P Rytilä

Publications of P Rytilä

• Effects of Inhaled Corticosteroids on Metalloproteinase-8 and Tissue Inhibitor of Metalloproteinase-1 in the Airways of Asthmatic Children.

  Authors: Y Obase, P Rytilä, T Metso, A S Pelkonen, T Tervahartiala, M Turpeinen, M Mäkelä, U Saarialho-Kere, O Selroos, T Sorsa, T Haahtela

  International archives of allergy and immunology. 09/2009; 151(3):247-254.

  Background: The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue areBackground: The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue are poorly characterized in vivo. Methods: We compared MMP-8 and TIMP-1 levels in induced sputum and their expression in airway inflammatory cells of healthy children (n = 27) and of children with newly diagnosed asthma with mild (n = 20) or moderate symptoms (n = 19), before and after 6 months of treatment with inhaled budesonide. Results: At baseline, MMP-8 was higher in asthmatic children with moderate symptoms, TIMP-1 was lower and the MMP-8/TIMP-1 ratio was higher in both groups of asthmatic children compared with controls. Inhaled budesonide increased TIMP-1 levels in both groups of asthmatic children and normalized the MMP-8/TIMP-1 ratio, and this paralleled the improvement in forced expiratory volume in 1 s in children with mild symptoms. At baseline, asthmatic children had significantly more MMP-8-positive macrophages than control children, whereas the number of TIMP-1-positive macrophages was almost the same. Budesonide decreased the percentage of MMP-8-positive macrophages and increased that of TIMP-1-positive macrophages; these changes were significant in asthmatic children with mild symptoms. Conclusions: Inhaled budesonide normalized the MMP-8/TIMP-1 ratio in asthmatic children by upregulation of TIMP-1 production and downregulation of MMP-8 production by airway macrophages. This change may be a biochemical marker of an effect on airway inflammation and possibly of an ongoing remodeling process that should be further investigated using biopsy specimens.

• Physical training does not increase allergic inflammation in asthmatic children.

  Authors: A Moreira, L Delgado, T Haahtela, J Fonseca, P Moreira, C Lopes, J Mota, P Santos, P Rytilä, M G Castel-Branco

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 09/2008;

  We studied the effects of a 3-month physical training program on airway inflammation and clinical outcomes in school-aged children with asthma.Thirty four subjects, 12.7+/-3.4 years, with persistentWe studied the effects of a 3-month physical training program on airway inflammation and clinical outcomes in school-aged children with asthma.Thirty four subjects, 12.7+/-3.4 years, with persistent allergic asthma were randomly allocated into training and control groups. Exercise consisted of twice-weekly 50 minutes sessions for 12 weeks. Inflammation was assessed by exhaled nitric oxide, blood eosinophils, eosinophil cationic protein, C-reactive protein, total and mite specific IgE. Lung volumes and bronchial responsiveness to metacholine were determined. Paediatric Asthma -and Caregiver's- Quality of Life Questionnaires were used to evaluate activity restrictions, symptoms and emotional stress. Efficacy of the training was assessed by accelerometry.After the program, exercise children had double daily minutes in moderate-to-vigorous activities compared to controls. No differences in changes were seen between groups for asthma outcomes. However, total IgE decreased more in the exercise group, as did mite specific IgE.Training did not increase inflammation in children with persistent asthma, and may have decrease both total and allergen specific IgE levels. We conclude there is no reason to discourage asthmatic children with a controlled disease to exercise.

• Treatment with inhaled steroids in patients with symptoms suggestive of asthma but with normal lung function.

  Authors: P Rytilä, L Ghaly, S Varghese, W Chung, O Selroos, T Haahtela

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 06/2008;

  A total of 144 patients with lower airway symptoms suggestive of asthma, but not fulfilling the functional criteria of asthma were included in a randomized, double-blind, placebo-controlled 8-weekA total of 144 patients with lower airway symptoms suggestive of asthma, but not fulfilling the functional criteria of asthma were included in a randomized, double-blind, placebo-controlled 8-week "proof-of-concept" study with mometasone furoate (MF), 400 microg once daily. The primary efficacy variable was the change from baseline in six mean morning (AM) and evening (PM) weekly symptom scores - cough, sputum production, wheeze, shortness of breath, chest tightness, and exercise-induced cough/wheeze. Total symptom scores were calculated after treatment for 4 and 8 weeks.Compared with placebo MF improved total AM symptom score at 8 weeks. Changes in total PM symptom scores did not differ between treatments. MF improved all individual symptom scores more than placebo although the differences in changes between treatments was not always statistically sig-nificant. Morning and evening peak expiratory flow rates increased with MF compared with placebo. MF reduced eosinophils and the levels of eosinophilic cationic protein in induced sputum.The results show that symptoms suggestive of asthma exist in patients without significant beta2-agonist reversibility or diurnal variability in peak flow. Once-daily MF may benefit some of these patients and a short course with inhaled corticosteroids may be tried. Responders should be identified better in further studies.

