Surrogate Marker Of Airway Inflammation Research Articles

Combination of Exhaled Breath Analysis with Parallel Lung Function and FeNO Measurements in Infants.

Breath analysis by secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) offers the possibility to measure comprehensive metabolic profiles. The technology is currently being deployed in several clinical settings in Switzerland and China. However, patients are required to exhale directly into the device located in a dedicated room. Consequently, clinical implementation in patients incapable of performing necessary exhalation maneuvers (e.g., infants) or immobile (e.g., too weak, elderly, or in intensive care) remains a challenge. The aim of this study was to develop a method to extend such breath analysis capabilities to this subpopulation of patients by collecting breath samples remotely (offline) and promptly (within 10 min) transfer them to SESI-HRMS for chemical analysis. We initially assessed the method in adults by comparing breath mass spectra collected offline with Nalophan bags against spectra of breath samples collected in real time. In total, 13 adults provided 176 pairs of real-time and offline measurements. Lin's concordance correlation coefficient (CCC) was used to estimate the agreement between offline and real-time analyses. Here, 1249 mass spectral features (55% of total detected) exhibited Lin's CCC > 0.6. Subsequently, the method was successfully deployed to analyze breath samples from infants (n = 16), obtaining as a result SESI-HRMS breath profiles. To demonstrate the clinical feasibility of the method, we measured in parallel other clinical variables: (i) lung function, which characterizes the breathing patterns, and (ii) nitric oxide, which is a surrogate marker of airway inflammation. As a showcase, we focused our analysis on the exhaled oxidative stress marker 4-hydroxynonenal and its association with nitric oxide and minute ventilation.

Upper and lower airway inflammation in severe asthmatics: a guide for a precision biologic treatment.

Background and aims:Severe asthma may require the prescription of one of the biologic drugs currently available, using surrogate markers of airway inflammation (serum IgE levels and allergic sensitization for anti-IgE, or blood eosinophils for anti-IL5/IL5R). Our objective: to assess upper and lower airway inflammation in severe asthmatics divided according to the eligibility criteria for one of the target biologic treatments.Methods:We selected 91 severe asthmatics, uncontrolled despite high-dose ICS-LABA, and followed for >6 months with optimization of asthma treatment. Patients underwent clinical, functional and biological assessment, including induced sputum and nasal cytology. They were then clustered according to the eligibility criteria for omalizumab or mepolizumab/benralizumab.Results:Four clusters were selected: A (eligible for omalizumab, n = 23), AB (both omalizumab and mepolizumab, n = 26), B (mepolizumab, n = 22) and C (non-eligible for both omalizumab and mepolizumab, n = 20). There was no difference among clusters for asthma control (Asthma Control Test and Asthma Control Questionnaire 7), pre-bronchodilator forced expiratory volume in 1 s, serum IgE and fractional exhaled nitric oxide levels. Sputum eosinophils were numerically higher in clusters AB and B, in agreement with the higher levels of blood eosinophils. Allergic rhinitis was more frequent in clusters A and AB, while chronic rhinosinusitis with nasal polyps prevalence increased progressively from A to C. Eosinophils in nasal cytology were higher in clusters AB, B and C.Conclusion:Eosinophilic upper and lower airway inflammation is present in the large majority of severe asthmatics, independently from the prescription criteria for the currently available biologics, and might suggest the use of anti-IL5/IL5R or anti IL4/13 also in patients without blood eosinophilia.The reviews of this paper are available via the supplemental material section.

