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The forced oscillation technique can identify a surrogate of closing volume (CVFOT). We investigated its relationship with the one measured by single-breath washout (CVSBW). CVFOT weakly correlates with CVSBW. The respective closing capacities were correlated, but their increases after methacholine challenge in asthmatics did not. Our results suggest that CVFOT is less sensitive than CVSBW to few flow-limited/closed airways but more specific in detecting increases in flow-limited/closed airways involving the majority of the lung.

FEV1 increase usually observed after tHe inhalation of short-acting β2-agonists in asthma patients tends to involve peripheral airways. This study shows that the heterogeneity of responses to short-acting β2-agonists in asthma not only involves distinct sites of bronchodilation, but also distinct sequences between these sites. This indicates that a detailed understanding of the bronchodilator effect of β2-agonists in asthma should not be limited to studying its early impact on FEV1.

Immunoglobulin E (IgE) is the treatment target of omalizumab, a monoclonal antibody indicated in the treatment of severe allergic asthma. Long-term variability of serum total IgE (sIgEtot) in asthmatics remains poorly documented., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Asthmatics have accelerated lung function decline over time compared with healthy individuals. OBJECTIVE: To evaluate risk factors for accelerated lung function decline. METHODS: In a longitudinal analysis on severe asthmatics enrolled in the Belgian Severe Asthma Registry with at least 2 visits a minimum of 12 months apart, we compared characteristics of patients with and without decline (loss of postbronchodilation forced expiratory volume in 1 s [FEV1] (% predicted)/y greater than zero) over time. Multiple linear regression was applied to study the factors independently associated with FEV1 decline. RESULTS: In the overall population (n = 318), median annual FEV1 decline was 0.27 (-4.22 to 3.80) % predicted/y over a period of 23 months (12-41 months). Asthma was less controlled at baseline in nondecliners than in decliners (53%). Lung function and residual volume at baseline were higher in the declining group. Decliners presented with increased bronchial reactivity (ie, a lower provocative concentration of methacholine causing a 20% fall in FEV1) at baseline. Twenty-five percent of nondecliners were started on anti-interleukin-5 (anti-IL-5) for severe eosinophilic asthma during the study compared with 10% of decliners. The multivariable model suggested that Asthma Control Questionnaire score at baseline, late-onset asthma, and addition of anti-IL-5 during follow-up were associated with lower FEV1 decline, independently from other variables such as evolution in exacerbations, smoking status, inhaled corticosteroids or oral corticosteroids dose, or add-on anti-immunoglobulin E over time, whereas reversibility to salbutamol and higher FEV1 were associated with accelerated FEV1 decline. CONCLUSIONS: Add-on therapy with anti-IL-5 in severe eosinophilic asthma was associated with an attenuated FEV1 decline. The causality of this observation should, however, be confirmed in future prospective controlled studies. (C) 2021 American Academy of Allergy, Asthma & Immunology

SCOPUS: le.j, info:eu-repo/semantics/published

We previously documented, in patients with asthma, three different profiles of bronchodilation induced by short-acting β-2 mimetics (SABA), characterized by dilation up to central, preacinar, and intra-acinar airways assessed by ventilation distribution tests and associated with no change, increase, and decrease of fractional exhaled nitric oxide concentration (FENO), respectively. To investigate the dynamics of these profiles over the entire SABA action period, assuming that bronchodilation of proximal and peripheral airways could exhibit varying kinetics due to differences in the distribution of β-2 receptors in both the central and peripheral human airways. FENO, forced expired volume in one second (FEV

Epidemiological studies suggest that patients with asthma are not at an increased risk of severe coronavirus disease 2019 (COVID-19) caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1–3]. Recent studies indicate that the severity of COVID-19 in patients with asthma is likely to depend on multiple factors. A type 2-low asthma phenotype, use of oral corticosteroids and severe asthma could be aggravating factors, while maintenance treatment with inhaled corticosteroids (ICS) and good asthma control are probably protective [4]. However, there is currently scarce information on the risk associated with COVID-19 in subjects with severe asthma and/or the use of biologics. Since eosinopenia is a biomarker for the severity of COVID-19 [5], the eosinophil depletion induced by anti-IL5 and anti-IL5 receptor blocking monoclonal antibodies raises concern in patients and their treating physicians., In a cohort of severe asthma patients, a small number of COVID-19 cases was found; none resulted in death or a very severe disease course. Use of biologics for severe allergic or severe eosinophilic asthma was not associated with a higher risk of COVID-19. https://bit.ly/3ndZmyD

