Marker Of Eosinophilic Inflammation Research Articles

Periostin as a marker of eosinophilic inflammation in patients with asthma and chronic obstructive pulmonary disease

BACKGROUND: Asthma and chronic obstructive pulmonary disease are common chronic respiratory diseases. Given their heterogeneity, the study of periostin is a relevant area for establishing the endotypes of airway inflammation and determining further therapy tactics. AIM: To evaluate periostin levels and determine its significance as a marker of eosinophilic inflammation in patients with asthma and chronic obstructive pulmonary disease. MATERIALS AND METHODS: The study included 59 patients with asthma and 33 patients with chronic obstructive pulmonary disease. The control group consisted of 37 apparently healthy people, comparable in age and sex, without allergic and bronchial obstructive diseases in anamnesis. The anamnesis data, the number of peripheral blood eosinophils and induced sputum, indices of external respiratory function were evaluated. Levels of specific immunoglobulin E to allergens, periostin level were determined in blood serum by immunoenzyme method. The obtained data were processed using STATISTICA 13 and SPSS Statistic 27 software systems. RESULTS: The maximum serum periostin concentration 22.5 (17–38) ng/ml was recorded in the patients with asthma, which was significantly higher than in the chronic obstructive pulmonary disease group [16 (12–21) ng/ml; p = 0.006] and control group [20.1 (14.6–24.8) ng/ml; p = 0.044]. The level of periostin in induced sputum in the patients with asthma was significantly higher than in the chronic obstructive pulmonary disease group — 0.05 (0.03–0.6) ng/ml vs 0.03 (0.02–0.04) ng/ml (p = 0.008). The study revealed the correlation between serum periostin level and eosinophil level (r = 0.406; p 0.05) and with forced expiratory volume in the first second after bronchodilator test (r = 0.366; p 0.05) as well as with forced expiratory volume in the first second divided by forced vital capacity after bronchodilator test (r = 0.572; p 0.05). CONCLUSIONS: Periostin is a promising marker of eosinophilic inflammation in patients with asthma, which can be considered as an indicator of fixed bronchial obstruction and a molecule linking T2-inflammation and airway remodelling. In a group of chronic obstructive pulmonary disease patients, the use of periostin for diagnostic and prognostic purposes requires further investigation and larger studies.

Use of fractional exhaled nitric oxide as a potential predictor of bronchodilator response.

Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV1): positive (BD+) and negative (BD-). Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count (BD+, P = .03; BD-, P = .04) and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127 (95% confidence interval,-0.269 to -0.486) and 0.696 (95% confidence interval, 0.246-0.899; P = .007), respectively. Measuring FENO levels may be useful for identifying patients with BD+.

Galectin-10 as a Potential Biomarker for Eosinophilic Diseases.

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot–Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot–Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases.

Serum Periostin Level in Children with Asthma.

ObjectivesTo determine the average serum periostin level in children with asthma between 6 and 16 y of age, and to find out if the levels correlated with markers of eosinophilic inflammation, asthma control, and severity.MethodsChildren under follow-up at a tertiary care centre were enrolled. Children with conditions causing elevated serum periostin other than asthma, or history of systemic steroid use in the past 6 mo were excluded. Serum total IgE and periostin were estimated by ELISA.ResultsThe median (IQR) serum periostin level was 52.6 (45.4, 58.3) ng/mL. Levels did not vary with age, gender, duration of symptoms, positive family history, or history of exacerbations in the last 6 mo. There was no significant correlation with anthropometric parameters or their z scores, or markers of eosinophilic inflammation in blood including serum total IgE, eosinophil percentage or absolute eosinophil count. There was no difference in median periostin levels of children with different asthma symptom control or asthma severity.ConclusionsIn a group of 26 Indian children with physician-diagnosed asthma, serum periostin showed no significant correlation to markers of eosinophilic inflammation.

Omalizumab Restores Response to Corticosteroids in Patients with Eosinophilic Chronic Rhinosinusitis and Severe Asthma.

