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(Chest. 2004;126:96S-104S.)
© 2004 American College of Chest Physicians

Rationale for the Dutch Hypothesis*

Allergy and Airway Hyperresponsiveness as Genetic Factors and Their Interaction With Environment in the Development of Asthma and COPD

Dirkje S. Postma, MD, PhD and H. Marike Boezen, PhD

* From the Departments of Pulmonology (Dr. Postma) and Epidemiology and Statistics (Dr. Boezen), University of Groningen, the Netherlands.

Correspondence to: Dirkje S. Postma, MD, PhD, Department of Pulmonology, University Hospital, University of Groningen, Postbus 30001, Hanseplein 1, 9700 RB Groningen, the Netherlands


   Abstract
TOP
 Abstract
Introduction
 The Role of AHR...
 The Role of Smoking...
 Conclusion
 References
 
The Dutch hypothesis, formulated in the 1960s, holds that the various forms of airway obstruction are different expressions of a single disease entity. It suggests that genetic factors (eg, airway hyperresponsiveness [AHR] and atopy), endogenous factors (eg, sex and age), and exogenous factors (eg, allergens, infections, and smoking) all play a role in the pathogenesis of chronic nonspecific lung disease. This review finds evidence that AHR and smoking are common risk factors for asthma and COPD. To prove the Dutch hypothesis definitively, however, genetic studies, preferably longitudinal, must be performed. Such studies must include subjects who have airway obstruction that does not necessarily meet the current strict definitions of asthma or COPD (ie, the extremes of these conditions) that are used in clinical studies.

Key Words: airway hyperresponsiveness • asthma • atopy • chronic bronchitis • COPD • Dutch hypothesis • emphysema • pathogenesis • smoking


   Introduction
TOP
 Abstract
 Introduction
The Role of AHR...
 The Role of Smoking...
 Conclusion
 References
 
The Dutch hypothesis was first advanced by Orie and coworkers in the 1960s.1234 At that time, tuberculosis was still the most prevalent disease causing respiratory symptoms. However, there was an increased awareness that some patients did not have tuberculosis, yet had respiratory symptoms with accompanying morbidity. When adequate treatment for tuberculosis became available, Orie and Sluiter1 realized that obstructive airway diseases were highly prevalent and that there were many similarities between younger and older patients. In 1961, during the first Bronchitis Symposium held in Groningen, the Netherlands, they put forward the hypothesis that various forms of airway obstruction such as asthma, chronic bronchitis, and emphysema should not be considered as separate diseases but rather as different expressions of one disease entity, a chronic nonspecific lung disease (CNSLD).1 They proposed that in this disease entity, both endogenous (host) and exogenous (environmental) factors play a role in pathogenesis. A hereditary predisposition to develop allergy and airway hyperresponsiveness (AHR) was considered to be an important factor in disease susceptibility, whereas diffuse airway obstruction was considered to be the common pathophysiologic characteristic. At the Third International Bronchitis Symposium in the Netherlands in September 1969, Fletcher and coworkers suggested the term Dutch hypothesis, and it has often been used since.5

The Dutch hypothesis suggests that asthma, chronic bronchitis, and emphysema have a number of defining characteristics in common. Besides the host factors AHR and atopy, the endogenous factors are sex and age. Important exogenous factors are allergens, viral infections, and pollutants, such as smoking. Orie and Sluiter1 suggested that host factors are not uniformly expressed clinically, but rather are affected by interactions with other characteristics. For instance, the manifestations of atopy and AHR are dependent on age, and so there is a characteristic pattern to many cases of asthma and bronchitis. Besides age, host factors can be modulated by airway geometry (which changes with age) and by environmental factors such as exposure to allergens, smoking, infections, and air pollution. The host factors affect not only the onset of CNSLD but also its course, as assessed by respiratory symptoms and lung function impairment.

As an example, smoking is an environmental stimulus that interacts with host factors. Cigarette smoke is the most prominent factor determining the increased prevalence and mortality of COPD worldwide, and the majority of COPD patients are cigarette smokers, yet only a minority of smokers (10 to 15%) develop COPD. This may signify a genetic disposition to COPD. As discussed below, there also is circumstantial evidence that smoking is associated with asthma development. Again, not all children or young adults exposed to cigarette smoke develop asthma. However, the nature of exposure (ie, active vs passive) and the time span in which an individual is exposed to smoking (ie, in utero, in early childhood, or in adulthood, at the time that lung growth has arrested) may determine the final expression of the effect of smoking in interaction with the genetic background. This example shows how the reasoning of Orie and coworkers in the 1960s contributed to the development of a better understanding of CNSLD as one disease with many different clinical expressions.