Patients with severe asthma require high-dose inhaled corticosteroids, with or without add-on treatments, to maintain asthma control. Because symptom control remains unsatisfactory in some patients despite these therapies, maintenance therapy with oral corticosteroids (OCS) remains considered a treatment option by physicians. Besides physician-diagnosed exacerbations, many patients intermittently self-medicate with OCS during episodes of worsening symptoms or as a prevention of such episodes. However, long-term OCS use is associated with several comorbidities that may decrease health-related quality of life, worsen prognosis, and should ideally require monitoring and management. In this review, we discuss the adverse effects of OCS use, the OCS-sparing effect of biologics in severe asthma, and the need for optimal referral pathways to ensure the best outcomes for those at-risk asthma patients.PubMed.Studies with results on the OCS-sparing effect of biologics in adult severe asthma were selected.Chronic and intermittent OCS use in asthma is associated with considerable adverse effects in asthma. Omalizumab, mepolizumab, benralizumab, and dupilumab reduce the need for OCS in severe asthma, while also reducing the exacerbation rate and improving several patient-related outcomes.Targeted biologic therapies have revolutionized the treatment of uncontrolled severe asthma by reducing or even eliminating the need for OCS and improving other major outcomes. Novel agents are now rapidly increasing the therapeutic armamentarium, but additional efforts are needed to optimize referral pathways in order to ensure sustainable access to these therapies.

The fraction of exhaled nitric oxide (FENO) in exhaled breath, at the recommended flow of 50 mL/s, reflects the production of NO in the airways in both health and disease. Current understanding of FENO in asthma is that it is a marker of type 2 inflammation, reflecting activation of IL-4 and IL-13 pathways. FENO is helpful in asthma diagnosis, monitoring of inhaled corticosteroid treatment effects and adherence to medication, and for selecting patients for biological treatment. The clinical use of FENO in asthma will likely increase when reference FENO values have been established, and the relationship between FENO and airway caliber is better understood. Nasal NO is useful in the diagnosis of primary ciliary dyskinesia. The devices for measuring FENO are becoming widely available, and the technological advances have led to devices for home monitoring in view of asthma control. This chapter reviews the use of FENO in clinical practice, presents recent advances, and discusses new challenges.

Asthma is a heterogeneous disease with regard to the inflammatory pathways activated. In recent years, biologic drugs (monoclonal antibodies) directed towards specific components of type 2 inflammation have been approved for the treatment of severe asthma. Phenotyping of patients with severe asthma and evaluation of biomarkers have been recommended to help identify patients who are candidates for treatment with biologics and to monitor treatment responses. Fractional exhaled Nitric Oxide (FeNO) is a biomarker of type 2 inflammation in asthma, signaling activation of Interleukin (IL)-4/IL-13 pathway. FeNO could be useful to assess treatment response or identify candidates for a specific drug that acts on type 2 inflammation mechanisms linked to Nitric Oxide (NO) production, such as the IL-4/IL-13 pathway or upstream processes. The value of FeNO as a biomarker predictive of responses to the biologics available for treating severe asthma is discussed based on the published studies at the moment of the review.

SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Exhaled nitric oxide (FENO) is a rather reliable marker of asthma control. Its ability is influenced by airway caliber variation (Michils et al. 2017) and should also be impacted by the type of airway inflammation (i.e. type 2- high vs low). Aim: To assess FENO as a marker of control in patients suffering from type 2-high vs type 2-low asthma, defined by FENO level, taking lung function into account. Methods: At each visit at the outpatient clinic, FEV1, asthma control questionnaire score (ACQ) and FENO were assessed. From patients with at least 4 visits, low (L-NO, 29 patients) and high (H-NO, 21 patients) FENO groups were constituted as having a mean FENO 60ppb. Between consecutive visits (pairs), an improvement or a worsening of control were defined as ΔACQ 0.5. An index β was 0 or 1 if ΔFEV1*ΔFENO =0 (same directions). Ability of FENO to reflect control change was assessed by the area under ROC curve (AUC [95% CI]). Results: AUC significantly differed from 0.5 in H-NO for improvement (0.63 [0.55-0.72]) and worsening (0.60 [0.52-0.70]) and never in L-NO. Considering only pairs with β=0 improved AUC in H-NO for improvement (0.78 [0.67-0.87]) and for worsening (0.81 [0.70-0.91]) and not in L-NO. Discussion: In type 2-low asthma patients, FENO never reflects asthma control. In contrast, FENO predicts control changes in type 2-high asthma patients and its ability is significantly improved when FENO and FEV1 change in opposite directions. Conclusion: FENO utility in asthma management appears maximal in a subgroup of type 2-high asthma patients easily identified by lung function in clinical practice.