Eosinophilic chronic rhinosinusitis (ECRS), which is a subgroup of chronic rhinosinusitis with nasal polyps, is characterized by eosinophilic airway inflammation extending across both the upper and lower airways. Some severe cases are refractory even after endoscopic sinus surgery, likely because of local steroid insensitivity. Although real-life studies indicate that treatment with omalizumab for severe allergic asthma improves the outcome of coexistent ECRS, the underlying mechanisms of omalizumab in eosinophilic airway inflammation have not been fully elucidated. Twenty-five patients with ECRS and severe asthma who were refractory to conventional treatments and who received omalizumab were evaluated. Nineteen of twenty-five patients were responsive to omalizumab according to physician-assessed global evaluation of treatment effectiveness. In the responders, the levels of peripheral blood eosinophils and fractionated exhaled nitric oxide (a marker of eosinophilic inflammation) and of CCL4 and soluble CD69 (markers of eosinophil activation) were reduced concomitantly with the restoration of corticosteroid sensitivity. Omalizumab restored the eosinophil-peroxidase-mediated PP2A inactivation and steroid insensitivity in BEAS-2B. In addition, the local inflammation simulant model using BEAS-2B cells incubated with diluted serum from each patient confirmed omalizumab’s effects on restoration of corticosteroid sensitivity via PP2A activation; thus, omalizumab could be a promising therapeutic option for refractory eosinophilic airway inflammation with corticosteroid resistance.

Predictive significance of arachidonate 15-lipoxygenase for eosinophilic chronic rhinosinusitis with nasal polyps

BackgroundEosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) exhibits a poorer outcome compared with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP), so it is significant to identify effective markers to differentiate ECRSwNP in guiding the treatment strategies of these patients. Although arachidonate 15-lipoxygenase (ALOX15) is positioned as a marker of eosinophilic inflammation, its study in differentiating ECRSwNP has not been reported. The aim of this study is to assess the potential of ALOX15 in distinguishing and predicting ECRSwNP.MethodsForty-eight patients with chronic rhinosinusitis with nasal polyps (CRSwNP), including 30 ECRSwNP and 18 nonECRSwNP patients, were enrolled. ALOX15 mRNA level was determined in polyps by real-time polymerase chain reaction (RT-PCR). The patients’ baseline characteristics were evaluated and analyzed for correlations with ALOX15. Receiver operating characteristic (ROC) curve was used to assess the predictive significance of the potential predictors for ECRSwNP.ResultsALOX15 mRNA level was significantly higher in ECRSwNP patients than in nonECRSwNP patients (P < 0.001). ALOX15 mRNA was significantly correlated with tissue and blood eosinophil percentages (r = 0.565, P < 0.001 and r = 0.395, P = 0.006), olfaction scores (r = 0.400, P = 0.005), total visual analogue scale (VAS) symptom scores (r = 0.383, P = 0.007), ethmoid/maxillary sinus (E/M) ratio (r = 0.463, P = 0.001), and endoscopy scores (r = 0.409, P = 0.004). Logistic regression analysis showed ALOX15 mRNA level and percentage of blood eosinophils to be predictive factors for ECRSwNP (P = 0.004 and P = 0.036, respectively). ROC curve indicated ALOX15 to have high predictive accuracy for ECRSwNP (area under the curve (AUC) = 0.909), which was further improved by combination of ALOX15 with percentage of blood eosinophils (AUC = 0.933).ConclusionsThe relative ALOX15 mRNA level alone or in combination with blood eosinophils might be a reliable biomarker for predicting a diagnosis of ECRSwNP.

The Charcot-Leyden crystal protein revisited-A lysopalmitoylphospholipase and more.

