studies suggest that elastin degradation occurs in asthma, and these changes have been dubbed “pseudoemphysema” as they are associated with loss of elastic recoil (9). In addition to physiology, there is significant pathologic overlap among the obstructive phenotypes of asthma, chronic bronchitis, and emphysema (9).

AHR and Atopy in Asthma and COPD

AHR and atopy are common mechanisms that drive obstructive phenotypes and might help to explain why physiologic and pathologic evaluations are not effective in distinguishing asthma and COPD definitively. The presence of AHR and its interaction with environmental insults such as cigarette smoking could explain why up to 40% of patients with obstructive airway disease exhibit features of both classical asthma and COPD. Certainly, AHR is a cardinal feature of asthma, and its presence during childhood, along with atopy, increases the risk for development of asthma (15). In patients with asthma who smoke, the severity of AHR correlates with the accelerated decline in lung function (16). Indeed, AHR itself may contribute to the development of chronic obstructive disease, because the presence of AHR in general is associated with lower lung function during adulthood, independent of smoking history (17). In fact, AHR alone can drive the presentation of chronic COPD-associated respiratory symptoms, including cough, chronic sputum production, and dyspnea (18). Furthermore, AHR has been documented in several studies, and its prevalence ranges from 46 to 70% (19). Importantly, the presence of AHR is also associated with a steeper decline in lung function in COPD (15).

The genetic factors driving AHR, while just starting to be unfolded, may ultimately prove the existence of links between asthma and COPD. A disintegrin and metalloproteinase (ADAM)-33 gene has been identified as a major susceptibility gene for asthma and AHR (20) and verified in two separate populations of patients with asthma (21). Recently, van Diemen and colleagues suggested that some of the same single nucleotide polymorphisms of ADAM-33 are also associated with COPD (22). These intriguing findings bring us closer to finding common roots in the origin of AHR in several phenotypes of obstructive airway disease.

Even with atopy, the relationship between atopy and development of asthma is strong (23) and there may be important links with COPD. Several studies of the COPD phenotype have suggested an inverse association with atopy, as defined by IgE level, and the FEV1/FVC ratio independent of smoking status (24).

Interaction of AHR and Atopy with Cigarette Smoking

If AHR and atopy can link asthma and COPD, what about smoking? In patients with asthma who smoke, lung function declines more rapidly, and this includes in utero exposure (16, 25). The interaction with AHR and cigarette smoke may be particularly important in both asthma and COPD, because the presence of AHR predicted baseline lung function but is also more common in smokers, and this association becomes stronger with increasing age (26). Therefore, the genetic factors that predispose to AHR may allow for the development of asthma, COPD, or mixed disease, with the specific phenotype determined by interaction with environmental stimuli, such as cigarette smoke.

How important is it to discriminate between the obstructive diseases? Certainly, therapeutic options other than oxygen therapy are similar between the phenotypes, as they are now both commonly treated with an inhaled corticosteroid and long-acting β2-agonist. The presence of eosinophils in COPD has provided evidence to consider treatment with a cysteinyl leukotriene receptor antagonist, and the presence of neutrophils in both diseases lends credence to the use of other antiinflammatory agents, such as 5-lipoxygenase inhibitors and theophylline. Anticholinergics, the mainstay of therapy of “British” COPD, are now being studied in asthma, and have been used with success in clinical trials evaluating chronic asthma (27).

Where the distinction might matter is in assessing prognosis. Certainly, prognosis of the phenotypes is different, as reported by Burrows and colleagues in 1987 (23). Interestingly, they pointed out that the large percentage of subjects (45 of 117) with features of both asthma and COPD exhibited an intermediate prognosis between the classical asthma and COPD phenotypes.