Introduction: Severe asthma is a heterogeneous disease with different asthma phenotypes. Since September 2016 add-on treatment with the anti-IL5 monoclonal antibody mepolizumab is reimbursed in Belgium. The aim of this study was to investigate time trends in patient characteristics and comorbidities using data of the prospective BSAR (F. Schleich et al, Respiratory Medicine 2014). Methods: Between June 2009 and September 2017, 571 adult patients with severe asthma were enrolled in the BSAR by 14 Belgian centres. The total population was stratified in two subgroups: 432 patients enrolled before and 139 patients enrolled after September 2016. Results: The demographics, asthma characteristics and comorbidities are shown in table 1. The median blood eosinophil count and the percentage of patients with a blood eosinophil count > 300 mm3/microl were significantly higher in the subgroup enrolled after September 2016. There was a significantly higher prevalence of emphysema, bronchiectasis, nasal polyposis, allergic bronchopulmonary aspergillosis and Eosinophilic Granulomatosis with polyangiitis and a lower prevalence of occupational asthma in the subgroup enrolled after September 2016. Conclusion: We demonstrated time trends in the clinical characteristics of patients with severe asthma and their comorbidities in the BSAR, which might be influenced by the availability of novel biologics.

Abnormal airway reactivity and overproduction of nitric oxide (NO) occurring in small airways have been found in asthma. If the “one airway, one disease” concept is consistent, such dysfunctions should also be detected in the peripheral airways of patients suffering from allergic rhinitis.We investigated whether peripheral airway reactivity and NO overproduction could be documented in distal airways in patients with allergic rhinitis. Exhaled NO fraction (FeNO) and the slope (S) of phase III of the single-breath washout test (SBWT) of helium (He) and sulfur hexafluoride (SF6) were measured in 31 patients with allergic asthma, 23 allergic rhinitis patients and 24 controls, before and after sputum induction. SBWT is sensitive to airway calibre change occurring in the lung periphery.The FeNO decrease was more significant in asthma and rhinitis than in controls (−55.1% and −50.0%, respectively, versus −40.8%) (p=0.007 and p=0.029, respectively). SSF6 and SHe increased in all groups. Change in SHe (ΔSHe) > ΔSSF6 was observed in rhinitis (p=0.004) and asthma (pSF6 = ΔSHe in controls (p=0.431).This study provides evidence of peripheral airway dysfunction in patients with allergic rhinitis quite similar to that described in asthma. Furthermore, a large proportion of the increased NO production reported in allergic rhinitis appears to originate in the peripheral airways.

Changes in airway calibre have the potential to modify exhaled nitric oxide fraction (FENO) values and could hamper how FENO captures changes in asthma control. Here, our objective was to assess whether forced expiratory volume in 1 s (FEV1) variations alter the ability of FENO to reflect asthma control. FENO, asthma control (Asthma Control Questionnaire (ACQ)) and FEV1 were measured at least two times in 527 patients during 1819 pairs of visits. Determinants of FENO–ACQ discordance probability were evaluated through a logistic regression analysis. The effectiveness of FENO at capturing either asthma control worsening or improvement between two visits was then assessed by undertaking a stratified receiver operating characteristic curves analysis. When FEV1 and FENO change in the same direction, the odds of FENO–ACQ being discordant are multiplied by 3 (p, Clinicians must take into account FEV1 changes when using FENO as a marker of asthma control http://ow.ly/XFmp30c4emj

Introduction: Patients with chronic airway disease may present features of both asthma and COPD, commonly referred to as asthma–COPD overlap syndrome (ACOS). Recommendations on their diagnosis are diffuse and inconsistent. This survey aimed to identify consensus on criteria for diagnosing ACOS. Methods: A Belgian expert panel developed a survey on ACOS diagnosis, which was completed by 87 pulmonologists. Answers chosen by ≥70% of survey respondents were considered as useful criteria for ACOS diagnosis. The two most frequently selected answers were considered as major criteria, others as minor criteria. The expert panel proposed a minimal requirement of two major criteria and one minor criterion for ACOS diagnosis. Respondents were also asked which criteria are important for considering inhaled corticosteroids prescription in a COPD patient. Results: To diagnose ACOS in COPD patients, major criteria were “high degree of variability in airway obstruction over time (change in forced expiratory volume in 1 second ≥400 mL)” and “high degree of response to bronchodilators (>200 mL and ≥12% predicted above baseline)”. Minor criteria were “personal/family history of atopy and/or IgE sensitivity to ≥1 airborne allergen”, “elevated blood/sputum eosinophil levels and/or increased fractional exhaled nitric oxide”, “diagnosis of asthma 40 years”; “emphysema on chest computed tomography scan”. Conclusion: Specific criteria were identified that may guide physicians to a more uniform diagnostic approach for ACOS in COPD or asthma patients. These criteria are largely similar to those used to prescribe inhaled corticosteroids in COPD., SCOPUS: ar.j, info:eu-repo/semantics/published

