Role of alveolar nitric oxide in gastroesophageal reflux-associated cough: prospective observational study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) measured at multiple exhalation flow rates can be used as a biomarker to differentiate central and peripheral airway inflammation. However, the role of alveolar nitric oxide (CaNO) indicating peripheral airway inflammation remains unclear in gastroesophageal reflux-associated cough (GERC). OBJECTIVES: We aimed to characterize the changes in alveolar nitric oxide (CaNO) and determine its clinical implication in GERC. DESIGN: This is a single-center prospective observational study. METHODS: FeNOs at exhalation flow rates of 50 and 200 ml/s were measured in 102 patients with GERC and 134 patients with other causes of chronic cough (non-GERC). CaNO was calculated based on a two-compartment model and the factors associated with CaNO were analyzed. The effect of anti-reflux therapy on CaNO was examined in 26 GERC patients with elevated CaNO. RESULTS: CaNO was significantly elevated in GERC compared with that in non-GERC (4.6 ± 4.4 ppb versus 2.8 ± 2.3 ppb, p < 0.001). GERC patients with high CaNO (>5 ppb) had more proximal reflux events (24 ± 15 versus 9 ± 9 episodes, p = 0.001) and a higher level of pepsin (984.8 ± 492.5 versus 634.5 ± 626.4 pg/ml, p = 0.002) in sputum supernatant than those with normal CaNO. More GERC patients with high CaNO required intensified anti-reflux therapy (χ2 = 3.963, p = 0.046), as predicted by a sensitivity of 41.7% and specificity of 83.3%. Cough relief paralleled a significant improvement in CaNO (8.3 ± 3.0 versus 4.8 ± 2.6 ppb, p < 0.001). CONCLUSION: Peripheral airway inflammation can be assessed by CaNO measurement in GERC. High CaNO indicates potential micro-aspiration and may predict a necessity for intensified anti-reflux therapy.

Role of CaNO in GERCWhy was the study done? This study aimed to investigate the role of concentration of alveolar nitric oxide (CaNO) as a biomarker for peripheral airway inflammation in patients with gastroesophageal reflux-associated cough (GERC). The evaluation of airway inflammation in GERC has not been widely practiced in clinical settings, and the potential of CaNO as a biomarker remained unclear.What did the researchers do? The researchers conducted a prospective study involving patients diagnosed with GERC and compared the changes in CaNO levels between GERC patients and those with cough due to other causes. The study also identified potential factors contributing to elevated CaNO levels in GERC patients relative to the normal range. Additionally, CaNO level changes were evaluated in a subgroup of GERC patients with initially elevated CaNO levels (n = 26).What did the researchers find? The study found that CaNO levels were significantly increased in GERC patients. Using a reference value for normal CaNO, the GERC patients were divided into a high CaNO cohort and a normal CaNO cohort. More proximal reflux episodes and higher level of pepsin in sputum supernatant were observed in the high CaNO cohort. Moreover, CaNO demonstrated moderate predictive value for the therapeutic efficacy of intensified anti-reflux therapy in GERC patients. After several weeks of anti-reflux therapy, CaNO levels significantly decreased along with the resolution of cough. These findings further confirmed the predictive value of CaNO for anti-reflux therapy.What do the findings mean? The findings suggest that CaNO may have the potential to be used as a non-invasive biomarker for detecting peripheral airway inflammation in GERC patients. Increased CaNO may be associated with potential micro-aspiration. Furthermore, high CaNO may predict the need for intensified anti-reflux therapy.

Associations between fine particulate air pollution with small-airway inflammation: A nationwide analysis in 122 Chinese cities.

