Els J. Weersink

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 FENO 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, FENO, 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 FENO 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.

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.

Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes

Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (≥3%) in different adult asthma phenotypes. Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex-)smoking and never-smoking asthma patients. Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78–0.87) for blood eosinophils, 0.82 (0.77–0.87) for FeNO and 0.69 (0.63–0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients. Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma. FeNO and blood eosinophils can be used to detect sputum eosinophilia in adult asthma patients regardless of phenotype http://ow.ly/MnGqF

Early and late asthmatic reaction after allergen challenge

In the early 1950s Herxheimer (1) clearly showed that two distinct components in the obstructive response to inhaled allergens could be discerned, which he named the immediate and late reaction. But it was not until the late 1960s before Pepys (2) and de Vries and coworkers (3) started to investigate the mechanisms of the immediate and late response to inhaled allergen by drug protection studies. Based on different effects of several drugs on the immediate and late reaction they concluded that different mechanisms must underlie these response patterns. It was suggested that the immediate reaction was due to constriction of the smooth airway muscles and the late reaction the result of inflammation. Gijkemeijer (4) showed that allergen challenge also leads to an increase in airway reactivity (AR). However, he found no relationship between the increase in AR and the immediate or late response. Then, Cockcroft et al. (5) demonstrated an increase in AR in association with the late allergic response (LAR). Later studies showed that subjects with an isolated EAR also develop an increase in AR, but to a much lesser extent than patients with a LAR (6). It has now generally been accepted that the increase in AR is usually associated with increased mucosal inflammation of the airways (7). Therefore, it is intriguing that AR is already increased 3 h after allergen challenge, when the FEV, has returned to prechallenge values, thus even preceding the LAR. With the introduction of fibreoptic bonchoscopy, in recent years, broncho-alveolar lavage (BAL) and biopsies have become new research tools to study the cellular events in asthmatic airways after allergen challenge which can be investigated directly by microscopic studies including sophisticated immunohistochemistry.

Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial

Background In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown. Objective To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FENO) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worsening asthma control or asthma-related quality of life. Methods In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n=43) or guided by a novel internet-based monitoring system (internet strategy) (n=52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV1), exacerbations, hospitalisations and patients satisfaction with the tapering strategy. Results Median cumulative sparing of prednisone was 205 (25–75th percentile −221 to 777) mg in the internet strategy group compared with 0 (−497 to 282) mg in the conventional treatment group (p=0.02). Changes in prednisone dose (mixed effect regression model) from baseline were −4.79 mg/day and +1.59 mg/day, respectively (p<0.001). Asthma control, asthma-related quality of life, FEV1, exacerbations, hospitalisations and satisfaction with the strategy were not different between groups. Conclusions An internet-based management tool including home monitoring of symptoms, lung function and FENO in severe asthma is superior to conventional treatment in reducing total corticosteroid consumption without compromising asthma control or asthma-related quality of life. Clinical trial registration number Clinical trial registered with http://www.trialregister.nl (Netherlands Trial Register number 1146).

High-altitude treatment in atopic and nonatopic patients with severe asthma

The beneficial effects of high-altitude treatment in asthma have been attributed to allergen avoidance. Recent evidence shows that this treatment also improves airway inflammation in nonallergic patients. We hypothesised that high-altitude treatment is clinically equally effective in patients with severe refractory asthma, with or without allergic sensitisation. In a prospective observational cohort study, 137 adults with severe refractory asthma (92 with allergic sensitisation), referred for high-altitude (1,600 m) treatment in Davos, Switzerland, were consecutively included. We measured asthma control (Asthma Control Questionnaire (ACQ)), asthma-related quality of life (Asthma-Related Quality of Life Questionnaire (AQLQ)), sino-nasal symptoms (Sino-Nasal Outcome Test (SNOT-20)), medication requirement, postbronchodilator (post-BD) forced expiratory volume in 1 s (FEV1), 6-min walking distance (6MWD), total immunoglobulin (Ig)E, blood eosinophils and exhaled nitric oxide fraction (FeNO) at admission and after 12 weeks. Sensitised and nonsensitised patients showed similar improvements in ACQ (-1.4 and -1.5, respectively; p=0.79), AQLQ (1.6 and 1.5, respectively; p=0.94), SNOT-20 (-0.7 and -0.5, respectively; p=0.18), post-BD FEV1 (6.1% and 5.8% pred, respectively; p=0.87), 6MWD (+125 m and +147 m, respectively; p=0.43) and oral steroids (40% versus 44%, respectively; p=0.51). Sensitised patients showed a larger decrease in total IgE, blood eosinophils and FeNO. High-altitude treatment improves clinical and functional parameters, and decreases oral corticosteroid requirement in patients with severe refractory asthma, irrespective of allergic sensitisation.