The increased fraction of exhaled nitric oxide (Feno) values observed in asthmatic patients are thought to reflect increased airway inflammation. However, Feno values can be affected by airway caliber reduction, representing a bias when using Feno values to assess asthma control.We sought to determine the effect of changes in both airway caliber and inflammation on Feno values using the allergen challenge model.FEV1 and Feno values were measured during early airway responses (EARs) and late airway responses after challenge with house dust mite allergens in 15 patients with mild allergic asthma. Helium and sulfur hexafluoride (SF6) phase III expired concentration slopes (SHe and SSF6, respectively) from single-breath washout tests were measured to identify sites of airway constriction.In EARs, FEV1 and Feno value decreases reached 36.8% and 22%, respectively (P.001). ΔSHe was greater than ΔSSF6 (+189.4% vs +82.2%, P = .001). In late airway responses FEV1 and Feno value decreases reached 31.7% and 28.7%, respectively (P.001), with the same ΔSHe and ΔSSF6 pattern (+155.8% vs +76%, P = .001). Eight hours after the EAR, FEV1 was still decreased (P.001), whereas Feno values had returned to baseline. At 24 hours, FEV1 had returned to baseline, with Feno values increased by 38.7% (P = .04).In patients with mild allergic asthma, airway caliber changes modulate changes in Feno values resulting from airway inflammation. Therefore Feno should no longer be considered solely an inflammation biomarker but rather a biomarker that integrates both airway inflammation and lung function changes. Furthermore, early and late phases resulting from allergen exposure were shown to involve similar lung regions.

The fraction of NO in exhaled air (FeNO) is a marker of inflammation in asthma. The aim of the present study was to assess, in a real-world setting, whether only high (⩾50 ppb) FeNO levels predict improvement in asthma control when being treated with inhaled corticosteroids (ICS), as suggested by current guidelines on the clinical use of FeNO.FeNO and asthma control were assessed in a retrospective observational study in 153 non-smoking, steroid-naïve, adult subjects with asthma with a mean age of 40 years both before and after 6 weeks (median follow-up time) of treatment with 500 μg beclomethasone (median).Having at the initial visit intermediate FeNO (⩾25 and50 ppb) and high FeNO (⩾50 ppb), compared to normal FeNO (25 ppb), were associated with a larger proportion of subjects achieving an improvement of Asthma Control Questionnaire (ACQ) score with ⩾1 (78% and 67% vs 43%, p0.05) or both ⩾1 improvement and asthma control at follow-up (31% and 37% vs 4%, p0.05). These associations were consistent in multiple logistic regression models after adjustments for confounders.It is not only high but also intermediate FeNO levels that are associated with a significant improvement in asthma control after starting ICS treatment. This challenges current clinical guidelines stating that only high FeNO levels predict response to ICS treatment.

RATIONALE Besides its role as an inflammatory marker in asthma, fractional exhaled nitric oxide (FENO) provides information on the extent of the airway obstruction process through evaluating its change after bronchodilation. OBJECTIVE To investigate whether FENO change after bronchodilation can identify different sites of airway obstruction in COPD patients. METHODS FENO, FEV1 and the slopes (S) of the alveolar plateau of the single breath washout test (SBWT) were measured in 61 stable COPD patients (FEV1 34.5% predicted) before and after the inhalation of 400 μg salbutamol. SBWT used Helium (He), and sulfur-hexafluoride (SF6). Obstruction relief occurring in pre-acinar and intra-acinar small airways is expected to decrease SHe and SSF6, respectively. Indices changes (Δ) after bronchodilation were expressed as a percentage of pre-bronchodilation values. RESULTS FENO stability (∣ΔFENO∣ ≤ 11%) was observed in 19 patients [-2.7(6.7)%] [mean (SD)] (NO = group); ΔFENO > 11% [+37.4(27.7)%] in 20 patients (NO+ group) and ΔFENO