The Charcot-Leyden crystal protein (CLC-P), a constituent of human and not mouse eosinophils, is one of the most abundant proteins within human eosinophils. It has a propensity to form crystalline structures, Charcot-Leyden crystals, which are hallmarks in their distinctive extracellular crystalline forms as markers of eosinophilic inflammation. The functions of CLC-P within eosinophils have been uncertain. Although the action of CLC-P as a lysophospholipase has been questioned, assays of chromatographically purified CLC-P and crystal-derived CLC-P as well as studies of transfected recombinant CLC-P have consistently documented that CLC-P endogenously expresses lysophospholipase activity, releasing free palmitate from substrate lysopalmitoylphosphatidylcholine. Rather than acting solely as a hydrolytic enzyme to release palmitate from a lysolipid substrate, some other lysophospholipases function more dominantly as acyl-protein thioesterases (APTs), enzymes that catalyze the removal of thioester-linked, long chain fatty acids, such as palmitate, from cysteine residues of proteins. As such APTs participate in palmitoylation, a post-translational modification that can affect membrane localization, vesicular transport, and secretion. CLC-P has attributes of an APT. Thus, whereas CLC-P expresses inherent lysophospholipase activity, like some other lysophospholipase enzymes, it likely also functions in regulating the dynamic palmitoylation cycle, including, given its dominant subplasmalemmal location, at the human eosinophil's plasma membrane.

Periostin concentration in exhaled breath condensate in children with mild asthma

Objective Periostin is considered to be a marker of eosinophilic inflammation in patients with asthma. However, there are no literature data on exhaled breath condensate (EBC) periostin level in pediatric patients with asthma. The aim of this study was to analyze EBC periostin concentration in children with mild asthma and to evaluate the potential usefulness of EBC periostin level as a biomarker for the disease. Methods EBC and serum periostin concentrations were measured by enzyme-linked immunosorbent assay in 23 children with asthma and 23 healthy controls. Results EBC periostin concentration was 250- to 780-fold lower than that found in serum. No significant differences between serum nor EBC periostin concentration in asthmatics and the control group were showed. The comparison between children with Th2 and non-Th2 type of asthma did not show significant differences in periostin concentration, both in serum and EBC. Serum periostin concentration inversely correlated with BMI and age not only in asthma patients but also in controls. Conclusions In children with mild asthma, periostin may be measured not only in serum but also in EBC. The low periostin level in patients with mild asthma and lack of difference between asthmatic subjects and controls indicate that EBC periostin may not be useful as an asthma biomarker in this group.

Diagnosis of Bronchial Asthma in Children 3–6 Years Old by Using Serum Periostin and Surrogate Markers of Eosinophilic Inflammation (Blood Eosinophils and Total IgE): a Cross-Sectional Study

Background. It is difficult to diagnose bronchial asthma (BA) in children under the age of 6 due to the limited ability to study respiratory function. Therefore, it is relevant to search for such diagnostic markers of BA that do not require the active participation of a child.Objective. Our aim was to assess the diagnostic value of serum periostin levels in comparison with surrogate markers of eosinophilic inflammation (total IgE and blood eosinophils) for the diagnosis of BA in preschool children.Methods. A cross-sectional study included children 3–6 years of age with BA and healthy peers. The levels of serum periostin (ELISA), total IgE (chemiluminescent method), blood eosinophils (counted on a hematological analyzer) were determined. To study the diagnostic value of peripheral blood parameters ROC-analysis was used.Results. Children with BA (n = 56) compared with the healthy group (n = 29) showed higher levels of serum periostin (median and quartile) — 5.7 (3.4, 8.0) and 2.7 (1, 7; 3.6) ng/ml (p &lt; 0.001), total IgE — 180 (122; 622) and 55 (45; 87) IU/ml (p &lt; 0.001), blood eosinophils — 6.1% (3.8; 8.0) and 3.6% (2.7; 4.1) (p &lt; 0.001). The area under the ROC curve (AUC) for serum periostin was 0.81 (95% CI 0.73–0.89), for total IgE — 0.86 (95% CI 0.77–0.92), for blood eosinophils — 0.77 (95% CI 0.67–0.86). Independent predictors of serum periostin were total IgE and the number of exacerbations of BA over the past 12 months &gt; 2 (R2 = 0.527).Conclusion. The level of serum periostin in preschool children with BA is higher than in their healthy peers. The diagnostic value of serum periostin in BA is in the range from moderate to good and is comparable to that for the levels of blood eosinophils and total IgE.