Alveolar nitric oxide is a non-invasive indicator of small-airway inflammation, a key pathophysiologic mechanism underlying lower respiratory diseases. However, no epidemiological studies have investigated the impact of fine particulate matter (PM2.5) exposure on the concentration of alveolar nitric oxide (CANO). To explore the associations between PM2.5 exposure in multiple periods and CANO, we conducted a nationwide cross-sectional study in 122 Chinese cities between 2019 and 2021. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched long-term, mid-term, and short-term PM2.5 exposure for 28,399 individuals based on their home addresses. Multivariable linear regression models were applied to estimate the associations between PM2.5 at multiple exposure windows and CANO. Stratified analyses were also performed to identify potentially vulnerable subgroups. We found that per interquartile range (IQR) unit higher in 1-year average, 1-month average, and 7-day average PM2.5 concentration was significantly associated with increments of 17.78% [95% confidence interval (95%CI): 12.54%, 23.26%], 8.76% (95%CI: 7.35%, 10.19%), and 4.00% (95%CI: 2.81%, 5.20%) increment in CANO, respectively. The exposure-response relationship curves consistently increased with the slope becoming statistically significant beyond 20 µg/m3. Males, children, smokers, individuals with respiratory symptoms or using inhaled corticosteroids, and those living in Southern China were more vulnerable to PM2.5 exposure. In conclusion, our study provided novel evidence that PM2.5 exposure in long-term, mid-term, and short-term periods could significantly elevate small-airway inflammation represented by CANO. Our results highlight the significance of CANO measurement as a non-invasive tool for early screening in the management of PM2.5-related inflammatory respiratory diseases.

Alveolar nitric oxide concentration plays an important role in identifying cough variant asthma and assessing asthma control in children.

OBJECTIVE: To study the value of alveolar nitric oxide concentration (CaNO) in the identification and disease control of cough variant asthma. METHODS: A retrospective study was conducted on cough variant asthma (CVA-Group), nonasthmatic cough (NAC-Group) and healthy control children (C-Group) aged 5-12 years. The exhaled nitric oxide and spirometry test results of the three groups were collected and compared. RESULTS: A total of 410 children were included in this study, including 190 in the CVA-Group, 183 in the NAC-Group, and 37 in the C-Group. The CaNO values of the CVA-Group [11.40 ppb (8.48-14.25)] were significantly higher than those of the NAC-Group and C-Group (all p values <.05). The MMEF %pred values of the CVA-Group [63.65 (56.28-73.58)] were significantly lower than those of the NAC-Group and C-Group (all p values <.05). FeNO50, JawNO and other spirometry indices (FVC %pred, FEV1%pred, FEV1/FVC %pred) showed no significant difference among the three groups. ROC curve analysis showed that the optimal cutoff point value of CaNO was 9.45 ppb, corresponding to 0.816 sensitivity and 0.736 specificity. Spearman correlation analysis showed a significant negative correlation between the CaNO measurement and CVA control score. CONCLUSIONS: CaNO can not only help identify CVA early in children aged 5-12 years with chronic cough but is also significantly negatively correlated with the CVA control score.

[Alveolar nitric oxide concentration has a potential value in the diagnosis and differential diagnosis of interstitial lung diseases].

OBJECTIVE: To investigate the value of exhaled nitric oxide (eNO) in the diagnosis and differential diagnosis of interstitial lung disease (ILD). METHODS: This study was conducted among 45 patients with interstitial lung disease, including 18 with connective tissue disease-related ILD (CTD-ILD) and 27 with non-CTD-ILD, with 68 healthy subjects as the control group. According to European Respiratory Association Guidelines, alveolar nitric oxide (CaNO) concentration and fractional exhaled nitric oxide (FeNO) level were measured at the flow rates of 50 and 200 mL/s. The predictive level of CaNO was analyzed using receiver-operating characteristic curve (ROC), and the correlations between CaNO and pulmonary function indicators were examined in the patients with ILD. RESULTS: CaNO, FeNO50, and FeNO200 levels were significantly higher in patients with ILD than in the healthy controls. Logistic regression analysis showed that lowered levels of CaNO and FeNO200 were risk factors for ILD. ROC curve analysis showed that the area under the curve (AUC) of CaNO combined with FeNO200 was 0.829 (95% CI: 0.752-0.906) for the diagnosis of ILD. In patients with ILD, CaNO levels were negatively correlated with DLCO%pred (r=-0.471, P < 0.05). Subgroup comparison showed a significantly higher CaNO level in CTD-ILD group than in non-CTD-ILD group. The AUC for CaNO to discriminate CTD-ILD from non-CTD-ILD was 0.725 (95% CI: 0.576 to 0.875). CONCLUSION: CaNO has a potential value in the diagnosis of ILD and differential diagnosis of CTD-ILD.

