Roland Riemersma

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) &kgr;&bgr; pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10−9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-&kgr;&bgr;, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution. This article provides suggestive evidence, but not firm evidence that there is overlap in genetics of asthma and COPD http://ow.ly/we9yE

Small airways in asthma: their independent contribution to the severity of hyperresponsiveness

To the Editor: Bronchial hyperresponsiveness (BHR), i.e. increased narrowing of the airways after exposure to non-allergic stimuli, is a hallmark of asthma. BHR is a risk factor for asthma development and, additionally, a marker of worse disease outcome in asthma [1, 2]. It is generally acknowledged that obstruction of the large airways due to inflammation and remodelling contributes to more severe BHR. This is plausible, given that BHR is expressed as the concentration or dose of a stimulus that induces a 20% fall in forced expiratory volume in 1 s (FEV1). Recent studies suggest that asthmatics with BHR have more severe small airways obstruction [3, 4]. However, little is known about the converse, i.e. the association between small airways obstruction and the severity of BHR. Our aim was to assess: 1) whether asthma patients with small airways obstruction express more severe BHR than those without small airways obstruction; and 2) whether small airways obstruction is associated with more severe BHR independently of FEV1. We analysed data from patients with mild-to-moderate asthma who were included in a previously published study on inhaled corticosteroids (ICS) in primary care [5]. All subjects underwent spirometry before and after 1 mg terbutaline, measuring FEV1, forced vital capacity (FVC) and mean expiratory flow at 50% of FVC (MEF50). BHR was assessed using a histamine challenge test, measuring the provocative dose causing a 20% fall in FEV1 (PD20) (histamine). All patients were hyperresponsive to histamine (PD …

Budesonide/formoterol maintenance and reliever therapy in primary care asthma management: effects on bronchial hyperresponsiveness and asthma control

BACKGROUND The management of asthma has changed since the introduction of budesonide/formoterol (Symbicort®) as both maintenance and reliever therapy (SMART). SMART and its effects on bronchial hyperresponsiveness (BHR) have not been studied in primary care. AIMS To compare the effects of SMART and guideline-driven usual care (UC) on BHR and clinical asthma severity in primary care practice. METHODS Patients with mild-to-moderate stable asthma were randomised to receive SMART treatment (n=54) (budesonide/formoterol 80/4.5 μg Turbuhaler®, two puffs once daily and extra inhalations as needed) or UC treatment (n=48) for 12 months. Diary data, Asthma Control Questionnaire scores, forced expiratory volume in 1 second (FEV1), and peak expiratory flow (PEF) measurements were collected during run-in and after 1, 3, 6, and 12 months of treatment. BHR, measured as the dose of histamine provoking a fall in FEV1 of 20% (PD20-histamine), was determined at randomisation and after 12 months. RESULTS One hundred and two patients with asthma participated in the study. The change in PD20-histamine during the study was not significantly different between the SMART and UC groups (p=0.26). The mean inhaled corticosteroid (ICS) dose was 326 μg beclomethasone dipropionate (BDP) equivalents/day (95% CI 254 to 399) with SMART, which was significantly lower (p<0.0001) than the mean ICS dose with UC treatment (798 μg BDP equivalents/day (95% CI 721 to 875). Morning and evening PEF values increased significantly with SMART treatment compared with UC; FEV1, symptoms and asthma control did not differ. CONCLUSIONS Despite a 59% lower dose of ICS, BHR and other clinical outcomes remained stable during SMART treatment while PEF values improved.

The minimal clinically important difference of the control of allergic rhinitis and asthma test (CARAT): Cross-cultural validation and relation with pollen counts

Background:The Control of Allergic Rhinitis and Asthma Test (CARAT) monitors control of asthma and allergic rhinitis.Aims:To determine the CARAT’s minimal clinically important difference (MCID) and to evaluate the psychometric properties of the Dutch CARAT.Methods:CARAT was applied in three measurements at 1-month intervals. Patients diagnosed with asthma and/or rhinitis were approached. MCID was evaluated using Global Rating of Change (GRC) and standard error of measurement (s.e.m.). Cronbach’s alpha was used to evaluate internal consistency. Spearman’s correlation coefficients were calculated between CARAT, the Asthma Control Questionnaire (ACQ5) and the Visual Analog Scale (VAS) on airway symptoms to determine construct and longitudinal validity. Test–retest reliability was evaluated with intra-class correlation coefficient (ICC). Changes in pollen counts were compared with delta CARAT and ACQ5 scores.Results:A total of 92 patients were included. The MCID of the CARAT was 3.50 based on GRC scores; the s.e.m. was 2.83. Cronbach’s alpha was 0.82. Correlation coefficients between CARAT and ACQ5 and VAS questions ranged from 0.64 to 0.76 (P<0.01). Longitudinally, correlation coefficients between delta CARAT scores and delta ACQ5 and VAS scores ranged from 0.41 to 0.67 (P<0.01). Test–retest reliability showed an ICC of 0.81 (P<0.01) and 0.80 (P<0.01). Correlations with pollen counts were higher for CARAT than for ACQ5.Conclusions:This is the first investigation of the MCID of the CARAT. The CARAT uses a whole-point scale, which suggests that the MCID is 4 points. The CARAT is a valid and reliable tool that is also applicable in the Dutch population.

