Jörgen Syk

Anti-inflammatory Treatment of Atopic Asthma Guided by Exhaled Nitric Oxide: A Randomized, Controlled Trial

BACKGROUND Atopic asthma is characterized by Th2 cytokine-driven inflammation of the airway mucosa, which is signaled by the fraction of exhaled nitric oxide (FENO). OBJECTIVE We tested whether an FENO-guided anti-inflammatory treatment algorithm could improve asthma-related quality of life and asthma symptom control, and reduce exacerbations in atopic asthmatics within primary care. METHODS Altogether, 187 patients with asthma and who were nonsmokers (age range, 18-64 years) with perennial allergy and who were on regular inhaled corticosteroid treatment were recruited at 17 primary health care centers, randomly assigned to 2 groups and followed up for 1 year. For the controls (n = 88), FENO measurement was blinded to both operator and patient, and anti-inflammatory treatment was adjusted according to usual care. In the active group (n = 93), treatment was adjusted according to FENO. Questionnaires on asthma-related quality of life (Mini Asthma Quality of Life Questionnaire) and asthma control (Asthma Control Questionnaire) were completed, and asthma events were noted. RESULTS The Asthma Control Questionnaire score change over 1 year improved significantly more in the FENO-guided group (-0.17 [interquartile range {IQR}, -0.67 to 0.17] vs 0 [-0.33 to 0.50]; P = .045), whereas the Mini Asthma Quality of Life Questionnaire score did not (0.23 [IQR, 0.07-0.73] vs 0.07 [IQR, -0.20 to 0.80]; P = .197). The change in Asthma Control Questionnaire was clinically important in subpopulations with poor control at baseline (P = .03). Furthermore, the exacerbation rate (exacerbations/patient/y) was reduced by almost 50% in the FENO-guided group (0.22 [CI, 0.14-0.34] vs 0.41 [CI, 0.29-0.58]; P = .024). Mean overall inhaled corticosteroid use was similar in both groups (P = .95). CONCLUSION Use of FENO to guide anti-inflammatory treatment within primary care significantly reduced the exacerbation rate and improved asthma symptom control without increasing overall inhaled corticosteroid use.

Relationship between exhaled nitric oxide and IgE sensitisation in patients with asthma: influence of steroid treatment.

Introduction:  The influence of the degree of immunoglobulin E (IgE) sensitisation on the fraction of expired nitric oxide (FENO) in asthma patients being treated with inhaled corticosteroids (ICS) is not well known.

Association between self-rated health and asthma: a population-based study

Introduction:  Self‐rated health (SRH) is a relevant measure of health as it can predict morbidity, mortality and health‐care use. Studies have shown an association between poor SRH and elevated levels of circulating inflammatory cytokines. It is therefore interesting to learn more about the association between asthma, a chronic inflammatory disease with a recognised systemic component and SRH.

Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial

BACKGROUND Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms. METHODS In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279. FINDINGS Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%]). INTERPRETATION FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease. FUNDING Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA.

Parallel reductions of IgE and exhaled nitric oxide after optimized anti-inflammatory asthma treatment

Immunoglobulin E (IgE) is crucial for the development of airway inflammation in atopic asthma, and inhibition of IgE using monoclonal antibodies is now part of asthma therapy. However, the impact of ordinary anti‐inflammatory treatment on IgE is unclear. The aim of this study was to investigate if optimization of treatment with inhaled corticosteroid (ICS) and leukotriene‐receptor antagonist (LTRA) according to symptoms or exhaled nitric oxide (FENO) levels over a one‐year period affects IgE concentrations. Altogether, 158 relatively well‐controlled but multi‐sensitized asthmatics (age 18–65 years), with ongoing ICS treatment at baseline, were included in this post hoc analysis of data from a randomized, controlled trial on FENO‐guided asthma therapy. Asthma control and quality of life (Juniper ACQ and mAQLQ), FENO, and serum IgE were measured at baseline and after one year. Concentrations of IgE antibodies to six common perennial aeroallergens were summed up (perennial IgE). We found that perennial and total IgE decreased by 10.2% and 16.0% (P < .001 both comparisons). This was not related to allergen exposure, whereas the total use of ICS and LTRA during the year correlated with the reduction in perennial IgE (P = .030 and P = .013). The decrease in perennial and total IgE correlated significantly with the reduction in FENO (P < .003 and P < .001), and with improvements in ACQ and mAQLQ scores (P < 0.05, all comparisons). We conclude that one year of optimization of treatment with ICS and LTRA in patients with persistent atopic asthma resulted in significant decreases in total IgE and IgE antibodies; these decreases correlated with a reduction in FENO and improvements in asthma control and quality of life. Thus, IgE is reduced by ordinary asthma controller medications and the effect on IgE seems to be clinically important.