Distal Lung Inflammation Assessed by Alveolar Concentration of Nitric Oxide Is an Individualised Biomarker of Severe COVID-19 Pneumonia.

Pulmonary sequelae as assessed by pulmonary function tests (PFTs) are often reported in patients infected by SARS-CoV-2 during the post-COVID-19 period. Little is known, however, about the status of pulmonary inflammation during clinical recovery after patients' discharge from the hospitals. We prospectively measured PFTs coupled with the exhaled nitric oxide (NO) stemming from the proximal airways (FeNO) and the distal lung (CaNO) in 169 consecutive patients with varying degrees of the severity of COVID-19 six weeks to one year after acute infection by SARS-CoV-2. The proportions of patients with abnormal PFTs, defined as the presence of either obstructive/restrictive patterns or impaired lung gas transfer, or both, increased with the severity of the initial lung disease (15, 30, and 52% in patients with mild, moderate, and severe COVID-19). FeNO values remained within normal ranges and did not differ between the three groups of patients. CaNO, however, was significantly higher in patients with severe or critical COVID-19, compared with patients with milder forms of the disease. There was also an inverse relationship between CaNO and DLCO. We conclude that the residual inflammation of the distal lung is still present in the post-COVID-19 follow-up period, in particular, in those patients with an initially severe form of COVID-19. This long-lasting alveolar inflammation might contribute to the long-term development of pulmonary fibrosis and warrants the regular monitoring of exhaled NO together with PFTs in patients with COVID-19.

Clinical implications of concentration of alveolar nitric oxide in asthmatic and non-asthmatic subacute cough.

Asthma is an important cause of subacute cough. The concentration of alveolar nitric oxide (CANO) is a sensitive inflammatory indicator in peripheral airways, and it has received much less attention than the fraction of exhaled nitric oxide (FeNO50). The main objective of this study was to explore the correlation between CANO and clinical parameters in asthmatic and non-asthmatic subacute cough, which might promote understanding of the clinical utility of CANO in these special patient populations. 155 patients with subacute cough were included consecutively, of which 25 were diagnosed as asthmatic. Data for demographic characteristics, FeNO50, CANO, baseline spirometry, bronchial provocation test (or bronchodilation test) and response dose ratio (RDR) were collected. Differences between the asthmatic and non-asthmatic groups were analyzed. Spearman's correlation coefficient (ρ) was used to evaluate the correlation between FeNO50, CANO and other clinical parameters. In patients with subacute cough, baseline CANO values did not differ between asthmatic and non-asthmatic patients (4.4(1.3, 11.4) versus 4.0(2.1, 6.8) ppb,P> 0.05). Besides, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO50. For asthmatic subacute cough, CANO was inversely correlated with FEV1/FVC (ρ= -0.69,P< 0.01) and small airway parameters including MEF25 (ρ= -0.47,P< 0.05) and MMEF (ρ= -0.45,P< 0.05). For non-asthmatic subacute cough, CANO was inversely correlated with MEF25 (ρ= -0.19,P< 0.05) and RDR (ρ= -0.21,P< 0.05). In subacute cough, asthmatic and non-asthmatic patients had similar values of baseline CANO. In both asthmatic and non-asthmatic subacute cough, CANO exhibited a stronger association with pulmonary function parameters when compared with FeNO50. A low CANO value in non-asthmatic subacute cough corresponded to a higher value of RDR, which implied a stronger tendency towards airway responsiveness.

High alveolar nitric oxide is associated with steeper lung function decline in foundry workers.