Long-term variability of serum total IgE (sIgE tot ) has been reported in asthmatics. This study evaluates the dynamics and the factors predictive of this variability. sIgE tot levels were prospectively measured over 1 year in 41 moderate-to-severe asthmatics treated with high-dose of inhaled corticosteroids and long-acting β 2 agonists (and untreated with omalizumab). Patients were divided into 3 groups according to their baseline sIgE tot level: low (≤75 IU/mL; n=10), intermediate (76-700 IU/mL; n=20) or high (>700 IU/mL; n=11). The sIgE tot variability and factors predictive of IgE tot variability were studied. The mean sIgE tot (whole group) fluctuated over 1 year and showed an overall non-significant decrease from baseline ( p =0.21). Four to 29% of the sIgE tot variability depended on within-patient variability. No factor predictive of the within-patient variability was identified in the intermediate sIgE tot group. In the low sIgE tot group, however, the level of sIgE tot increased over 1 year in patients exposed to allergens ( p p =0.011), and the odds of having an exacerbation since the previous visit increased by 30% if sIgE tot increased by 100 IU/mL ( p tot group, the odds of having an exacerbation since the previous visit decreased by 5% if sIgE tot increased by 100 IU/mL ( p =0.005). These trends should be confirmed in a bigger cohort. In this small cohort of moderate-to-severe asthmatics, a limited within-patient variability of sIgE tot levels was observed over 1 year. This variability depended on allergen exposure, OCS use (probably related to exacerbation management) and exacerbations in patients with low and high baseline sIgE tot .

Background: We showed that FENO remains stable, increases or decreases in asthma patients 209 min after salbutamol (SABA) inhalation depending on the site of bronchoconstriction relief: up to central, pre-acinar and intra-acinar airways respectively (A. Michils JACI-In press). This may impact the use of FENO in asthma management if these effects are prolonged all over the period of SABA action. Aim: To evaluate the FENO changes induced by SABA in asthma patients over 4 hours. Methods: FENO, FEV 1 , and the slope (S) of phase III of He, and SF 6 from a single-breath test were measured in stable asthma patients (n=17)before and up to 4 hours after SABA (400µg). S He and S SF6 decrease reflects pre- and intra-acinar obstruction relief respectively. Results: Patients (4F/13M, age: 51±18 years) were divided in groups with positive (FENO+, n=9) and negative (FENO-, n=8) FENO change at 209 after SABA inhalation, compared to baseline. Discussion: At 209, we confirm a dilation up to pre- and intra acinar airways in the FENO+ and FENO-, respectively. After 4 hrs, FENO still slightly increased for both groups, indicating that SABA use should be stopped 4 hrs prior FENO measurement. The results also suggest that, in the FENO- group, the early dilation of acinar airways fades away in favour of a late dilation of pre-acinar airways indicating a different duration of the proximal and peripheral SABA effects.

Omalizumab (OMA) (Xolair ® ) is an anti-IgE monoclonal antibody indicated for the maintenance treatment of persistent severe allergic asthma (PSAA). OMA treatment requires (once/twice) monthly injections causing concerns for persistence and adherence to treatment; hereto, the long-term use of OMA was studied in a real-life setting. A prospective observational study was conducted over 120 weeks in 50 PSAA patients treated with OMA. As from week 16 (evaluation time point for clinical response to OMA), the persistence to treatment, the appointment adherence and the OMA effectiveness were evaluated. OMA effectiveness was defined as a change ≥0.5 point from week 0 in asthma quality of life questionnaire (AQLQ) total score (or sub-score); and/or an absence of severe exacerbation; and/or a reduction in oral corticosteroid use. At least 92% of the patients (46/50) were responders to OMA at week 16. From these 46 responders, 39 (85%), 33 (72%), 31 (67%) and 30 (65%) were persistent to treatment at week 52, 68, 104 and 120, respectively (all p from visit-to-visit p >0.05 from week 16 to week 52, then all p from visit-to-visit p from visit-to-visit >0.05). In this limited cohort of PSAA patients, initial persistence and adherence to OMA treatment were high in real-life. Subsequently, physicians and patients must optimize long-term persistence and adherence, as OMA proved effectiveness over 120 weeks in most patients.

Background: We have shown that the change of exhaled nitric oxide (FENO) after bronchodilation allows to identify the site of airway obstruction in asthma: FENO stability, increase, or decrease reflects obstruction relief by bronchodilation up to central, pre-acinar and intra-acinar airways (1). Aim: To investigate whether FENO change after bronchodilation is able to identify different sites of airway obstruction in COPD patients. Methods: FENO, FEV 1 , and the slope (S) of phase III of He, and SF 6 from a single-breath test were measured in 41 stable COPD patients with median(range) FEV1 of 48(20-78)%predicted before and 20 minutes after inhalation of 400 µg salbutamol. S He and S SF6 decrease reflects pre- and intra-acinar obstruction relief respectively. Changes (Δ) were expressed as a percentage of baseline. Results: No FENO change (|ΔFENO|≤10%) was found in 8 patients [-1.7 (7.7)%] [mean (SD)] (FENO=); ΔFENO>10% [+44 (38)%] was found in 18 patients (FENO+) and ΔFENO 1 (p=0.445; [+10 (8)%]). In FENO= and FENO+ groups, neither S He nor S SF6 changed, whereas in FENO- both S He [-25(25)%, p SF6 [-26 (23)%, p Conclusion: Three FENO behaviours were observed in response to β2-agonists in COPD patients: a decrease likely due to relief of an intra-acinar airway obstruction; an increase or a stability associated with a more proximal dilation. These preliminary results suggest that FENO might be useful to assess the sites of obstruction that appear to differ among COPD patients. (1) Michils A et al. J Allergy Clin Immunol (In press).

