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Background Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FENO) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FENO reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FENO can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes. Objectives The scope of this review is to provide an overview of the most important clinical studies using FENO in asthma management and to summarise the implications of FENO measurements in clinical practice. Results and Conclusion In several studies, FENO measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FENO can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.

Introduction: Respiratory allergic disorders like rhinitis and asthma are common conditions that not only affect target organs, but complicate the daily life of affected children and adolescents. Objectives: The aim of this study was to investigate the QoL (Quality of Life) in children with grass pollen allergy in and out of grass pollen season. Methods: We used the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ), a disease specific questionnaire including both asthma and rhinitis symptoms. We also used the DISABKIDS questionnaire, a generic questionnaire covering non-organ specific effects of disease. Results: 98 children 7-18 years old with grass pollen allergy were included. 89 children (91%) completed the study. The QoL was significantly decreased during pollen season assessed both with DISABKIDS and PADQLQ. The correlation between the questionnaires was 0.73. Not only the physical domain score (p=0.00093) but also the emotional domain score (p=0.034) was significantly lowered. Children with multiple manifestations (asthma and rhinitis) had lower QoL than children with rhinitis alone (p= 0.01). Multiple regression analysis showed a highly significant impact on QoL for symptoms from nose, eyes and lungs. They were equally important (standardized coefficient 047, 0.47 and 0.46 respectively). Conclusion: The quality of life in children and adolescents with respiratory allergy deteriorates during pollen season. This was shown both with generic (DISABKIDS) and disease specific instrument (PADQLQ). © 2012 Blackwell Publishing Ltd.

Introduction: During the last decade, small airway (SA) involvement in asthma and Chronic Obstructive Pulmonary Disease (COPD) have reached increasing attention. Originally referred to as the 'silent zone', SA may not be that silent after all. Important clinical correlates are asthma exacerbations and airways remodelling, exercise asthma and nocturnal asthma. Thus, to control pathology in the SA has become a desirable goal in asthma management. Objectives: The scope of this review is to give a brief overview of the current status on SA in asthma, how to monitor and to diagnose SA inflammation and finally highlight some important treatment strategies. Results/Conclusion: New tools have been developed to monitor SA function; these implies the use of imaging techniques and respiratory physiology, targeting SA function. Fractional exhaled nitric oxide and the combined use of hyperresponsiveness testing with impulsoscillometry is another option. The introduction of ultrafine aerosols has provided new tools for to treat SA inflammation. The challenge for the future will be to define the optimal particle size and device for maximal deposition in entire lung, including the small airways. Moreover, we also need strategies for increasing the therapeutic ratio, i.e. increasing lung deposition without increasing systemic side effects. Another challenge is to design and to perform clinical trials, targeting effects in SA, proving the clinical importance of SA treatment in a large number of patients. The latter also imply education of our medical authorities, communicating that asthma is more than a beta-2 agonist responsive central airway disorder of the lungs.

Introduction: Testing for airway hyperresponsiveness with indirect stimuli as exercise or mannitol has been proposed to better reflect underlying airway inflammation, as compared with methacholine (MCh), believed to act directly on airway smooth muscle cells. Objective: To investigate whether different direct and indirect stimuli induces different patterns of obstruction, recorded as central and peripheral resistance, and to see whether baseline resistance could predict a positive response to direct or indirect provocation. Methods: Thirty-four mild asthmatics and 15 controls underwent MCh, mannitol and eucapnic voluntary hyperventilation (EVH) challenge tests. The response was evaluated with spirometry and impulse oscillometry (IOS). Results: Twenty-three out of 34 asthmatics were positive to either EVH (22) or mannitol (13). Those positive to mannitol had a significant increased baseline value of IOS parameters such as ΔR5-R20 and AX. Twelve of the asthmatics had a 10% fall or more in forced expiratory volume in 1 s (FEV(1) ) in all three challenge tests. However, the response pattern measured by IOS did not differ between the tests. When the limit for a positive mannitol provocation was set to 10% fall in FEV(1) , 16 out of 19 mannitol-positive patients were also positive to EVH. Conclusion: Even in mild asthmatics, a substantial number had a positive indirect test. Mannitol FEV(1) provocative dose to decrease FEV(1) by 10% from baseline (PD10) was closely associated to EVH10%. No difference in bronchoconstrictive pattern could be seen between the different provocation tests, but those positive to mannitol had more peripheral airway involvement at baseline. This supports the idea that peripheral airway involvement is an important predictor of asthma airway reactivity. Please cite this paper as: Aronsson D, Tufvesson E, Bjermer L. Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics. Clin Respir J 2011; 5: 10-18. (Less)