• Competitive swimmers with allergic asthma show a mixed type of airway inflammation.

  Authors: A Moreira, L Delgado, C Palmares, C Lopes, T Jacinto, P Rytilä, J A Silva, M G Castel-Branco, T Haahtela

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 06/2008; 31(5):1139-41.

• Thiol proteins, redox modulation and parenchymal lung disease.

  Authors: V L Kinnula, K Vuorinen, H Ilumets, P Rytilä, M Myllärniemi

  Current medicinal chemistry. 02/2007; 14(2):213-22.

  The lung is a unique organ in terms of its direct exposure to high levels of oxygen and reactive compounds. Several parenchymal lung diseases (e.g. emphysema associated with smoking and a number ofThe lung is a unique organ in terms of its direct exposure to high levels of oxygen and reactive compounds. Several parenchymal lung diseases (e.g. emphysema associated with smoking and a number of fibrotic lung disorders) have been proposed to be due to the exposure of the lung to exogenous irritants leading to local redox imbalance in the alveolar epithelium. The disease progression of emphysema/chronic obstructive pulmonary disease (COPD) and fibrosis share several common factors, such as the role of reactive oxygen species, disturbances of the pulmonary thiol status and activation of growth factors and tissue destructing proteases. Importantly in COPD or fibrosis, medication does not provide any significant therapeutic effect. This review concentrates on the key thiol (-SH)-regulated mechanisms leading to the development of COPD and/or pulmonary fibrosis and the major redox-regulated defense/oxidant repair mechanisms, thioredoxin/peroxiredoxin and glutaredoxin protein families in the lung. Redox-regulated proteins, both proteases and oxidant repair enzymes, undergo conformational changes during oxidative stress, a process that modulates their activation or inactivation. In addition, some of the redox-regulated proteins influence the metabolism of glutathione (GSH), a major small molecular antioxidant of human lung, and participate in the crosstalk between numbers of GSH associated enzymes functioning in the detoxification pathways of human lung. An understanding of the processes involved in oxidant-mediated lung damage may provide the key to devising interventional strategies that can actually prevent the progression of lung parenchymal disease.

• 8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD.

  Authors: V L Kinnula, H Ilumets, M Myllärniemi, A Sovijärvi, P Rytilä

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 02/2007; 29(1):51-5.

  8-Isoprostane is a potential in vivo marker for oxidant burden, but its usefulness in induced sputum of smokers and chronic obstructive pulmonary disease (COPD) has not been investigated. The current8-Isoprostane is a potential in vivo marker for oxidant burden, but its usefulness in induced sputum of smokers and chronic obstructive pulmonary disease (COPD) has not been investigated. The current study investigated 58 subjects comprising 11 never-smokers, 11 ex-smokers, 13 healthy current smokers and 23 COPD with stage 0-III disease (according to the Global Initiative for Chronic Obstructive Lung Disease criteria). 8-Isoprostane was determined from induced sputum by enzyme immunoassay. Sputum 8-isoprostane levels were similar in the never-smokers and ex-smokers, but were elevated in the healthy smokers compared with nonsmokers, and in those with stage I-III COPD. Sputum 8-isoprostane levels could not differentiate nonsymptomatic smokers from those with Stage 0 COPD. There was a correlation between sputum 8-isoprostane level and lung function parameters (forced expiratory volume in one second/forced vital capacity and sputum neutrophils. In conclusion, sputum 8-isoprostane levels correlate with the severity of chronic obstructive pulmonary disease. However, they do not appear to differentiate healthy smokers from those who are at risk of developing chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease stage 0).

• Airway neutrophilia in COPD is not associated with increased neutrophil survival.

  Authors: P Rytilä, M Plataki, F Bucchieri, M Uddin, G Nong, V L Kinnula, R Djukanovic

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 01/2007; 28(6):1163-9.