Predictors for the development of progressive severity in new-onset adult asthma

BACKGROUND A proportion of patients with adult-onset asthma have severe disease. Risk factors for an increase in asthma severity are poorly known. OBJECTIVE We sought to identify predictors for the development of severe asthma in adults. METHODS A cohort of 200 adults with new-onset asthma was prospectively followed for 2 years. At baseline, patients underwent a comprehensive assessment of clinical, functional, and inflammatory parameters. After 2 years, change in asthma severity was assessed by using the Global Initiative for Asthma score (range, 1-4), which is based on asthma control (Asthma Control Questionnaire), lung function (FEV1), and inhaled corticosteroid requirement. ANOVA and multiple regression equations were used in the analysis. RESULTS One hundred twenty-eight patients completed 2 years of follow-up. Seventeen (13.3%) patients had an increase in asthma severity, whereas 53 (41.4%) patients had a decrease. A lower postbronchodilator FEV1/forced vital capacity ratio and a higher number of cigarette pack years smoked at baseline were significantly associated with an increase in asthma severity at follow-up. Multiple regression equations showed that only the number of cigarette pack years smoked was independently associated with an increase in asthma severity, with an odds ratio of 1.4 (95% CI, 1.02-1.91) for every 10 pack years smoked. CONCLUSION A history of cigarette smoking in patients with new-onset adult asthma predicts an increase in asthma severity during the first 2 years of the disease in a dose-dependent manner.

A randomised controlled trial on the effect of inhaled hypertonic saline on quality of life in primary ciliary dyskinesia

Hypertonic saline inhalation lowers airway mucous viscosity. Increased cough transportability may improve quality of life (QoL) in primary ciliary dyskinesia (PCD). In this randomised controlled trial (RCT), PCD patients received twice-daily inhalations of hypertonic (7%) saline or isotonic (0.9%) saline for 12 weeks, with 4 weeks washout during crossover. Primary outcome was change in QoL measured by the St Georges Respiratory Questionnaire (SGRQ) total score. Secondary outcomes were SGRQ subscores, Quality of Life Questionnaire-Bronchiectasis (QoL-B) scores, lower respiratory tract infection symptoms, exacerbations, spirometry, systemic and sputum inflammatory markers, adherence, and adverse events. There was no significant change in median (interquartile range) SGRQ total score between hypertonic saline (−2.6 (−9.0–1.5)) and isotonic saline (−0.3 (−8.1–6.1)) in 22 patients (age range 22–73 years) (p=0.38). QoL-B Health Perception scale improved with hypertonic saline (p=0.03). Adverse events occurred more frequently with hypertonic saline, but were mild. 12 weeks of inhaled hypertonic saline did not improve SGRQ total score in adult PCD patients in this RCT, but the sample size was small. On the secondary and more disease-specific end-point of the QoL-B, a significant improvement was observed in the Health Perception scale. This study found little evidence to support the hypothesis that hypertonic saline improves QoL in PCD patients. We advise the use of disease-specific outcome measures in future trials. RCT in PCD: hypertonic saline does not improve SGRQ scores, but improves health perception http://ow.ly/uL6x306Dmzh

Clinical predictors of remission and persistence of adult-onset asthma

Background: Adult‐onset asthma is an important but relatively understudied asthma phenotype and little is known about its natural course and prognosis. The remission rate is believed to be low, and it is still obscure which factors predict remission or persistence of the disease. Objective: This study sought to determine the remission rate and identify predictors of persistence and remission of adult‐onset asthma. Methods: Two hundred adult patients with recently diagnosed (<1 year) asthma were recruited from secondary and tertiary pulmonary clinics and prospectively followed for 5 years. Clinical, functional, and inflammatory parameters were assessed at baseline and at yearly visits. Asthma remission was defined as absence of asthma symptoms for ≥1 year and no asthma medication use for ≥1 year. Descriptive statistics and logistic regression analysis were performed. Results: Five‐year follow‐up data of 170 patients (85%) was available. Of these, 27 patients (15.9%) experienced asthma remission. Patients with asthma persistence were older, had worse asthma control, required higher doses of inhaled corticosteroids, had more severe airway hyperresponsiveness, more often nasal polyps, and higher levels of blood neutrophils as compared to patients who experienced clinical remission. In a multivariable logistic regression analysis, only moderate to severe bronchial hyperresponsiveness and nasal polyps were independent predictors of asthma persistence. Patients with these 2 characteristics had <1% chance of asthma remission. Conclusions: One in 6 patients with adult‐onset asthma experiences remission within the first 5 years of the disease. In patients with moderate to severe bronchial hyperresponsiveness and nasal polyposis, the chance of remission is close to zero.

Blood biomarkers in chronic airways diseases and their role in diagnosis and management

ABSTRACT Introduction: The complexity and heterogeneous nature of asthma and chronic obstructive pulmonary disease (COPD) results in difficulties in diagnosing and treating patients. Biomarkers that can identify underlying mechanisms, identify patient phenotypes and to predict treatment response could be of great value for adequate treatment. Areas covered: Biomarkers play an important role for the development of novel targeted therapies in airways disease. Blood biomarkers are relatively non-invasive, easy to obtain and easy to apply in routine care. Several blood biomarkers are being used to diagnose and monitor chronic airways diseases, as well as to predict response to treatment and long-term prognosis. Blood eosinophils are the best studied biomarker, the most applied in clinical practice, and until now the most promising of all blood biomarkers. Other blood biomarkers, including serum periostin, IgE and ECP and plasma fibrinogen are less studied and less relevant in clinical practice. Recent developments include the use of antibody assays of many different cytokines at the same time, and ‘omics’ techniques and systems medicine. Expert commentary: With the exception of blood eosinophils, the use of blood biomarkers in asthma and COPD has been rather disappointing. Future research using new technologies like big-data analysis of blood samples from real-life patient cohorts will probably gain better insight into underlying mechanisms of different disease phenotypes. Identification of specific molecular pathways and associated biomarkers will then allow the development of new targets for precision medicine.