Feasibility and effectiveness of an asthma/COPD service for primary care: a cross-sectional baseline description and longitudinal results.

Background:In 2007, an Asthma/chronic obstructive pulmonary disease (COPD) (AC) service was implemented in the North of the Netherlands to support General Practitioners (GPs) by providing advice from pulmonologists on a systematic basis.Aims:To evaluate the feasibility and effectiveness of this service on patient-related outcomes.Methods:We report baseline data on 11,401 patients and follow-up data from 2,556 patients. GPs can refer all patients with possible obstructive airway disease (OAD) to the service, which is conducted by the local laboratory. Patients are assessed in the laboratory using questionnaires and spirometry. Pulmonologists inspect the data through the internet and send the GP diagnosis and management advice.Results:A total of 11,401 patients were assessed by the service, covering almost 60% of all adult patients with projected asthma or COPD in the area. In all, 46% (n=5,268) of the patients were diagnosed with asthma, 18% (n=2,019) with COPD and 7% (n=788) with the overlap syndrome. A total of 740 (7%) patients were followed up after 3 months because the GP advised them to change medication. In this group, the proportion of unstable COPD patients (Clinical COPD Questionnaire (CCQ)⩾1) decreased from 63% (n=92) at baseline to 49% (n=72). The proportion of patients with uncontrolled asthma (Asthma Control Questionnaire (ACQ)⩾1.5) decreased from 41% (n=204) to 23% (n=115). In all, 938 (8%) patients were followed up after 12 months. From these patients, the proportion of unstable COPD patients (CCQ⩾1) decreased from 47% (n=115) to 44% (n=107). The proportion of patients with uncontrolled asthma (ACQ⩾1.5) decreased from 16% (n=95) to 14% (n=85).Conclusion:The AC service assessed a considerable proportion of patients with OAD in the area, improved patients’ outcomes, and is considered to be feasible and effective.

Development of a questionnaire for the assessment of bronchial hyperresponsiveness

INTRODUCTION Bronchial hyperresponsiveness (BHR) is a hallmark of asthma. Treatment approaches based on BHR severity have been shown to be effective. However, challenge tests are expensive, inconvenient to patients, time consuming, and not easily accessible to general practitioners. Assessment of BHR by a questionnaire would be advantageous in the diagnosis and management of asthma. AIM To select a set of respiratory symptoms and provoking stimuli related to BHR to compose a reliable Bronchial Hyperresponsiveness Questionnaire (BHQ). METHOD A list of 33 symptoms and 68 stimuli were selected by in-depth interviews, focus group discussions with asthma patients, and literature review. After a histamine challenge test patients (n=302) were asked to score each question on a 7-point scale (0=no; 6=severe complaints). Factor analysis was performed to identify clusters of interrelated symptoms associated with PC20-histamine. The sensitivity to detect the presence of BHR was analysed by Receiver Operating Curves (ROC). The correlation between the PC20-score and the scores on the questions was analysed. RESULTS 15 symptoms and 19 provoking stimuli were ultimately selected for the BHQ. CONCLUSION The BHQ was developed according to FDA-approved standards and is a condition-specific questionnaire able to assess the presence of BHR.

An economic evaluation of budesonide/formoterol for maintenance and reliever treatment in asthma in general practice

IntroductionIn budesonide/formoterol (Symbicort® Turbuhaler®, AstraZeneca, Lund, Sweden) maintenance and reliever therapy (SMART), patients with asthma take a daily maintenance dose of budesonide/formoterol, with the option of taking additional doses for symptom relief instead of a short-acting β2-agonist (SABA). This study assesses the cost-effectiveness of SMART compared with usual care in patients with mild-to-moderate persistent asthma treated by general practitioners in the Netherlands from a societal perspective.MethodsThe study was linked to a randomized, active-controlled, open-label, multicenter, 12-month clinical trial, with a prospective collection of resource use. One hundred and two patients ≥18 years with mild-to-moderate persistent asthma and daily inhaled corticosteroids (ICS) prior to the trial were included. SMART was given as two inhalations of budesonide/formoterol (100/6 μg) once daily, plus additional doses as needed. The control group was treated according to guidelines, which prescribe medium daily doses of ICS plus an SABA if needed. A long-acting β2-agonist (LABA) is added if necessary. Effectiveness was measured as the proportion of asthma-control days, Asthma Control Questionnaire (ACQ) scores, the net proportion of patients with relevant ACQ improvement, and the proportion of well-controlled patients. Costs included asthma medication, physician contacts, and absence from work.ResultsMean total costs for SMART were €134.81 lower (95% CI: −€439.48; €44.85). Production losses were €94.10 (95% CI: −€300.60; €0.29) lower for SMART (€10.77 vs. €104.87). No significant differences in health outcomes were seen, with 3.81 fewer asthma-control days per patient-year for SMART (95% CI: −36.8; 30.8), a 0.049 better ACQ score (95% CI: −0.21; 0.29), a 5.8% larger net proportion of improved patients (95% CI: t15.6%; 27.3%), and a 2.1% (95% CI: −25.5; 20.8%) smaller increase in the proportion of well-controlled patients.ConclusionsTreating primary care patients with mild-to-moderate persistent asthma with SMART instead of ICS plus bronchodilators does not affect health outcomes and does not increase costs; therefore, is likely to be an alternative for guideline-directed treatment, from a health and economic perspective.