  Neutrophilic airway inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD) and correlates with disease severity. The mechanisms that determine the extent of neutrophiliaNeutrophilic airway inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD) and correlates with disease severity. The mechanisms that determine the extent of neutrophilia could involve increased influx or prolonged survival of neutrophils. The aim of the study was to assess whether neutrophil pro-survival mechanisms are increased in the airways of subjects with COPD owing to the presence of anti-apoptotic factors in the bronchial lining fluid. Induced sputum samples were collected from 20 subjects with stable COPD, 14 healthy smokers and 14 healthy controls. Quantification of apoptotic neutrophils was based on typical morphological cell changes. Anti-apoptotic, pro-survival activity in the sputum was studied by culturing peripheral blood neutrophils with the fluid phase of induced sputum. Apoptosis was assessed both by morphology and flow cytometry using Annexin V/7-aminoactinomycin D staining. COPD patients and healthy smokers had significantly higher percentages of sputum neutrophils than healthy controls. However, there were no significant differences between the three subject groups in either the proportion of apoptotic neutrophils in sputum or the in vitro anti-apoptotic activity detected in the sputum fluid phase. In conclusion, prolonged survival of neutrophils in sputum is not a feature of chronic obstructive pulmonary disease and cannot explain the increased numbers of airway neutrophils in this disease.

• Respiratory symptoms, bronchial hyper-responsiveness, and eosinophilic airway inflammation in patients with moderate-to-severe atopic dermatitis.

  Authors: H Kyllönen, P Malmberg, A Remitz, P Rytilä, T Metso, I Helenius, T Haahtela, S Reitamo

  Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 02/2006; 36(2):192-7.

  BACKGROUND: Patients with atopic dermatitis (AD) often have symptoms suggestive of asthma or rhinitis. The prevalence and signs of respiratory disease in AD patients have been studied to a limitedBACKGROUND: Patients with atopic dermatitis (AD) often have symptoms suggestive of asthma or rhinitis. The prevalence and signs of respiratory disease in AD patients have been studied to a limited extent. OBJECTIVES: To assess the prevalence and clustering of respiratory symptoms, bronchial hyper-responsiveness (BHR), and eosinophilic airway inflammation in patients with moderate-to-severe AD. METHODS: Eighty-six consecutive patients with moderate-to-severe AD and 49 randomly selected control subjects without AD were studied by questionnaire, flow volume spirometry, histamine challenge to detect BHR, induced sputum test to detect eosinophilic airway inflammation, and skin prick tests (SPTs) and total serum immunoglobulin (Ig)E measurements to detect atopy. RESULTS: The patients with AD showed increased risk of physician-diagnosed asthma (36% vs. 2%, odds ratio (OR) 10.1, confidence interval (CI) 1.3-79.7, P=0.03), physician-diagnosed allergic rhinitis (AR) (45% vs. 6%, OR 4.5, CI 1.2-16.7, P=0.02), BHR (51% vs. 10%, OR 5.5, CI 1.5-20.1, P=0.01), and sputum eosinophilia (81% vs. 11%, OR 76.1, CI 9.3-623.5, P<0.0001) compared with the control subjects. In AD patients, elevated s-IgE and positive SPTs were associated with the occurrence of physician-diagnosed asthma and AR, BHR, and the presence of sputum eosinophilia. CONCLUSIONS: BHR and eosinophilic airway inflammation are more common in patients with AD than in control subjects. The highest prevalences were seen in patients with AD who were SPT positive and had high IgE levels. Longitudinal studies are needed to assess the outcome of patients with signs of airway disease, in order to identify those who need early initiation of asthma treatment.

• Determinants of increased exhaled nitric oxide in patients with suspected asthma.

  Authors: L P Malmberg, H Turpeinen, P Rytilä, S Sarna, T Haahtela

  Allergy. 05/2005; 60(4):464-8.

