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Rain Jõgi,1 Leena Mattila,2 Mikko Vahteristo,3 Aino Takala,2 Satu Lähelmä,4 Ville A Vartiainen,2 Ari Lindqvist5 1Tartu University Hospital, Lung Clinic, Tartu, Estonia; 2Medical Affairs, Orion Corporation, Espoo, Finland; 3Research Unit of Pulmonary Diseases, Helsinki University Hospital and Helsinki University, Helsinki, Finland; 4Inhalation Platform, Orion Corporation, Espoo, Finland; 5Biostatistics and Data Analytics, Orion Corporation, Espoo, FinlandCorrespondence: Rain JõgiTartu University Hospital, Lung Clinic, Riia 167, Tartu, 50104, EstoniaTel +372 5331 8918Email Rain.Jogi@kliinikum.eeIntroduction: Achieving correct inhalation technique through an inhaler to ensure effective drug delivery is key to managing symptoms in patients with chronic obstructive pulmonary disease (COPD). However, many patients struggle to use their inhalers correctly, with the resultant reduction in therapeutic benefit. Consequently, appropriate inhaler choice is important to maximize clinical benefit. The primary objective of this study was to characterize inspiratory flow parameters across two Easyhaler® inhalers and the HandiHaler® inhaler in patients with COPD and healthy volunteers.Methods: In this randomized, open-label, crossover study, subjects (100 patients with COPD; 100 healthy volunteers) were trained to perform inhalations of placebo powder via two variants of Easyhaler and placebo capsules via the HandiHaler inhalers. Subjects then performed three placebo inhalations through each inhaler in a random sequence. Inspiratory flow parameters were assessed, including peak inspiratory flow (PIF), for each inhaler. A parallel sub-study was conducted in patients with COPD from the main study to assess correct use of the inhalers, patient’s preference, ability to learn to use the inhalers, and the feasibility of the In-Check Dial device to measure PIF values.Results: Mean PIF rates and inspiratory volumes through the three inhalers were similar between patients with COPD and healthy volunteers, and all subjects achieved the 30 L/min PIF required for effective use of Easyhaler. Almost 70% of the 88 patients enrolled in the sub-study used the Easyhaler and HandiHaler inhalers without errors. The Easyhaler was preferred by 51% of patients, while 25% favored the HandiHaler. Teaching the use of both inhalers to almost 70% of patients was very easy. The In-Check Dial PIF values and those obtained via spirometry were strongly correlated (p< 0.0001) for all three inhalers.Conclusion: The respiratory performance of patients with COPD does not appear to be a limiting factor in the use of Easyhaler.Keywords: COPD, crossover study, Easyhaler, HandiHaler, dry powder inhaler, peak inspiratory flow

Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.

Summary Background/aim Monitoring of lung function alone does not adequately identify the high-risk patients among elderly asthma and COPD cohorts. The additional value of Health-Related Quality of Life (HRQoL) development in the detection of patients with a disabling disease in clinical practice is unclear. The aim of this study was to statistically examine the individual development of HRQoL measured using respiratory-specific AQ20 and generic 15D questionnaires. Materials and methods The HRQoL of COPD ( N = 739) and asthma ( N = 1329) patients was evaluated at 0, 1, 2, and 4 years after recruitment. To determine a five-year HRQoL change for each patient we used mixed-effects modelling for linear trend. Results In COPD, the majority (60–80%) of the individuals showed declining trend, whereas in asthma, the majority (46–71%) showed no attenuation in HRQoL. The proportion of constant decliners was estimated higher with the 15D both in asthma (6.3%) and COPD (6.3%) than with AQ20 (3.5 and 4.5%, respectively). The first measurement of HRQoL was found to predict future development of HRQoL. In asthma, obesity-related diseases such as hypertension, diabetes and gastro-esophageal reflux disease best explained the decline, whereas in COPD, age and the level of bronchial obstruction were the main determinants. Conclusion Based on the five-year follow-up, the HRQoL trends significantly diverging from each other could be identified both among the asthma and COPD patients. Compared to cross-sectional HRQoL, the HRQoL trend over a clinically relevant period of time allows us to ignore, to a great extent, the random error of self-assessed HRQoL and thus, it may offer a more accurate measure to describe the disease process.