SYMPTOM-GUIDED APPROACH FOR ALLERGIC RHINITIS TREATMENT AUGMENTED WITH POWDER METHYLCELLULOSE SEALANT

Introduction Powder methyl-cellulose (hydroxyl-propyl-methyl-cellulose powder, pHPMC) insufflated intra-nasally in subjects with rhinitis symptoms used after other locally applied drugs prolongs and enhances their pharmacological effects. Based on this approach on objective measures of efficacy, we propose an algorithm to manage patients with moderate/severe allergic rhinitis. Methods 22 patients sensitized to grass pollen had their in-season symptoms treated by intra-nasal drugs following a set of simple recommendations: squirt oxymetazoline if the nose is totally plugged; squirt azelastine if rhinorrhea/itching/sneezing are prevalent; squirt mometasone if all symptoms are present. Patients could also make a mix of any of the drugs. They were randomized to use after any drug application a puff of either HPMC or powder lactose (placebo). Symptoms were assessed by visual-analogue scale (VAS). The pre- and in-season objective outcomes were peak nasal expiratory flow (PNIF), saccharine test (ScchT) and exhaled breath temperature (EBT, a surrogate marker of airway inflammation). The before-/in-season differences were computed and compared. Results The before-/in-season differences for PNIF and EBT favored the HPMC group vs. placebo: PNIF -53.3±0.06 (mean±s.e.m.) vs. - 26.5±0.04[L/min], P=0.037; EBT 0.24±0.15 vs. -0.46±0.20[°C], P=0.010. There was no statistical difference for ScchT (P=0.448). HPMC appears to augment the local therapeutic responses by suppressing symptoms, nasal congestion (PNIF) and airway inflammation (EBT), while still preserving normal cilia beat (ScchT). Conclusions Proper patient instructions on to how manage their symptoms using HPMC as a sealant for nasal drugs significantly improves seasonal allergic rhinitis management.

Fractional Exhaled Nitric Oxide (FeNO) in the Screening and Diagnosis Work-Up of Occupational Asthma

FeNO is a simple non-invasive tool used as a surrogate marker of airway inflammation in the management of asthma. FeNO has been assessed in several populations of workers exposed to high- and low-molecular weight agents. However, there are many confounding factors to consider in the interpretation of FeNO. As such, its use in the investigation of occupational asthma (OA) has yielded inconsistent results. In screening studies of OA to high molecular weight (HMW) agents, an increase of FeNO over time has been associated with the development of bronchial hyperresponsiveness (BHR). When used in the investigation of OA, increases in FeNO show high positive predictive values for a positive specific inhalation challenge (SIC) to HMW agents. Subjects with high specific IgE to their workplace allergens seem to present higher increases in FeNO than subjects without specific IgE to causal agent. Changes in FeNO have less frequently been observed in studies of OA to low molecular weight (LMW) agents than OA to HMW agents, except for isocyanate-induced OA. Cluster analyses of patients exposed to various HMW and LMW agents have documented significant increases of FeNO in clusters of patients with OA to HMW agents, but not LMW. Recent studies have provided useful information for improving our understanding of the pathophysiology of exhaled NO in OA despite the previously reported conflicting results. Future studies are still required to clarify its role in the screening, investigation, and management of OA.

NIOX VERO: Individualized Asthma Management in Clinical Practice

As we move toward an era of precision medicine, novel biomarkers of disease will enable the identification and personalized treatment of new endotypes. In asthma, fractional exhaled nitric oxide (FeNO) serves as a surrogate marker of airway inflammation that often correlates with the presence of sputum eosinophils. The increase in FeNO is driven by an upregulation of inducible nitric oxide synthase (iNOS) by cytokines, which are released as a result of type-2 airway inflammation. Scientific evidence supports using FeNO in routine clinical practice. In steroid-naive patients and in patients with mild asthma, FeNO levels decrease within days after corticosteroid treatment in a dose-dependent fashion and increase after steroid withdrawal. In difficult asthma, FeNO testing correlates with anti-inflammatory therapy compliance. Assessing adherence by FeNO testing can remove the confrontational aspect of questioning a patient about compliance and change the conversation to one of goal setting and ways to improve disease management. However, the most important aspect of incorporating FeNO in asthma management is the reduction in the risk of exacerbations. In a recent primary care study, reduction of exacerbation rates and improved symptom control without increasing overall inhaled corticosteroid (ICS) use were demonstrated when a FeNO-guided anti-inflammatory treatment algorithm was assessed and compared to the standard care. A truly personalized asthma management approach—showing reduction of exacerbation rates, overall use of ICS and neonatal hospitalizations—was demonstrated when FeNO testing was applied as part of the treatment algorithm that managed asthma during pregnancy. The aim of this article is to describe how FeNO and the NIOX VERO® analyzer can help to optimize diagnosis and treatment choices and to aid in the monitoring and improvement of clinical asthma outcomes in children and adults.