  Exhaled nitric oxide (FENO) has been proposed as a marker of asthmatic inflammation, but it is unclear whether FENO in clinical use selects patients primarily according to their atopic or asthmaticExhaled nitric oxide (FENO) has been proposed as a marker of asthmatic inflammation, but it is unclear whether FENO in clinical use selects patients primarily according to their atopic or asthmatic status. The aim of this study was to investigate the determinants of increased FENO in patients with suspected asthma, by means of multinomial logistic regression analysis. The FENO of 132 patients referred because of symptoms suggestive of asthma were studied, and the explanatory factors tested included atopy according to prick skin tests, clinical asthma according to lung function tests, sputum eosinophilia and bronchial hyperresponsiveness (BHR). Slightly elevated FE(NO) levels were significantly explained only by sputum eosinophilia (OR: 3.7; 95% CI: 1.1-13.1; P=0.04), but for high levels of FE(NO) (> or =3 SD of predicted), clinical asthma (OR: 16.3; 95% CI: 5.4-49.7; P <0.0001) and sputum eosinophilia (OR: 12.0; 95% CI: 4.1-35.0; P >0.0001) were the characteristics with the highest prediction, followed by atopy and BHR. A significant interaction between asthma and atopy was observed relating to the effect on high FENO, but further analyses stratified by atopy showed significant associations between asthma and high FENO both in atopic and nonatopic patients. We conclude that in patients with symptoms suggesting asthma, slightly elevated and high levels of FENO are associated with sputum eosinophilia, whereas asthma is significantly associated only with high levels of FENO, irrespective of atopy. The results suggest that FENO is primarily a marker of airway eosinophilia, and that only high values of FENO may be useful to identify patients with atopic or nonatopic asthma.

• Induced sputum in children with newly diagnosed mild asthma: the effect of 6 months of treatment with budesonide or disodium cromoglycate.

  Authors: P Rytilä, A S Pelkonen, T Metso, K Nikander, T Haahtela, M Turpeinen

  Allergy. 08/2004; 59(8):839-44.

  BACKGROUND: There are few controlled studies on the effects of anti-inflammatory treatment on airway inflammation in newly diagnosed childhood asthma. METHODS: Sixty children with newly diagnosedBACKGROUND: There are few controlled studies on the effects of anti-inflammatory treatment on airway inflammation in newly diagnosed childhood asthma. METHODS: Sixty children with newly diagnosed mild persistent asthma, 5-10 years of age, and 17 healthy control subjects were studied. Asthmatic children were randomized into an open study with two treatment groups: (1) budesonide 400 microg twice daily for 1 month, 200 microg twice daily for 5 months and (2) disodium cromoglycate (DSCG) 10 mg three-times daily for 6 months. All exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. Symptoms and lung function were recorded throughout the study. RESULTS: Sputum induction was safe and the overall success rate was 71%. This improved with age and decreased after treatment. At baseline, the asthmatic children had more eosinophils in blood (0.26 vs 0.18 x 10(9)/l, P = 0.03) and sputum (1.1 vs 0.0 %, P = 0.0001) than the control subjects. The numbers of sputum eosinophils correlated with bronchial responsiveness (R = -0.58, P = 0.0002). Eosinophils were higher in children with atopic asthma than with nonatopic asthma (P < 0.0001), and in children with a history wheezing than in children without wheezing (P = 0.02). Six months of budesonide treatment, but not of DSCG, improved lung function (P = 0.007), decreased symptoms (P = 0.007) and sputum eosinophils (P = 0.003). The effects of budesonide were pronounced in children with intense sputum eosinophilia (>3%). CONCLUSION: Sputum eosinophilia is present in children with newly diagnosed mild persistent asthma. Treatment with inhaled budesonide, but not with DSCG, decreases sputum eosinophils along with clinical and functional improvement.

• No effect of montelukast on asthma-like symptoms in elite ice hockey players.

  Authors: I Helenius, A Lumme, J Ounap, Y Obase, P Rytilä, S Sarna, A Alaranta, V Remes, T Haahtela

  Allergy. 02/2004; 59(1):39-44.