The continuing rise in asthma prevalence has been questioned, with recent reports suggesting a plateau. To assess a 10-year trend in the age-adjusted prevalence of physician-diagnosed asthma, respiratory and allergic symptoms, and use of asthma medication in the adult population of Helsinki during the Finnish Asthma Programme from 1994 to 2004. Two cross-sectional postal surveys were conducted among random Finnish National Population Registry samples 10 years apart using the same protocol. A total of 6,062 subjects (75.9%) and 2,449 subjects (61.9%) participated in 1996 and 2006, respectively. The prevalence of physician-diagnosed asthma increased from 6.5% in 1996 to 10.0% in 2006 (p

In clinical practice, patients whose airway disease shares features of both asthma and chronic obstructive pulmonary disease (COPD) remain poorly recognized.The study population consisted of 1546 patients with a diagnosis of asthma or COPD or both. Based on patient-reported outcomes and retrospective medical record data, the study population was divided into three groups: ( 1 ) asthma only, ( 2 ) COPD only, and ( 3 ) both asthma and COPD (overlap syndrome group). We evaluated patient characteristics associated with health-related quality of life (HRQoL).In many respects, the overlap group fell between the asthma and COPD groups. In the overlap group, however, HRQoL was the poorest of all. In the logistic regression model, with the asthma group as the reference, both the overlap and the COPD group showed higher risk for low HRQoL [odd ratio (OR): 1.9; 95% confidence interval (CI): 1.2-3.2; and OR: 1.8, 95% CI: 1.0-3.2; respectively]. In addition, female gender, obesity, duration of disease, disability pension, and coexisting cardiovascular disease were associated with low HRQoL across the study population.Patients with overlapping asthma and COPD differed from those patients with asthma or COPD only. Overlap syndrome was associated with low HRQoL.

Background: Elevated fractional exhaled nitric oxide (FENO) associates positively with symptomatic atopy among asthmatics and in the general population. It is, however, unclear whether sensitization to common allergens per se– as verified with positive skin prick tests – affects FENO in healthy individuals. Objective: The aim of this study was to examine the association between FENO and sensitization to common allergens in healthy nonsmoking adults with no signs or symptoms of airway disorders. Methods: FENO measurements (flow rate: 50 mL/s), skin prick tests to common inhalant allergens, structured interviews, spirometry, bronchodilatation tests and bronchial histamine challenges were performed on a randomly selected population of 248 subjects. Seventy-three of them (29%) were nonsmoking asymptomatic adults with no history of asthma, persistent or recurrent upper or lower airway symptoms and no signs of airway disorders in the tests listed above. Results: FENO concentrations were similar in skin prick test positive (n = 32) and negative (n = 41) healthy subjects, with median values of 13.2 and 15.5 ppb, respectively (P = 0.304). No correlation appeared between FENO and the number of positive reactions (r = −0.138; P = 0.244), or the total sum of wheal diameters (r = −0.135; P = 0.254). The nonparametric one-tailed 95% upper limits of FENO among skin prick positive and negative healthy nonsmoking subjects were 29 and 31 ppb, respectively. Conclusions: Atopic constitution defined as positive skin prick test results does not increase FENO in healthy nonsmoking adults with no signs or symptoms of airway disorders. This suggests that same reference ranges for FENO can be applied to both skin prick test positive and negative subjects. Please cite this paper as: Rouhos A, Kainu A, Karjalainen J, Lindqvist A, Piirila P, Sarna S, Haahtela T and Sovijarvi ARA. Atopic sensitization to common allergens without symptoms or signs of airway disorders does not increase exhaled nitric oxide. The Clinical Respiratory Journal 2008; 2: 141–148.