BACKGROUND: Nitrogen (N2) single breath washout (SBW) and Forced Oscillation Technique (FOT) are sensitive to airway closures and choke points by different physical mechanisms. AIM: to characterize SBW and FOT in healthy and asthmatics pre and post methacholine challenge (Mch) and to compare the information provided by the two approaches. METHODS: Lung function was evaluated in 13 healthy subjects (9F/4M, 46±13years) and 12 stable asthmatics (7F/3M, 37±13years) by SBW and within-breath FOT at 5, 11 and 19Hz. Closing volume (CV N2 ) and the slope of phaseIII (SIII) from SBW were identified by a blinded expert. Resistance (R 5 ), reactance (X 5 ) and frequency dependence of resistance (R 5 -R 19 ) were measured during quiet breathing and during a slow vital capacity maneuver (SVC). CV FOT was defined as the volume corresponding to X 5 =-7 cmH2O*s/l during SVC. Asthmatics were studied also post Mch at 20% fall in FEV 1 . RESULTS: No differences in FOT and SBW parameters were found between healthy and asthmatics pre-Mch. However, all of them changed significantly in asthmatics after Mch, with CV FOT showing the biggest change for all the patients (minimal change=103% vs -3% in CV N2 ; 8% in SIII; 22% in R 5 ; 48% in X 5 and 75% in R 5 -R 19 ). pIII N2 correlates with all FOT parameters while CV N2 showed only a weak correlation with CV FOT (Spearman, p=0.04). CONCLUSION: CV FOT might be useful to assess in a more accurate and sensitive way the response to bronchial challenge.

Background It has been claimed that exhaled nitric oxide (FeNO) could be regarded as a surrogate marker for sputum eosinophil count in patients with asthma. However, the FeNO threshold value that identifies a sputum eosinophil count $3% in an unselected population of patients with asthma has been poorly studied. Methods This retrospective study was conducted in 295 patients with asthma aged 15e84 years recruited from the asthma clinic of University Hospital of Liege. Receiver-operating characteristic (ROC) curve and logistic regression analysis were used to assess the relationship between sputum eosinophil count and FeNO, taking into account covariates such as inhaled corticosteroids (ICS), smoking, atopy, age and sex. Results Derived from the ROC curve, FeNO $41 ppb gave 65% sensitivity and 79% specificity (AUC¼0.777, p¼0.0001) for identifying a sputum eosinophil count $3%. Using logistic regression analysis, a threshold of 42 ppb was found to discriminate between eosinophilic and non-eosinophilic asthma (p

Background: Characterizing the interactions between the upper and lower airways is important for the management of asthma. This study aimed at assessing the specific impact of concomitant rhinitis on asthma-related quality of life (QOL) and asthma control. Methods: A cross-sectional, observational survey was conducted among 1173 patients with asthma (aged 12-45) recruited by general practitioners and chest physicians. AR was defined by self-reported rhinitis symptoms and previously documented sensitization to inhalant allergens. The primary outcomes were (1) asthma control assessed by the Asthma Control Questionnaire (ACQ) and (2) asthma-specific QOL evaluated through the Mini Asthma Quality of Life Questionnaire (mAQLQ). Results: AR was present in 73.9% of the population with asthma and nonallergic rhinitis (NAR) in 13.6%. AR and NAR were associated with an increased risk of uncontrolled asthma (i.e. ACQ score > 1.5) with adjusted odds ratios (OR) of 2.00 (95% confidence interval [CI]: 1.35-2.97) and 1.77 (95%CI: 1.09-2.89), respectively. Multivariate linear regression analysis showed that AR and NAR had a modest, although significant, negative impact on the global mAQLQ score (beta coefficient: -0.293, standard error [SE]: 0.063 and beta coefficient: -0.221, SE: 0.080, P < 0.001, respectively), even after adjustment for the level of asthma control and demographic characteristics. Conclusion: This survey provides direct evidence that AR and NAR are associated with an incremental adverse impact on the disease-specific QOL of patients with asthma and the level of asthma control. Further investigations are required to determine whether appropriate treatment of rhinitis would efficiently reduce asthma morbidity.