Since there was thought to be no fundamental difference among the clinical entities of CNSLD (ie, asthma, chronic bronchitis, and emphysema), Orie and coworkers2 abandoned the use of these names. At the second Bronchitis Symposium,2 they stressed the necessity of exactly describing the individual patient rather than categorizing a patient with a specific disease label. Apart from standard examination, the following phenotypes had to be used for clinical characterization:

hyperreactivity (reaction to histamine) and its degree;
allergy (reaction to allergens) and its degree;
bronchial obstruction and its degree;
reversibility of bronchial obstruction;
bacterial bronchial inflammation; and
sputum eosinophilia

Notably, bacterial infection was considered to be a secondary phenomenon that was due to airway obstruction, whereas it was thought that viral infection could be a primary cause of CNSLD. Orie and Sluiter2 also recommended noting the presence of fibrosis and bronchiectasis, which were thought to be complications of CNSLD, as well as simultaneously existing diseases (sarcoidosis, tuberculosis, silicosis, and mitral stenosis were specifically mentioned), since they were thought to alter the clinical expression. In addition, the age of the individual was always taken into account, because age is one of the most important factors affecting the expression of an individual’s genetic background. Indeed, it was shown that some older patients with obvious emphysema still could have a reversible component of airway obstruction and that some clearly asthmatic patients might already have lung function loss at young ages.

These observations may lend support to the Dutch hypothesis, yet so far the hypothesis has not been proven. Only genetic studies investigating both asthma and COPD patients who have been observed over a lifetime will provide definite proof. Lifetime environmental exposures cannot be taken into account accurately in cross-sectional studies; therefore, such studies underestimate or overestimate the relevance of the exposures regarding the development of clinical features in specific disease categories.

There are more notes of caution. First, in studies that try to establish the accuracy of the Dutch hypothesis, it is important to include patients who have airway obstruction but do not meet the tight definitions applied to asthma and COPD today. Current clinical studies on asthma generally only include atopic, nonsmoking patients who are about 30 to 40 years of age with clearly shown reversibility, whereas studies on COPD only include smoking patients > 45 years of age without atopy and without reversibility of airway obstruction. By using fully exclusive criteria, one never can establish whether underlying mechanisms may be the same. Second, it is important to measure objective phenotypes adequately (see above and reference 2) and to measure environmental exposures in relation to each other, not separately or incompletely.

The Dutch hypothesis has generated much research and better insight into the underlying mechanisms of asthma and COPD. In support of the hypothesis, atopy and AHR are both present in patients with asthma and COPD, and are activated by environmental stimuli to express the disease. However, it has yet to be established whether there are shared risk factors for asthma and COPD according to the principles of the Dutch hypothesis. Below we focus on the role of two potential common risk factors, AHR and smoking, in the development and progression of asthma and COPD.


   The Role of AHR in the Development of Asthma and COPD
TOP
 Abstract
 Introduction
 The Role of AHR...
The Role of Smoking...
 Conclusion
 References
 
Asthma
AHR and Asthma in Childhood:
AHR can be present in very young patients, and it appears to be a determinant of further lung development. One study6 showed that more severe AHR at 1 month after birth was associated with a lower level of lung function at the age of 6 years. Longitudinal studies78 have shown that persistent AHR in early childhood may constitute a risk factor for the development of asthma. Persistent AHR in early childhood also has been associated with a progressive reduction in airway caliber and ongoing symptoms of asthma, suggesting abnormal growth of airways that results in reduced levels of FEV1.9

The combination of wheeze and AHR especially distinguishes the asthmatic group with ongoing significant respiratory impairment.7 AHR is persistent in children with persisting symptoms,10 but it generally improves in young asthmatic individuals in their teens.1112 In a longitudinal study of an Australian cohort, it was shown that the coexistence of AHR and wheeze during early childhood identifies individuals who are at increased risk of persistent wheezing who might reasonably be described as having persistent asthma.13 In a longitudinal cohort study, Grol and colleagues14 showed that lower FEV1 values in childhood are independent predictors of more severe AHR at ages 32 to 42 years. The presence of AHR just after birth is associated with less lung function improvement, and this in its turn predicts more severe AHR in adulthood.15 This shows the intricate interplay between lung function and AHR. Although they are associated, they each have an independent effect on asthma as well.