A Phase IV, 4-week, open, randomized multicenter parallel group trial compared correct use and acceptability of Diskus, Turbuhaler, and Easyhaler powder inhalers among 326 inhaler naive asthmatics/symptomatics. The subjects were asked to read the instruction leaflet before taking one dose at the first visit. The correct use was evaluated when the subject took the dose. After that, the subjects were instructed in correct use. The use of the devices was also videotaped at every visit, and independent referees judged correct use. Acceptability was evaluated by a questionnaire. At the first visit, the proportions of subjects who used the devices correctly were as follows: Easyhaler, 45%; Diskus, 43%; and Turbuhaler, 51%. The corresponding figures at the last visit were 84%, 89%, and 81%. The differences at any visit were not statistically significant. Acceptability was greater for Easyhaler and Diskus for three of eight items throughout the study, all pertaining to receiving the powder from the device and control of the inhalation of the powder. Patient education in the use of devices is important, because only half of the subjects used the devices correctly, and still after 4 weeks 10-20% could not use the devices satisfactorily, regardless of which device.

The relationship between oesophageal pressure variation and amplitude variation in the static-charge-sensitive bed (SCSB) ballistocardiogram suggests that changes in intrathoracic pressure can be detected using the SCSB method. We investigated whether amplitude variation in the static-charge-sensitive bed ballistocardiogram (SAV) is related to severity of airway obstruction in patients with asthma and chronic obstructive pulmonary disease. The ability of SAV to detect an increase in airway obstruction induced by histamine challenge was also tested. Twenty-six patients suffering from asthma and 12 patients with chronic obstructive pulmonary disease (COPD) were enrolled in the study. SAV, amplitude from the SCSB ballistocardiogram, respiratory amplitude from the SCSB respiratory wave form and heart rate from the electrocardiogram (ECG) were computed using analysing software (Biorec, Helsinki, Finland) during a 7-min supine rest. SAV was related to forced expiratory volume in one second (FEV1) immediately after signal recording. Asthma patients participated in a standardized histamine challenge test to reveal the effect of acute bronchoconstriction on SAV. An inverse relationship existed between baseline FEV1 and SAV in asthma and COPD. In the histamine inhalation test, FEV1 fell by 0.7 +/- 0.3 l or 26% +/- 11% (P < 0.0001) and SAV increased by 12% +/- 5% (P < 0.0001) in 12 asthma patients. The fall in FEV1 induced by histamine followed regularly and correlated significantly with the rise in SAV (n = 24, r = -0.58, P = 0.002). Changes in respiratory amplitude or heart rate did not explain changes in SAV. SAV may not separate the upper airway obstruction from the bronchial obstruction but it is related to severity of airway obstruction. The clinically significant increase in airway obstruction induced by histamine inhalation increases amplitude variation in SCSB.

Study objective — The study assessed the physiological validity of an automatic thermal stimulation method to induce synchronised oscillations in the neural cardiovascular control system. Design — Automatic alternating rhythmic warm and cool immersion of different skin areas of 18 males was done at different frequencies and water temperatures. The neurally mediated responses to the periodic thermal stimulation were measured from skin blood flow and heart rate and compared to those of a sham stimulation. Respiration was monitored for control purposes. The reproducibility of the stimulation and responses was examined. Subjects — 18 young males volunteered for the study. Measurements and main results — The water bath method produced reproducible thermal stimulation and responses of skin blood flow and heart rate. Rhythmic thermal stimulation at 0.013-0.096 Hz synchronised the oscillations of the forearm skin blood flow when the thermal stimulus amplitude exceeded 10°C. The increase in the stimulus amplitude or enlargement of the stimulus area did not further increase the oscillatory response of skin blood flow. Sham stimulation or mean temperature of the periodic thermal stimulation in the range 23-33°C did not influence the oscillations of skin blood flow. Local cooling of the stimulated lower legs attenuated the response of skin blood flow. Both thermal stimulation and sham stimulation affected heart rate, but no stable synchronisation of the periodic heart rate variability was found at supine rest. Thermal stimulation of the sitting subjects' forearm instead of legs increased the synchronisation of the periodic heart rate variability. Conclusions — The response of skin blood flow agreed with the theory of the thermal entrainment. In a supine man, both thermal stimulation and non-specific central nervous influences induced significant and reproducible interactions with periodic heart rate variability and respiration.

