Baseline FeNO Research Articles

Bronchodilator reversibility in the GAN severe asthma cohort.

Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit negative BDR test.To describe frequency of positive and negative BDR in patients with severe asthma and associations with phenotypic characteristics. Positive BDR was defined as FEV1 increase > 200 ml AND > 12% upon testing with a short-acting beta-agonist (SABA). Out of 2013 patients included in the German Asthma Net (GAN) severe asthma registry, 793 had data on BDR. Hereof, 250 (31.5%) had a positive and 543 (68.5%) had a negative BDR test. Comorbidities significantly associated with negative BDR were gastro-esophageal reflux (GERD) (28.0% vs 40.0%, p<0.01) and EGPA (0.4% vs 3.0%; p<0.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and COPD comorbidity (5.2% vs 7.2%) were similar in both groups. Patients with positive BDR had worse asthma control (median ACQ-5 3.4 vs 3.0, p<0.05), reported dyspnea at rest (26.8% vs 16.4%, p<0.001) and chest tightness (36.4% vs 26.2%, p<0.001) more frequently, had more severe airway obstruction at baseline (FEV1% pred: 56 vs 64, p<0.001) and higher FeNO levels (41 vs 33 ppb, p<0.05), while diffusion capacity did not differ (DLCO-SB % pred. 70% vs 71%). Multivariate linear regression analysis identified association of lower baseline FEV1% (p<0.001) and chest tightness (p<0.05) with positive, and GERD (p<0.05) with negative BDR. In this real-life setting the majority of patients with severe asthma exhibited negative BDR. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

Dupilumab Improves Lung Function Parameters in Pediatric Type 2 Asthma: VOYAGE Study

Uncontrolled asthma in growing children can impair lung growth that may lead to adverse complications in later life. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4 and IL-13, key drivers of type 2 inflammation. To extensively evaluate the effect of dupilumab on lung function in children (6-11 years) with moderate-to-severe asthma enrolled in phase 3 LIBERTY ASTHMA VOYAGE (NCT02948959). Children with asthma were randomized 2:1 to add-on dupilumab 100/200 mg by bodyweight or placebo every 2 weeks, for 52 weeks. We analyzed spirometry parameters in children with type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥20 parts per billion [ppb] at baseline) and within subgroups defined by baseline blood eosinophils or FeNO values. A total of 116 (49%) dupilumab-treated children and 59 (52%) on placebo had impaired lung function (prebronchodilator percent-predicted forced expiratory volume in 1 second [ppFEV1] <80%) at baseline. Dupilumab improved pre- and postbronchodilator ppFEV1 as early as week 2, sustained for up to 52 weeks (least-squares mean difference vs placebo at week 52: 7.79 percentage points; 95% confidence interval [CI]: 4.36-11.22; P < .001 and 4.37 points; 95% CI: 0.95-7.78; P= .01, respectively). Sustained improvements were also observed in other lung function parameters, including pre- and postbronchodilator forced vital capacity (FVC), prebronchodilator forced expiratory flow, and FEV1/FVC ratio across all populations. Dupilumab led to significant, sustained lung function improvements across a range of lung function measures in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma.

Exhaled Nitric Oxide and Pulmonary Oxygen Toxicity Susceptibility.

Individual susceptibility to pulmonary oxygen toxicity (PO2tox) is highly variable and currently lacks a reliable biomarker for predicting pulmonary hyperoxic stress. As nitric oxide (NO) is involved in many respiratory system processes and functions, we aimed to determine if expired nitric oxide (FENO) levels can provide an indication of PO2tox susceptibility in humans. Eight U.S. Navy-trained divers volunteered as subjects. The hyperoxic exposures consisted of six- and eight-hour hyperbaric chamber dives conducted on consecutive days in which subjects breathed 100% oxygen at 202.65 kPa. Subjects' individual variability in pulmonary function and FENO was measured twice daily over five days and compared with their post-dive values to assess susceptibility to PO2tox. Only subjects who showed no decrements in pulmonary function following the six-hour exposure conducted the eight-hour dive. FENO decreased by 55% immediately following the six-hour oxygen exposure (n = 8, p < 0.0001) and by 63% following the eight-hour exposure (n = 4, p < 0.0001). Four subjects showed significant decreases in pulmonary function immediately following the six-hour exposure. These subjects had the lowest baseline FENO, had the lowest post-dive FENO, and had clinical symptoms of PO2tox. Individuals with low FENO were the first to develop PO2tox symptoms and deficits in pulmonary function from the hyperoxic exposures. These data suggest that endogenous levels of NO in the lungs may protect against the development of PO2tox.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of ICS dose.

Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

1-Year Prospective Study of the Relationship of Serial Exhaled Nitric Oxide Level and Asthma Control.

Previous studies found that the fractional nitric oxide concentration in exhaled breath (FeNO) levels in healthy Chinese adults was higher than in White adults. More understanding of serial changes of FeNO levels with asthma control in a real-life clinical setting would be important to explore the utility of this biomarker in routine asthma management. This study assessed the FeNO levels of Chinese asthma subjects with different levels of asthma control and the serial changes with respect to the changes in asthma control over 1 year. A 12-month prospective study (subjects recruited between November 2019 and January 2021) with serial measurement of FeNO levels at baseline, 4, 8 and 12 months. Asthma control was assessed by the Global Initiative for Asthma classification, Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ). Altogether, 136 subjects (mean age 51.51±15.09 years, 46[33.8%] male) had successful baseline FeNO measurements. At baseline, the FeNO levels did not show a statistically significant difference for controlled, partly controlled and uncontrolled asthma according to GINA classification, ACT and ACQ. FeNO levels decreased with improving asthma control and stayed at similar levels with unchanged or worsening asthma control for all subjects. For subjects with baseline blood eosinophil levels ≥300 cells/µL(n=59), FeNO levels decreased with improving asthma control, stayed similar without change for asthma control and increased with worsening asthma control. Receiver operating characteristic (ROC) analysis with the highest area under curve (AUC) for changes in FeNO levels for improving asthma control was between ≤ -10 to -25 ppb at various time points in the 12-month study. Changes in FeNO levels over time were associated with changes in clinical asthma control, particularly in those with higher blood eosinophil count and are likely more useful than a single time point measurement in managing asthma.

Baseline FeNO Independently Predicts the Dupilumab Response in Patients With Moderate-to-Severe Asthma

FeNO may have a role as both a prognostic and predictive biomarker in combination with eosinophils for assessing responsiveness to some biological therapies. We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled moderate-to-severe asthma. We performed a post hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged 12 years and older with uncontrolled moderate-to-severe asthma, who received dupilumab 200 or 300 mg, or placebo every 2 weeks up to 52 weeks. We assessed the annualized event rate of severe exacerbations and least-squares mean change from baseline in prebronchodilator FEV1 at weeks 12 and 52 in relationship to baseline FeNO, adjusted for eosinophils and other clinical characteristics. The annualized event rate increased with increasing baseline FeNO in placebo and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab versus placebo for the FeNO less than 25, 25 to less than 50, and 50 and greater parts per billion subgroups. The magnitude of FEV1 improvement increased with higher baseline FeNO for dupilumab and was consistent across the continuum of FeNO levels in placebo. Both findings were independent of blood eosinophil levels. Significant differences were observed between FeNO subgroups. Increased baseline FeNO was associated with greater clinical effects in dupilumab versus placebo independently of eosinophil levels and other clinical characteristics.

EFFECT OF TEZEPELUMAB ON ASTHMA INFLAMMATORY BIOMARKER LEVELS VARIES BY BASELINE BIOMARKER LEVELS

<h3>Introduction</h3> In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations irrespective of baseline biomarkers, and substantially reduced levels of inflammatory biomarkers (blood eosinophil count [BEC], fractional exhaled nitric oxide [FeNO], and serum total immunoglobulin E [IgE]) in patients with severe, uncontrolled asthma. This <i>post hoc</i> analysis assessed the effect of tezepelumab on biomarker levels in patients grouped by baseline biomarker levels. <h3>Methods</h3> NAVIGATOR (NCT03347279) was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Changes from baseline to week 52 in BEC, FeNO levels and serum total IgE levels were assessed in patients grouped by baseline levels of the respective biomarker. <h3>Results</h3> Overall, 1059 patients received either tezepelumab (n=528) or placebo (n=531). At week 52, tezepelumab reduced BEC, FeNO levels and serum total IgE levels in those with elevated biomarkers at baseline (<b>Figure</b>). Mean relative reductions from baseline with tezepelumab were generally greater in those with higher baseline biomarker levels versus those with lower baseline biomarker levels. For the lowest baseline BEC and FeNO level subgroups, small decreases from baseline were observed with tezepelumab, while placebo recipients demonstrated an increase from baseline at week 52. <h3>Conclusion</h3> Tezepelumab reduced levels of all key inflammatory biomarkers in patients with severe, uncontrolled asthma, with greater reductions in patients with higher baseline levels of the respective biomarker. These data further support the anti-inflammatory effects of tezepelumab in patients with severe asthma.

