LAMA improve tissue oxygenation more than LABA in patients with COPD.

Background The effect of bronchodilators is mainly assessed with forced expiratory volume in 1s (FEV1) in COPD. Their impact on oxygenation and lung periphery is less known. Objectives To compare the action of long-acting ß2-agonists (LABA-olodaterol) and muscarinic antagonists (LAMA-tiotropium) on tissue oxygenation in COPD, considering their impact on proximal and peripheral ventilation as well as lung perfusion. Methods FEV1, Helium slope (SHe) from a single-breath washout test (SHe decrease reflecting a peripheral ventilation improvement), frequency dependence of resistance (R5-R19), area under reactance (AX), lung capillary blood volume (Vc) from double diffusion (DLNO/DLCO) and transcutaneous oxygenation (TcO2) were measured before and 2 hours post-LABA (day 1) and LAMA (day 3) in 30 COPD patients (FEV1 54±18% pred; GOLD A 31%/B 48%/E 21%) after 5-7 days of washout, respectively. Results TcO2 increased more (p=0.03) after LAMA (11±12%from baseline, p<0001) compared to LABA (4±11%, p=0.06) despite a lower FEV1 increase (p=0.03) and similar SHe (p=0.98), AX (p=0.63) and R5-R19 decreases (p=0.37). TcO2 and SHe changes were negatively correlated (r=-0.47, p=0.01) after LABA, not after LAMA (r=0.10, p=0.65). DLNO/DLCO decreased and Vc increased after LAMA (p=0.04; p=0.01, respectively) but not after LABA (p=0.53; p=0.24). Conclusion LAMA significantly improved tissue oxygenation in COPD patients, while only a trend was observed with LABA. The mechanisms involved may differ between both drugs: LABA increased peripheral ventilation while LAMA increased lung capillary blood volume. Should oxygenation differences persist over time, LAMA could arguably become the first therapeutic choice in COPD.

The Impact of Airway Obstruction on Feno Values in Asthma Patients.

BACKGROUND: Exhaled nitric oxide (Feno) is used as a marker of type-2 airway inflammation in asthma management. Studies with airway challenges demonstrated that a reduction in airway caliber decreases Feno levels. OBJECTIVE: To evaluate the impact of airway caliber reduction occurring spontaneously in patients with asthma on Feno values in daily clinical practice. METHODS: In this post hoc analysis, Feno, FEV1, and asthma control questionnaire scores were recorded on each visit for 120 (1073 visits) adult patients with asthma. Blood eosinophils were measured intermittently. The intraindividual relationship between Feno and FEV1 was evaluated via a linear mixed model. The determinants of the individual mean Feno were measured by a stepwise multivariate linear model including individual mean FEV1, inhaled corticosteroid dose, asthma control questionnaire score, and blood eosinophils. RESULTS: Variations in the negative Feno-FEV1 relationship within individuals at different times were significantly determined by the individual's mean FEV1. This relationship did not hold for individuals above the 75th and below the 25th quartiles. The best explanatory variables for individual mean Feno were FEV1 (+4.3 parts per billion/10%pred) and blood eosinophil count (+1 part per billion per 100 cells/mm3). DISCUSSION: In the presence of variable degrees of heterogeneous patterns of airway inflammation, airway caliber is shown to be an independent and significant determinant of Feno when measured in patients with asthma. We would propose a +4-parts-per-billion correction factor to the measured Feno value for each 10% reduction below 100% predicted FEV1. Doing this should improve the rigor of interpretation of Feno as an indicator of type-2 inflammation in patients with low FEV1.

Anti-Interleukin-5 Therapy Is Associated with Attenuated Lung Function Decline in Severe Eosinophilic Asthma Patients From the Belgian Severe Asthma Registry.

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 post-bronchodilation 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.

Exploring the sites and kinetics of bronchodilator response to ß-2 agonists in asthma.