Exhaled nitric oxide fraction (F(eNO)), which is a reliable marker of eosinophilic airway inflammation, is partially suppressed by tobacco smoking. Consequently, its potential as a biomarker in asthma management has never been evaluated in smoking patients. In the present study, the authors tested the validity of F(eNO) to predict asthma control in this population. F(eNO) and the Asthma Control Questionnaire (ACQ) were recorded at least once in 411 nonsmoking (345 with at least two visits) and 59 smoking (51 with at least two visits) asthma patients. Despite similar mean ACQ scores (1.5 versus 1.7), F(eNO) was reduced in smoking asthmatics (18.1 ppb versus 33.7 ppb). A decrease in F(eNO) of

Alveolar nitric oxide (NO) concentration (FaNO), increasingly considered in asthma, is currently interpreted as a reflection of NO production in the alveoli. Recent modeling studies showed that axial molecular diffusion brings NO molecules from the airways back into the alveolar compartment during exhalation (backdiffusion) and contributes to FaNO. Our objectives in this study were 1) to simulate the impact of backdiffusion on FaNOand to estimate the alveolar concentration actually due to in situ production (FaNO,prod); and 2) to determine actual alveolar production in stable asthma patients with a broad range of NO bronchial productions. A model incorporating convection and diffusion transport and NO sources was used to simulate FaNOand exhaled NO concentration at 50 ml/s expired flow (FeNO) for a range of alveolar and bronchial NO productions. FaNOand FeNOwere measured in 10 healthy subjects (8 men; age 38 ± 14 yr) and in 21 asthma patients with stable asthma [16 men; age 33 ± 13 yr; forced expiratory volume during 1 s (FEV1) = 98.0 ± 11.9%predicted]. The Asthma Control Questionnaire (Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Chest 115: 1265–1270, 1999) assessed asthma control. Simulations predict that, because of backdiffusion, FaNOand FeNOare linearly related. Experimental results confirm this relationship. FaNO,prodmay be derived by FaNO,prod= (FaNO− 0.08·FeNO)/0.92 ( Eq. 1 ). Based on Eq. 1 , FaNO,prodis similar in asthma patients and in healthy subjects. In conclusion, the backdiffusion mechanism is an important determinant of NO alveolar concentration. In stable and unobstructed asthma patients, even with increased bronchial NO production, alveolar production is normal when appropriately corrected for backdiffusion.

The flow cytometric basophil activation test (BAT), based on the detection of allergen-induced CD63 expression, has been proved effective in the diagnosis of various IgE-mediated allergies. However, there is not yet consensus about the suitability of CD203c expression as a specific basophil activation marker and its diagnostic reliability. The goal of the present study was to compare measurement of CD63 and CD203c expression using BAT in a model of cat allergy and to determine optimal experimental conditions for both markers. Heparinized whole blood samples from 20 cat allergic patients and 19 controls were incubated with Fel d1 (relevant allergen) or anti-FcepsilonRI (positive control) either in IL-3 or IL-3-free conditions. An optimal gating of basophils was achieved in triple staining protocols: anti-IgE PE/anti-CD45 PerCP/anti-CD63 FITC or anti-IgE FITC/anti-CD45 PerCP/anti-CD203c PE. We demonstrated that IL-3 significantly enhanced CD63-induced expression by basophils obtained from cat allergic patients in response to Fel d1. Sensitivity was found to be 100%. The CD203c protocol, when performed under IL-3-free conditions, also demonstrated 100% sensitivity. Only one of the control subjects was positive in both tests. In conclusion, using well-defined experimental conditions, the measurement of CD203c up-regulation on basophils in response to specific allergens is as reliable as CD63-BAT for the in vitro diagnosis of patients with IgE-mediated allergy.

Background: Induced sputum (IS) is considered as the gold standard non invasive technique to assess airway inflammation. So far, the impact of the procedure on peripheral airways function is unknown. Aim: to assess whether IS procedure is associated with airways alterations using both ventilation distribution test (single-breathwashout, SBWO) and exhaled nitric oxide (FENO) as markers of peripheral airway impairment. Methods: We measured, before and after 209 of induction with hypertonic saline, FEV 1 , FENO and the phase III slope (S) of the SBWO, using gases with different diffusivities, helium (He) and sulfur hexafluoride (SF 6 ), in 17 asthma patients, 10 rhinitis subjects and 13 healthy subjects. Results: After nebulisation, all changes (Δ in %baseline) were significant except for FEV 1 in healthy subjects. ΔS He >ΔS SF6 in rhinitis (+184±198 vs 123±123%; p=0.008) and in asthma (+92±55 vs +49±36%; p=0.016) whereas ΔS He = ΔS SF6 in healthy subjects (83±70 vs 100±80%; p=0.953). ΔFENO is larger in rhinitis (-56±14%, p=0.006) and in asthma (-56%±11%, p=0.001) than in healthy subjects (-36±13%). ΔFEV 1 is greater in asthma patients (-19±14%) than in rhinitis (-6±3%, p=0.005) and in normal subjects (-6±9%; p=0.039). Discussion: SI resulted in airway alterations in the 3 subjects categories. However, the impairment location appears to be different: proximal and up to lung periphery in asthma while restricted mostly to small airways in healthy and allergic subjects. Conclusion: SI impacts peripheral airways in all subjects tested in this study. However, asthma patients differ from all other subjects by an additional response in more proximal airways.