Introduction: Airway remodelling refers to a wide pattern of patophysiological mechanisms involving smooth muscle cell hyperplasia, increase of activated fibroblasts and myofibroblasts with deposition of extracellular matrix. In asthma, it includes alterations of the epithelial cell layer with goblet cell hyperplasia, thickening of basement membranes, peri-bronchial and peri-broncheolar fibrosis. Moreover, airway remodelling occurs not only in asthma but also in several pulmonary disorders such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and systemic sclerosis. Asthma treatment with inhaled corticosteroids does not fully prevent airway remodelling and thus have restricted influence on the natural course of the disease. Objectives: This review highlights the role of different fibroblast phenotypes and potential origins of these cells in airway remodelling. Results: During inflammatory conditions, such as asthma, fibroblasts can differentiate into an active, more contractile phenotype termed myofibroblast, with expression of stress fibres and alpha-smooth muscle actin. The origin of myofibroblasts has lately been debated, and three sources have been identified: recruitment and differentiation of resident tissue fibroblasts; fibrocytes - circulating progenitor cells; and epithelial-mesenchymal transition. Conclusion: It is clear that airway mesenchymal cells, including fibroblasts/myofibroblasts, are more dynamic in terms of differentiation and origin than has previously been recognised. Considering that these cells are key players in the remodelling process, it is of utmost importance to characterise specific markers for the various fibroblast phenotypes and to explore factors that drive the differentiation to develop future diagnostic and therapeutic tools for asthma patients. Please cite this paper as: Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjoland A, Hallgren O, Marko-Varga G and Bjermer L. Pathological airway remodelling in inflammation. Clin Respir J 2010; 4 (Suppl. 1): 1-8. (Less)

Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FE(NO)) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FE(NO) reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FE(NO) can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes.The scope of this review is to provide an overview of the most important clinical studies using FE(NO) in asthma management and to summarise the implications of FE(NO) measurements in clinical practice.In several studies, FE(NO) measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FE(NO) can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.

Respiratory allergic disorders like rhinitis and asthma are common conditions that not only affect target organs, but complicate the daily life of affected children and adolescents.The aim of this study was to investigate the QoL (quality of life) in children with grass pollen allergy in and out of grass pollen season.We used the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ), a disease-specific questionnaire including both asthma and rhinitis symptoms. We also used the DISABKIDS (a European project which aims at enhancing the quality of life and the independence of children with chronic health conditions and their families) questionnaire, a generic questionnaire covering non-organ-specific effects of disease.Ninety-eight children 7–18 years old with grass pollen allergy were included. Eighty-nine children (91%) completed the study. The QoL was significantly decreased during pollen season assessed both with DISABKIDS and PADQLQ. The correlation between the questionnaires was 0.73. Not only the physical domain score (P = 0.00093) but also the emotional domain score (P = 0.034) was significantly lowered. Children with multiple manifestations (asthma and rhinitis) had lower QoL than children with rhinitis alone (P = 0.01). Multiple regression analysis showed a highly significant impact on QoL for symptoms from nose, eyes and lungs. They were equally important (standardized coefficient 047, 0.47 and 0.46, respectively).The QoL in children and adolescents with respiratory allergy deteriorates during pollen season. This was shown both with generic (DISABKIDS) and disease-specific instrument (PADQLQ).

During the last decade, small airway (SA) involvement in asthma and Chronic Obstructive Pulmonary Disease (COPD) have reached increasing attention. Originally referred to as the 'silent zone', SA may not be that silent after all. Important clinical correlates are asthma exacerbations and airways remodelling, exercise asthma and nocturnal asthma. Thus, to control pathology in the SA has become a desirable goal in asthma management.The scope of this review is to give a brief overview of the current status on SA in asthma, how to monitor and to diagnose SA inflammation and finally highlight some important treatment strategies.New tools have been developed to monitor SA function; these implies the use of imaging techniques and respiratory physiology, targeting SA function. Fractional exhaled nitric oxide and the combined use of hyperresponsiveness testing with impulsoscillometry is another option. The introduction of ultrafine aerosols has provided new tools for to treat SA inflammation. The challenge for the future will be to define the optimal particle size and device for maximal deposition in entire lung, including the small airways. Moreover, we also need strategies for increasing the therapeutic ratio, i.e. increasing lung deposition without increasing systemic side effects. Another challenge is to design and to perform clinical trials, targeting effects in SA, proving the clinical importance of SA treatment in a large number of patients. The latter also imply education of our medical authorities, communicating that asthma is more than a beta-2 agonist responsive central airway disorder of the lungs.