Nasal eosinophilia and eosinophil peroxidase in children and adolescents with rhinitis.

BackgroundResearchers have shown that eosinophil peroxidase (EPO) is a relatively accurate marker of eosinophilia and eosinophil activity. However, its use as a marker of eosinophilic inflammation in nasal secretions is limited because the diagnostic cutoff values of EPO for use as a one-time test for allergic diseases such as allergic rhinitis have not been established.PurposeTo identify the correlation between nasal eosinophil count and EPO in children and adolescents with rhinitis.MethodsWe recruited patients <18 years of age with rhinitis for more than 2 weeks or more than 2 episodes a year whose nasal eosinophil and EPO were measured at a single allergy clinic. The eosinophil percentage was calculated by dividing the eosinophil count by the number of total cells under light microscopy at ×1,000 magnification. EPO and protein were measured from nasal secretions. We retrospectively analyzed the correlation between nasal eosinophils and protein-corrected EPO (EPO/protein) value.ResultsOf the 67 patients enrolled, 41 were male (61.2%); the mean age was 8.2±4.0 years. The median nasal eosinophil count was 1 and percentage was 1%. The median protein-corrected EPO value was 12.5 ng/μg (range, 0–31 ng/μg). There was a statistically significant correlation between eosinophil count and percentage (P<0.001). However, the eosinophil percentage and EPO did not correlate. The eosinophil count and EPO had a statistically significant correlation (P =0.01). The EPO cutoff value examined for nasal eosinophil counts of 2, 5, 10, and 20 was 17.57 ng/μg regardless of the reference count. The largest area under the curve value was obtained when the receiver operating characteristic curve was drawn using the eosinophil count of 2.ConclusionNasal eosinophil count was significantly associated with protein-corrected EPO.

The Role of FeNO in Predicting Asthma.

Asthma-like symptoms like wheezing and dyspnea affect 1 in every 3 preschool children. An easily available biomarker that predicts later asthma or unfavorable lung growth in these children may be helpful in targeting the right child with the right drugs and avoiding exposure to potentially harmful drugs in others. The fraction of exhaled nitric oxide (FeNO) has been suggested as a marker of eosinophilic inflammation. FeNO can be measured in a standardized way from the age of 4 but several methods have been developed to measure FeNO also in younger children. Several studies have assessed the predictive value of FeNO in preschool wheezing children for asthma later in life. These studies have shown that FeNO may be helpful in defining different preschool wheezing phenotypes, and in assessing the risk of later asthma or impaired lung growth. However, data are conflicting on the added value over clinical parameters. In two studies in school children, high FeNO was predictive for asthma development during follow up and also predicted lower lung function growth. In school children with respiratory symptoms suggestive of asthma, particularly in atopic children, FeNO has diagnostic value for an asthma diagnosis, mostly for ruling in asthma. There are not enough data to assess if FeNO has a predictive value for lung development in school children.

The profile of respiratory pathogens in induced sputum of elderly and non-elderly asthmatics.

IntroductionRespiratory pathogens are thought to be involved in the pathogenesis and exacerbations of asthma at all ages; however, little is known about the airway microbiome in the elderly.Aim of the studyTo identify respiratory pathogens in the induced sputum (IS) of elderly asthmatics, and to determine the association between pathogens and the markers of asthma activity.Material and methodsTwenty-nine subjects with stable asthma, 15 above 65 years of age and 14 aged 30-49 years, underwent clinical evaluation, fractional exhaled nitric oxide measurement, and sputum induction. Pathogens were detected by multiplex reverse transcription polymerase chain reaction. The periostin concentration of IS supernatants was measured by enzyme-linked immunosorbent assay. Serum eosinophil cationic protein and total IgE levels were measured by Immun^oCAP.ResultsElderly patients, as compared to non-elderly, had significantly higher eosinophilia in IS, although other markers of eosinophilic inflammation were comparable. Half of the subjects were positive for Haemophilus influenzae. Chlamydophila pneumoniae was found in two subjects. Respiratory viruses were detected in more than 70% of patients. The detection rates and profiles of atypical bacteria and respiratory viruses were similar in both groups. Only in the elderly asthmatics was influenza A positivity associated with lower predicted FVC%, RSV A positivity connected with decreased tIgE concentration, and RSV B positivity related to a lower percentage of lymphocytes in IS.ConclusionsDespite the existence of differences in some clinical and inflammatory characteristics of asthma between elderly and non-elderly asthmatics, the pathogen detection rates in the IS from the two groups are similar.

