Associations Between Different Eosinophil Activity Markers and Clinical Outcomes in Young Asthmatics.

We have reported that increased fraction of exhaled nitric oxide (FeNO), a measure of TH2 -driven airway inflammation, and blood eosinophil count, a marker of systemic eosinophil inflammation, correlated with asthma attacks in a population-based study. To investigate the relation between simultaneously elevated FeNO and serum eosinophil cationic protein (S-ECP) levels and asthma events among asthmatics. Measurements of FeNO (elevated ≥ 25 ppb) and S-ECP (elevated ≥ 20 ng/mL) were performed in 339 adult asthmatics. Asthma events (attacks and symptoms) were self-reported. Simultaneously normal S-ECP and FeNO levels were found in 48% of the subjects. Subjects with simultaneously elevated S-ECP and FeNO (13% of the population) had a higher prevalence of asthma attacks in the preceding 3 months than subjects with normal S-ECP and FeNO (51% vs. 25%, P = 0.001). This was not found for subjects with singly elevated S-ECP (P = 0.14) or FeNO (P = 0.34) levels. Elevated S-ECP and FeNO levels were independently associated with asthma attacks in the preceding 3 months after adjusting for potential confounders (OR (95% CI) 4.2 (2.0-8.8). Simultaneously elevated FeNO and S-ECP levels were related to a higher likelihood of asthma attacks in the preceding 3 months. This indicates that there is a value in measuring both FeNO and systemic eosinophilic inflammation in patients with asthma to identify individuals at high risk of exacerbations. FeNO and S-ECP are markers for inflammation in asthma, but are dependent on different inflammatory pathways and weakly correlated. Simultaneous measurements of both offer better risk characterization of adult asthmatics.

The usefulness of inflammatory markers in monitoring treatment responses in asthma

Simultaneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity

Background: There is increasing interest in the role of indirect bronchial challenges because clinical studies have shown that indirect airway hyperresponsiveness (AHR) reflects underlying airway inflammation better than direct AHR. Fractional exhaled nitric oxide (FeNO) appears to be a useful clinical tool for assessing airway inflammation noninvasively. We examined whether FeNO is more closely related to AHR to indirect stimuli than AHR to direct stimuli in children with mild to moderate asthma. Methods: Fifty-nine asthmatic children aged 6-16 years without rhinitis, underwent spirometry, FeNO measurement and blood tests for serum total IgE, blood eosinophil count and serum eosinophil cationic protein (ECP). All subjects underwent methacholine and adenosine 5-monophosphate (AMP) challenge tests at intervals of 3 days. Results: In a univariate linear regression analysis, FeNO was significantly associated with both PC₂₀ AMP (R² = 0.341, p < 0.001) and PC₂₀ methacholine (R² = 0.188, p = 0.001). After adjustment for age, sex, serum total IgE and blood eosinophil count, the association between FeNO and PC₂₀ AMP (β = -1.98, p = 0.001) was more robust than that between FeNO and PC₂₀ methacholine (β = -0.87, p = 0.081). The significant correlation between FeNO and PC₂₀ AMP was observed in the steroid-naïve group (β = -2.48, p = 0.001), but not in the steroid-treated group (β = 0.88, p = 0.463). Conclusions: FeNO levels were more closely associated with PC₂₀ AMP than with PC₂₀ methacholine. This relationship could only be seen in the steroid-naïve subjects. These results suggest that FeNO levels in children with asthma may be more closely related to indirect AHR than to direct AHR.

<b>Bakground:</b> We have recently reported that increased blood eosinophil (B-Eos) count relates to lower lung function and higher degree of bronchial hyperresponsiveness (BHR) in young subjects with asthma. Other markers of eosinophil activation are serum eosinophil cationic protein (S-ECP) and plasma eosinophil-derived neurotoxin (P-EDN, formerly EPX). The aim of the present study was to compare these three markers in relation to lung function and BHR. <b>Methods:</b> Increased B-Eos (≥300 cells/mm³), increased S-ECP (≥20 µg/L) and increased P-EPX (≥22.5 µg/L, corresponding to upper quartile) were tested in relation to lung function and BHR to methacholine in 405 subjects (207 females) with physician-diagnosed asthma, aged 10-35 years. <b>Results:</b> The best correlation between eosinophil markers was found for B-Eos and S-ECP (R²=0.50), followed by B-Eos and P-EDN (R²=0.32), and then S-ECP and P-EDN (R²=0.18). All three markers correlated with total IgE (p&lt;0.001). Increased B-Eos count related to having FEV₁&lt;80% predicted (p=0.002) but not increased S-ECP (p=0.76) or increased P-EDN (p=0.09). Moderate-severe BHR to methacholine related to (OR (95%CI)) increased B-Eos (4.7 (2.9, 7.6)), S-ECP (3.6 (2.2, 5.9)) and P-EDN (2.4 (1.5, 4.0)). Similar ORs (95%CI) were found for having either increased B-Eos, or simultaneously increased B-Eos and S-ECP or B-Eos and P-EDN: 4.0 (1.7, 9.7) vs 4.4 (2.5, 7.7) vs 6.0 (3.2, 11.4). <b>Conclusion:</b> The eosinophil markers were all related to each other, and to total IgE. Blood eosinophil count was more closely associated with lung function and bronchial responsiveness than serum ECP or plasma EDN. No clear additive value was found for the two soluble markers.