Exhaled nitric oxide in relation to asthma control: A real-life survey

BackgroundAsthma is characterised by chronic airway inflammation, a complex cascade of events, mostly sustained by eosinophil recruitment and activation. Fractional exhaled nitric oxide (FeNO) is a surrogate marker of airway inflammation closely associated with bronchial eosinophilia. FeNO is used to define asthma phenotype, to assess eosinophilic inflammatory severity and to predict corticosteroid responsiveness. ObjectiveThe aim of this study was to investigate whether FeNO may be associated with some clinical and functional factors in asthmatics evaluated in a real life setting. MethodsGlobally 363 patients (150 males, mean age 46.3 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including comorbidities, physical examination, body mass index (BMI), lung function, asthma control grade, asthma control test (ACT), and FeNO. ResultsFeNO values were significantly higher in patients with poorly controlled asthma (p<0.01), asthma symptoms (p=0.015), wheezing (p<0.001), rhinitis diagnosis, (p=0.049) and rhinitis symptoms (p=0.019), but lower in patients with GERD (p=0.024) and pneumonia history (p=0.048). FeNO values increased in patients with the lowest corticosteroid dose (p=0.031). FeNO values>25ppb were associated with poorly controlled asthma (OR 3.71), asthma signs (OR 3.5) and symptoms (OR 1.79). A FeNO value cut-off of 29.9ppb was fairly predictive of (AUC 0.7) poorly controlled asthma. ConclusionsFeNO assessment in clinical practice may be a useful tool for monitoring asthmatics as it is associated with several clinical factors, including asthma control.

Exhaled Nitric Oxide as a Marker of Lung Involvement in Crohn's Disease

Crohn's disease is an inflammatory bowel disease associated with a variety of systemic manifestations, including large and small airway involvement. The latter is most often a subclinical one, and requires expensive and invasive diagnostic approaches. Nitric oxide (NO) can be detected non-invasively in the exhaled air (eNO) and be considered as a surrogate marker of airway inflammation. eNO tested at multiple expiratory flows can be used to distinguish the alveolar concentration of NO (CalvNO) from the total amount of fractional eNO (FeNO). The aim of our study is to compare FeNO and concentration of alveolar nitric oxide (CalvNO) levels and to assess their relationship with pulmonary involvement in Crohn's patients differing in clinical stage and therapeutic regimens versus a group of healthy subjects. Thirty Crohn's patients not showing clinical evidence of pulmonary diseases and 21 non-smoking, non-atopic healthy controls were enrolled. FeNO (14.9±10.2 ppb vs 10.1±6.3 ppb, p=0.049) and CalvNO (4.4±2.2 ppb vs 2.6±1.9; p=0.006) values were found to be significantly higher in Crohn's patients than in healthy controls. Both FeNO and CalvNO correlated positively with the Crohn's Disease Activity Index. In conclusion, our results for FeNO and CalvNO confirm the presence of subclinical pulmonary involvement in Crohn's disease. eNO measurement may be of clinical value in the follow-up of Crohn's patients.

Serial Exhaled Nitric Oxide Measurements With a Portable NO Analyzer in Healthy Obstructive Sleep Apnea Patients

PURPOSE: Upper airway inflammation has been implicated in the pathogenesis of obstructive sleep apnea (OSA) and may be linked to cardiovascular consequences. Fractional exhaled nitric oxide (FeNO), a surrogate marker of airway inflammation, measured non-invasively with non-portable machines has been shown inconsistently to be high in OSA patients and decreased following continuous positive airway pressure (CPAP) therapy. Using a recently FDA approved portable NIOX MINO (r) NO analyzer (aerocrine; Sweden), we examined FeNO levels in otherwise healthy OSA patients and assessed its utility as a bedside monitoring tool.