CHARACTERIZATION OF PATIENTS WITH ASTHMA TREATED WITH DUPILUMAB IN A REAL-WORLD SETTING: THE RAPID REGISTRY

CHARACTERIZATION OF PATIENTS WITH ASTHMA TREATED WITH DUPILUMAB IN A REAL-WORLD SETTING: THE RAPID REGISTRY

Efficacy of Dupilumab in Quadrants of Elevated- vs Low- Type 2 Biomarkers in Children With Uncontrolled, Moderate-to-Severe Asthma: LIBERTY ASTHMA VOYAGE

Dupilumab, a human mAb, blocks the shared receptor component for IL-4/13, key and central drivers of type 2 inflammation. In VOYAGE (NCT02948959), dupilumab 100/200mg vs placebo every 2 weeks for 52 weeks reduced severe asthma annualized exacerbation rate (AER) and improved percent predicted pre-bronchodilator FEV1 (ppFEV1) in children aged 6-11 years with uncontrolled, moderate-to-severe asthma. We evaluated the predictive value of baseline blood eosinophil and FeNO levels as biomarkers for dupilumab response.

Post-hoc Analyses of Lebrikizumab Phase 3 Trials (LAVOLTA I and II): Enhanced Efficacy in Patients With Prior Exacerbations and Elevated Baseline FENO or Blood Eosinophilia

LAVOLTA I and II (LI&II) were duplicate placebo-controlled Phase 3 trials of lebrikizumab (LEB) in moderate-to-severe asthma that enrolled patients irrespective of asthma exacerbation history, baseline blood eosinophilia, or FENO. Two dose groups were studied: 125 mg and 37.5 mg Q4W. Primary endpoint was adjusted exacerbation rate ratio (AERR) in “Type 2 (T2) biomarker positive” patients (defined as periostin >50 ng/mL or blood eosinophils >300 cells/μL). LI&II failed to show consistently significant results in AERR or a dose response.

Use of computational fluid dynamics (CFD) to model observed nasal nitric oxide levels in human subjects.

Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and nasal NO (nNO) levels typically exceed those in exhaled breath (fractional exhaled NO [FeNO]). Elevated concentrations of NO sampled from the nose, in turn, reflect even higher concentrations in the paranasal sinuses, suggesting a "reservoir" role for the latter. However, the dynamics of NO flux within the sinonasal compartment are poorly understood. Data from 10 human subjects who had previously undergone both real-time nNO sampling and computed tomography (CT) scanning of the sinuses were analyzed using computational fluid dynamics (CFD) methods. Modeled and observed nNO values during the initial 2-s transient ("spike") during nasal exhalation were then compared. Examining the initial 2-s transient spike for each subject (as well as the pooled group), there was a statistically significant correlation between modeled and observed nNO levels, with r values ranging from 0.43 to 0.89 (p values ranging from<0.05 to<0.0001). Model performance varied between subjects, with weaker correlations evident in those with high background (FeNO) levels. In addition, the CFD simulation suggests that ethmoid sinuses (>60%) and diffusion process (>54%) contributed most to total nasal NO emissions. Analysis of this dataset confirms that CFD is a valuable modeling tool for nNO dynamics, and highlights the importance of the ethmoid sinuses, as well as the role of diffusion as an initiating step in sinonasal NO flux. Future model iterations may apply more generally if baseline FeNO is taken into account.

Eucapnic voluntary hyperventilation test decreases exhaled nitric oxide level in children.