Background FeNO has been used as a marker for Th2-mediated airway inflammation in asthma. There is evidence which recommends the use of this biomarker in asthma management. Little is known about whether the FeNO test alone or in combination with the ACT score can reflect asthma control in Vietnamese patients. Materials and Methods A cross-sectional study was conducted in asthmatic patients (≥18 years old) recruited at the University Medical Center, Ho Chi Minh City, Vietnam from March 2016 to March 2017. Asthma control levels were assessed following the GINA 2017 guidelines, and FeNO was measured by a Niox Mino device. FeNO cut-offs predicting asthma control status were determined using the ROC curve analysis. The combination of FeNO and ACT was investigated in detecting well-controlled and uncontrolled asthma. The results of the study are as follows: 278 patients with 68% females, mean age of 44 years, and mean asthma duration of 10 years were analyzed. All patients were treated following step 2 to 4 of GINA guidelines. Mean (SD) FeNO was 30.6 (24) ppb. Patients with uncontrolled (16%), partly controlled (29%), and well-controlled asthma (55%) had a median (IQR) FeNO of 50.0 (74), 25.0 (23), and 21.0 (22.3) ppb, respectively, and the mean of FeNO in the uncontrolled group was significantly higher than that in other groups (p < 0.001). The area under the ROC curve (AUC) for FeNO detecting uncontrolled asthma was 0.730 with an optimal cut-off point of FeNO > 50 ppb, and this AUC increased to 0.89 when combining FeNO and ACT. The AUC for FeNO detecting well-controlled asthma was 0.601 with an optimal cut-off point of FeNO <25 ppb and this AUC increased to 0.78 if combining FeNO and ACT. Conclusions FeNO can predict asthma control status with an estimated cut-off point of <25 ppb for well-controlled and >50 ppb for uncontrolled asthma. The combination of FeNO and ACT provides better information regarding asthma control than FeNO alone, and this combination is useful to predict asthma control statuses in asthmatic patients in Viet Nam.

Rationale: Increased Fractional Exhaled Nitric Oxide (FeNO) and Blood Eosinophil counts (BEC) are established biomarkers of IL-13 driven airway inflammation and IL-5 driven systemic eosinophilic inflammation respectively. In contrast to the Global Initiative for Asthma (GINA), the European Respiratory Society (ERS) and British Thoracic Society (BTS) recommend the use of Type 2 (T2)-biomarkers FeNO and/or BEC for the diagnosis of asthma. Both biomarkers have been shown to be independently associated with a higher risk of asthma-related outcomes (1). In this study, we analyzed National Health and Nutrition Examination Survey (NHANES) data to investigate the associations between FeNO, BEC and asthma prevalence, with a particular focus on a BEC threshold of 150 cells/μL and sex-specific differences. Methods: Participants aged 6-80 years old with complete data for FeNO and BEC from NHANES 2007-2012 were included. Current asthma was defined as ever-physician-diagnosed asthma combined with self-reported current asthma. BEC were stratified to low (&amp;lt;150/μL), moderate (150-300/μL), high (300-500/μL) and very high (&amp;gt;500/μL); FeNO was defined as normal (&amp;lt;20 ppb/25 ppb for &amp;lt;12 years old/≥12 years old respectively), intermediate (20-35 ppb/25-50 ppb) and high (≥35 ppb/ ≥50 ppb). Multiple linear regression analysis was performed, adjusting for age, sex and BMI (model 1); and additionally for hay fever and use of oral or inhaled corticosteroids (model 2). Results: In 18,319 NHANES participants, overall asthma prevalence ranged from 5.9% in participants with normal FeNO and BEC &amp;lt;150/μL to 31.7% in those with high FeNO and BEC &amp;gt;500/μL. While asthma prevalence was higher in women with low T2-biomarkers than in men (7.2% vs. 4.3%), men had a higher asthma prevalence in case of marked FeNO and BEC elevation (34% vs. 27.9%). Compared to individuals with low BEC and normal FeNO, moderate increases in BEC (150-300/μL) were associated with 1.3- to 3.2-fold higher odds of having current asthma depending on FeNO levels, irrespective of sex. Consistent increases of the asthma prevalence and odds of current asthma were found with increasing FeNO levels within each stratum of BEC. In participants with the highest BEC and FeNO, a 3.7- and 7.1-fold higher odds of asthma was found in women and men respectively (Figure 1). Conclusions: Our results further support the complementary role of FeNO and BEC in the diagnosis of asthma. Even in adults with moderate increases in BEC (150-300/μL), there is a significant increase in asthma prevalence. We suggest adding FeNO and BEC to the diagnostic algorithms for asthma.

