Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.

BACKGROUND: Beneficial effects of pulmonary rehabilitation at high-altitude (HAPR) in patients with severe refractory asthma have been reported earlier, but evidence for the effectiveness is limited. AIM: To investigate the effectiveness of high-altitude pulmonary rehabilitation to comparable treatment at sea-level (LAPR) on patient outcome parameters. METHODS: Adults with severe refractory asthma living in The Netherlands were included. Treatment consisted of a 12-week personalized multidisciplinary rehabilitation program either at high-altitude (Davos Switzerland) (n = 93) or in a tertiary lung center at sea-level in The Netherlands (n = 45). At baseline, after treatment, and during 12 months follow-up asthma related quality of life (AQLQ), asthma control (ACQ), pulmonary function and OCS-dose were assessed. Patients could not be randomized resulting in different asthma populations. Groups were compared using linear regression analysis (ANCOVA) adjusted for baseline values, in addition to age, atopy, smoking history, BMI and gender. RESULTS: After treatment, and at 12 months follow-up, improved AQLQ(0.92,p < 0.001 and 0.82,p = 0.001, respectively), ACQ(-0.87,p < 0.001 and -0.69,p = 0.008, respectively) and lower maintenance OCS dose (Unadjusted linear regression analysis-5.29 mg, p = 0.003 and Crude Odds Ratio-1.67, p = 0.003, respectively) were observed in the HAPR-group compared to the LAPR group. Patients receiving HAPR also had less asthma exacerbations (≥1 exacerbation: 20% vs 60%,p < 0.001) and showed improvement in lung function (%predFEV1 3.4%,p = 0.014) compared to the LAPR group, but at 12 months no differences between groups were observed. CONCLUSION: HAPR resulted in a larger improvement in patient outcome parameters compared to LAPR, on the long run the improvement in patient reported symptoms and lower maintenance OCS-dose persists. Underlying factors that explain this observed effect need to be investigated.

External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma.

BACKGROUND: Monitoring sputum eosinophils in asthma predicts exacerbations and improves management of asthma. Thus far, blood eosinophils and FE(NO) show contradictory results in predicting eosinophilic airway inflammation. More recently, serum periostin was proposed as a novel biomarker for eosinophilic inflammation. OBJECTIVES: Quantifying the mutual relationships of blood eosinophils, FE(NO), and serum periostin with sputum eosinophils by external validation in two independent cohorts across various severities of asthma. METHODS: The first cohort consisted of 110 patients with mild to moderate asthma (external validation cohort). The replication cohort consisted of 37 patients with moderate to severe asthma. Both cohorts were evaluated cross-sectionally. Sputum was induced for the assessment of eosinophils. In parallel, blood eosinophil counts, serum periostin concentrations and FENO were assessed. The diagnostic accuracy of these markers to identify eosinophilic asthma (sputum eosinophils ≥3%) was calculated using receiver operating characteristics area under the curve (ROC AUC). RESULTS: In the external validation cohort, ROC AUC for blood eosinophils was 89% (p<0.001) and for FE(NO) level 78% (p<0.001) to detect sputum eosinophilia ≥3%. Serum periostin was not able to distinguish eosinophilic from non-eosinophilic airway inflammation (ROC AUC=55%, p=0.44). When combining these three variables, no improvement was seen. The diagnostic value of blood eosinophils was confirmed in the replication cohort (ROC AUC 85%, p<0.001). CONCLUSIONS: In patients with mild to moderate asthma, as well as patients with more severe asthma, blood eosinophils had the highest accuracy in the identification of sputum eosinophilia in asthma. The use of blood eosinophils can facilitate individualised treatment and management of asthma. TRIAL REGISTRATION: NTR1846 and NTR2364.

Three phenotypes of adult-onset asthma.