Macrophage Phagocytosis and Allergen Avoidance in Children With Asthma.

Background and Objective: Airway macrophages perform the crucial functions of presenting antigens, clearing pathogens, and apoptotic cells. Macrophage phagocytosis is increased in adults with mild asthma and allergen exposure is known to activate macrophages. However, it is not clear whether the mechanism behind this is due to a primary defect or environmental factors such as allergen or lipopolysaccaride (LPS) exposure. Our aim was to assess the phagocytic function of airway macrophages in children with mild to moderate asthma after residence in a low allergen\\LPS environment at high altitude.Methods: Sputum induction was performed in children with asthma at baseline and after residence for a 3 weeks' period at a high-altitude asthma center that has very low ambient allergen levels. The markers of eosinophilic inflammation (including percentage of macrophage cytoplasm with red hue) and phagocytosis of fluorescein isothiocyanate-labeled, heat-killed Staphylococcus aureus by airway macrophages was analyzed. Internalized bacteria were quantified using confocal microscopy.Results: The median bacterial count [mean (standard deviation)] per macrophage was significantly lower [39.55 (4.51) vs. 73.26 (39.42) (p = 0.006)] after residence at high altitude. No association was observed between markers of eosinophilic inflammation and bacterial phagocytosis.Conclusions: The results suggest that the mechanism behind the enhanced phagocytosis of bacteria in childhood asthma may be secondary to allergen or possibly LPS exposure.

Bacterial biogeography of adult airways in atopic asthma

BackgroundPerturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma.ResultsBacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p < 0.001), compositional similarity was greatest for BB-IS, particularly in AAs and ANAs. The abundance of genera detected in BB correlated with those detected in IS and OW (r median [IQR] 0.869 [0.748–0.942] and 0.822 [0.687–0.909] respectively), but not with those in NB (r = 0.004 [− 0.003–0.011]). The number of taxa shared between IS-BB and NB-BB was greater in AAs than in HCs (p < 0.05) and included taxa previously associated with asthma.Of the genera abundant in NB, only Moraxella correlated positively with abundance in BB; specific members of this genus were shared between the two compartments only in AAs. Relative abundance of Moraxella in NB of AAs correlated negatively with that of Corynebacterium but positively with markers of eosinophilic inflammation in the blood and BAL fluid. The genus, Corynebacterium, trended to dominate all NB samples of HCs but only half of AAs (p = 0.07), in whom abundance of this genus was negatively associated with markers of eosinophilic inflammation.ConclusionsInduced sputum is superior to nasal brush or oral wash for assessing bronchial microbiota composition in asthmatic adults. Although compositionally similar to the bronchial microbiota, the microbiota in induced sputum are distinct, reflecting enrichment of oral bacteria. Specific bacterial genera are shared between the nasal and the bronchial mucosa which are associated with markers of systemic and bronchial inflammation.