Determinants of asthma control and exacerbations in moderate to severe asthma

Objective To investigate the fractional exhaled nitric oxide (FeNO) value and blood eosinophil (EOS) count in eosinophilic asthma and analyze their correlation. Methods A retrospective analysis was made based on the clinical data of 83 eosinophilic asthmatic patients and normal subjects from January 2015 to January 2016.The level of FeNO and blood EOS count were detected in all subjects and the correlation between FeNO values and blood EOS counts in asthma was also calculated.The FeNO value and blood EOS count were investigated again in 24 of all asthmatics after treatment. Results The FeNO values and blood EOS count were 74(123-54) ppb and 0.36(0.55-0.20)×109/L in asthmatics, 20(27-13) ppb and 0.14(0.22-0.07)×109/L in the control group.FeNO was positively correlated with EOS in asthmatics(r=0.593, P<0.01). The EOS decreased at the same time the FeNO decreased obviously in 19 of asthmatics.The EOS unchanged at the same time the FeNO had no obvious reduction. Conclusions Blood EOS count correlates to FeNO value in eosinophilic asthma.The change of EOS and FeNO has the consistency.Blood EOS count could be a useful indicator of control in eosinophilic asthma. Key words: Eosinophilic asthma; Fractional exhaled nitric oxide; Blood eosinophil

Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects

To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.

Comparison of Bronchodilator Responsiveness After Methacholine-induced and AMP-induced Bronchoconstriciton in Asthmatic Children

BackgroundThe relationship between pre-treatment levels of blood eosinophil count (BEC), fractional exhaled nitric oxide (FENO) and sputum eosinophils (Sp-EOS) and treatment response to monoclonal antibodies (mAbs) in severe eosinophilic asthma (SEA) remains unclear. We evaluated pre-treatment levels of BEC, FENO, Sp-EOS and their combinations as predictors of treatment responses in patients with SEA undergoing anti-interleukin (IL)-5/IL-5Rα or anti-IL-4Rα antibody therapies.MethodsThe study included 153 adult patients with SEA (59 anti-IL-5/IL-5Rα and 94 anti-IL-4Rα users). Logistic regression models were used to evaluate the association between predictors and 12-month treatment responses and clinical remission across four domains: exacerbation rate, maintenance of oral corticosteroid dose, forced expiratory volume in 1 s (FEV1) and asthma control test (ACT) improvement.ResultsPre-treatment BEC and Sp-EOS were not associated with treatment responses in either mAb group. For combined data from anti-IL-5/IL-5Rα and anti-IL-4Rα users, the adjusted odds ratios (95% confidence intervals) for a 1-unit increase in log-transformed FENO were 1.8 (1.21–2.74) for FEV1 response and 2.15 (1.29–3.75) for ACT response. For anti-IL-4Rα users, these values were 2.34 (1.39–4.17) and 3.6 (1.73–8.84), respectively. No significant association between FENO and treatment response was found among anti-IL-5/IL-5Rα users. Additionally, no associations were observed between BEC, Sp-EOS or FENO and clinical remission across mAb categories. Combining biomarkers did not significantly enhance predictive ability.ConclusionIn patients with SEA treated with anti-IL-4Rα antibodies, pre-treatment FENO may be a good predictor for certain treatment response domains.

Introduction and ObjectivesAsthma is characterised by distinct inflammatory phenotypes, with 50–70% of severe cases involving type-2 (eosinophilic) inflammation. This can be evaluated using fractional exhaled nitric oxide (FeNO) and blood...

Patients with asthma have high levels of Nitric Oxide (NO) in their exhaled breath and elevated blood eosinophil counts. No study identifying the correlation of FeNO and absolute eosinophil count with the level of bronchial asthma control has been done among Filipinos. We determined the correlation between the fractional exhaled Nitric Oxide levels, and absolute blood eosinophil count with levels of asthma control. Spirometry was done for participants who were diagnosed with asthma based on symptoms only. FeNO analysis was performed on the same visit. Eosinophil counts were collected and recorded. Correlation between Asthma severity and FeNO levels was determined and tested using Spearman correlation analysis. The level of significance was set at 0.05. Older age groups (mean age 60) had the tendency to develop uncontrolled asthma, and higher FeNO levels. Higher FeNO levels were strongly correlated with uncontrolled asthma, r=0.78 and was highly sensitive and specific in predicting uncontrolled Bronchial Asthma. On the other hand, the difference in the absolute eosinophil count among the groups was not statistically significant, p=0.90, but still revealed a weak positive correlation, r=0.33. This study was able to ascertain that FeNO levels equal or above 41 ppb is associated with uncontrolled Asthma. Although absolute eosinophil count above or equal to 0.4 ×109/L is sensitive in predicting uncontrolled asthma, this parameter was not specific. Hence, an elevated FeNO measurement is more sensitive in accurately predicting uncontrolled asthma as compared to absolute eosinophil counts.