In conclusion, many of our patients with obstructive airway disease exhibit physiologic and pathologic characteristics of both classical asthma and COPD phenotypes. Unfortunately, most subjects with this mixed phenotype are not included in clinical intervention trials. The hypothesis that genetic predisposition to AHR interacts with environmental insults and leads to one of several obstructive airway phenotypes is plausible and suggests a common origin of these diseases. Further studies may prove the common origin of these diseases: a genetic predisposition to AHR with environmental insults leading to a specific obstructive disease phenotype. Ultimate elucidation of the mechanisms generating these obstructive phenotypes requires thoughtful, long-term studies. Therefore, I implore you not to ask what your country can do for you, but what you can do for your patients!

1. Orie NGM, Sluiter HJ, De Vries K, Tammeling GJ, Witkop J. The host factor in bronchitis. In: Orie NGM, Sluiter HJ, editors, Bronchitis. Assen, the Netherlands: Royal Van Gorcum; 1961. pp. 43–59.
2. Orie NGM, van der Lende R, editors. Bronchitis III: Third international symposium on bronchitis. Assen, the Netherlands: Royal van Gorcum; 1970. p. 115.
3. Kesten S, Rebuck AS. Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD? Chest 1994;105:1042–1045.
4. Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2000;160:1683–1689.
5. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:967–975.
6. Pare PD, Lawson LM, Brooks LA. Patterns of response to inhaled bronchodilators in asthmatics. Am Rev Respir Dis 1983;127:680–685.
7. Magnussen H, Richter K, Taube C. Are chronic obstructive pulmonary disease (COPD) and asthma different diseases? Clin Exp Allergy 1998;28:187–194. [Discussion, 203–185.]
8. Gelb AF, Licuanan J, Shinar CM, Zamel N. Unsuspected loss of lung elastic recoil in chronic persistent asthma. Chest 2002;121:715–721.
9. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162:1778–1782.
10. Kraft MPJ, Cairns CB, Ellison M, Irvin C, Wenzel SE. Improvement in distal lung function correlates with asthma symptoms after treatment with oral montelukast. Chest (In press)
11. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, Maestrelli P, Ciaccia A. Fabbri LM. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:822–826.
12. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001–1008.
13. Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri, MP, Roggeri A, Calcagni P, Mapp CE, Ciaccia A, Fabbri LM. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994;150:1646–1652.
14. Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest 1999;104:1001–1006.
15. Postma DS, Boezen HM. Rationale for the Dutch hypothesis: allergy and airway hyperresponsiveness as genetic factors and their interaction with environment in the development of asthma and COPD. Chest 2004;126:96S–104S. [Discussion, 159S–161S.]
16. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194–1200.
17. Rijcken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. The relationship between airway responsiveness to histamine and pulmonary function level in a random population sample. Am Rev Respir Dis 1988;137:826–832.
18. Xu X, Rijcken B, Schouten JP, Weiss ST. Airways responsiveness and development and remission of chronic respiratory symptoms in adults. Lancet 1997;350:1431–1434.
19. Yan K, Salome CM, Woolcock AJ. Prevalence and nature of bronchial hyperresponsiveness in subjects with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:25–29.
20. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002;418:426–430.
21. Jongepier H, Boezen HM, Dijkstra A, Howard TD, Vonk JM, Koppelman GH, Zheng SL, Meyers DA, Bleecker ER, Postma DS. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 2004;34:757–760.
22. van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am J Respir Crit Care Med 2005;172:329–333.
23. Burrows B, Bloom JW, Traver GA, Cline MG. The course and prognosis of different forms of chronic airways obstruction in a sample from the general population. N Engl J Med 1987;317:1309–1314.
24. Sherrill DL, Lebowitz MD, Halonen M, Barbee RA, Burrows B. Longitudinal evaluation of the association between pulmonary function and total serum IgE. Am J Respir Crit Care Med 1995;152:98–102.
25. Gilliland FD, Berhane K, Li YF, Rappaport EB, Peters JM. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med 2003;167:917–924.
26. Burney PG, Britton JR, Chinn S, Tattersfield AE, Papacosta AO, Kelson MC, Anderson F, Corfield DR. Descriptive epidemiology of bronchial reactivity in an adult population: results from a community study. Thorax 1987;42:38–44.
27. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505–1512.


No related items
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record