Lauri Lehtimäki

Increased alveolar nitric oxide concentration in asthmatic patients with nocturnal symptoms.

Nocturnal asthma symptoms and impaired lung function at night are related to inflammatory activity in the peripheral lung compartment. Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates can be used to separately assess alveolar and bronchial NO production and inflammation. The authors hypothesised that asthmatic patients with nocturnal symptoms have a higher alveolar NO concentration than those with only daytime symptoms. The authors asked 40 patients with newly-diagnosed steroid-naïve asthma about their nocturnal asthma symptoms through the use of a written questionnaire. Alveolar NO concentration and bronchial NO flux were assessed in the 40 asthmatics and 40 healthy controls. Nineteen of the 40 patients reported nocturnal symptoms. Patients with nocturnal symptoms had a higher alveolar NO concentration (1.7±0.3 (mean±sem) parts per billion (ppb)) than patients without nocturnal symptoms (0.8±0.3 ppb, p=0.012) or healthy controls (1.0±0.1 ppb, p=0.032). Bronchial NO flux was higher both in patients with (2.4±0.4 nL·s−1, p<0.001) and without (2.6±0.4 nL·s−1, p<0.001) nocturnal symptoms, compared to controls (0.7±0.1 nL·s−1). Nocturnal symptoms in asthmatic patients are related to a higher alveolar nitric oxide concentration. The results suggest that assessment of alveolar nitric oxide concentration can be used to detect the parenchymal inflammation in asthmatic patients with nocturnal symptoms.

Inhaled fluticasone decreases bronchial but not alveolar nitric oxide output in asthma

Exhaled nitric oxide (NO) concentration is a noninvasive measure of airway inflammation and is increased in asthma. Inhaled glucocorticoids decrease exhaled NO concentration, but the relative contributions of alveolar and bronchial levels to the decrease in exhaled NO concentration are unknown. Alveolar NO concentration and bronchial NO flux can be separately approximated by measuring exhaled NO at several exhalation flow rates. The effect of steroid treatment on alveolar and bronchial NO output in asthma was studied. Alveolar NO concentration and bronchial NO flux were assessed in 16 patients with asthma before and during treatment with inhaled fluticasone for 8 weeks and in 16 healthy controls. Before the treatment, asthmatics had increased bronchial NO flux (mean+/-SEM: 3.6+/-0.4 versus 0.7+/-0.1 nL x s(-1), p<0.001) but normal alveolar NO concentration (1.2+/-0.5 versus 1.0+/-0.2 parts per billion (ppb), p>0.05) compared with controls. Inhaled fluticasone decreased bronchial NO flux from 3.6+/-0.4 to 0.7+/-0.1 nL x s(-1) (p<0.01) but had no effect on alveolar NO concentration (before: 1.2+/-0.5; after: 1.2+/-0.1 ppb, p>0.05). The forced expiratory volume in one second improved, whereas asthma symptom score and serum levels of eosinophil cationic protein and eosinophil protein X decreased during the treatment. In conclusion, inhaled fluticasone decreases bronchial but not alveolar nitric oxide output simultaneously with clinical improvement in patients with asthma.

Increased bronchial nitric oxide production in patients with asthma measured with a novel method of different exhalation flow rates

The concentration of nitric oxide (NO) in exhaled air is increased in patients with asthma, suggesting that measuring fractional exhaled NO concentration (FENO) may be used to monitor asthmatic airway inflammation. However, increased FENO is not specific for asthma, as other inflammatory lung diseases may also increase FENO. To augment the specificity of FENO measurement, we tested a novel theoretical modelling of pulmonary NO dynamics that allows the approximation of alveolar NO concentration and bronchial NO flux separately by measuring FENO at several exhalation flow rates. We measured FENO at four exhalation flow rates in 10 steroid-naive asthmatics, 5 patients with extrinsic allergic alveolitis, and in 10 healthy controls. Both the asthmatics and the patients with alveolitis had significantly higher FENO than the healthy controls. The increased NO concentration originated from the bronchial level in the asthmatics and from the alveolar level in the patients with alveolitis. In the second part of the study we assessed the repeatability of FENO test, within-day and day-to-day (during two weeks) variation in FENO, and the effects of mouth pressure and cigarette smoking on FENO in healthy volunteers. Repeatability of 10 subsequent measurements was high (coefficient of variation (CV) 4.6% ± 0.4%), and no diurnal variation was found. The day-to-day variation during a 2-week period gave a CV of 10.6% ± 1.0%. The magnitude of mouth pressure (5-20 cmH2O in adults, 5-40 cmH2O in children) during measurement had no effect on FENO. Smoking a cigarette caused a small and transient but statistically significant increase in FENO at 1 and 5 min after smoking. In conclusion, FENO measurement is highly repeatable with low day-to-day variation among healthy subjects. Our results also suggest that the present novel method of measuring FENO at several exhalation flow rates can be used to approximate alveolar and bronchial contributions to FENO separately and thus increase the clinical value of this test.

Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease: The Finnish Guidelines

The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD). The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma–COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short-acting β2-agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol–ipratropium) is recommended in patients with less symptoms. If short-acting bronchodilators are not enough to control symptoms, a long-acting β2-agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting β2-agonist (budesonide–formoterol, beclomethasone dipropionate–formoterol, fluticasone propionate–salmeterol or fluticasone furoate–vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium–indacaterol or umeclidinium–vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting β2-agonist and a long-acting anticholinergic. If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD. Thus, evidence-based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (β2-agonist or anticholinergic or both).

Increased alveolar nitric oxide concentration and high levels of leukotriene B4 and 8-isoprostane in exhaled breath condensate in patients with asbestosis

Background: Inhaled asbestos fibres can cause inflammation and fibrosis in the lungs called asbestosis. However, there are no non-invasive means to assess and follow the severity of the inflammation. Exhaled nitric oxide (NO) measured at multiple exhalation flow rates can be used to assess the alveolar NO concentration and bronchial NO flux, which reflect inflammation in the lung parenchyma and airways, respectively. The aim of the present study was to investigate whether exhaled NO or markers in exhaled breath condensate could be used to assess inflammation in asbestosis. Methods: Exhaled NO and inflammatory markers (leukotriene B4 and 8-isoprostane) in exhaled breath condensate were measured in 15 non-smoking patients with asbestosis and in 15 healthy controls. Exhaled NO concentrations were measured at four constant exhalation flow rates (50, 100, 200 and 300 ml/s) and alveolar NO concentration and bronchial NO flux were calculated according to the linear model of pulmonary NO dynamics. Results: The mean (SE) alveolar NO concentration was significantly higher in patients with asbestosis than in controls (3.2 (0.4) vs 2.0 (0.2) ppb, p = 0.008). There was no difference in bronchial NO flux (0.9 (0.1) vs 0.9 (0.1) nl/s, p = 0.93) or NO concentration measured at ATS standard flow rate of 50 ml/s (20.0 (2.0) vs 19.7 (1.8) ppb, p = 0.89). Patients with asbestosis had increased levels of leukotriene B4 (39.5 (6.0) vs 15.4 (2.9) pg/ml, p = 0.002) and 8-isoprostane (33.5 (9.6) vs 11.9 (2.8) pg/ml, p = 0.048) in exhaled breath condensate and raised serum levels of C-reactive protein (2.3 (0.3) vs 1.1 (0.2) μg/ml, p = 0.003), interleukin-6 (3.5 (0.5) vs 1.7 (0.4) pg/ml, p = 0.007) and myeloperoxidase (356 (48) vs 240 (20) ng/ml, p = 0.034) compared with healthy controls. Conclusions: Patients with asbestosis have an increased alveolar NO concentration and high levels of leukotriene B4 and 8-isoprostane in exhaled breath. Measurement of exhaled NO at multiple exhalation flow rates and analysis of inflammatory markers in exhaled breath condensate are promising non-invasive means for assessing inflammation in patients with asbestosis.

A European Respiratory Society technical standard: exhaled biomarkers in lung disease

Breath tests cover the fraction of nitric oxide in expired gas (FENO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FENO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FENO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management. Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members. Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised. Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice. ERS technical standard: exhaled biomarkers in lung disease http://ow.ly/mAjr309DBOP

Peripheral inflammation in patients with asthmatic symptoms but normal lung function.

Some patients with asthmatic symptoms and eosinophilic airway inflammation have normal lung function and thus do not meet the current diagnostic criteria of asthma. Exhaled nitric oxide (NO) measurement at multiple exhalation flow rates can be used to assess alveolar and bronchial NO output and inflammation. We tested whether alveolar or bronchial NO output is increased in subjects having asthmatic symptoms but normal lung function. Exhaled NO concentration was measured at three exhalation flow rates (100, 175, and 370 mL/s) to assess alveolar NO concentration and bronchial NO flux in 23 patients with asthmatic symptoms but normal lung function (“asthmatic symptoms group”), 40 patients with asthma, and 40 healthy control subjects. The asthmatic symptoms group had increased bronchial NO flux (1.7 ± 0.3 nL/s, p = 0.016) and alveolar NO concentration (1.8 ± 0.2 parts per billiant (ppb), p = 0.010) compared with healthy controls (0.7 ± 0.1 nL/s and 1.0 ± 0.1 ppb, respectively). Patients with asthma had even higher bronchial NO flux (2.5 ± 0.3 nL/s, p = 0.024) but normal alveolar NO concentration (1.1 ± 0.2 ppb, p = 0.664). In asthmatic symptoms group, alveolar NO concentration correlated positively with blood eosinophil count and negatively with small airway function (FEF50% and FEF75%). In conclusion, patients with asthmatic symptoms but normal lung function have increased alveolar NO concentration and mildly elevated bronchial NO flux suggesting a more peripheral inflammation than in patients with asthma.