Increase in Exhaled Nitric Oxide Is Associated with Bronchial Hyperresponsiveness among Apprentices

Airway inflammation is a hallmark of asthma. Several studies have validated the use of the fractional concentration of exhaled nitric oxide (Fe(NO)) as a surrogate marker of airway inflammation in asthma. We examined how the change in Fe(NO) levels, since the beginning of occupational exposure, could be associated with the incidence of bronchial hyperresponsiveness (BHR) among baker, pastry maker, and hairdresser apprentices during their 2-year training. A standardized questionnaire was administered; skin prick tests for common and specific occupational allergens were done; methacholine challenge and measurement of Fe(NO) were performed 6, 12, and 15 months after the first examination. Of 441 apprentices initially included, 351 completed the study. The increase in Fe(NO), since the beginning of exposure, was associated with the incidence of BHR (odds ratio, 2.00 [95% confidence interval, 1.21-3.32] per unit increase in log parts per billion) both in atopic and nonatopic subjects. The average increase in Fe(NO) was similar in atopic and nonatopic subjects and was unrelated to past or current smoking habits, sex, or training track. Atopy in bakers/pastry makers and sensitization to alkaline persulfates in hairdressers were also independently associated with the incidence of BHR. BHR occurred sooner among bakers/pastry makers than among hairdressers, but its incidence leveled off later. Our results suggest that measurement of Fe(NO), a simple and reproducible test, could be useful in the screening of BHR in workers newly exposed to agents known to cause occupational asthma.

Exhaled Breath Temperature Increases during Mild Exacerbations in Children with Virus-Induced Asthma

Background: Exhaled breath temperature (EBT) has been suggested as a non-invasive surrogate marker of airway inflammation in asthma. The aim of the study was to evaluate differences in EBT between periods of controlled disease and during exacerbations in children with virus-induced asthma. Methods: Twenty-nine children (aged 6–14 years) with a history of intermittent, virus-induced asthma were included in this case-control study. Cases presented with a common cold and/or mild exacerbation of asthma, while controls were free of asthmatic or common cold symptoms during the previous 6 weeks. A baseline questionnaire was obtained. Atopy assessment, central temperature and a spirometric measurement were recorded. EBT was measured with a new device (Delmedica, Singapore). A nasal wash (for identification of common respiratory viruses) was obtained. Results: Twenty-four children (12 from each group) completed the study. Groups were homogeneous with respect to baseline characteristics. PCR revealed the presence of a virus in 3 out of 17 controls and 10 out of 12 cases (17.6 and 83.3%, respectively, p = 0.002). The most commonly identified virus was rhinovirus (3/3 controls and 7/10 cases, p = 0.02). EBT values were significantly higher for cases (34.91 ± 0.62°C) compared to controls (34.18 ± 1.1°C, p = 0.032). No important differences were observed in the increase rate of EBT (Δe°T) between groups. Conclusions: Changes in airway inflammation during virus-induced asthma exacerbations are reflected in EBT changes. These preliminary data suggest a possible role of EBT measurements in the assessment of airway inflammation in children with virus-induced asthma.