AHR and Asthma in Adulthood:
AHR usually precedes the development of asthma,16 as has been observed not only in children and young adults1617 but also in middle-aged men who were not selected for a history of allergy.18 In general populations of adults, AHR has a continuous, log-normal distribution, with subjects at the more responsive end of the distribution most likely to have asthma.19202122 The unimodal rather than bimodal distribution of AHR suggests that AHR is genetically not dominantly regulated and/or expressed after interaction with environmental stimuli. Epidemiologic studies have noted an association between the presence of AHR, and both the presence and subsequent development of respiratory symptoms. The prevalence of asthma-like symptoms such as wheeze, nocturnal dyspnea, and chest tightness is higher in hyperresponsive subjects compared with nonresponders.23 Furthermore, asymptomatic subjects with AHR are at increased risk of developing asthma and asthmalike symptoms compared with subjects without AHR.162024252627282930 Jansen and colleagues31 showed that adults who have both AHR and markers of allergy such as blood eosinophilia are at an increased risk of developing asthma attacks and asthma-related symptoms such as wheeze.

AHR and Asthma Prognosis:
The presence of AHR is an important determinant of the course of asthma. Roorda and coworkers32 observed a cohort of 406 10-year-old asthmatic children for approximately 15 years. Respiratory symptoms persisted or recurred during young adulthood in the majority of subjects (76%), with a less favorable prognosis for children with more symptoms, more severe AHR, and low FEV1. Several studies1718323334 in which airway responsiveness was measured in school-aged children have shown that AHR in childhood predicts the outcome of asthma in adulthood. In particular, the combination of wheeze and AHR characterizes asthmatic subjects who will have ongoing respiratory symptoms. This has been demonstrated in the East Boston Childhood Respiratory Disease Study35 of 770 children who were 5 to 9 years of age at study entry. More severe AHR in childhood was associated with an elevated risk of onset of wheeze and recurrent asthma in young adulthood.

It is now generally accepted that AHR is associated with an underlying inflammatory process in the large and small airways, and that its persistence is likely to affect the course of lung function. This is supported by the observation that therapy with inhaled corticosteroids can improve lung function and AHR during long-term follow-up. Kerstjens and colleagues36 showed that the extent of FEV1 improvement on inhaled steroid treatment is dependent on the severity of AHR before the initiation of treatment, since individuals with more severe AHR improved more in their FEV1. Haahtela and coworkers37 further showed that delayed the introduction of therapy with inhaled steroids is associated with less improvement in lung function and AHR. Thus, ongoing inflammation may be associated with more severe AHR and an accelerated loss of FEV1 in asthma patients. Indeed, several studies38394041424344 have shown an excess decline in FEV1 of approximately 20 mL per year in asthmatic subjects. The excess decline is larger in asthmatic subjects who smoke, but it is also present in asthmatic subjects who do not smoke, as a group,384041 although of course not all asthmatic subjects exhibit the excess decline. Other factors associated with the excess decline in FEV1 appear to be low baseline FEV1 percent predicted,4344 less reversibility with the use of ß2-agonists,42 more severe AHR,33444546 mucus production,38 and male gender.40 Thus, again it appears that AHR is one of the key features in asthma and is associated with the progression of disease.

COPD
Most studies on the development and progression of COPD have involved older subjects, but risk factors for COPD can affect respiratory health during the whole life span. This is of particular interest when the interrelationships of smoking with atopy and AHR are studied, because these host factors may be present from an early age onward. However, there is hardly any literature investigating childhood risk factors for COPD development in association with long-term follow-up into adulthood, so whether AHR in childhood is a risk factor for COPD has not been evaluated.

AHR and Lung Function Loss:
It is clear that AHR contributes to the development of low lung function in several phases of the growth and decline of the FEV1/FVC ratio over a lifetime (Fig 1 ). Cross-sectional studies have shown a relationship between a low level of lung function and AHR.2747484950515253 One study showed that adult men (aged > 21 years) with hyperresponsiveness to histamine had on average a 325-mL lower FEV1 than nonresponsive individuals (305 mL lower in women).54 These significant differences were independent of smoking and symptom status. The loss in lung function in responders was already apparent in younger subjects (ie, aged 15 to 21 years), suggesting that the association persists from young adulthood into older age. However, this does not resolve the question of whether AHR is a predictor or a consequence of low FEV1 and the development of COPD.



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  		Figure 1. Growth pattern of expected FEV1/FVC ratio in boys and girls with and without AHR. Reprinted with permission from Xuan et al,9 © American Thoracic Society.