  BACKGROUND: Controlled clinical trials on the effects of leukotriene antagonists on asthma-like symptoms, bronchial hyperresponsiveness and airway inflammation have not been performed in eliteBACKGROUND: Controlled clinical trials on the effects of leukotriene antagonists on asthma-like symptoms, bronchial hyperresponsiveness and airway inflammation have not been performed in elite athletes. METHODS: In 2001, we examined 88 of 102 (86%) players from three junior, national league ice hockey teams in Helsinki. Athletes were included in the intervention if they reported at least two exercise-induced bronchial symptoms (wheeze, cough, shortness of breath) weekly during the previous month on a previously validated respiratory-symptom questionnaire. Sixteen male ice hockey players fulfilled the study criteria. A double-blind, randomized, cross-over, placebo-controlled study included 4-week active treatment (10 mg oral montelukast, bedtime), 1-week washout period, and 4-week placebo treatment. Before entering the study, all patients were clinically examined, skin prick tested, filled in a respiratory symptom questionnaire, performed a spirometry and a histamine challenge test, and gave induced sputum samples. Exhaled NO was measured. These measures were repeated after both treatment periods. During the treatment the athletes kept daily diary on lower respiratory tract symptoms on a scale from 0 (no symptoms) to 10 (most severe symptoms), morning peak expiratory flow (PEF), training amount, and use of study medication. Primary end-point was daily lower respiratory tract symptom score. RESULTS: Montelukast had no effect on daily lower respiratory symptom scores, spirometry parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, PEF], bronchial hyperresponsiveness, sputum eosinophil or neutrophil cell counts, exhaled NO measurements, or morning PEF. Nine subjects were atopic in skin prick test, but their results did not differ from the nonatopic subjects. CONCLUSION: A leukotriene antagonist, montelukast, was of no benefit in the treatment of asthma-like symptoms, increased bronchial hyperresponsiveness or a mixed type of eosinophilic and neutrophilic airway inflammation in highly-trained ice hockey players.

• Smoking and atopy as determinants of sputum eosinophilia and bronchial hyper-responsiveness in adults with normal lung function.

  Authors: T Petäys, L von Hertzen, T Metso, P Rytilä, P Jousilahti, I Helenius, E Vartiainen, T Haahtela

  Respiratory medicine. 09/2003; 97(8):947-54.

  Data concerning the determinants of sputum eosinophilia and bronchial hyper-responsiveness (BHR) in large cohorts of individuals with normal lung function are limited. Here, we assessed theData concerning the determinants of sputum eosinophilia and bronchial hyper-responsiveness (BHR) in large cohorts of individuals with normal lung function are limited. Here, we assessed the occurrence of sputum eosinophilia and BHR and identified the risk factors for these variables in two populations living in North Karelia, Finland, and in Pitkäranta, the Republic of Karelia, Russia. These areas are geographically adjacent, but differ, however, fundamentally in major cultural, socioeconomical and lifestyle aspects. The study population comprised 790 Finns and 387 Russian, aged 25-54 years, who were randomly enrolled from the population registers. A methacholine challenge test to measure BHR was successfully performed in 581 (74%) Finns and 307 (79%) Russians with virtually normal lung function (FEV1 > 70% of predicted). Of these, induced sputum samples were obtained from 41% of the Finns and from 67% of the Russians. The proportion of current smokers was 27% among the former and 42% among the latter. Sputum eosinophilia was assessed using a semi-quantitative method, and total concentrations of sputum eosinophilic cationic protein (ECP) and myeloperoxidase (MPO) were measured using an immunoassay. Risk factors for BHR and sputum eosinophilia were identified with a regression analysis. The prevalence of sputum eosinophilia was 22% among the Finns and 19% among the Russians, and the respective figures for BHR were 14% and 13%. The median ECP concentration in sputum was significantly higher among the Russians as compared with the Finns (P<0.001), whereas for MPO, the difference did not achieve significance. Current smoking was significantly associated with both sputum eosinophilia and BHR in Russia (OR 3.1, 95% CI 1.2-7.6 for sputum eosinophilia, 2.8, 1.3-6.1 for BHR) and with BHR in Finland (2.1, 1.3-3.7). Atopy showed a tendency to be another risk factor for BHR in Finland (1.6, 0.98-2.6). In conclusion, sputum eosinophilia and BHR occurred commonly among the Finns and the Russians with normal lung function. Current smoking was significantly associated with BHR in both countries and additionally with sputum eosinophilia in Russia. Atopy was identified as a risk factor, albeit of borderline significance, for BHR in Finland only, suggesting that there may be differences in the aetiology and nature of BHR between the two countries.

• Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players.

  Authors: A Lumme, T Haahtela, J Ounap, P Rytilä, Y Obase, M Helenius, V Remes, I Helenius

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 08/2003; 22(1):113-7.

