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Breath tests cover the fraction of nitric oxide in expired gas ( F eNO ), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for F eNO , 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 F eNO , 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., Competing Interests: Conflict of interest: T. Tonia acts as a methodologist for the European Respiratory Society. Further disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Asthma control, evaluated by symptoms, exacerbations rate and lung function may be greatly influenced by comorbidities, particularly chronic rhinosinusitis (CRS). Measurement of nasal nitric oxide (nNO) is a simple way to assess the severity of CRS. We aimed to analyze the relationship between asthma control and nasal NO. All patients with moderate-to-severe asthma on regular follow-up at our Outpatients' Clinic between November 2009 and April 2010 were included into the study. All patients were evaluated for asthma control by asthma control questionnaire (ACQ) and comorbidities (rhinitis, chronic rhinosinusitis with (CRSwNP) or without nasal polyps, obesity). Exhaled nitric oxide and nNO were obtained in all patients. Eighty-two patients were enrolled (mean age: 48 years, range: 21-80; 42 females). According to ACQ, 53 patients (64.6%) reported controlled asthma. Patients with uncontrolled asthma had lower nNO and higher prevalence of CRSwNP, with a significant correlation between nNO and ACQ. nNO is a biomarker negatively related to asthma control. As low nNO values were associated to CRSwNP, our results indicate that asthma control is highly influenced by this comorbidity.

Exhaled nitric oxide (F(E)NO) represents the only exhaled biomarker that has reached clinical practice even in primary care settings, due to the non-invasiveness of its assessment and ease of repeat measurements, even in patients with severe airflow obstruction. While F(E)NO has been suggested as a readily determined biomarker that can aid in the diagnosis and management of asthma, its potential role in pathophysiology of non-pulmonary diseases is less clear and therefore remains to be established. The purpose of the present review is to highlight the current literature investigating the use of F(E)NO in the diagnosis and management of non-pulmonary diseases.

Background: Exhaled nitric oxide (NO), commonly accepted marker of airways inflammation, may be generated both by specific enzymes, NO synthases, as well as by nonenzymatic reduction in its metabolites. During asthma exacerbations, owing to lower airways pH, it has been reported that nitrite reduction may contribute to the increase in exhaled NO. Allergen exposure, an important cause of asthma exacerbations, is also known to increase exhaled NO., Design: To investigate whether cat allergen exposure of cat-sensitized asthmatics leads to airway acidification, which could explain the expected increase in exhaled NO. Twelve nonsmoking, cat-sensitized patients (nine women) aged 33·5 (22-54) years with mild intermittent asthma performed a cat allergen challenge. Exhaled NO at 50-200 mL s(-1), nasal NO, exhaled breath condensate (EBC) pH, nitrite and nitrate were measured before, 8 and 24 h after allergen challenge., Results: A significant increase in FE(NO 50) was observed 24 h after allergen challenge compared to baseline: 110 ppb (34, 143) vs. 60 ppb (19, 122), P = 0·006. This was mainly explained by an increase in bronchial NO flux (P = 0·02), while no changes in EBC pH were observed (P = 0·35)., Conclusions: Allergen exposure is not associated with airways acidification, implying that the observed increase in exhaled NO is probably because of enzymatic NO production., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Chronic rhinosinusitis (CRS) has been reported to be associated with increased values of exhaled nitric oxide (ENO), which could not be entirely explained by the association between CRS and asthma. The aim of this study was to investigate the variables associated with increased ENO in patients with CRS., Methods: This was a prospective cross-sectional descriptive study of 93 consecutive patients with CRS. The effect on ENO of age, gender, atopy, asthma, respiratory symptoms without bronchial hyperresponsiveness (BHR), and nasal polyps was evaluated by multiple regression analysis., Results: Nasal polyps (P = .01), asthma (P < .001), and respiratory symptoms without BHR (P = .01) were the only independent variables associated with increased ENO. The prevalence of asthma was significantly higher in subjects with nasal polyps (61% vs 29.4%), P = .005, whereas the prevalence of respiratory symptoms without BHR was higher in those without nasal polyps (44.1% vs 15.3%, P = .003). Respiratory symptoms without BHR were associated with significantly higher ENO and prevalence of sputum eosinophilia (eosinophils > 3%) in patients with nasal polyps compared with those without nasal polyps (68.2 vs 24.0 ppb, P = .001; 60% vs 8.3%, P = .03, respectively)., Conclusions: The presence of nasal polyps in patients with CRS was associated with increased asthma prevalence as well as increased ENO levels. Respiratory symptoms without BHR were associated with eosinophilic airway inflammation and increased ENO only in patients with nasal polyps. These findings suggest important clinical and biologic differences between the two types of CRS, with and without nasal polyps.