Exhaled nitric oxide (FeNO) measurements and eucapnic voluntary hyperventilation (EVH) tests have been used as diagnostic tools for asthma. Data on the impact of hyperventilation on the level of FeNO are limited. We aimed to evaluate whether EVH tests affect the level of FeNO in children aged 10-16years. A total of 234 children aged 10-16years had a 6-min EVH test performed. In total, FeNO values for 153 of 234 children were measured before the test and within 15min after the test. According to a baseline FeNO level of 20ppb, children were divided into two groups: those with low values (FeNO<20ppb) and those with high values (FeNO≥20ppb). The median age of the children was 13.4years (interquartile range 12.3-15.3years); 58% were boys and 42% were girls. Of these children, 51% were sensitized to aeroallergens. In 101 of 153 children (66%), the FeNO values decreased after the EVH test. In children with low and high baseline levels, the median level of FeNO decreased after the EVH test: 10.5ppb before versus 9.5ppb after (p<.011), and 31.0ppb before versus 28.0ppb after (p<.011), respectively. The decrease in FeNO after EVH test was not associated with induced bronchoconstriction expressed as a change in FEV1 (Rs =.19). The EVH test decreases FeNO levels. Therefore, FeNO should be measured before an EVH test is performed.

Detection of type2 biomarkers for response in COPD

Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory lung disease. It is important to identify patients who would respond to anti-inflammatory treatment. This prospective study aims to determine how inflammatory biomarkers could be used to predict the potential effect of inhaled corticosteroids (ICS) in terms of symptoms and lung function. We evaluated the levels of blood eosinophils, exhaled nitric oxide fraction at a flow rate of 50 ml s−1 (FeNO), alveolar nitric oxide concentration (Calv), immunoglobulin E and atopy in 43 patients with symptomatic COPD and correlated these expression levels with the changes in the COPD Assessment Test (CAT) and lung function by 12 weeks of add-on therapy with ciclesonide 400 μg d−1 on bronchodilators. The mean changes in the CAT score and FEV1 were −1.4 points and +90 ml, respectively, with significant variation in the levels of change. The area under the receiver’s operating characteristic curve (AUC) for FeNO in predicting improvements in both the CAT score and FEV1 was 0.92. The AUC for Calv and blood eosinophils was 0.82 and 0.65. Two cutoffs were chosen, one corresponding to a high value of FeNO associated with certainty for response inclusion (FeNO = 35 ppb; sensitivity = 0.67, specificity = 0.94; positive predictive value = 0.80) and the other with certainty for response exclusion (FeNO = 20 ppb; sensitivity = 1.00, specificity = 0.58, negative predictive value = 1.00). Baseline FeNO values were significantly correlated with changes in FEV1 and CAT (all p < 0.0001). FeNO could be a valuable biomarker for identifying individuals who respond to steroid therapy among patients with symptomatic COPD in terms of symptoms and airflow limitation. The study was prospectively registered with the University Hospital Medical Information Network (UMIN) in Japan (protocol ID 000010711).

The Effect of a five-Day Educational Program for Children with Asthma on Airway inflammation: A two-year study

The aim of this study was to investigate the effectiveness of a 5 day educational program in children with asthma on airway inflammation as measured by FeNO during 2 consecutive years. Ninety-four children with asthma were enrolled in Camp Wheez. Written consent was obtained for each participant. Children were educated on the early signs of asthma, identifying triggers and the use of controller medications. The curriculum was provided by the Asthma Camp consortium of the AAAAI. The NIOX Vero was used as a 6 to10 second, single breath, incentive quantitative measurement. We measured FeNO on day one (baseline) and day 5 (end of camp), 2018 and 2019. Ninety-four children were enrolled during the 5 day asthma camp 2018 and 2019. The average baseline FeNO was 36.3 ppb, compared to an average of 33.1 ppb on day 5. The average FeNO levels were the same at day 1 and day 5 in campers with a low (<20ppb) and intermediate FeNO (20-35 ppb.) However, in the 36 campers who had a high baseline FeNO >35 ppb there was a significant improvement in FeNO from an average 75 ppb down to 67 ppb. There was a 10% improvement overall at the end of camp. None of the campers were informed on their baseline levels nor received individual coaching. This 2 year study demonstrated the effectiveness of a 5-day asthma education program on 94 children with asthma. Our results showed a significant improvement in FeNo with a 10% improvement (p=.001) at the conclusion of asthma education.