  There is little information of lower respiratory symptoms, bronchial hyperresponsiveness and airway inflammation in elite ice hockey players. A total of 88 highly trained ice hockey players and 47There is little information of lower respiratory symptoms, bronchial hyperresponsiveness and airway inflammation in elite ice hockey players. A total of 88 highly trained ice hockey players and 47 control subjects were studied. All the subjects were subjected to skin-prick tests, resting spirometry examinations and histamine-challenge tests. Adequate induced sputum samples were obtained from 68 of the ice hockey players and from 18 symptom-free control subjects on a separate day. Bronchial hyperresponsiveness in a histamine-challenge test was found in 21 (24%) of the athletes and in five (11%) of the controls. Current asthma (current asthmatic symptoms and increased bronchial responsiveness) was observed in 13 (15%) of the athletes and in one (2%) of the control subjects. Total asthma (current asthma or previously physician-diagnosed asthma) occurred in 19 (22%) of the athletes and in two (4%) of the controls. Atopy, according to skin-prick tests, was observed in 51 (58%) of the athletes and 17 (36%) of the control subjects. The differential cell counts of eosinophils (2.6 versus 0.2%) and neutrophils (80.9 versus 29.9%) in the sputum samples of the ice hockey players were significantly higher than in those of the control subjects. Asthma is common in elite ice hockey players and they show signs of a mixed type of neutrophilic and eosinophilic airway inflammation. Inhalation of cold air associated with exposure to indoor pollutants during intensive training is a possible causative factor.

• Safety, tolerability and acceptability of two dry powder inhalers in the administration of budesonide in steroid-treated asthmatic patients.

  Authors: H Tukiainen, P Rytilä, K M Hämäläinen, M S L Silvasti, J Keski-Karhu

  Respiratory medicine. 05/2002; 96(4):221-9.

  The purpose of this randomized, double-blind parallel group study was to compare the safety, tolerability and acceptability of Easyhaler and Turbuhaler dry powder inhalers for the delivery ofThe purpose of this randomized, double-blind parallel group study was to compare the safety, tolerability and acceptability of Easyhaler and Turbuhaler dry powder inhalers for the delivery of budesonide 800 microg day(-1) in adult asthmatic patients who had already been treated with inhaled corticosteroids for at least 6 months prior to the study Additionally the efficacy of the products was evaluated. The main objective was to evaluate the systemic safety of budesonide inhaled from Easyhaler (Giona Easyhaler, Orion Pharma, Finland) as determined by serum and urine cortisol measurements. The secondary objective was to compare the tolerability acceptability and efficacy of the two devices in the administration of budesonide. After a 2-week run-in period (baseline), patients were randomized on a 2:1 basis to receive budesonide from Easyhaler (n = 103) or from Turbuhaler (Pulmicort Turbuhaler, AstraZeneca, Sweden) (n = 58) 200 g dose(-1), two inhalations twice daily for 12 weeks.There was no statistically significant change in morning serum cortisol values from baseline to the end of treatment in either group.Urine free cortisol and urine cortisol/ creatinine ratio increased from baseline in both groups. There were no significant differences between the groups in terms of morning serum cortisol, urine cortisol, adverse events or efficacy variables, but Easyhaler was generally considered more acceptable to the patients. In conclusion, at 800 microg day(-1), Giona Easyhaler is as safe and efficacious as Pulmicort Turbuhaler in adult asthmatic patients previously treated with corticosteroids, but more acceptable to patients.

• Eosinophilic airway inflammation as an underlying mechanism of undiagnosed prolonged cough in primary healthcare patients.

  Authors: P Rytilä, T Metso, T Petäys, A Sohlman, H Työlahti, P Kohonen-Jalonen, P Kiviniemi, T Haahtela

  Respiratory medicine. 02/2002; 96(1):52-8.

  Prolonged cough is a common problem in patients seen in general practice. Using a simple method of sputum induction and processing of sputum samples, we determined whether eosinophilic airwayProlonged cough is a common problem in patients seen in general practice. Using a simple method of sputum induction and processing of sputum samples, we determined whether eosinophilic airway inflammation could be a cause of undiagnosed prolonged cough. Eighty-two patients who had had cough for more than 1 month were enrolled into the study, in six primary healthcare centres. Patients with known pulmonary disease, including asthma or chronic obstructive pulmonary disease (COPD), or who were known to have another cause of cough, or to have recently suffered from a respiratory infection, were excluded. Fifty-three healthy individuals served as controls. Sputum was induced by inhalation of 3% saline. Inflammatory cells in smears were studied semi-quantitatively. Concentrations of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO) and human neutrophilic lipocalin (HNL) were determined. Sputum induction proved safe and adequate samples were obtained from 91%. Sputum eosinophilia (eosinophils accounting for more than 5% of all cells in smears) was present in 14 patients with prolonged cough (19%) but in no healthy individual (P=0.001). Five of the 14 individuals (36%) who exhibited sputum eosinophilia appeared to have asthma, while nine of the 14 (64%) did not. Concentrations of ECP and EPO were higher in patients with prolonged cough than in healthy individuals (P=0.02 for ECP; 0.005 for EPO).We conclude that eosinophilic airway inflammation is a fairly common cause of prolonged cough, even in patients not suffering from asthma or COPD, or in whom no other cause of cough is known to be present. Induced sputum samples obtained in health centres can be studied in a central laboratory. Detection of eosinophilic airway inflammation could aid the decision regarding treatment.