 
It has long been assumed that the presence of AHR in COPD patients is solely due to airway geometry, and that AHR is not an independent feature in COPD. A longitudinal follow-up of large population-based cohorts has shown that this is not the case.484950515253 The presence of AHR precedes the development of chronic airway symptoms53 and also predicts an accelerated decline in lung function, after adjustment for baseline FEV1.505152 Some studies were flawed either because no adjustment was made for baseline FEV1 or because assessment of AHR was performed at the end of the follow-up. Since the severity of AHR and the level of FEV1 are inversely related, a longitudinal association could be spurious, reflecting a lower initial FEV1 and more severe AHR at the end of the study in those individuals who had the steepest fall in FEV1. However, other studies have assessed AHR at the beginning of follow-up and have detected the same association. In this way, Rijcken et al49 found an excess loss in FEV1 of 12 mL per year in hyperresponsive men and 11.5 mL per year in hyperresponsive women, independent of smoking, symptoms, area of residence, age, survey period, and initial level of FEV1. Others have found515254 the same relationship, independent of skin test positivity, IgE and smoking, and appropriate adjustment for initial FEV1.

AHR and Development of COPD Symptoms:
Xu and coworkers55 studied whether adult subjects in the Vlagtwedde/Vlaardingen cohort who had AHR but no symptoms at the beginning of a 3-year follow-up period were likely to develop COPD-like respiratory symptoms. They showed that the risk of developing chronic cough (odds ratio [OR], 1.9), chronic phlegm (OR, 2.0), and dyspnea grade 3 (OR, 2.3) was significantly increased in subjects with AHR compared with those without AHR.24 These associations were independent of smoking status. Moreover, the odds of remission of these COPD-like symptoms were negatively associated with the presence of AHR, thus supporting and strengthening the evidence of a link between AHR and respiratory symptoms (Fig 2 , left).55 In the same population, Jansen and colleagues showed that the risk of developing respiratory symptoms was further increased in an individual with AHR if eosinophilia was present (Fig 2, right).31



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  		Figure 2. AHR predicts the development of symptoms compatible with asthma and COPD. Left: adapted from Xu et al.24 Right: adapted from Jansen et al.31 EO = eosinophilia.

 
AHR and Prognosis of COPD:
AHR is not a hallmark of COPD, but nevertheless it has been documented frequently in patients with the disease. Its prevalence was 64% in a study by Bahous and colleagues,56 70% in a series from Ramsdale and colleagues,57 46% in a study by Yan and colleagues,58 and 68% in the Lung Health Study sponsored by the US National Institutes of Health.59 Increased AHR was related to a steeper decline in lung function in some older and uncontrolled studies.606162 The prognostic relevance of AHR has been confirmed in the Lung Health Study,59 in which 5,773 participants with early COPD were followed for 5 years in a randomized controlled trial. In a random-effects linear model, the methacholine dose-response slope was a strong predictor of change in FEV1 percent predicted, after adjustment for baseline lung function, age, sex, baseline smoking history, and changes in smoking status.

Remarkably few data are available on the relation between AHR and survival in COPD. Our group investigated the effect of increased histamine AHR but could not demonstrate a relation to the 5-year or 10-year survival rate.63 However, Hospers and coworkers64 traced the causes of death of the subjects in the Dutch Vlagtwedde/Vlaardingen cohort and showed a dose-response relationship between level of AHR and the relative risk of mortality caused by COPD. The lower the provocative concentration of histamine causing a 10% fall in FEV1 that a subject receives, the higher is the risk of mortality caused by COPD. Extreme responders (provocative concentration of 1 mg/mL histamine) were > 15 times more likely to die of COPD than were nonresponders. Although this trend was more pronounced in smokers, it was also noted among individuals who had never smoked.64


   The Role of Smoking in the Development of Asthma and COPD
TOP
 Abstract
 Introduction
 The Role of AHR...
 The Role of Smoking...
Conclusion
 References
 
Asthma
In Utero Smoke Exposure and Asthma:
In utero exposure to cigarette smoke has been shown to have a negative effect on lung function.6566 The effect persists for a long time. Boezen and colleagues67 showed that FEV1 values at age 6 years were lower in children who had been exposed in utero to cigarette smoke. Large, persistent deficits in lung function have been documented in children who developed asthma.68

Parental Smoking and Asthma:
Figures from the United States69 suggest that, of the 17 million children exposed currently to environmental tobacco smoke, 380,000 (2%) will experience asthma and/or wheeze as a result. A review of the effects of parental smoking on the respiratory health of children indicated that there is much evidence of a positive association between maternal smoking and asthma development.70 Parental smoking, especially cigarette smoke exposure in utero and in the first few months of life, appears to be a risk factor for the development of atopy and asthma.7071727374 Meijer and colleagues75 showed that in children who have already developed asthma, parental smoking is a risk factor for instability of the disease, which is reflected in a large circadian variation in peak expiratory flow. Finally, parental smoking had clinically significant effects on the FEV1/FVC ratio among adolescents with wheeze and asthma in a longitudinal study.76 Similar results were found in a cross-sectional population-based study in China.77