Baseline FeNO as a Prognostic Biomarker for Subsequent Severe Asthma Exacerbations in Patients With Uncontrolled, Moderate-to-Severe Asthma Receiving Placebo in the LIBERTY ASTHMA QUEST Study

Baseline FeNO as a Prognostic Biomarker for Subsequent Severe Asthma Exacerbations in Patients With Uncontrolled, Moderate-to-Severe Asthma Receiving Placebo in the LIBERTY ASTHMA QUEST Study

The effect of dupilumab on lung function parameters in patients with oral corticosteroid-dependent severe asthma

BackgroundIn Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214), add-on dupilumab reduced oral corticosteroid (OCS) use while reducing severe exacerbations and improving pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) in OCS-dependent severe asthma patients. ObjectiveThis post hoc study evaluated dupilumab's efficacy based on several lung function parameters for the overall population and subgroups defined by baseline biomarkers. MethodsLung function parameters were pre- and post-BD FEV1, pre-BD forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow 25–75% (FEF25–75%). Dupilumab's steroid-sparing efficacy according to FEV1 improvement (≥ 200 mL vs < 200 mL) or in patients with 0 exacerbations was also assessed. ResultsAt Week 24 in the overall population, pre- and post-BD FEV1 had improved by 0.22 L (95% CI 0.09–0.34; p = 0.0007) and 0.19 L (95% CI 0.08–0.30; p = 0.0009) vs placebo, respectively; FVC by 0.27 L (95% CI 0.13–0.41; p = 0.0003); FEV1/FVC by 1.90% (95% CI -0.26–4.07; p = 0.08); and FEF25–75% by 0.15 L/s (95% CI 0.02–0.28; p = 0.02). Improvements were early and generally sustained over 24-weeks’ treatment. Improvements were observed regardless of baseline eosinophils or FeNO and were generally greatest in patients with eosinophils ≥ 300 cells/μL. Significant steroid-sparing effects were observed with dupilumab irrespective of FEV1 improvement, and in exacerbation-free patients. ConclusionsDupilumab rapidly improved various lung function measures regardless of baseline biomarkers in OCS-dependent severe asthma patients. It showed steroid-sparing effects regardless of FEV1 improvement, and in exacerbation-free patients. This population appears to be highly skewed toward type 2 inflammation.

Efficacy of mepolizumab for patients with severe asthma and eosinophilic chronic rhinosinusitis

BackgroundSeveral major randomized control studies have demonstrated that mepolizumab, an anti-IL-5 monoclonal antibody, is effective for patients with severe eosinophilic asthma who show exacerbation or require systemic corticosteroid maintenance therapy. However, the predictive factors of the response to mepolizumab other than blood eosinophil count are unclear in clinical practice.ObjectiveTo elucidate the predictive factors of the response to mepolizumab for patients with severe eosinophilic asthma.MethodsFrom July 2016 to December 2017, 28 patients with severe asthma received mepolizumab in our hospital. To determine the predictive factors, we retrospectively evaluated patient characteristics, comorbidities, biomarkers, pulmonary function, maintenance dose of systemic corticosteroids and number of exacerbations.ResultsThe response rate to mepolizumab treatment was 70% (19/27; one pregnant woman was excluded from analysis). Compared with 11 patients without eosinophilic chronic rhinosinusitis (ECRS), 16 patients with ECRS showed significantly improved systemic corticosteroid-sparing effects [− 71.3 ± 37.0% vs − 10.7 ± 20.1%, P = 0.006], change from baseline FeNO [− 19 ± 57 (%) vs 30 ± 77 (%), P = 0.023] and symptoms [14 patients (88%) vs five patients (45%), P = 0.033]. ECRS was identified as a predictive factor of the response to mepolizumab in a multivariate logistic regression analysis [odds ratio = 22.5, 95% CI (1.5–336), P = 0.024]. Of the eight patients previously administered omalizumab, five responded to mepolizumab. Staphylococcus aureus enterotoxin B IgE results were negative in 80% of responders (P = 0.14).ConclusionBoth groups showed improved symptom scores and a decreased number of exacerbations. Mepolizumab substantially improved the clinical variables of patients with eosinophilic asthma complicated with ECRS.

Urinary and exhaled biomarkers of exercise-induced bronchoconstriction in atopic asthmatic children.

