Reviews and feature article
Revisiting the Dutch hypothesis

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The Dutch hypothesis was first articulated in 1961, when many novel and advanced scientific techniques were not available, such as genomics techniques for pinpointing genes, gene expression, lipid and protein profiles, and the microbiome. In addition, computed tomographic scans and advanced analysis techniques to dissect (small) airways disease and emphysema were not available. At that time, the group of researchers under the visionary guidance of Professor N. G. M. Orie put forward that both genetic and environmental factors can determine whether one would have airway obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Moreover, they stipulated that the phenotype of obstructive airway disease could be affected by sex and changes with aging. Orie and colleagues' call to carefully phenotype patients with obstructive airways diseases has been adopted by many current researchers in an attempt to determine the heterogeneity of both asthma and COPD to better define these diseases and optimize their treatment. The founders of the Dutch hypothesis were far ahead of their time, and we can learn from their insights. We should fully characterize all patients in our clinical practice and not just state that they have asthma, COPD, or asthma and COPD overlap syndrome. This detailed phenotyping can help in understanding these obstructive airway diseases and provide guidance for disease management.

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The history of the Dutch hypothesis

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Genetics

Twin and family studies indicate that both asthma and COPD have a strong genetic contribution. Over the past 10 years, GWASs have shown that multiple prevalent single nucleotide polymorphisms (SNPs) explain a limited proportion of asthma and COPD. Candidate gene studies for asthma and COPD have suggested that there are shared genetic origins for asthma and COPD, such as matrix metalloproteinase 9 (MMP9) and TGFB1.7 However, SNPs identified by using GWASs for asthma and COPD separately show no

Lung function

The classic dichotomy of asthma as a disease of variable lung function reverting to normal between symptomatic episodes and COPD as a disease of fixed airways obstruction that never reverts to normal and is relentlessly progressive is no longer tenable. A subset of asthmatic patients has increased lung function decrease and low lung function,23, 29 with an at best incomplete response to therapy (ie, persistent obstruction). Greater lung function decrease over time seems to occur especially with

BHR

At least 3 different clinical trials have investigated algorithms to use BHR as a disease marker guiding asthma treatment. The first study was a 2-year randomized controlled trial (RCT) performed in 75 adults with mild-to-moderate asthma with 3-month BHR assessments. In the control group treatment level was based on clinical symptoms, β-agonist use, and peak expiratory flow variation, and in the BHR arm the level was based additionally on BHR severity. Patients treated with ICS doses according

Summary and future perspectives

The Dutch hypothesis was first articulated in 1961,1 when many novel and advanced scientific techniques were not available, such as genomics techniques for pinpointing genes, gene expression, lipid and protein profiles, and the microbiome. In addition, CT scans and advanced analysis techniques used to dissect small-airways disease and emphysema were unavailable.24, 25, 72 At that time, a group of researchers under the visionary guidance of Professor N. G. M. Orie put forward that both genetic

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