We previously documented, in patients with asthma, three different profiles of bronchodilation induced by short-acting ß-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 ß-2 receptors in both the central and peripheral human airways. FENO, forced expired volume in one second (FEV1), and the slope (S) of He and SF6 phase III (single-breath test) were measured in asthma patients before, and up to 6 h after SABA inhalation (salbutamol 400 µg). SHe and SSF6 decrease reflects pre- and intra-acinar obstruction relief, respectively. Thirty patients with asthma (12F/18M, aged 45 ± 18 yr) were divided into groups with positive (NO+, n = 9), negative (NO-, n = 11), and no (NO=, n = 10) FENO acute change. In the NO- group, FEV1 increased for up to 4 h, whereas FENO, SHe, and SF6 decreased in the early phase only. In stark contrast, in the NO+ group, FEV1 increased in the early phase only whereas the FENO increase and the SHe decrease lasted for up to 4 h. This study documents various profiles of SABA-induced bronchodilation in patients with asthma, differing both by sites and dynamics of the bronchodilator process. So, detailed understanding of the bronchodilator effect of ß2-agonists in asthma should not solely be limited to studying their impact on FEV1.NEW & NOTEWORTHY FEV1 increase usually observed after the inhalation of short-acting ß2-agonists in asthma patients tends to involve peripheral airways. This study shows that the heterogeneity of responses to short-acting ß2-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 ß2-agonists in asthma should not be limited to studying its early impact on FEV1.

Closing volume detection by single-breath gas washout and forced oscillation technique.

Closing volume (CV) is commonly measured by single-breath nitrogen washout (CVSBW). A method based on the forced oscillation technique was recently introduced to detect a surrogate CV (CVFOT). As the two approaches are based on different physiological mechanisms, we aim to investigate CVFOT and CVSBW relationship at different degrees and patterns of airway obstruction. A mathematical model was developed to evaluate the CVSBW and CVFOT sensitivity to different patterns of airway obstruction, either located in a specific lung region or equally distributed throughout the lung. The two CVs were also assessed during slow vital capacity (VC) maneuvers in triplicate in 13 healthy subjects and pre- and postmethacholine challenge (Mch) in 12 subjects with mild-moderate asthma. Model simulations suggest that CVSBW is more sensitive than CVFOT to the presence of few flow-limited or closed airways that modify the contribution of tracer-poor and tracer-rich lung regions to the overall exhaled gas. Conversely, CVFOT occurs only when at least ∼65% of lung units are flow limited or closed, regardless of their regional distribution. CVSBW did not differ between healthy subjects and those with asthma (17 ± 9% VC vs. 22 ± 10% VC), whereas CVFOT did (16 ± 5% VC vs. 23 ± 6% VC, P < 0.01). In patients with asthma, both CVSBW and CVFOT increased post-Mch (33 ± 7% VC P < 0.001 and 43 ± 12% VC P < 0.001, respectively). CVSBW weakly correlated with CVFOT (r = 0.45, P < 0.01). The closing capacities (CV + residual volume) were correlated (r = 0.74, P < 0.001), but the changes with Mch in both CVs and closing capacities did not correlate. CVFOT is easy to measure and provides a reproducible parameter useful for describing airway impairment in obstructive respiratory diseases.NEW & NOTEWORTHY 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.

Severe asthma: oral corticosteroid alternatives and the need for optimal referral pathways.

OBJECTIVE: 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. DATA SOURCES: PubMed. STUDY SELECTION: Studies with results on the OCS-sparing effect of biologics in adult severe asthma were selected. RESULTS: 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. CONCLUSION: 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.

An Emerging Role for Exhaled Nitric Oxide in Guiding Biological Treatment in Severe Asthma.

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.

Variability in total serum IgE over 1 year in severe asthmatics.