Exercise-induced bronchoconstriction (EIB) reflects poor asthma control. Assessing noninvasive biomarkers associated with EIB could help to monitor patients in the pediatric age. To test exhaled and urinary biomarkers for assessing EIB in atopic asthmatic children. In 45 atopic patients (11.1 ± 1.8 years, 25 males) we measured the fractional exhaled nitric oxide (FENO ), its alveolar (CaNO), and bronchial (J'awNO) components corrected for the trumpet shape of the airways and axial NO diffusion (TMAD), concentrations of urinary adenosine and 8-hydroxy-2'-deoxyguanosine (8-OxodG), blood eosinophils count, total immunoglobulin E , skin prick tests, and baseline spirometry before a treadmill exercise challenge. Forty healthy control subjects participated solely to baseline measurements. Patients yielded higher FENO and urinary adenosine concentrations than healthy controls. After the challenge, 18 patients (40%) had EIB; these patients had higher levels of CaNO, CaNO TMAD, and urinary adenosine than patients without EIB. Baseline spirometry, FE NO , JawNO, JawNO TMAD, urinary 8-OxodG, allergy, and blood eosinophil counts were found similar in both groups. In multiple linear regression, the fall in FEV 1 was explained by CaNO TMAD, urinary adenosine and blood eosinophil count, whereas the fall in FEF 25-75 was explained by CaNO TMAD and blood eosinophil count. Both CaNO TMAD ≥10.5 ppb and urinary adenosine ≥406 nmol/mmol Cr predicted a fall in FEV 1 ≥10%, while only CaNO TMAD ≥10.5 ppb predicted a fall in FEF 25-75 ≥26%. Concentrations of peripheral airway NO are complementary with urinary adenosine for assessing EIB and promising tools of asthma control in pediatric patients with the atopic phenotype.

DUPILUMAB EFFICACY IN UNCONTROLLED, MODERATE-TO-SEVERE ALLERGIC ASTHMA IN THE PHASE 3 LIBERTY ASTHMA QUEST STUDY

Introduction Dupilumab, a fully human interleukin (IL)-4 receptor-α monoclonal antibody inhibiting IL-4/IL-13 signaling pathways, key drivers of Type 2 inflammation, is approved for treating adults with inadequately controlled moderate-to-severe atopic dermatitis. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), dupilumab 200mg and 300mg administered every 2 weeks versus matched placebo reduced annualized severe exacerbation rates and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) and quality-of-life measures, and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma (≥12 years, without minimum baseline Type 2 inflammatory biomarkers). This post-hoc analysis assessed the efficacy of dupilumab in patients with and without allergic asthma. Methods Allergic asthma was defined as total serum IgE ≥30 kU/L and ≥1 positive perennial aeroallergen-specific IgE (≥0.35 kU/L) at baseline. Endpoints were annualized severe exacerbation rates over the 52-week treatment period and change from baseline to Week 12 in pre-bronchodilator FEV1 (L). Results 56% (n=1,066) of the intent-to-treat population met the criteria for allergic asthma. In patients with and without allergic asthma, dupilumab vs placebo significantly reduced annualized severe exacerbation rates during the treatment period (all P1 (L) at Week 12 (all PFigure). In both subgroups, improvements were greater with higher baseline blood eosinophil and FeNO levels. The most frequent adverse event in the dupilumab-treated groups versus placebo was injection-site reactions (15%/18% versus 5%/10%, respectively). Conclusions Add-on dupilumab reduced severe exacerbations and improved lung function in patients with allergic and non-allergic uncontrolled, moderate-to-severe asthma and was generally well tolerated. Figure. Change from baseline to Week 12 in pre-bronchodilator FEV1 (L) and annualized severe exacerbation rate during the 52-week treatment period in patients with and without allergic asthma and in subgroups defined by baseline blood-eosinophil counts and FeNO levels.

Tralokinumab unsuccessful for management of severe, uncontrolled asthma

In the past decade, substantial efforts have been made to develop therapies based on biologics, particularly those targeting type 2 immune cytokines such as interleukins 4, 5, and 13, and as a result of these efforts, anti-interleukin-5 and anti-interleukin-5 receptor-α antibodies for the treatment of severe eosinophilic asthma are now available. 1 Chung KF Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015; 386: 1086-1096 Summary Full Text Full Text PDF PubMed Scopus (190) Google Scholar Interleukin 13—a cytokine produced by T-helper 2 lymphocytes, type-2 innate lymphoid cells, mast cells, and eosinophils—has been implicated in the pathogenesis of asthma with its ability to induce goblet cell hyperplasia, lung eosinophilia, and bronchial hyper-responsiveness, in addition to its contribution to airway wall remodelling. 2 Hirose K Iwata A Tamachi T Nakajima H Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev. 2017; 278: 145-161 Crossref PubMed Scopus (85) Google Scholar It is therefore not surprising that interleukin 13 has been considered as another target for the treatment of asthma associated with type 2 inflammation. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trialsTralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. Full-Text PDF Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trialTralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. Full-Text PDF