Occupational dust exposure induces inflammatory responses that often precede the onset of clinical disease. Inflammation in the peripheral part of the lung can be demonstrated by measuring the alveolar NO concentration (CANO) in exhaled breath. The aim of the study was to assess whether cumulative dust exposure affects the change in CANO during follow-up and whether baseline CANO can predict an impairment in lung function during follow-up in foundry workers. We examined 74 dust-exposed and 42 nonexposed foundry workers and measured CANO and lung function at baseline and after 7 years of follow-up. An increase in CANO during the follow-up period was positively associated with cumulative dust exposure in foundry work (p= 0.035). Furthermore, a higher baseline CANO was associated with an accelerated decline in the forced vital capacity (FVC) during the follow-up period (absolute decrease in FVCp= 0.021, relative decrease in FVCp= 0.017). Higher cumulative dust exposure in foundry work is associated with a greater increase in CANO during follow-up, suggesting ongoing pulmonary inflammation in these subjects. Importantly, a high baseline CANO is associated with an accelerated decline in lung function, suggesting that CANO measurements might serve as a screening tool for high-risk workers.

Small airway inflammation is associated with residual airway hyperresponsiveness in Th2-high asthma.

Background: Asthma is characterized by airway inflammation, variable airflow obstruction, and airway hyperresponsiveness (AHR). Generally, AHR takes longer to resolve than does airflow obstruction or clinical symptoms. AHR occasionally persists despite adequate asthma treatment.Objective: To evaluate factors which associates with residual AHR in patients with seemingly remitted airway inflammation.Methods: Patients who exhibited high fractional exhaled nitric oxide (FeNO) levels (>25 ppb) at the first visit (Visit 1) and normalized FeNO levels (<25 ppb) after adequate asthma treatment, including inhaled corticosteroid administration (Visit 2), were analyzed. Patients underwent a blood test, FeNO and small airway/alveolar nitric oxide concentration (CANO) measurements and a methacholine challenge test (continuous inhalation method) at both visits. Clinical indices were compared between patients with and without residual AHR.Results: Fifty patients were analyzed. All exhibited high FeNO levels at Visit 1 [mean, 54.0 ppb (95% confidence interval, 42.4-65.5)] and improvement of FeNO levels at Visit 2 [20.4 (19.2-21.6)] (p < 0.0001). Thirty-three patients (66%) had remission of AHR at Visit 2. No significant differences were observed between patients with and without residual AHR in terms of FeNO levels, lung function parameters and blood eosinophil counts at both visits. CANO level at Visit 2 was the only factor that significantly differed between patients with residual AHR [2.7 (1.9-3.6)] and those who achieved AHR remission [0.8 (0.5-1.0)] (p < 0.0001).Conclusion: Small airway inflammation, as assessed by CANO, was associated with residual AHR in patients with Th2-high asthma.

Alveolar concentration of nitric oxide as a prognostic biomarker in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease leading to respiratory failure and death in 2-5 years from diagnosis. To date, clinical course of disease and prognosis cannot be predicted with an acceptable accuracy. Recently, alveolar concentration of nitric oxide (CaNO) has been proposed as a marker of severity of IPF, but its prognostic value in this setting is unknown. AIM OF THE STUDY: To evaluate the reliability of CaNO as a prognostic biomarker in patients with IPF. METHODS: In the Siena Referral Centre for Interstitial Lung Diseases, multiple-flows exhaled nitric oxide analysis was performed to measure CaNO in a cohort of 88 patients with IPF and in 60 healthy controls. In this population, we evaluate functional disease progression and survival according to the follow-up of our Centre. Clinical, functional and radiological data were collected at baseline to investigate correlations with CaNO levels. RESULTS: IPF patients showed significantly higher levels of CaNO than healthy controls (p < 0.0001); CaNO was significantly correlated with many pulmonary functional parameters. Survival analysis showed that all patients with CaNO ≥6 ppb reported a significantly worse outcome. Disease progression, expressed as FVC time to decline to 10% (TTD10), occurred significantly earlier in patients with CaNO ≥ 9 ppb. CONCLUSION: We confirm that CaNO was significantly higher in IPF patients than in healthy controls and its correlation with functional parameters. Moreover, CaNO ≥6 and ≥9 ppb were significantly correlated with mortality and disease progression, respectively. These data suggest that CaNO, a non-invasive and reproducible biomarker, may predict disease progression and survival outcome in patients with IPF.