BACKGROUND: 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. METHODS: In this prospective study, sIgEtot levels were measured over 1 year at 7 time points in 41 severe asthmatics treated with high-dose of inhaled corticosteroids and long-acting ß2 agonists. 33 patients were atopic based on at least one positive RAST to common aeroallergens. Patients were divided into three groups according to their baseline sIgEtot level: low (< 76 IU/mL; n = 10), intermediate (76-700 IU/mL; n = 20) or high (> 700 IU/mL; n = 11). Patients also completed the six-item Juniper Asthma Control Questionnaire (ACQ6). The sIgEtot variability and factors predictive for this variability were studied, as well as ACQ6 outcomes. RESULTS: The variation in sIgEtot level was mostly the consequence of between patient-variability, which represented 96%, 71% and 96% of the total variability in the low, intermediate and high sIgEtot subgroups, respectively. The residual within-patient variability was therefore limited. In 10/41 patients, sIgEtot levels increased or decreased, for at least one visit, beyond the predefined range of the subgroups to which they were assigned (< 76 IU/mL; 76-700 IU/mL; > 700 IU/mL). There was a significant but weak correlation between sIgEtot and ACQ6 score over all time points (r = 0.15, p = 0.02), but sIgEtot failed to associate with severe exacerbation. sIgEtot decreased by 3% with any additional year of age for the whole group (p = 0.01) and increased by 5% per one unit of allergen exposure score in atopic patients (p = 0.002). CONCLUSION: In severe asthmatics, limited within-patient variability of sIgEtot levels was observed over 1 year as opposed to marked between-subject variability. sIgEtot decreases with age. Variation in sIgEtot weakly associates with asthma control but not with exacerbation.

COPD patients with peripheral airway obstruction reversibility identified by exhaled nitric oxide.

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 < -11% in 22 patients [-31.2(9.8)%] (NO- group). A similar ΔFEV1 (p = 0.583; [+9.4(9.6)%]) was found in the three groups. In NO = and NO+ groups, neither SHe nor SSF6 changed; in NO- both SHe [-12.4(27.5)%, p = 0.007] and SSF6 [-20.2(20.4)%, p < 0.001] significantly decreased. CONCLUSION: Different patterns of FENO response to ß 2-agonists were observed in COPD most likely depending on the extent of the dilation process. A profile of airway obstruction with an extensive ß 2-agonist response down to lung periphery is identified by FENO reduction after acute bronchodilation in 30% of COPD patients. The clinical relevance of this profile requires further investigation.

Small airways dysfunction: the link between allergic rhinitis and allergic asthma.

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 (p<0.001), whereas ΔSSF6 = 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.

Airway calibre variation is a major determinant of exhaled nitric oxide's ability to capture asthma control.

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<0.001). The area under the curve values were 0.765 (95% CI 0.713-0.805) (improvement; p<0.001) and 0.769 (95% 0.706-0.810) (worsening; p<0.001) or 0.590 (95% 0.531-0.653) (improvement; p=0.001) and 0.498 (95% 0.416-0.567) (worsening; p=0.482) when FEV1 and FENO changed in the opposite or same direction, respectively.The manner in which FENO and FEV1 vary concomitantly when asthma control changes determines the ability of FENO to capture this change: parallel or opposite changes in FEV1 and FENO either decrease or increase this ability to capture asthma control changes.

A Belgian survey on the diagnosis of asthma-COPD overlap syndrome.

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 of age"; "symptom variability", and "age (in favor of asthma)". To diagnose ACOS in asthma patients, major criteria were "persistence of airflow obstruction over time (forced expiratory volume in 1 second/forced vital capacity ratio <0.7)" and "exposure to noxious particles/gases, with ≥10 pack-years for (ex-)smokers"; minor criteria were "lack of response on acute bronchodilator test"; "reduced diffusion capacity"; "limited variability in airway obstruction"; "age >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.

Different patterns of exhaled nitric oxide response to ß2-agonists in asthmatic patients according to the site of bronchodilation.

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 ß2-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, FEV1, 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 ΔFEV1 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 < .001) and S(SF6) (-27.2% [23.3%], P < .001) decreased. DISCUSSION: Three FENO behaviors were observed in response to ß2-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.

FeNO as a predictor of asthma control improvement after starting inhaled steroid treatment.

INTRODUCTION: 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. METHODS: 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). RESULTS: Having at the initial visit intermediate FeNO (⩾25 and <50 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%, p<0.05) or both ⩾1 improvement and asthma control at follow-up (31% and 37% vs 4%, p<0.05). These associations were consistent in multiple logistic regression models after adjustments for confounders. CONCLUSIONS: 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.