• Granulocyte markers in induced sputum in patients with respiratory disorders and healthy persons obtained by two sputum-processing methods.

  Authors: T Metso, P Rytilä, C Peterson, T Haahtela

  Respiratory medicine. 01/2001; 95(1):48-55.

  Induced sputum is increasingly used to detect and monitor airway inflammation in respiratory diseases. However, the processing of sputum has been rather laborious for clinical practice. The aim ofInduced sputum is increasingly used to detect and monitor airway inflammation in respiratory diseases. However, the processing of sputum has been rather laborious for clinical practice. The aim of this study was to improve the practicality of induced-sputum studies by simplifying sample processing. Eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), neutrophil lipocalin (HNL) and myeloperoxidase (MPO) were used as biochemical markers of airway inflammation and the results of the study method were compared with a previously validated (reference) method. Induced sputum was obtained from 42 healthy controls, 10 subjects with acute respiratory infection, eight patients with chronic obstructive pulmonary disease (COPD) and 17 asthmatics. The sputum sample was divided into two parts and treated either: (i) by the reference method (released markers), where sputum was homogenized with dithiotreitol and centrifuged to yield cell-free supernatant and a cell pellet, or (ii) by the study method (total markers), where the cells were lysed after homogenization so that cell-associated markers were released and solubilized. For comparison, the four biochemical markers were measured in sputum supernatant and in sputum lysate. The differential cell count was performed from the cell pellet in the reference method. Repeatability was assessed in a group of 16 subjects. The effect of reagents and the recovery of assays were also evaluated. Released and total markers correlated well (ECP r(s)=0.80, P<0.0001; EPO r(s)=0.49, P<0.0001; HNL r(s)=0.87, P<0.0001; MPO r(s)=0.71, P<0.0001). Incubation with dithiotreitol and lysis reagent had no negative influence on marker assays. The within-subject variability of total ECP, MPO and HNL in both methods was small in two measurements taken I week apart. The study method, measuring total inflammatory markers, gave comparable results to the reference method, measuring released markers. In the study method the sputum processing was simplified, which may improve its applicability.

• Airway inflammation in patients with symptoms suggesting asthma but with normal lung function.

  Authors: P Rytilä, T Metso, K Heikkinen, P Saarelainen, I J Helenius, T Haahtela

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 11/2000; 16(5):824-30.

  The hypothesis that eosinophilic airway inflammation is present in many patients presenting with respiratory symptoms suggestive of asthma but with normal lung function was tested. Thirty-sixThe hypothesis that eosinophilic airway inflammation is present in many patients presenting with respiratory symptoms suggestive of asthma but with normal lung function was tested. Thirty-six consecutive patients presenting with these features were studied. Twenty-five asthmatics and 43 healthy volunteers served as control groups. Signs of eosinophilic inflammation in blood and induced sputum were studied. Patients with respiratory symptoms were single-blindly treated with inhaled beclomethasone dipropionate (BDP), 800 microg daily, or placebo for 3 months, and re-examined at 3 months and 1 yr. Patients with respiratory symptoms had higher numbers of blood and sputum eosinophils than healthy persons (p<0.0001), but the degree of eosinophilic inflammation was less pronounced than in asthmatics (p<0.01). Three-month's treatment with BDP significantly reduced total symptom score (p<0.001), cough score (p<0.0001), and the number of blood eosinophils (p<0.01). For cough alone, the improvement was significant compared with placebo (p<0.05). The patients were followed-up for 1 yr, and 17 (55%) still had symptoms but retained normal lung function. Four (13%) patients had developed asthma and another 10 (32%) had become free of symptoms. Using lung function measurements and induced sputum analyses, a group of patients with symptoms suggestive of asthma and signs of eosinophilic airway inflammation but without enough airflow variability to be diagnosed as asthmatics were detected. They seemed to respond favourably to inhaled beclomethasone dipropionate treatment.