Adipokine resistin predicts anti-inflammatory effect of glucocorticoids in asthma

BackgroundAdipokines are protein mediators secreted by adipose tissue. Recently, adipokines have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma especially in obese female patients. We assessed if adipokines predict responsiveness to glucocorticoids and if plasma adipokine levels are associated with lung function or inflammatory activity also in non-obese (body mass index (BMI) ≤ 30 kg/m2) women with newly-diagnosed steroid-naïve asthma.MethodsLung function, exhaled NO, plasma levels of adipokines leptin, resistin, adiponectin and adipsin, and inflammatory markers were measured in 35 steroid-naïve female asthmatics and in healthy controls. The measurements were repeated in a subgroup of asthmatics after 8 weeks of treatment with inhaled fluticasone. Adipokine concentrations in plasma were adjusted for BMI.ResultsHigh baseline resistin concentrations were associated with a more pronounced decrease in serum levels of eosinophil cationic protein (ECP) (r = -0.745, p = 0.013), eosinophil protein X (EPX) (r = -0.733, p = 0.016) and myeloperoxidase (MPO) (r = -0.721, p = 0.019) during fluticasone treatment. In asthmatics, leptin correlated positively with asthma symptom score and negatively with lung function. However, no significant differences in plasma adipokine levels between non-obese asthmatics and healthy controls were found. The effects of resistin were also investigated in human macrophages in cell culture. Interestingly, resistin increased the production of proinflammatory factors IL-6 and TNF-α and that was inhibited by fluticasone.ConclusionsHigh resistin levels predicted favourable anti-inflammatory effect of inhaled glucocorticoids suggesting that resistin may be a marker of steroid-sensitive phenotype in asthma. High leptin levels were associated with a more severe disease suggesting that the link between leptin and asthma is not restricted to obesity.

Bronchial nitric oxide is related to symptom relief during fluticasone treatment in COPD

High levels of exhaled nitric oxide (NO) predict favourable response to inhaled corticosteroids in asthma, but the ability of exhaled NO or inflammatory markers in exhaled breath condensate (EBC) to predict steroid responsiveness in chronic obstructive pulmonary disease (COPD) is not known. We measured alveolar and bronchial NO output, levels of leukotriene B4 (LTB4), cysteinyl leukotrienes (cysLTs) and 8-isoprostane in EBC, spirometry, body plethysmography and symptoms in 40 subjects with COPD before and after 4 weeks of treatment with inhaled fluticasone (500 μg b.i.d.). Five subjects (12.5%) with COPD had significant improvement in lung function during fluticasone treatment, whereas 20 subjects (50%) had significant decrease in symptoms. High baseline bronchial NO flux was associated with higher increase in forced expiratory volume in 1 s to forced vital capacity ratio (r = 0.334, p = 0.038) and more symptom relief (r =  -0.317, p = 0.049) during the treatment. Baseline EBC levels of LTB4, cysLTs or 8-isoprostane were not related to response to fluticasone treatment. Inhaled fluticasone decreased bronchial NO flux but not alveolar NO concentration or markers in EBC. High levels of bronchial NO flux are related to symptom relief and improvement of airway obstruction during treatment with inhaled fluticasone in COPD. Markers of inflammation or oxidative stress in EBC are not related to steroid responsiveness in COPD.

Attenuation of TNF production and experimentally induced inflammation by PDE4 inhibitor rolipram is mediated by MAPK phosphatase‐1

3′,5′‐Cyclic nucleotide PDE4 is expressed in several inflammatory and immune cells, and PDE4 catalyses the hydrolysis of cAMP to 5′AMP, down‐regulating cAMP signalling in cells. MAPK phosphatase‐1 (MKP‐1) is an endogenous p38 MAPK signalling suppressor and limits inflammatory gene expression and inflammation. In the present study, we investigated the effect of a PDE4 inhibitor rolipram on MKP‐1 expression and whether MKP‐1 is involved in the anti‐inflammatory effects of rolipram.