Active Smoking and Asthma:
It has not been established whether active smoking is a risk factor for development of asthma. Flodin et al78 have suggested that it is, yet this is not invariably the case. However, self-selection toward smoking initiation or favoring quitting may mask cross-sectional associations between current smoking and asthma. Such associations also may be masked if some smoking asthmatic subjects are labeled with another diagnosis.79 One study80 showed that active smoking was associated with lower FEV1 in young adults with nonatopic asthma. Other studies384041 have shown that asthmatic subjects who smoke have a more rapid decline of lung function. Lynch and colleagues81 have shown that asthmatic subjects who smoke more frequently are more likely to have evidence of emphysema, as assessed by high-resolution CT scan, than patients with asthma who do not smoke. Vonk and colleagues82 recently investigated the presence of emphysema in 228 asthmatic subjects who had been observed for > 26 years. They showed that 38 of the 165 patients tested (23%) had a reduced diffusion capacity, which was associated with a longer smoking history. However, not all persistent smokers had a reduced diffusion capacity. Thus, factors other than atopy and AHR, which were present in virtually all persons in this asthmatic population, must be needed to develop COPD.

COPD
COPD is generally assessed in adulthood and is characterized by low FEV1 values and accelerated loss of lung function over time. This was first demonstrated in working men by Fletcher and colleagues.83 However, the invariably low FEV1 values in COPD patients may well have been present in childhood or young adulthood.

Smoke Exposure, Smoking, and COPD:
In utero smoke exposure has been shown to be associated with lower lung function in childhood,656667 although not in all children. However, so far, longitudinal studies are lacking to show whether in utero smoke exposure is indeed a risk factor for COPD. The observation that active smoking during adolescence is associated with a shortening of the plateau phase of FEV1 that generally occurs between 20 and 35 years of age84 suggests that there is also an overall negative effect of smoking in adolescence. Smoking cessation during adolescence has a positive impact on lung growth.85 Passive smoking has been associated in cross-sectional studies7786 with increases in pulmonary symptoms that are compatible with both asthma and COPD, and with lower FEV1. There is a dose-response relationship between the number of pack-years of smoking and lung function decline, yet with large interindividual variability.8788 The latter observation supports the hypothesis that other factors, for instance AHR, contribute as well.899091

Interaction of Smoking and AHR in the Development of COPD:
There is a clear relation between AHR and smoking. Epidemiologic studies have shown that AHR is more common in smokers than in former smokers or in those who have never smoked92 and that cigarette smoking is associated with AHR,93 an association that becomes more explicit with increasing age.94 Furthermore, as noted above, the Lung Health Study59 on the effects of smoking intervention in early COPD showed that the methacholine dose-response slope at the start of the longitudinal study was a strong predictor of change for FEV1 percent predicted, after adjustment for baseline lung function, age, sex, baseline smoking history, and changes in smoking status. Significant interactions were found between airway responsiveness and smoking behavior. In the first year, participants who quit smoking showed improvement in FEV1, whereas those who continued smoking showed worsening. Between years 1 and 5, lung function declined to a greater extent in continuing smokers than in sustained quitters. For both groups, the decline was correlated with the severity of AHR.


   Conclusion
TOP
 Abstract
 Introduction
 The Role of AHR...
 The Role of Smoking...
 Conclusion
References
 
There seems to be epidemiologic evidence that AHR and smoking predispose patients toward the development of asthma and COPD. Subjects with the "host factor" AHR are more susceptible to environmental stimuli that increase the risk of obstructive airway disease. In utero smoke exposure is an established risk factor for asthma, whereas active smoking has been shown to be a risk factor for COPD in a subset of the general population and in a subset of asthmatic subjects (all of whom were hyperresponsive). Furthermore, there is an interaction between AHR and smoking, leading to more lung function loss. However, it has not been established whether the underlying mechanisms of the AHR that predisposes a person to asthma and the AHR that predisposes a person to COPD are the same. This will be a challenge for future research in the genetics of asthma and COPD.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; CNSLD = chronic nonspecific lung disease; OR = odds ratio


   References
TOP
 Abstract
 Introduction
 The Role of AHR...
 The Role of Smoking...
 Conclusion
 References
 

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