Clinical aspects of exhaled nitric oxide in adults : Associations with atopy, bronchial hyperresponsiveness, smoking and chronic obstruction

Measurement of fractional exhaled nitric oxide (FENO) has proven useful in assessment of patients with respiratory symptoms, especially in predicting steroid response. The objective of these studies was to clarify issues relevant for the clinical use of FENO. The influence of allergic sensitization per se on FENO in healthy asymptomatic subjects was studied, the association between airway inflammation and bronchial hyperresponsiveness (BHR) in steroid-naive subjects with symptoms suggesting asthma was examined, as well as the possible difference in this association between atopic and nonatopic subjects. Influence of smoking on FENO was compared between atopic and nonatopic steroid-naive asthmatics and healthy subjects. The short-term repeatability of FENO in COPD patients was examined in order to assess whether the degree of chronic obstruction influences the repeatability. For these purposes, we studied a random sample of 248 citizens of Helsinki, 227 army conscripts with current symptoms suggesting asthma, 19 COPD patients, and 39 healthy subjects. FENO measurement, spirometry and bronchodilatation test, structured interview. skin prick tests, and histamine and exercise challenges were performed. Among healthy subjects with no signs of airway diseases, median FENO was similar in skin prick test-positive and –negative subjects, and the upper normal limit of FENO was 30 ppb. In atopic and nonatopic subjects with symptoms suggesting asthma, FENO associated with severity of exercise- or histamine-induced BHR only in atopic patients. FENO in smokers with steroid-naive asthma was significantly higher than in healthy smokers and nonsmokers. Among atopic asthmatics, FENO was significantly lower in smokers than in nonsmokers, whereas no difference appeared among nonatopic asthmatics. The 24-h repeatability of FENO was equally good in COPD patients as in healthy subjects. These findings indicate that allergic sensitization per se does not influence FENO, supporting the view that elevated FENO indicates NO-producing airway inflammation, and that same reference range can be applied to both skin prick test-positive and -negative subjects. The significant correlation between FENO and degree of BHR only in atopic steroid-naive subjects with current asthmatic symptoms supports the view that pathogenesis of BHR in atopic asthma is strongly involved in NO-producing airway inflammation, whereas in development of BHR in nonatopic asthma other mechanisms may dominate. Attenuation of FENO only in atopic but not in nonatopic smokers with steroid-naive asthma may result from differences in mechanisms of FENO formation as well as in sensitivity of these mechanisms to smoking in atopic and nonatopic asthma. The results suggest, however, that in young adult smokers, FENO measurement may prove useful in assessment of airway inflammation. The short-term repeatability of FENO in COPD patients with moderate to very severe disease and in healthy subjects was equally good.Uloshengitysilman typpioksidi (FENO) on osoittautunut hyödylliseksi menetelmäksi hengitystieoireiden selvittelyssä: koholla olevan FENO-tason on todettu assosioituvan eosinofiiliseen hengitystietulehdukseen, joka puolestaan ennustaa yleensä hyvää vastetta steroidihoidolle riippumatta kliinisestä diagnoosista (esim. astma, keuhkoahtaumatauti tai astman kaltainen tulehdus). Tässä väitöskirjatyössä pyrittiin selventämään FENO-mittauksen kliinisen käytön kannalta keskeisiä kysymyksiä koskien pelkän allergisen herkistymisen (atopian) vaikutusta FENO-tasoon, FENO:n ja keuhkoputkien supistumisherkkyyden yhteyttä sekä tupakoinnin vaikutusta FENO-tasoon atooppisessa ja ei-atooppisessa astmassa, FENO-mittauksen käyttökelpoisuutta tupakoijan hengitystieoireiden selvittelyssä, sekä kroonisen obstruktion vaikutusta FENO-mittauksen toistettavuuteen. Väitöskirjatyön aineisto koostui aikuisikäisen (27-61-v.) helsinkiläisväestön satunnaisotoksesta (n=248), astmaepäilyn vuoksi tutkimuksiin lähetetyistä varusmiehistä (n=227) ja kontrolliryhmästä (n=19) sekä keuhkoahtaumatautia sairastavista potilaista (n=19) ja heidän kontrolliryhmästään (n=20). Tutkimusmenetelminä käytettiin FENO-mittausta, spirometriaa ja bronkodilataatiotestausta, strukturoitua haastattelua, ihopistotestejä (prick-testit), ja keuhkoputkien supistumis¬herkkyyden testausta sekä suoralla (histamiinialtistus) että epäsuoralla (juoksurasitus) menetelmällä. Väitöskirjatyö osoitti, että pelkkä allerginen herkistyminen (ihotesti-positiivisuus) ei nosta FENO-tasoa henkilöllä, jolla ei ole hengityselinsairauksiin viittaavia oireita tai löydöksiä. Tämä havainto tukee käsitystä siitä, että kohonnut FENO-taso viitaa hengitysteiden eosinofiiliseen inflammaatioon. Tutkimuksen perusteella saatiin määritettyä suomalaisen aikuisväestön FENO-viitearvot: viitealueen ylärajan todettiin olevan 30 ppb, ja samoja viitearvoja voidaan käyttää edellä olevaan perustuen sekä atoopikoille että ei-atoopikoille. Typpioksidia tuottavan hengitystie-inflammaation todettiin korreloivan keuhkoputkien supistumisherkkyyteen vain atooppisilla astmaoireisilla henkilöillä, kun taas ei-atooppisilla henkilöillä muut mekanismit ovat tärkeämpiä hyperreaktiviteetin synnylle. Atooppisessa astmassa FENO oli matalampi tupakoivilla kuin tupakoimattomilla, ei-atooppisessa astmassa puolestaan ei eroa näiden ryhmien välillä todettu. Sekä atooppisessa että ei-atooppisessa astmassa tupakoijien FENO-taso oli kuitenkin merkitsevästi korkeampi kuin terveillä, joten FENO-mittausta voidaan hyödyntää myös tupakoijan hengitystieoireita selviteltäessä ainakin nuorilla aikuisilla. Krooninen obstruktio ei heikentänyt FENO-mittauksen toistettavuutta, joten menetelmä on siltä osin käyttökelpoinen myös COPD-potilailla

