Measurement of bronchial hyperreactivity : comparison of three Nordic dosimetric methods

Clinical testing of bronchial hyperreactivity (BHR) provides valuable information in asthma diagnostics. Nevertheless, the test results depend to a great extent on the testing procedure: test substance, apparatus and protocol. In Nordic countries, three protocols predominate in the testing field: Per Malmberg, Nieminen and Sovijarvi methods. However, knowledge of their equivalence is limited. We aimed to find equivalent provocative doses (PD) to obtain similar bronchoconstrictive responses for the three protocols. We recruited 31 patients with suspected asthma and health care workers and performed BHR testing with methacholine according to Malmberg and Nieminen methods, and with histamine according to Sovijarvi. We obtained the individual response-dose slopes for each method and predicted equivalent PD values. Applying a mixed-model, we found significant differences in the mean (standard error of mean) response-dose (forced expiratory volume in one second (FEV1)%/mg): Sovijarvi 7.2 (1.5), Nieminen 13.8 (4.2) and Malmberg 26 (7.3). We found that the earlier reported cut-point values for moderate BHR and marked BHR between the Sovijarvi (PD15) and Nieminen (PD20) methods were similar, but with the Malmberg method a significant bronchoconstrictive reaction was measured with lower PD20 values. We obtained a relationship between slope values and PD (mg) between different methods, useful in epidemiological research and clinical practice.Peer reviewe

Fractional exhaled nitric oxide — F ENO — methodology and application in asthma epidemiology in Northern Europe

In Northern Europe, the prevalence of asthma differs between countries, but an objective clinical comparison of bronchial inflammation is missing. Therefore, we aimed to study the fractional exhaled nitric oxide FENO, a biomarker of airway inflammation, in population samples of the general populations of Sweden, Finland and Estonia. We further aimed to analyse methodological and physiological features of FENO acquisition, such as mouthwashes and dependency of expiratory flow. We performed clinical interviews (n = 2658), FENO (n = 1498) and skin prick tests (SPT) in a random population from Sweden (Stockholm and Örebro), Finland (Helsinki), and Estonia (Narva and Saaremaa), during 1997–2003. To analyse the methodology of FENO, we performed two pilot clinical studies. Firstly, we measured FENO with an expiratory flow rate of 50 mL/s in a small random sample (12 asthmatic or healthy) and acquired a baseline, then repeated measurements (for 20 min) after a mouthwash with tap water or carbonated water. Additionally, we obtained FENO from 30 volunteers for multiple expiratory flow rates of 50, 30, 100 and 300 mL/s, after different mouthwash settings. With this dataset, we analysed the influence of mouthwashes in multiple-flow FENO and developed a conversion model, with a further cross-validation in five populations: healthy adults, healthy children, and patients with chronic obstructive pulmonary disease (COPD), asthma and alveolitis. In the pilot studies, the tap water mouthwash reduced FENO for only 2 min. The mouthwash with carbonated water lowered FENO more notably, for 12 min. Compared to the tap water mouthwash, the carbonated water mouthwash reduced FENO at all expiratory flows — 50, 30, 100 and 300 mL/s. The carbonated water mouthwash also lowered the maximum airway NO flux (_JawNO), but not the alveolar NO concentration (CANO) or capacity of the airways for NO diffusion (DawNO). We developed a non-linear model to perform FENO estimations obtained at different flows. The cross-validation resulted in a low deviation between estimated ^FENO (from 100 mL/s to 50 mL/s) and measured FENO (at 50 mL/s) in children (0.27 ppb), the mixed adult population (0.28 ppb), and in healthy adults (0.44 ppb). The deviation was higher in patients with COPD (1.16 ppb), alveolitis (1.47 ppb), and asthma (1.68 ppb). We applied the non-linear model to standardise the FENO values at 50 mL/s in the epidemiological study. In the population study, the median (interquartile range) of FENO (ppb) was 15.5 (9.3) in Sweden, in Finland 15.4 (13.6), and in Estonia 12.5 (9.6). We found the lowest FENO in Estonian centres —Saaremaa 13.1 (9.5) and Narva 11.8 (8.6). Asthma was associated with FENO≥25 ppb, odds ratio (OR) 3.91 (95% confidence interval: 2.29–6.32) and adjusted for skin prick test (SPT), iv Paul G. Lassmann-Klee smoking, sex and study centre. Atopy increased the likelihood of asthma, OR 3.19 (2.02–5.11). Having asthma was more likely in Stockholm OR 5.54 (2.18–14.79), Örebro OR 3.38 (1.59– 8.09), Helsinki OR 2.40 (1.04–6.02), and Narva OR 2.45 (1.05–6.19), compared to Saaremaa. We conclude that a carbonated water mouthwash reduces oral NO contamination for 12 min, and is more pronounced than tap water, with multiple flows, without affecting CANO or DawNO. We established a model for converting FENO between multiple expiratory flows, with further tentative use of predicting extended flow parameters, _JawNO and CANO. We confirmed the higher prevalence of allergic airway inflammation and asthma in Sweden and Finland, compared to Estonia. An increased FENO and atopy were independently associated with a higher risk of asthma. Our epidemiological findings support the west–east disparity of allergic diseases

Converting FENO by different flows to standard flow FENO

In clinical practice, assessment of expiratory nitric oxide (F-ENO) may reveal eosinophilic airway inflammation in asthmatic and other pulmonary diseases. Currently, measuring of F-ENO is standardized to exhaled flow level of 50 ml s(-1), since the expiratory flow rate affects the F-ENO results. To enable the comparison of F-ENO measured with different expiratory flows, we firstly aimed to establish a conversion model to estimate F-ENO at the standard flow level, and secondly, validate it in five external populations. F-ENO measurements were obtained from 30 volunteers (mixed adult population) at the following multiple expiratory flow rates: 50, 30, 100 and 300 ml s(-1), after different mouthwash settings, and a conversion model was developed. We tested the conversion model in five populations: healthy adults, healthy children, and patients with COPD, asthma and alveolitis. F-ENO conversions in the mixed adult population, in healthy adults and in children, showed the lowest deviation between estimated FENO from 100 ml s(-1) and measured F-ENO at 50 mL s(-1): -0 center dot 28 ppb, -0 center dot 44 ppb and 0 center dot 27 ppb, respectively. In patients with COPD, asthma and alveolitis, the deviation was -1 center dot 16 ppb, -1 center dot 68 ppb and 1 center dot 47 ppb, respectively. We proposed a valid model to convert F-ENO in healthy or mixed populations, as well as in subjects with obstructive pulmonary diseases and found it suitable for converting F-ENO measured with different expiratory flows to the standard flow in large epidemiological data, but not on individual level. In conclusion, a model to convert F-ENO from different flows to the standard flow was established and validated.Peer reviewe