Background In asthmatic patients undergoing airway challenge, fraction of exhaled nitric oxide (Feno) levels decrease after bronchoconstriction. In contrast, model simulations have predicted both decreased and increased Feno levels after bronchodilation, depending on the site of airway obstruction relief. Objective We sought to investigate whether β 2 -agonists might induce divergent effects on Feno values in asthmatic patients as a result of airway obstruction relief occurring at different lung depths. Methods Feno, FEV 1 , and the slope of phase III of the single-breath washout test (S) of He (S He ) and sulfur hexafluoride (S SF6 ) were measured in 68 asthmatic patients before and after salbutamol inhalation. S He and S SF6 decreases reflected preacinar and intra-acinar obstruction relief, respectively. Changes (Δ) were expressed as a percentage from the baseline. Results No Feno change (|ΔFeno| ≤ 10%) was found in 16 patients (mean [SD]: 2.5% [5.2%]; ie, Feno=group); a ΔFeno value of greater than 10% was found in 23 patients (31.7% [20.3%]; ie, the Feno+ group); and a ΔFeno value of less than −10% was found in 29 patients (−31.5% [17.3%]; ie, the Feno− group). All groups had similar ΔFEV 1 values. In the Feno=group neither S He nor S SF6 changed, in the Feno+ group only S He decreased significantly (−21.8% [SD 28.5%], P = .03), and in the Feno− group both S He (−29.8% [24.0%], P SF6 (−27.2% [23.3%], P Discussion Three Feno behaviors were observed in response to β 2 -agonists: a decrease likely caused by relief of an intra-acinar airway obstruction that we propose reflects amplification of nitric oxide back-diffusion, an increase likely associated with a predominant dilation up to the preacinar airways, and Feno stability when obstruction relief involved predominantly the central airways. In combination, these results suggest a new role for Feno in identifying the site of airway obstruction in asthmatic patients.

Summary Asthma guidelines support adjustable maintenance dosing and the use of guided self-management for long-term asthma management and advocate the use of inhaled corticosteroids and long-acting β2-agonists to control symptoms. In this context, budesonide/formoterol in a single inhaler may be used with either a fixed-dosing or adjustable maintenance dosing treatment regimen. Eight randomised studies compared the efficacy and tolerability of budesonide/formoterol adjustable maintenance dosing (one to two inhalations bid with a temporary step-up to four inhalations bid maximum) with fixed-dosing (two inhalations bid). In three studies (≥6 months in duration), a reduced incidence of exacerbations was reported with adjustable maintenance dosing compared with fixed-dosing. In all studies, adjustable maintenance dosing reduced the mean number of inhalations of budesonide/formoterol per patient per day compared with fixed-dosing while maintaining or improving asthma control. Adjustable maintenance dosing with budesonide/formoterol is well tolerated and has proven to be a more effective treatment strategy for asthma management, despite using less amount of drug compared with fixed-dosing.

In animals, tumor-derived heat shock proteins (HSP) induce immune-mediated protection against autologous cancer. We investigated whether HSP-70 derived from human lung carcinoma are also complexed to tumor-specific antigens. Peripheral blood mononuclear cells collected 10 days after surgery from patients with lung cancer were stimulated with HSP-70 purified from autologous and heterologous tumors. The stimulation index (SI) obtained when stimulating cells with autologous tumor-derived HSP-70 averaged 3.07 +/- 0.75 in patients with lung cancer and 1.57 +/- 0.33 in control subjects (p < 0.001 by analysis of variance). No significant stimulation was observed with HSP-70 derived either from the majority of heterologous tumors or from autologous tumor-free lung tissue. SI decreased from 3.59 +/- 0.65 to 1.65 +/- 0.38 in six patients tested again 3 months after surgery (p = 0.02 by Wilcoxon test for paired data). HSP-70 derived from lung carcinoma are shown to be associated with T cell antigens. The T cell reactivity appears transient and restricted to antigens complexed to HSP-70 derived from autologous tumors only. This suggests that the antigenicity of human lung tumors is unique, which may be crucial for the design of new vaccines.