Testing for airway hyperresponsiveness with indirect stimuli as exercise or mannitol has been proposed to better reflect underlying airway inflammation, as compared with methacholine (MCh), believed to act directly on airway smooth muscle cells.To investigate whether different direct and indirect stimuli induces different patterns of obstruction, recorded as central and peripheral resistance, and to see whether baseline resistance could predict a positive response to direct or indirect provocation.Thirty-four mild asthmatics and 15 controls underwent MCh, mannitol and eucapnic voluntary hyperventilation (EVH) challenge tests. The response was evaluated with spirometry and impulse oscillometry (IOS).Twenty-three out of 34 asthmatics were positive to either EVH (22) or mannitol (13). Those positive to mannitol had a significant increased baseline value of IOS parameters such as ΔR5-R20 and AX. Twelve of the asthmatics had a 10% fall or more in forced expiratory volume in 1 s (FEV(1)) in all three challenge tests. However, the response pattern measured by IOS did not differ between the tests. When the limit for a positive mannitol provocation was set to 10% fall in FEV(1), 16 out of 19 mannitol-positive patients were also positive to EVH.Even in mild asthmatics, a substantial number had a positive indirect test. Mannitol FEV(1) provocative dose to decrease FEV(1) by 10% from baseline (PD10) was closely associated to EVH10%. No difference in bronchoconstrictive pattern could be seen between the different provocation tests, but those positive to mannitol had more peripheral airway involvement at baseline. This supports the idea that peripheral airway involvement is an important predictor of asthma airway reactivity.

Background and Aims: Saliva contamination has been suggested to be a major contributor to levels of cysteinyl leukotrienes in exhaled breath condensate (EBC). The aim of this study was to compare the levels of cysteinyl-leukotrienes (CysLT) and alpha-amylase activity in EBC to induced sputum and saliva collected from the same subjects (asthmatics and control). We thereby aimed to find out whether saliva contamination could be a plausible explanation to the levels found in EBC or not. Methods: EBC, saliva and induced sputum were collected from 11 asthmatic and 19 healthy adults. These samples were analyzed for CysLT concentration and alpha-amylase activity. Results: No significant correlation was found between CysLT concentration and alpha-amylase activity in EBC, saliva or sputum. In addition, we show that the saliva contamination (measured as alpha-amylase activity) was negligible, as the relative amount of saliva CysLT was only 0.6% of that found in EBC. The amount of CysLT correlated between all three compartments (EBC, saliva and sputum), but no similar correlation was seen for the alpha-amylase activity in EBC compared to saliva and sputum. The levels of CysLT were higher in asthmatic patients compared to healthy controls in EBC, saliva and sputum. Conclusion: We conclude that the amount of CysLT in EBC cannot be explained by saliva contamination. Please cite this paper as: Tufvesson E, van Weele LJ, Ekedahl H and Bjermer L. Levels of cysteinyl-leukotrienes in exhaled breath condensate are not due to saliva contamination. The Clinical Respiratory Journal 2010; 4: 83-88.

The current view on inflammation in COPD is foremost based on examinations of luminal samples and bronchial tissues. Inflammation in peripheral lung tissues has however remained relatively unexplored. Our research characterises structural alterations of the lung immune system (i.e. “immune remodelling”) in COPD. With focus on changes in lymphoid tissues and lymphatic vessels, immune remodelling was studied in patients with different severities of COPD and compared to never-smoking and smoking control subjects. The results confirmed an expansion of bronchiolar-associated lymphoid tissue (BALT) in COPD but also revealed increased lymphoid tissues in pulmonary vessels and the alveolar parenchyma. While the lymphoid structures in COPD had a leukocyte composition similar to controls, several leukocyte populations were activated, with e.g. increased expression of CXCL13 and ETS-1. In COPD lungs, increased numbers and size of lymphatic vessels were found in bronchiolar wall, pulmonary vessel, and alveolar compartments. Lymphatic vessels also displayed increased immunoreactivity for the cell traffic regulating chemokine CCL21. Altogether, our data suggest that in COPD all major lung compartments are subjected to immune remodelling with expansion and activation of lymphoid tissues and lymphatic vessels as significant features. These observations may have implications for the abnormal cell traffic and chronic inflammation in COPD.