Alveolar and Bronchial Nitric Oxide in Chronic Obstructive Pulmonary Disease and Asthma-COPD Overlap. / Óxido nítrico alveolar y bronquial en la enfermedad pulmonar obstructiva crónica y el solapamiento de asma y EPOC (ACO).

INTRODUCTION: Exhaled nitric oxide (FENO) measurements differentiate COPD phenotypes from asthma-COPD overlap (ACO). To date, no study has been conducted to determine whether alveolar and bronchial components differ in this group of patients. METHODS: This was an observational cross-sectional study recruiting ambulatory COPD patients. FENO was measured, differentiating alveolar (CANO) from bronchial (JawNO) components using a multiple-flow technique. CANO and JawNO values were compared between eosinophilic COPD patients (defined as ≥ 300 eosinophils/µL in peripheral blood test, or ≥ 2% eosinophils or ≥ 3% eosinophils), and a linear regression analysis was performed to determine clinical and biological variables related to these measurements. RESULTS: 73 COPD patients were included in the study. Eosinophil counts were associated with increased values of CANO and JawNO (for the latter only the association with ≥ 300 or ≥ 3% eosinophils was significant). CANO was also associated with CRP, and JawNO with smoking. CONCLUSIONS: Patients with COPD and ACO characteristics show increased inflammation in the large and small airways. CANO and JawNO are associated with clinical and biological variables.

Plasma Vascular Endothelial Growth Factor Concentration and Alveolar Nitric Oxide as Potential Predictors of Disease Progression and Mortality in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Declining lung function signifies disease progression in idiopathic pulmonary fibrosis (IPF). Vascular endothelial growth factor (VEGF) concentration is associated with declining lung function in 6 and 12-month studies. Alveolar nitric oxide concentration (CANO) is increased in patients with IPF, however its significance is unclear. This study investigated whether baseline plasma VEGF concentration and CANO are associated with disease progression or mortality in IPF. METHODS: 27 IPF patients were studied (maximum follow-up 65 months). Baseline plasma VEGF concentration, CANO and pulmonary function tests (PFTs) were measured. PFTs were performed the preceding year and subsequent PFTs and data regarding mortality were collected. Disease progression was defined as one of: death, relative decrease of ≥10% in baseline forced vital capacity (FVC) % predicted, or relative decrease of ≥15% in baseline single breath diffusion capacity of carbon monoxide (TLCO-SB) % predicted. RESULTS: Plasma VEGF concentration was not associated with progression-free survival or mortality. There was a trend towards shorter time to disease progression and death with higher CANO. CANO was significantly higher in patients with previous declining versus stable lung function. CONCLUSION: The role of VEGF in IPF remains uncertain. It may be of value to further investigate CANO in IPF.

Techniques for assessing small airways function: Possible applications in asthma and COPD.

In recent years special interest has been expressed for the contribution of small airways in the pathophysiology, clinical manifestations and treatment of asthma and COPD. Small airways contribute little to the total respiratory resistance so that extensive damage of small airways may occur before the appearance of any symptoms, and this is the reason why they are characterized as the "silent zone" of airways. Furthermore, the peripheral localization of the small airways and their small diameter constitutes difficult their direct assessment. Thus, they are usually studied indirectly, taking advantage of the effects of their obstruction, such as premature closure, air trapping, heterogeneity of ventilation, and lung volume dependence of airflow limitation. Today, several heterogeneous methods for the assessment of small airways are available. These can be either functional (spirometry, plethysmography, resistance measurements, nitrogen washout, alveolar nitric oxide, frequency dependence of compliance, flow-volume curves breathing mixture of helium-oxygen) or imaging (mainly through high resolution computed tomography). The above-mentioned methods are summarized in Table 1. However, no method is currently considered as the "gold standard" and it seems that combinations of tests are needed. Furthermore, it is not clear whether the small airways are affected in all patients with asthma or COPD and their clinical significance remains under investigation. Well-designed future studies with large numbers of patients are expected to reveal which of the methods for assessing the small airways is the most accurate, reliable and reproducible, for which patients, and which can be used for the evaluation of the effects of treatment.