Background: Hypoxia and snoring-related mechanical trauma contribute to airway inflammation in obstructive sleep apnoea (OSA). Increased exhaled nitric oxide (FENO), an airway inflammation marker, has been reported in OSA patients. We propose the measure of NO in the oral cavity (oNO) as marker of oropharyngeal inflammation in OSA., Methods: We compared oNO and FENO of 39 OSA patients with those of 26 mild asthmatics (ASTHMA), 15 patients with chronic rhinitis or rhinosinusitis (CRS) and 24 healthy subjects. A special device was used for oNO measurement. Apnoea/hypopnoea index (AHI), oxygen desaturation index, mean and nadir SaO2 were calculated from the polysomnography., Results: oNO was significantly increased in OSA (104.2 95%CI 80.2-135.5ppb) as compared to ASTHMA (71.9 95%CI 56.3-91.9ppb; p=0.015), CRS (54.4 95%CI 40.2-73.7ppb; p=0.009) and healthy subjects (63.6 95%CI 59-73ppb; p<0.001). oNO was directly related to AHI (r=0.466, p=0.003) and to minutes slept with SaO2 <90% (r=0.471, p=0.011) and it was inversely related to nadirSaO2 (r=-0.393, p=0.018). FENO was highest in asthmatics (40.3 95%CI 32.5-50.1ppb) and only slightly elevated in OSA (23.1 95%CI 19,8-28.3ppb) and CRS (22.8 95%CI 16.8-32.5ppb)., Conclusions: The finding that oral NO is increased in OSA and is related to upper airway obstructive episodes and to hypoxemia severity, strengthens the clinical and pathogenic role of oral inflammation in OSA.

Background: The relationship between exhaled nitric oxide (FENO) and the diagnosis of asthma in the general adult population is not completely clear., Objectives: To investigate the association between FENO and asthma, after controlling for atopy and rhinitis, in a general population sample of adults (mean age 43 years)., Methods: The cohort of subjects was a sample of subjects who gave their consent to participate in the European Community Respiratory Health Survey II study., Results: Atopy, rhinitis and current asthma were positively and current smoking was negatively associated with FENO. Multivariate analysis showed that asthma had a significant predictive effect on FENO (beta = 0.53; 95% CI 0.21-0.84, p = 0.001), and the increase in FENO was significantly associated with the risk of current asthma (OR = 1.07, 95% CI 1.00-1.14) by the logistic regression model. Receiver-operator characteristic curve showed that FENO >or=18.5 ppb had the best combination of sensitivity (69.2%) and specificity (71%), with a positive predictive value of 24% and a negative predictive value of 95%, for the diagnosis of asthma., Conclusions: Measuring FENO seems to be suitable as an adjunct to questionnaire in the evaluation of asthma in the general population., ((c) 2007 S. Karger AG, Basel.)

Background: Rhinitis and asthma represent the manifestation of one syndrome. Our hypothesis is that in patients with symptoms of persistent rhinitis, lower airway inflammation, lower respiratory symptoms, and lung function abnormalities compatible with asthma are more frequently associated with the diagnosis of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) than with nonallergic rhinitis (NAR)., Methods: One hundred eight of 590 consecutive patients referred in 1 year for rhinitis were enrolled on the basis of nasal symptoms lasting > 4 weeks. Asthma was diagnosed on the basis of symptoms and a positive bronchodilation testing result and/or methacholine hyperresponsiveness. Exhaled nitric oxide (Feno) was measured with the single exhalation method at 50 mL/s., Results: AR was diagnosed in 39%, NAR in 21%, and CRS in 40%. The prevalence of asthma was significantly higher in AR patients (33%) and CRS patients (42%) than in NAR patients (8.7%) [p = 0.036 and p = 0.005, respectively]. Feno was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34 to 54 ppb; and 53 ppb; 95% CI, 42 to 64 ppb; vs 22 ppb; 95% CI, 18 to 27 ppb; p = 0.002 and p = 0.001, respectively). Patients with asthma had Feno values significantly higher than patients without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001)., Conclusions: The diagnostic classification of persistent rhinitis helps to predict lower airway inflammation (increased Feno) and prevalence of asthma: AR and CRS are associated with higher mean Feno values and higher prevalence of asthma than NAR.