Sensitization to Staphylococcus aureus enterotoxins in smokers with asthma

BackgroundSensitization to Staphylococcus aureus enterotoxins (SEs) augments eosinophilic inflammation in asthma. Recent epidemiologic studies demonstrate that sensitization to SEs is increased in healthy smokers; however, there is no evidence on the association between sensitization to SEs and eosinophilic inflammation in smokers with asthma. ObjectiveTo clarify the role of SEs on clinical indexes, including eosinophilic inflammation and lung function in smokers with asthma. MethodsThe frequency of atopic sensitization to SEs was examined in adult patients with asthma. In current or ex-smokers with asthma, the association of sensitization to SEs with eosinophilic inflammation, airflow limitation, or treatment steps was determined. Clinical indexes were examined at the first visit, and treatment steps were assessed 6 months after enrollment. ResultsOverall, 23 current smokers, 40 ex-smokers, and 118 never smokers with asthma were enrolled. The frequency of sensitization to SEs, but not to other aeroallergens, was significantly higher in current, ex-, and never smokers, in decreasing order. In current or ex-smokers with asthma, patients with sensitization to SEs exhibited higher serum levels of total and specific IgE to aeroallergens, higher blood eosinophil counts, greater airflow limitation, and more severe disease 6 months later than those without sensitization to SE. A longer smoking abstinence period was associated with serum specific IgE levels to SEs, and 3 years was the best cutoff of abstinence period to predict the absence of sensitization to SEs. ConclusionSensitization to SEs is increased in smokers with asthma, and it may be a marker of eosinophilic inflammation and severe asthma in smokers with asthma. Trial Registrationumin.ac.jp Identifier: UMIN000007818.

Exhaled nitric oxide levels to guide treatment for children with asthma.

Asthma guidelines aim to guide health practitioners to optimise treatment for patients to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise health using minimum doses. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation and tailoring asthma medications in accordance to airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations, or both. To evaluate the efficacy of tailoring asthma interventions based on fractional exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is, management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines (or both), for asthma-related outcomes in children. We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and reference lists of articles. The last searches were in June 2016. All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on FeNO levels compared to those not using FeNO, that is, management based on clinical symptoms or asthma guidelines (or both) involving children. We reviewed results of searches against predetermined criteria for inclusion. Two review authors independently selected relevant studies, assessed trial quality and extracted data. We contacted study authors for further information with responses provided from three. The review included nine studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut-off levels used (12 parts per billion (ppb) to 30 ppb), the way in which FeNO was used to adjust therapy and duration of study (6 to 12 months). Of 1426 children randomised, 1329 completed the studies. The inclusion criteria for the participants in each study varied but all had a diagnosis of asthma. There was a significant difference in the number of children having one or more asthma exacerbations over the study period, they were significantly lower in the FeNO group in comparison to the control group (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.45 to 0.75; 1279 participants; 8 studies). The number needed to treat for an additional beneficial outcome (NNTB) over 52 weeks was 9 (95% CI 6 to 15). There was no difference between the groups when comparing exacerbation rates (mean difference (MD) -0.37, 95% CI -0.8 to 0.06; 736 participants; 4 studies; I2 = 67%). The number of children in the FeNO group requiring oral corticosteroid courses was lower in comparison to the children in the control group (OR 0.63, 95% CI 0.48 to 0.83; 1169 participants; 7 studies; I2 = 0%). There was no statistically significant difference between the groups for exacerbations requiring hospitalisation (OR 0.75, 95% CI 0.41 to 1.36; 1110 participants; 6 studies; I2 = 0%). There were no significant differences between the groups for any of the secondary outcomes (forced expiratory volume in one second (FEV1), FeNO levels, symptom scores or inhaled corticosteroid doses at final visit). The included studies recorded no adverse events.Three studies had inadequate blinding and were thus considered to have a high risk of bias. However, when these studies were removed in subgroup analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'Number of participants who had one or more exacerbations over the study period') to very low (for the outcome 'Exacerbation rates'), based on lack of blinding, statistical heterogeneity and imprecision. In this updated review with five new included studies, tailoring asthma medications based on FeNO levels (in comparison with primarily guideline management) significantly decreased the number of children who had one or more exacerbations over the study period but did not impact on the day-to-day clinical symptoms or inhaled corticosteroid doses. Therefore, the use of FeNO to guide asthma therapy in children may be beneficial in a subset of children, it cannot be universally recommended for all children with asthma.Further RCTs need to be conducted and these should encompass different asthma severities, different settings including primary care and less affluent settings, and consider different FeNO cut-offs.