Spirometry effects on conventional and multiple flow exhaled nitric oxide in children.

OBJECTIVE: Clinical and research settings often require sequencing multiple respiratory tests in a brief visit. Guidelines recommend measuring the concentration of exhaled nitric oxide (FeNO) before spirometry, but evidence for a spirometry carryover effect on FeNO is mixed. Only one study has investigated spirometry carryover effects on multiple flow FeNO analysis. The objective of this study was to evaluate evidence for carryover effects of recent spirometry on three exhaled NO summary measures: FeNO at 50 ml/s, airway wall NO flux [J'awNO] and alveolar NO concentration [CANO] in a population-based sample of schoolchildren. METHODS: Participants were 1146 children (191 with asthma), ages 12-15, from the Southern California Children's Health Study who performed spirometry and multiple flow FeNO on the same day. Approximately, half the children performed spirometry first. Multiple linear regression was used to estimate differences in exhaled NO summary measures associated with recent spirometry testing, adjusting for potential confounders. RESULTS: In the population-based sample, we found no evidence of spirometry carryover effects. However, for children with asthma, there was a suggestion that exhaled NO summary measures assessed ≤6 min after spirometry were lower (FeNO: 25.8% lower, 95% CI: -6.2%, 48.2%; J'awNO: 15.1% lower 95% CI: -26.5%, 43.0%; and CANO 0.43 parts per billion lower, 95% CI: -0.12, 0.98). CONCLUSIONS: In clinical settings, it is prudent to assess multiple flow FeNO before spirometry. In studies of healthy subjects, it may not be necessary to assess FeNO first.

Inflammatory patterns in asthmatic children based on alveolar nitric oxide determination.

INTRODUCTION: Nitric oxide (NO) levels can be measured at proximal (maximum airway NO flux [J'aw(NO)]) and distal (alveolar NO concentration [C(ANO)]) levels. Four inflammatory patterns have been described in asthmatic individuals, although their relevance has not been well established. The objective was to determine J'aw(NO) and C(ANO) in order to establish four inflammatory categories in asthmatics. MATERIAL AND METHODS: Cross-sectional study of a sample consisting of healthy and asthmatic children. Exhaled NO was determined at multiple flows. J'aw(NO) and C(ANO) were obtained according to the two-compartment model. The asthma control questionnaire (ACQ) and spirometry were administered to asthmatic children. Patients were categorized as type I (normal J'aw(NO) and C(ANO)), type II (elevated J'aw(NO) and normal C(ANO)), type III (elevated J'aw(NO) and C(ANO)) and type IV (normal J'aw(NO) and elevated C(ANO)). Correlation between FE(NO,50), J'aw(NO) and C(ANO) was analyzed using Spearman's R Correlation Test. Analysis of variance and paired comparisons were performed using the Bonferroni correction. RESULTS: One hundred sixty-two children were studied, of whom 49 (32.23%) were healthy controls and 103 (67.76%) asthmatics. In the control subjects, FE(NO,50) (ppb)(median and range) was 11.5 (1.6 to 27.3), J'aw(NO) (pl/s) was 516 (98.3 to 1470) and C(ANO) (ppb) was 2.2 (0.1 to 4.5). Forty-four (42.7%) of the asthmatic participants were categorized as type I, 41 (39.8%) as type II, 14 (13.5%) as type III and 4 (3.88%) as type IV. Good correlation was observed between J'aw(NO) and FE(NO,50) (r=0.97). There was no association between J'aw(NO) and C(ANO). FEV1/FVC decreased significantly in type III (mean 79.8±7.5). Morbidity was significantly higher in types III and IV. CONCLUSIONS: Normal values obtained are similar to those previously reported. Asthmatics with high C(ANO) showed higher morbidity. No correlation was found between proximal and distal inflammation.

Alveolar and exhaled NO in relation to asthma characteristics--effects of correction for axial diffusion.