Background: Rhinitis is a major risk factor for asthma, so that evaluation of the lower airways is recommended in patients with rhinitis. Exhaled nitric oxide (FE(NO)) is considered a marker of airway inflammation and it has been found to be useful for the screening of patients with suspected diagnosis of asthma. Our aim was to assess the validity and accuracy of FE(NO) to identify patients with asthma in 48 non-smoking patients with persistent rhinitis and asthma-like symptoms., Methods: Asthma was diagnosed on the basis of 12% improvement in FEV1 after salbutamol or a methocholine PD(20)FEV1<800 microg. Prior to lung function FE(NO) was measured with the single exhalation method at 50 ml/s., Results: The geometric mean (95% confidence interval) FE(NO) was significantly higher in the 18/48 asthmatics than in the non-asthmatic patients (60 ppb, CI 95%: 50-89, versus 30 ppb, CI 95%: 28-45, P=0.001). Receiver operating characteristic (ROC) curve for the diagnosis of asthma indicated that FE(NO) is an acceptable discriminator between patients with and without asthma (area under the ROC curve=0.78). None of the asthmatic patients had FE(NO) values<25 ppb and all the patients with FE(NO)>100 ppb (n=5) were asthmatics. The sensitivity and specificity of FE(NO) for detecting asthma, using 36 ppb as cut-off point, were 78% and 60% and the positive and negative predictive values were 54% and 82%, respectively., Conclusions: Measuring FE(NO) may be useful for the screening of rhinitic patients with asthma-like symptoms.

Background: Exhaled nitric oxide (NO) levels may be elevated in patients with liver cirrhosis and autoimmune diseases. Primary biliary cirrhosis (PBC) is often associated with keratoconjunctivitis sicca (Sjogren syndrome [SS]), an extrahepatic autoimmune manifestation. The aim of this study was to evaluate the source of increased exhaled NO (ie, alveolar vs airway) in patients with PBC, whether associated with SS or not, and to evaluate its impact on oxygenation abnormalities., Design: Observational controlled study., Setting: University hospital., Methods: The fractional alveolar NO concentration (FANO) and airway flux of NO (QbrNO) were measured by the multiple flows technique in 34 patients with PBC, 12 with associated SS, and were compared to 20 control subjects and 12 patients with primary SS., Results: FANO was significantly higher in patients with PBC, associated with SS (mean [+/- SEM], 8.9 +/- 0.8 parts per billion [ppb]) or not (mean, 7.7 +/- 0.7 ppb) compared to healthy control subjects (mean, 4.6 +/- 0.5 ppb; p < 0.001) and to patients with primary SS (mean, 4.3 +/- 0.5 ppb; p < 0.001). FANO was significantly higher in cirrhotic patients with increased alveolar-arterial oxygen pressure difference (P[A-a]O(2)) compared to patients with normal P(A-a)O(2) values (9.8 +/- 0.8 vs 7.3 +/- 0.7, respectively; p = 0.018). When compared with control subjects and with patients with PBC not associated with SS, QbrNO was significantly increased in patients with both primary SS and SS associated with PBC., Conclusions: Increased exhaled NO levels found in PBC are from both alveolar and airway sources in patients with associated SS, but only FANO is associated with oxygenation impairment.