COPD in Helsinki, Finland: socioeconomic status based on occupation has an important impact on prevalence

Peer reviewe

Bevasitsumabi ei-pienisoluisen keuhkosyövän hoidossa

Edenneen tai levinneen ei-pienisoluisen keuhkosyövän hoito nykyisillä solunsalpaajilla parhaimmillaan vain hidastaa taudin etenemistä, eikä parantavaa hoitoa tunneta. Uusien antiangiogeneettisten lääkkeiden, kuten bevasitsumabin, on odotettu muuttavan taudin hoitoa ja ennustetta. Bevasitsumabista on tehty kaksi satunnaistettua tutkimusta, joissa sen todettiin tehostavan hoitoa yhdistettynä platinasolunsalpaajayhdistelmään valikoidussa potilasryhmässä. Mielestämme nykyinen tutkimusnäyttö ei kuitenkaan puolla bevasitsumabin käyttöä keuhkosyövän standardihoitona. Haittavaikutukset on opittu hallitsemaan hyvin, mutta vielä tulisi pystyä määrittämään se ryhmä hoitoon soveltuvista potilaista, joka hyötyisi merkittävästi. Tämän ryhmän löytämiseksi tarvitaan kliinisten ennustetekijöiden ja mahdollisten biologisten merkkiaineiden tutkimusta. English summary: Bevasizumab in the treatment of non-small cell lung cancer Treatment of advanced or metastatic non-small cell lung cancer with current cytotoxic agents is at its best able to only slow down the progression of the disease, while no curative treatment is known. Novel antiangiogenetic agents such as Bevacizumab have been expected to bring about a change in the treatment and prognosis of this disease. Two randomized studies have been conducted with Bevacizumab, whereby it was observed to make the therapeutic results more effective when combined with a cytotoxic platinum agent in a selected patient group. In our opinion the current scientific evidence does not yet support the use of Bevacizumab as the standard therapy for lung cancer