BACKGROUND: Inflammation in the small airways might contribute to incomplete asthma disease control despite intensive treatment in some subgroups of patients. Exhaled NO (FeNO) is a marker of inflammation in asthma and the estimated NO contribution from small airways (CalvNO ) is believed to reflect distal inflammation. Recent studies recommend adjustments of CalvNO for trumpet model and axial diffusion (TMAD-adj). This study aimed to investigate the clinical correlates of CalvNO , both TMAD-adjusted and unadjusted. METHODS: Asthma symptoms, asthma control, lung function, bronchial responsiveness, blood eosinophils, atopy and treatment level were assessed in 410 subjects, aged 10-35 years. Exhaled NO was measured at different flow-rates and CalvNO calculated, with TMAD-adjustment according to Condorelli. RESULTS: Trumpet model and axial diffusion-adjusted CalvNO was not related to daytime wheeze (P = 0.27), FEF50 (P = 0.23) or bronchial responsiveness (P = 0.52). On the other hand, unadjusted CalvNO was increased in subjects with daytime wheeze (P < 0.001), decreased FEF50 (P = 0.02) and with moderate-to-severe compared to normal bronchial responsiveness (P < 0.001). All these characteristics correlated with increased FeNO (all P < 0.05). Unadjusted CalvNO was positively related to bronchial NO flux (J'awNO ) (r = 0.22, P < 0.001) while TMAD-adjCalvNO was negatively related to J'awNO (r = -0.38, P < 0.001). CONCLUSIONS: Adjusted CalvNO was not associated with any asthma characteristics studied in this large asthma cohort. However, both FeNO and unadjusted CalvNO related to asthma symptoms, lung function and bronchial responsiveness. We suggest a potential overadjustment by current TMAD-corrections, validated in healthy or unobstructed asthmatics. Further studies assessing axial diffusion in asthmatics with different degrees of airway obstruction and the validity of proposed TMAD-corrections are warranted.

Switching from salmeterol/fluticasone to formoterol/budesonide combinations improves peripheral airway/alveolar inflammation in asthma.

BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) in a single inhaler is the mainstay of asthma management. We previously showed that switching from salmeterol/fluticasone combination (SFC) 50/250 µg bid to a fixed-dose formoterol/budesonide combination (FBC) 9/320 µg bid improved asthma control and pulmonary functions, but not fractional exhaled nitric oxide (FeNO), in patients with asthma not adequately controlled under the former treatment regimen. OBJECTIVE: To assess whether switching from SFC to FBC improves peripheral airway/alveolar inflammation in asthma (UMIN000009619). METHODS: Subjects included 66 patients with mild to moderate asthma receiving SFC 50/250 µg bid for more than 8 weeks. Patients were randomized into FBC 9/320 µg bid or continued the same dose of SFC for 12 weeks. Asthma Control Questionnaire, 5-item version (ACQ5) score, peak expiratory flow, spirometry, FeNO, alveolar NO concentration (CANO), and maximal NO flux in the conductive airways (J'awNO) were measured. RESULTS: Sixty-one patients completed the study. The proportion of patients with an improvement in ACQ5 was significantly higher in the FBC group than in the SFC group (51.6% vs 16.7%, respectively, p = 0.003). A significant decrease in CANO was observed in the FBC group (from 8.8 ± 9.2 ppb to 4.0 ± 2.6 ppb; p = 0.007) compared to the SFC group (from 7.4 ± 7.8 ppb to 6.4 ± 5.0 ppb; p = 0.266) although there was no significant difference in the changes in pulmonary functions between the 2 groups. Similar significant differences were found in the CANO corrected for the axial back diffusion of NO (FBC, from 6.5 ± 8.2 ppb to 2.3 ± 2.5 ppb; and SFC, from 4.3 ± 5.3 ppb to 3.9 ± 4.3 ppb). There was no difference in the changes in FeNO or J'awNO between the 2 groups. CONCLUSIONS: Switching therapy from SFC to FBC improves asthma control and peripheral airway/alveolar inflammation even though there is no improvement in pulmonary functions, and FeNO in asthmatic patients.