RATIONALE: Adult-onset asthma differs from childhood-onset asthma in many respects. It is more heterogeneous, often severe and frequently associated with loss of lung function. To identify underlying mechanisms of adult-onset asthma and to capture predictors of disease progression, detailed characterization and phenotyping is necessary. OBJECTIVES: To characterize adult-onset asthma and identify subphenotypes of adult-onset asthma. METHODS: A cohort of 200 patients with adult-onset (>18 year) asthma (age 54 (26-75) year) was recruited from one academic and three nonacademic pulmonary outpatient clinics in Amsterdam, the Netherlands. These patients were fully characterized with respect to clinical, functional and inflammatory markers. After data reduction, K-means nonhierarchical cluster analysis was performed to identify clusters of adult-onset asthma. MEASUREMENTS AND MAIN RESULTS: Patients with adult-onset asthma were predominately female (61%) and nonatopic (55%). Within this group of patients were identified three clusters of adult-onset asthma. Cluster 1 (n = 69) consisted of patients with severe eosinophilic inflammation-predominant asthma and persistent airflow limitation despite high-intensity anti-inflammatory treatment, with relatively low symptom scores. The second cluster was characterized by obese women with frequent symptoms, high healthcare utilization and low sputum eosinophils. The third cluster consisted of patients with mild-to-moderate, well-controlled asthma with normal lung function and low inflammatory markers. Repeatability accuracy was 98.2%. CONCLUSIONS: Amongst patients with adult-onset asthma, three subphenotypes can be identified with distinct clinical and inflammatory characteristics. These subphenotypes help to understand the underlying pathobiology and provide clinicians with directions for personalized management.

Non-atopic males with adult onset asthma are at risk of persistent airflow limitation.

BACKGROUND: Patients with asthma have on average a more rapid decline in FEV (1) as compared with the general population. Recent cluster analysis has revealed different asthma phenotypes that can be distinguished by age of onset and reversibility of airflow limitation. OBJECTIVE: This study aimed at detecting risk factors associated with persistent airflow limitation in patients with the adult onset asthma phenotype. METHODS: We recruited 88 patients with adult onset (≥ 18 years) asthma from an academic pulmonary outpatient clinic in the Netherlands. The associations of age, age of asthma onset, asthma duration, gender, race, atopy, smoking pack-years, BMI, use of oral corticosteroids with post-bronchodilator FEV (1) /FVC were investigated. RESULTS: Multiple linear regression analysis showed an association of absence of atopy (r = -0.27, B = -0.26, P = 0.01) and male gender (r = 0.31, B = 0.30, P = 0.004) with post-bronchodilator FEV (1) /FVC. Multiple logistic regression analysis showed that male patients were 10.8 (CI: 2.6-45.2) times the odds than women to have an FEV (1) /FVC < 0.7, and non-atopic patients were 5.2 (CI: 1.3-20.3) times the odds to have an FEV (1) /FVC < 0.7 than atopic patients. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that in patients with adult onset asthma, male gender and absence of atopy are associated with persistent airflow limitation. This might suggest that amongst patients with adult onset asthma, non-atopic male patients are at increased risk of accelerated decline in lung function.

Exhaled air molecular profiling in relation to inflammatory subtype and activity in COPD.

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is predictive for responses to inhaled steroids. We hypothesised that the inflammatory subtype in mild and moderate COPD can be assessed by exhaled breath metabolomics. Exhaled compounds were analysed using gas chromatography and mass spectrometry (GC-MS) and electronic nose (eNose) in 28 COPD patients (12/16 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II, respectively). Differential cell counts, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were measured in induced sputum. Relationships between exhaled compounds, eNose breathprints and sputum inflammatory markers were analysed and receiver operating characteristic (ROC) curves were constructed. Exhaled compounds were highly associated with sputum cell counts (eight compounds with eosinophils, 17 with neutrophils; p < 0.01). Only one compound (alkylated benzene) overlapped between eosinophilic and neutrophilic profiles. GC-MS and eNose breathprints were associated with markers of inflammatory activity in GOLD stage I (ECP: 19 compounds, p < 0.01; eNose breathprint r = 0.84, p = 0.002) (MPO: four compounds, p < 0.01; eNose r = 0.72, p = 0.008). ROC analysis for eNose showed high sensitivity and specificity for inflammatory activity in mild COPD (ECP: area under the curve (AUC) 1.00; MPO: AUC 0.96) but not for moderate COPD. Exhaled molecular profiles are closely associated with the type of inflammatory cell and their activation status in mild and moderate COPD. This suggests that breath analysis may be used for assessment and monitoring of airway inflammation in COPD.