Exhaled nitric oxide levels to guide treatment for adults with asthma.

Asthma guidelines aim to guide health practitioners to optimise treatment for patients so as to minimise symptoms, improve or maintain good lung function, and prevent acute exacerbations or flare-ups. The principle of asthma guidelines is based on a step-up or step-down regimen of asthma medications to maximise good health outcomes using minimum medications. Asthma maintenance therapies reduce airway inflammation that is usually eosinophilic. Tailoring asthma medications in accordance with airway eosinophilic levels may improve asthma outcomes such as indices of control or reduce exacerbations or both. Fractional exhaled nitric oxide (FeNO) is a marker of eosinophilic inflammation, and as it is easy to measure, has an advantage over other measurements of eosinophilic inflammation (for example sputum eosinophils). To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide (FeNO), in comparison to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both, for asthma-related outcomes in adults. We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and reference lists of articles. The last searches were undertaken in June 2016. All randomised controlled trials (RCTs) comparing adjustment of asthma medications based on exhaled nitric oxide levels compared to not using FeNO, that is management based on clinical symptoms (with or without spirometry/peak flow) or asthma guidelines or both. We reviewed results of searches against predetermined criteria for inclusion. We independently selected relevant studies in duplicate. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information, receiving responses from four. We included seven adult studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cutoff levels used (15 to 35 ppb), the way in which FeNO was used to adjust therapy, and duration of study (4 to 12 months). Of 1700 randomised participants, 1546 completed the trials. The mean ages of the participants ranged from 28 to 54 years old. The inclusion criteria for the participants in each study varied, but all had a diagnosis of asthma and required asthma medications. In the meta-analysis, there was a significant difference in the primary outcome of asthma exacerbations between the groups, favouring the FeNO group. The number of people having one or more asthma exacerbations was significantly lower in the FeNO group compared to the control group (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.43 to 0.84). The number needed to treat to benefit (NNTB) over 52 weeks was 12 (95% CI 8 to 32). Those in the FeNO group were also significantly more likely to have a lower exacerbation rate than the controls (rate ratio 0.59, 95% CI 0.45 to 0.77). However, we did not find a difference between the groups for exacerbations requiring hospitalisation (OR 0.14, 95% CI 0.01 to 2.67) or rescue oral corticosteroids (OR 0.86, 95% CI 0.50 to 1.48). There was also no significant difference between groups for any of the secondary outcomes (FEV1, FeNO levels, symptoms scores, or inhaled corticosteroid doses at final visit).We considered three included studies that had inadequate blinding to have a high risk of bias. However, when these studies were excluded from the meta-analysis, the difference between the groups for the primary outcomes (exacerbations) remained statistically significant. The GRADE quality of the evidence ranged from moderate (for the outcome 'exacerbations') to very low (for the outcome 'inhaled corticosteroid dose at final visit') based on the lack of blinding and statistical heterogeneity. Six of the seven studies were industry supported, but the company had no role in the study design or data analyses. With new studies included since the last version of this review, which included adults and children, this updated meta-analysis in adults with asthma showed that tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreased the frequency of asthma exacerbations but did not impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose. Thus, the universal use of FeNO to help guide therapy in adults with asthma cannot be advocated. As the main benefit shown in the studies in this review was a reduction in asthma exacerbations, the intervention may be most useful in adults who have frequent exacerbations. Further RCTs encompassing different asthma severity, ethnic groups in less affluent settings, and taking into account different FeNO cutoffs are required.

Asthma-COPD Overlap Syndrome (ACOS): Single disease entity or not? Could exhaled nitric oxide be a useful biomarker for the differentiation of ACOS, asthma and COPD?