• Respiratory symptoms, bronchial responsiveness, and cellular characteristics of induced sputum in elite swimmers.

  Authors: I J Helenius, P Rytilä, T Metso, T Haahtela, P Venge, H O Tikkanen

  Allergy. 04/1998; 53(4):346-52.

  To investigate respiratory symptoms, increased bronchial responsiveness, and signs of airway inflammation in elite swimmers, we examined 29 swimmers from the Finnish national team and 19 healthyTo investigate respiratory symptoms, increased bronchial responsiveness, and signs of airway inflammation in elite swimmers, we examined 29 swimmers from the Finnish national team and 19 healthy control subjects (nonasthmatic, symptom-free). They answered a questionnaire and were interviewed for respiratory symptoms. Lung volumes were measured and bronchial responsiveness assessed by a histamine challenge test. Induced sputum samples were also collected. Fourteen (48%) of the swimmers and three (16%) of the control subjects showed increased bronchial responsiveness (P<0.05). The sputum cell differential counts of eosinophils (mean 2.7% vs 0.2%) and neutrophils (54.7% vs 29.9%) from swimmers were significantly higher than those from controls (P<0.01). Eosinophilia (sputum differential eosinophil count of >4%) was observed in six (21%) of the swimmers and in none of the controls (P<0.05). Symptomatic swimmers had significantly more sputum eosinophils than did the symptom-free. The concentrations of sputum eosinophil peroxidase (EPO) and human neutrophil lipocalin (HNL) were significantly higher in swimmers than control subjects (P<0.001 and P=0.05). We conclude that elite swimmers had significantly more often increased bronchial responsiveness than control subjects. Sputum from swimmers contained a higher percentage of eosinophils and neutrophils, and higher concentrations of EPO and HNL than sputum from controls. Long-term and repeated exposure to chlorine compounds in swimming pools during training and competition may contribute to the increased occurrence of bronchial hyperresponsiveness and airway inflammation in swimmers.

• A rapid dosimetric method with controlled tidal breathing for histamine challenge. Repeatability and distribution of bronchial reactivity in a clinical material.

  Authors: A R Sovijärvi, L P Malmberg, K Reinikainen, P Rytilä, H Poppius

  Chest. 08/1993; 104(1):164-70.

  A rapid dosimetric method with controlled tidal breathing for histamine challenge was evaluated by assessment of its repeatability, by comparing to a present nondosimetric standard method, and byA rapid dosimetric method with controlled tidal breathing for histamine challenge was evaluated by assessment of its repeatability, by comparing to a present nondosimetric standard method, and by application to adult patients with recent asthma (n = 31), chronic asthma (n = 33), chronic cough (n = 71) or chronic rhinitis (n = 41) and to healthy controls (n = 31). An automatic inhalation-synchronized dosimetric jet nebulizer with a known lung deposition of the aerosol was used to administer histamine and to control breathing. The non-cumulative doses of histamine diphosphate were 0.025, 0.1, 0.4 and 1.6 mg, administered during 0.4 s following tidal inspiration of 100 ml of air. The test procedure required 1 inhalation of histamine 4 mg/ml and followed by 1, 4 and 16 inhalations of histamine 16 mg/ml from the device, and its duration was about 30 minutes. The intraindividual correlation coefficient of the histamine dose causing a reduction of 15 percent in FEV1 (PD15FEV1) on 2 consecutive days in 14 asthmatic subjects was 0.937; the standard error of the single determination was 13 percent of the mean PD15 FEV1. A PD15FEV1 value below 0.4 mg was found only in asthmatic subjects; in chronic asthma, below 0.5 mg; in recent asthma, between 0.1 mg and 1.6 mg or more. In patients with chronic cough and chronic rhinitis, 20 and 32 percent, respectively, the PD15FEV1 values between 0.4 and 1.6 mg, the other patients in these groups were non-responsive. In all healthy control subjects, the PD15FEV1 was over 1.0 mg, 80 percent of them were nonresponsive to the maximum 1.6 mg dose. This new test allows rapid, accurate, and quantitative assessment of bronchial responsiveness to histamine.

• [A rapid dosimetric method for histamine challenge in asthma diagnosis]

  Authors: A Sovijärvi, P Malmberg, K Reinikainen, P Rytilä, H Poppius

  Duodecim; lääketieteellinen aikakauskirja. 02/1993; 109(11):991-8.