Longitudinal co-variations between inflammatory cytokines, lung function and patient reported outcomes in patients with asthma

Background Asthma is a chronic inflammatory respiratory disorder associated with reduced lung function and poor quality of life. The condition is also associated with poor self-rated health, a major predictor of objective health trajectories. Of biological correlates to self-rated health, evidence suggests a role for inflammatory cytokines and related sickness behaviours. However, this is mainly based on cross-sectional data, and the relation has not been investigated in patients with chronic inflammatory conditions. Objective To investigate inflammatory cytokines, lung function, sickness behaviour and asthma-related quality of life as determinants of self-rated health in patients with asthma, and to investigate if these variables co-vary over time. Methods Plasma cytokines (IL-5, IL-6), lung function (FEV1), sickness behaviour, asthma-related quality of life and self-rated health were assessed in 181 patients with allergic asthma aged 18–64 years in a one-year longitudinal study. Mixed effect regression models and Spearman’s correlation were performed to analyse the associations between repeated measurements. Results More sickness behaviour and poorer asthma-related quality of life were associated with poorer self-rated health (p’s<0.001). In men, both low and high levels of interleukin (IL)-6 and poorer lung function were related with poorer self-rated health (p’s<0.05). Over the year, improved asthma-related quality of life was associated with better self-rated health (Spearman’s rho = -0.34 women,-0.36 men, p’s<0.01). Further, if sickness behaviour decreased, self-rated health improved, but only in women (Rho = -0.21, p<0.05). Increased FEV1 in men was associated with an increase in IL-6 (Rho = 0.24, p<0.05) as well as improved self-rated health (Rho = -0.21, p<0.05) and asthma-related quality of life (Rho = 0.29, p<0.01) over the year. Conclusion The study highlights the importance of subjectively perceived sickness behaviour and asthma-related quality of life together with lung function as determinants of self-rated health in asthmatic patients. The importance of inflammatory activation for patient reported outcomes in chronic inflammatory conditions need further investigation.

Associations between self-rated health, sickness behaviour and inflammatory markers in primary care patients with allergic asthma : a longitudinal study

Allergic asthma is a chronic inflammatory disorder associated with elevated levels of immunoglobulin E (IgE), serum eosinophilic cationic protein (S-ECP), plasma eosinophil-derived neurotoxin (P-EDN) and fraction of exhaled nitric oxide (FENO). Poor self-rated health and sickness behaviour has repeatedly been associated with inflammatory markers, but the nature of this relationship in chronic inflammatory disease is not known. Likewise, such findings largely rely on cross-sectional investigations. Self-rated health (How would you rate your general state of health?), sickness behaviour (mean rating of satisfaction with energy, sleep, fitness, appetite and memory), IgE, S-ECP, P-EDN, and FENO were assessed in 181 non-smoking primary care patients with asthma in a 1-year longitudinal study. Associations between repeated measurements were calculated using mixed regression models and Spearman’s correlations for change scores. Poor self-rated health was associated with high levels of seasonal IgE (p = 0.05) and food IgE (p = 0.04), but not total IgE or inflammatory markers. An increase over 1 year in perennial IgE was associated with a worsening of self-rated health (ρ = 0.16, p = 0.04). Poor self-rated health was associated with more pronounced sickness behaviour (p < 0.001), and a worsening in sickness behaviour was associated with a worsening of self-rated health over time (ρ = 0.21, p = 0.007). The study corroborates the importance of sickness behaviour as a determinant of self-rated health by showing that these factors co-vary over a 1-year period in a group of patients with allergic asthma. The importance of specific IgE for perceived health in primary care patients with mild to moderate asthma needs further investigation.Allergic asthma: association between perceived health and inflammationPatient perceptions of their overall health are associated with increased sickness behaviours and spikes in specific allergy antibody levels. Allergic asthma is a chronic inflammatory condition that can trigger associated “sickness behaviours” including extreme fatigue, increased pain sensitivity and anorexia. Certain inflammatory markers are increased in patients with poor self-rated health, but the relationship between perceived health and inflammation is unclear. Karin Lodin at the Karolinska Institute, Sweden, and co-workers investigated levels of four key inflammatory markers alongside self-rated health and sickness behaviours in 181 allergic asthma patients over 12 months. Poor self-rated health was associated with more pronounced sickness behaviours and with high levels of specific immunoglobin E antibodies, particularly those related to food and seasonal changes. However, there was no association between poor self-rated health and the three other pro-inflammatory markers.