Forced expiratory time (FET) has gained new interest in the joint recommendation of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) for the assessment of spirometry. Interpretation of FET is, however, difficult as limited information is available on spirometric and anthropometric determinants of FET in populations.We studied a non-selected population sample including healthy non-smokers with a structured interview and flow-volume spirometry. Regular medication, if any, was continued. Spirometry of 603 individuals (248 men, 355 women) fulfilled predefined quality criteria based on modified ATS recommendations. FET from the flow-volume curve with the largest sum of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) was used in analyses.The mean FET in the population sample was 10.7 (95% CI 10.4-11.1) s and in healthy non-smokers 9.8 (9.2-10.4) s. Men had on average longer FET (11.3 s versus 10.3 s), but the gender difference was not significant when FEV1/FVC was used as a covariate. FEV1/FVC (r = -0.613, P0.01) and maximal mid-expiratory flow (MMEF) correlated negatively and age (r = 0.279, P0.01), body mass index (BMI) and smoking pack-years positively with FET.The findings indicate that mean FET is around 11 s in a non-selected adult population and around 10 s in healthy non-smokers. FET increases slightly with age and BMI, suggesting age- and weight-related changes in pulmonary mechanics. The negative correlation of FET with FEV1/FVC and MMEF even in healthy non-smokers indicates that airflow limitation, either pathological or physiological, tends to prolong FET.

Study objective – The aim of the study was to investigate the effect of posture on thermally stimulated cardiovascular oscillations. Design – The effect of increased gravitational stress (rising from sitting to standing position) on the thermally stimulated cardiovascular oscillations was measured in young male volunteers. Extensive cardiovascular function data were obtained using a cardiovascular investigation protocol. Subjects – The volunteers were five fit young men, aged 20-21 years. Experiments and main results – Cardiovascular changes from sitting to standing indicated increased sympathetic and decreased parasympathetic influence on heart and skin blood vessels; mean heart rate increased, beat to beat heart rate variability diminished, high frequency periodic heart rate variability decreased, low frequency heart rate oscillations and ratio of low frequency to high frequency heart rate variability increased, mean skin blood flow and oscillations of skin blood flow decreased (all p

Background To examine risk factors for asthma patients’ emergency room (ER) visits in a well organized asthma care setting. Methods A random sample of 344 asthma patients from a Pulmonary Clinic of a University Hospital were followed through medical records from 1995 to 2006. All the ER visits due to dyspnea, respiratory infections, chest pain, and discomfort were evaluated. Results The mean age of the study population was 56 years (SD 13 years), 72% being women. 117 (34%) of the patients had had at least one ER visit during the follow-up (mean 0.5 emergency visits per patient year, range 0–7). Asthma exacerbation, lower and upper respiratory infections accounted for the 71% of the ER visits and 77% of the hospitalizations. The patients with ER visits were older, had suffered longer from asthma and more frequently from chronic sinusitis, were more often ex- or current smokers, and had lower lung function parameters compared to the patients without emergency visits. Previous (HR 1.9, CI 1.3-3.1) and current smoking (HR 3.6, CI 1.6-8.2), poor self-reported health related quality of life (HRQoL) (HR 2.5, CI 1.5-4), and poor lung function (FEV1

Six healthy volunteers received 15 mg midazolam, 50 mg ephedrine, or placebo orally before a 50-minute aerobic treadmill exercise and in a control session. Plasma drug concentrations for pharmacokinetic calculations were estimated from samples drawn up to 24 hours after drug intake. Heart rate, blood pressure, critical flicker fusion test, Maddox wing test, and visual analog scales relating to mood and feelings of tiredness were included in the sessions as pharmacodynamic measures. These tests were made at 35, 55, and 75 minutes and at 2, 2 1/2, 3 1/2, and 5 hours after drug intake. Exercise impaired the absorption of midazolam and counteracted the midazolam-induced decrement in flicker fusion threshold. Whether the effect on flicker fusion was caused mainly by the pharmacokinetic changes or by a general alerting effect of exercise cannot be verified by this experiment. The kinetics of ephedrine was not affected by exercise, but exercise enhanced the tachycardic response to ephedrine and abolished its pressor effect.