Asthma and chronic obstructive pulmonary disease (COPD) represent two major public health problems. However, there is a significant proportion of patients with a mixed asthma-COPD phenotype. This condition is defined as asthma-COPD overlap syndrome (ACOS). Since there are no internationally accepted criteria for the diagnosis of that syndrome, its management remains difficult. Given the fact that patients with ACOS have an increased risk of exacerbation and hospitalization, there is a pressing need for a more targeted approach and better management. We propose that fractional exhaled nitric oxide (FeNO), a marker of eosinophilic inflammation, could help clinicians differentiate ACOS from asthma and COPD. We evaluate this hypothesis, using data derived from the existing literature.

Both exhaled nitric oxide and blood eosinophil count were associated with mild allergic asthma only in non-smokers.

The fractional exhaled nitric oxide (FENO) and the blood eosinophil count (B-eos) are markers of eosinophilic inflammation used in the diagnosis and management of asthma. The relationships between smoking cigarette and both FENO and B-eos are complex and raise questions about the association between these markers and asthma in smokers. To determine the relationships between both FENO and B-eos on one hand and asthma and atopy on the other, according to smoking status. FENO and B-eos were measured in, respectively, 1579 and 1496 of the 1607 middle-aged adults randomly selected from the general population in the cross-sectional ELISABET survey. Allergic asthma was defined as asthma (a self-report of physician-diagnosed asthma, and wheezing in the previous 12months or the use of asthma medications) with atopy (allergic rhinitis or hayfever in the previous 12months, or a previous positive prick test or allergen desensitization therapy). Non-allergic asthma was defined as asthma without atopy. The analysis included 812 (51.4%) never, 473 (30%) former and 294 (18.6%) current smokers. A total of 490 (32%) participants were atopic, 80 (5.1%) had allergic asthma, and 31 (2%) had non-allergic asthma. Only 16.2% (18/111) of asthmatics were treated with glucocorticoid inhalants, suggesting that among them a majority of participants had mild asthma. A positive interaction between smoking status and allergic asthma was observed in multivariate models explaining FENO (P=0.003) and B-eos (P=0.001). Thus, compared to those without allergic asthma, participants with allergic asthma had higher FENO values (+63.4%, 95% CI=[39; 92]) and higher B-eos (+63.2% [38.2; 92.7]) in never and former smokers, but not in current smokers. Lastly, an analysis of receiver-operating characteristic curves showed that each of the two markers was able to discriminate moderately allergic asthma but only in non-smokers. FENO and B-eos were associated with the presence of mild allergic asthma only in non-smokers, not in current smokers. These findings raise questions about the clinical value of FENO and B-eos in smokers.

Cross-shift Reduction in Fractional Exhaled Nitric Oxide among Cement Workers

Objective: Assessment of changes in fractional exhaled nitric oxide (FENO) across the shift was performed among cement production workers and controls. FENO was used as a possible marker of eosinophilic inflammation in the airways. In addition, the relations between personal total dust exposure and FENO changes across the work shift were examined. Methods: Pre-and post-shift FENO levels were determined among 55 non-smoking dust exposed cement production workers and among 31 non-smoking mineral water factory workers as controls. The FENO levels were examined for three consecutive days among the exposed and two consecutive days among controls. Personal total dust levels were collected in the breathing zone of each participant using cellulose acetate filters on the first day of FENO examination. A three-piece Millipore cassette was used to place the filters and the cassette was connected to a Side Kick Cassela pump at a flow rate of 2 l/minute. Results: There was a statistically significant reduction in FENO levels among exposed workers, but not among controls. The reduction in FENO levels among the exposed was observed on each day of FENO examination. The cross-shift reduction in FENO levels among the exposed did not show possible associations with personal total dust exposure levels (r=-0.175, 95% CI: -0.36, 0.04). The geometrical mean for total dust exposure were 8.3 mg/m3 and 0.28 mg/m3, among exposed workers and controls, respectively. Conclusion: The results show a cross-shift reduction of FENO among cement workers and indicate that dust exposure is not associated with this finding. The reason for the reduction in FENO across the shift is unknown. Researchers in this field should be aware of potential unknown confounders when performing future studies.