Background: Omalizumab may modulate airway remodeling in severe asthma. Using forced expiratory volume in 1 second (FEV1) as a surrogate of airway remodeling, we aimed to investigate if an omalizumab add-on in severe allergic asthma may lead to a persistent reversal of airway obstruction and to evaluate the potential biomarkers of airway obstruction reversibility. Methods: Data were collected before (T0) and after omalizumab add-on for 1 year (T1, 32 patients), 2 years (T2, 26 patients) and 4 years (T4, 13 patients). All patients had baseline FEV1 below 80 % predicted (60.5 ± 12.5 %). After omalizumab, 18 patients showed FEV1 normalization (reversible airway obstruction; RAO+) already at T1 (88.7 ± 14.9 %, p < 0.0001) that persisted up to T4 (83.2 ± 7.9, p < 0.01), while 14 patients (RAO−) had FEV1 persistently decreased, from T1 (65.2 ± 8.4%, p < 0.05) up to T4 (61.4 ± 6.2%, not significant). Both groups had significant improvement of symptoms and exacerbations after omalizumab at T1, which persisted up to T4. The comparison between pretreatment characteristics of the two groups showed that RAO+ patients, had higher values of circulating eosinophils, exhaled nitric oxide (FENO), prevalence of rhinitis and nasal polyps, need of oral corticosteroids, shorter asthma duration, higher FEV1 and response to albuterol test. The optimal cut-off points predicting FEV1 normalization after omalizumab add-on were 30.5 ppb for FENO and 305 cells/µl for eosinophils. Conclusions: This study suggests that omalizumab add-on contributes to the persistent reversal of airway obstruction in a consistent number of patients with severe allergic asthma, and this beneficial effect is predicted by elevated pretreatment FENO and circulating eosinophils. [ABSTRACT FROM AUTHOR]

Introduction: Lung cancer is the second most frequent malignancy worldwide, but its aetiology is still unclear. Inflammatory cytokines and Th cells, including Th17, are now emerging as being involved in NSCLC pathways, thus postulating a role of IL-17 in tumour angiogenesis by stimulating the vascular endothelial growth factor and the release of nitric oxide. Despite the fact that many biomarkers are used for chest malignancy diagnosis, data on FeNO levels and inflammatory cytokines in NSCLC are still few. Our study aimed to evaluate the relationship between pulmonary nitric oxide production and VEGF and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. Methods: FeNO measurement and lung function tests were performed in both patients affected by NCSLC and controls; EBC samples were also taken, and Th1 (IL-1, IL-6, IL-12, IFN-g, TNF-a), Th17 (IL-17, IL-23) and Th2 (IL-4, IL-5, IL-13) related cytokines were measured. Results: Th1 and Th17-related cytokines in EBC, except for IFN-gamma and TNF-alpha, were significantly higher in patients than in healthy controls, whereas no differences were seen for Th2-related cytokines. FeNO at the flow rate of 50 mL/s, JawNO and CalvNO levels were significantly higher in patients affected by NSCLC compared to controls. Significant correlations were found between FeNO 50 mL/s and IL-17, IL-1 and VEGF. JawNO levels positively correlated with IL-6, IL-17 and VEGF. No correlations were found between FeNO and Th2-related cytokines. Conclusion: This is the first report assessing a relationship between FeNO levels and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. IL-17, which could promote angiogenesis through the VEGF pathway, might be indirectly responsible for the increased lung production of NO in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide may be involved in the impaired oxygenation of cirrhotic patients, a condition that improves in most patients after liver transplantation.Objective: To compare oxygenation and nitric oxide concentrations before and after liver transplantation.Design: Before-and-after observational study.Setting: Academic medical center.Patients: 18 patients with cirrhosis and no obvious cardiopulmonary disease who underwent successful orthotopic liver transplantation.Intervention: Orthotopic liver transplantation.Measurements: Blood gas analysis, measurement of exhaled nitric oxide, contrast-enhanced echocardiography, and pulmonary function tests.Results: Before transplantation, the mean (+/- SD) exhaled nitric oxide concentration was higher in patients than in normal controls (13 +/- 4.9 parts per billion [ppb] compared with 5.75 +/- 1.9 ppb; P < 0.001). After transplantation, the alveolar-arterial oxygen gradient significantly decreased (from 17.3 +/- 7.1 mm Hg to 9 +/- 5.2 mm Hg; P < 0.001), as did the exhaled nitric oxide concentration (from 13 +/- 4.9 ppb to 6.2 +/- 2.8 ppb; P < 0.001). The decrease in the exhaled nitric oxide concentration was significantly correlated with the decrease in the alveolar-arterial oxygen gradient (r = 0.56; P = 0.014). Five patients met the criteria for the diagnosis of the hepatopulmonary syndrome before transplantation; the syndrome was cured by transplantation.Conclusions: The correlation between the decrease in exhaled nitric oxide concentration after liver transplantation and the improvement in oxygenation reinforces the hypothesis that nitric oxide is an important mediator of impaired oxygenation in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

An abstract of the study "Pulmonary Artery Pressure and Bronchial Nitric Oxide Flux" by Caterina Bucca and colleagues is presented.