Parallel gradients in FENO and in the prevalences of asthma and atopy in adult general populations of Sweden, Finland and Estonia : A Nordic EpiLung study

The prevalence of asthma is higher in Sweden and Finland than in neighbouring eastern countries including Estonia. Corresponding difference in bronchial eosinophilic inflammation could be studied by FENO measurements. We aimed to compare FENO in adult general populations of Sweden, Finland, and Estonia, to test the plausibility of the west-east disparity hypothesis of allergic diseases. We conducted clinical interviews (N = 2658) with participants randomly selected from the general populations in Sweden (Stockholm and Örebro), Finland (Helsinki), and Estonia (Narva and Saaremaa), and performed FENO (n = 1498) and skin prick tests (SPT) in 1997–2003. The median (interquartile range) of FENO (ppb) was 15.5 (9.3) in Sweden, 15.4 (13.6) in Finland and 12.5 (9.6) in Estonia. We found the lowest median FENO values in the Estonian centres Saaremaa 13.1 (9.5) and Narva 11.8 (8.6). In the pooled population, asthma was associated with FENO ≥25 ppb, odds ratio (OR) 3.91 (95% confidence intervals: 2.29–6.32) after adjusting for SPT result, smoking, gender and study centre. A positive SPT test increased the likelihood of asthma OR 3.19 (2.02–5.11). Compared to Saaremaa, the likelihood of having asthma was higher in Helsinki OR 2.40 (1.04–6.02), Narva OR 2.45 (1.05–6.19), Örebro OR 3.38 (1.59–8.09), and Stockholm OR 5.54 (2.18–14.79). There was a higher prevalence of asthma and allergic airway inflammation in adult general populations of Sweden and Finland compared to those of Estonia. Atopy and elevated FENO level were independently associated with an increased risk of asthma. In conclusion, the findings support the earlier west-east disparity hypothesis of allergic diseases.Peer reviewe

Associations of airway inflammation and responsiveness markers in non asthmatic subjects at start of apprenticeship

<p>Abstract</p> <p>Background</p> <p>Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma?</p> <p>Methods</p> <p>Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed.</p> <p>Results</p> <p>Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy.</p> <p>Conclusions</p> <p>Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question.</p

A randomized controlled trial to assess the clinical and cost effectiveness of a nurse-led Antenatal Asthma Management Service in South Australia (AAMS study)

Background: Pregnancy presents a unique situation for the management of asthma as it can alter the course of asthma severity and its treatment, which in turn can affect pregnancy outcomes. Despite awareness of the substantial adverse effects associated with asthma during pregnancy, little has been done to improve its management and reduce associated perinatal morbidity and mortality. The aim of this randomized controlled trial is to evaluate the clinical and cost effectiveness of an Antenatal Asthma Management Service. Methods/design: Design: Multicentre, randomized controlled trial. Inclusion criteria: Women with physician diagnosed asthma, which is not currently in remission, who are less than 20 weeks gestation with a singleton pregnancy and do not have a chronic medical condition. Trial entry and randomization: Eligible women with asthma, stratified by treatment site, disease severity and parity, will be randomized into either the ‘Standard Care Group’ or the ‘Intervention Group’. Study groups: Both groups will be followed prospectively throughout pregnancy. Women in the ‘Standard Care Group’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the ‘Intervention Group’ will receive additional care through the nurse-led Antenatal Asthma Management Service, based in the antenatal outpatient clinic. Women will receive asthma education with a full assessment of their asthma at 18, 24, 30 and 36 weeks gestation. Each antenatal visit will include a 60 min session where asthma management skills are assessed including: medication adherence and knowledge, inhaler device technique, recognition of asthma deterioration and possession of a written asthma action plan. Furthermore, subjects will receive education about asthma control and management skills including trigger avoidance and smoking cessation counseling when appropriate. Primary study outcome: Asthma exacerbations during pregnancy. Sample size: A sample size of 378 women will be sufficient to show an absolute reduction in asthma exacerbations during pregnancy of 20% (alpha 0.05 two-tailed, 90% power, 5% loss to follow-up). Discussion: The integration of an asthma education program within the antenatal clinic setting has the significant potential to improve the participation of pregnant women in the self-management of their asthma, reduce asthma exacerbations and improve perinatal health outcomes.Luke E Grzeskowiak, Gustaaf Dekker, Karen Rivers, Kate Roberts-Thomson, Anil Roy, Brian Smith, Jeffery Bowden, Robert Bryce, Michael Davies, Justin Beilby, Anne Wilson, Philippa Middleton, Richard Ruffin, Jonathan Karnon, Vicki L Clifton and for the AAMS study grou

Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with increased oxidative and nitrosative stress. The aim of our study was to assess the importance of these factors in the airways of healthy smokers and symptomatic smokers without airway obstruction, i.e. individuals with GOLD stage 0 COPD. Methods Exhaled NO (FENO) and induced sputum samples were collected from 22 current smokers (13 healthy smokers without any respiratory symptoms and 9 with symptoms i.e. stage 0 COPD) and 22 healthy age-matched non-smokers (11 never smokers and 11 ex-smokers). Sputum cell differential counts, and expressions of inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE) were analysed from cytospins by immunocytochemistry. Eosinophil cationic protein (ECP) and lactoferrin were measured from sputum supernatants by ELISA. Results FENO was significantly decreased in smokers, mean (SD) 11.0 (6.7) ppb, compared to non-smokers, 22.9 (10.0), p Conclusion Our results clearly indicate that several markers of oxidative/nitrosative stress are increased in current cigarette smokers compared to non-smokers and no major differences can be observed in these biomarkers between non-symptomatic smokers and subjects with GOLD stage 0 COPD.</p

Bevasitsumabi ei-pienisoluisen keuhkosyövän hoidossa

Edenneen tai levinneen ei-pienisoluisen keuhkosyövän hoito nykyisillä solunsalpaajilla parhaimmillaan vain hidastaa taudin etenemistä, eikä parantavaa hoitoa tunneta. Uusien antiangiogeneettisten lääkkeiden, kuten bevasitsumabin, on odotettu muuttavan taudin hoitoa ja ennustetta. Bevasitsumabista on tehty kaksi satunnaistettua tutkimusta, joissa sen todettiin tehostavan hoitoa yhdistettynä platinasolunsalpaajayhdistelmään valikoidussa potilasryhmässä. Mielestämme nykyinen tutkimusnäyttö ei kuitenkaan puolla bevasitsumabin käyttöä keuhkosyövän standardihoitona. Haittavaikutukset on opittu hallitsemaan hyvin, mutta vielä tulisi pystyä määrittämään se ryhmä hoitoon soveltuvista potilaista, joka hyötyisi merkittävästi. Tämän ryhmän löytämiseksi tarvitaan kliinisten ennustetekijöiden ja mahdollisten biologisten merkkiaineiden tutkimusta. English summary: Bevasizumab in the treatment of non-small cell lung cancer Treatment of advanced or metastatic non-small cell lung cancer with current cytotoxic agents is at its best able to only slow down the progression of the disease, while no curative treatment is known. Novel antiangiogenetic agents such as Bevacizumab have been expected to bring about a change in the treatment and prognosis of this disease. Two randomized studies have been conducted with Bevacizumab, whereby it was observed to make the therapeutic results more effective when combined with a cytotoxic platinum agent in a selected patient group. In our opinion the current scientific evidence does not yet support the use of Bevacizumab as the standard therapy for lung cancer