Polyvalent killed influenza virus vaccine or saline was administered subcutaneously to 27 asthmatics to investigate the effect of influenza vaccine on respiratory function and on airway responsiveness to inhaled histamine. The patients were adults with mild to moderate asthma. Airway resistance (Raw) and intrathoracic gas volume (ITGV) were measured immediately before and 2, 3 and 21 days after vaccine or saline injection. Raw and ITGV values were used to calculate specific airway conductance (SGaw). Bronchial reactivity was expressed as the provocative dose of histamine diphosphate producing a decrease of 40% in SGaw (PD40). Fourteen (87%) of 16 asthmatics who received killed virus vaccine displayed a significant rise in serum antibody level as measured by single radial haemolysis in gel test. No significant alterations in mean Raw, ITGV and SGaw values were observed after viral vaccination. The median PD40 values for histamine also remained unchanged. However, an increased bronchial reactivity was observed in some patients after administration of virus vaccine or saline. Subclinical natural infection or allergen exposure cannot be excluded as possible causes of the increased airway reactivity in these patients. The side-effects of vaccination were minimal and no more harmful than those produced by saline injection. We conclude that the killed influenza virus vaccine used is effective in boosting serum antibody levels and is suitable for adult asthmatics when prophylactic immunisation is indicated.

Udgivelsesdato: 2008-Oct BACKGROUND: The control of daytime and nighttime symptoms is an important measure of effectiveness of asthma therapy, especially, when administered once-daily. OBJECTIVE: To evaluate the efficacy of evening and morning administrations of mometasone furoate administered via a dry powder inhaler (MF-DPI) 400 microg once-daily (QD) to show equivalence. METHODS: Open-label, randomized, parallel-group study in adult patients with mild to moderate asthma with a > or = 3-month history of ICS use. Patients received MF-DPI 400 microg QD either in the morning (AM) or evening (PM) for 12 weeks. The primary measure was the change in asthma symptoms from baseline to week 12. Secondary outcomes included response to treatment, adherence, inhaler device evaluation, use of rescue medication, urinary cortisol levels, and differential white blood cell count. RESULTS: A total of 1537 patients were randomized; the efficacy population comprised 543 and 479 patients in the MF-DPI QD morning and evening groups, respectively. Mean improvements from baseline in daytime symptom scores at week 12 with morning and evening administration of MF-DPI 400 microg were -0.11+/-0.59 and -0.12+/-0.68, respectively (95% CI, -0.095 to 0.061) and the corresponding improvements in nighttime symptom scores were -0.08+/-0.59 and -0.07+/-0.50, respectively (95% CI, -0.067 to 0.068). Use of rescue medication was the same in both groups (1 puff/day). MF-DPI QD was well tolerated regardless of time of administration. CONCLUSIONS: This open-label study did not identify differences between morning and evening dosing of MF-DPI 400 microg QD. A better effect of evening dosing compared to morning dosing found in previous double-blind placebo-controlled studies could not be confirmed.

Adherence to maintenance therapy is often poor in patients with asthma. Simplifying dosing regimens has the potential to improve both adherence and asthma-related morbidity. In this 12-week, randomized, double-blind, double-dummy, parallel-group study, 617 patients with mild to moderate persistent asthma (mean forced expiratory volume in 1s [FEV1] 78.5% predicted) who were not optimally controlled on inhaled corticosteroids (200-500 microg/day) were randomized to once-daily budesonide/formoterol (80/4.5 microg, 2 inhalations in the evening), twice-daily budesonide/formoterol (80/4.5 microg, 1 inhalation), or a corresponding dose of budesonide once-daily (200 microg, 1 inhalation in the evening). All patients received budesonide (100 microg twice daily) during a 2-week run-in. Changes in mean morning peak expiratory flow (PEF) were similar for od budesonide/formoterol (23.4 l/min) and twice-daily budesonide/formoterol (24.1 l/min), and both were greater than with budesonide (5.5 l/min; both P0.001). Evening PEF, symptom-free days, reliever-free days, and asthma control days were improved with budesonide/formoterol therapy vs. budesonide (P0.05 vs. budesonide for all variables). All treatments were well tolerated. Budesonide/formoterol administered once daily in the evening is a convenient treatment regimen that is as effective in improving asthma control as twice-daily dosing in patients with mild to moderate persistent asthma.