Toward a Personalized Pharmacotherapy of Respiratory Diseases

Toward a Personalized Pharmacotherapy of Respiratory Diseases

High sensitivity C-reactive protein in asthma

Asthma is characterised by chronic inflammation of the airways, but the relevance of high-sensitivity assays for C-reactive protein (hs-CRP), which are known to be a sensitive marker of low-grade systemic inflammation, has not been fully studied in asthma. The objective was to examine serum hs-CRP levels in patients with asthma and their relationship to clinical characteristics and degree of airway inflammation. Serum hs-CRP levels were cross-sectionally examined in steroid-naive (n = 22) and steroid-inhaling (n = 23) adult patients with asthma and healthy controls (n = 14). All were nonsmokers. Serum hs-CRP levels were significantly increased in steroid-naive patients (mean+/-sd 1.33+/-1.48 mg.L(-1)) compared with controls (0.21+/-0.30 mg.L(-1)), but not in patients on inhaled corticosteroid. Among steroid-naive patients, serum hs-CRP levels significantly negatively correlated with indices of pulmonary function (forced expiratory volume in one second/forced vital capacity and forced mid-expiratory flow) and positively with sputum eosinophil count. Among patients on inhaled corticosteroid, hs-CRP levels did not correlate with any indices. In conclusion, an increase in serum C-reactive protein levels measured by high-sensitivity assays may be associated with airflow obstruction and airway inflammation, and may serve as a surrogate marker of airway inflammation in asthma.

The usefulness of inflammatory markers in monitoring treatment responses in asthma

The usefulness of inflammatory markers in monitoring treatment responses in asthma

No impairment of peripheral deposition in novel asthmatics treated with an MDI corticosteroid with spacer

Pulmonary distribution and lung functions were evaluated during a 4-month inhaled corticosteroid treatment period in 10 steroid-naı̈ve novel asthmatics with normal or slightly reduced lung functions. Patients were given a total daily dose of 1000 μg of beclomethasone dipropionate aerosol twice a day via a pressured metered dose inhaler with a large-volume chamber device (Volumatic, GlaxoSmithKline, U.K.). Gamma lung scintigraphy and lung function tests were performed before and after 2 months and 4 months. Inhaled 99mTc-labelled beclomethasone dipropionate liposomes were used to assess lung deposition patterns during inhaled steroid therapy. Serum eosinophil cationic protein (ECP) concentration was used as a surrogate marker of asthmatic inflammation. Following beclomethasone treatment, all lung functions were enhanced, but only FVC values showed significant improvement. The FEV 1/FVC ratio remained slightly reduced in spite of inhaled corticosteroid therapy. However, the association between changes in improved FVC values and reduced ECP levels proved to be statistically significant. In lung scintigraphy, no evidence of changes in pulmonary deposition patterns were seen during the follow-up period. We conclude that inhaled corticosteroid therapy can lead to improvements in lung functions and surrogate markers of airway inflammation in novel asthma without affecting the peripheral deposition pattern of aerosols.

The editors' choice

The editors' choice

Surrogate markers of airway inflammation: inflammometry in paediatric respiratory medicine

Until recently, there has not been any practical way to assess airway inflammation non-invasively in paediatrics. Surrogate markers of airway inflammation are potentially of great importance in the diagnosis and monitoring of inflammatory airways disease in children. A large number of substances in blood, urine and exhaled air or induced sputum are currently under study to evaluate their possible usefulness as markers of airway inflammation. To be useful, a marker should be valid, preferably non-invasive, quick, reproducible, repeatable and cheap. In addition, markers should be studied in relation to their specific purpose because different markers may be useful for different types of airway inflammation. Few, if any, markers will fulfill all these requirements. Most research has focused on applications of markers in asthma, some data refer to cystic fibrosis, infections and ciliary dyskinesia. Of all surrogate markers, exhaled nitric oxide has been studied the most and seems to offer information that should be evaluated for its relevance to clinical practice. Before introducing markers of inflammation into daily practice, analysis of benefits and costs are needed. There is little doubt that 'inflammometry' will be a major step forward and will be useful in differentiating airways diseases and improving treatment.

Effects of adding a leukotriene antagonist or a long-acting beta 2-agonist in asthmatic patients with the glycine-16 beta 2-adrenoceptor genotype

PURPOSE: In the United Kingdom, about 40% of patients with asthma are homozygous for the glycine-16 beta 2-adrenoceptor polymorphism, which predisposes them to agonist-induced down-regulation and desensitization of the beta 2-adrenoceptor. We assessed the effects of adding treatment with either a long-acting beta 2-agonist (inhaled formoterol, 12 μg twice daily) or a leukotriene receptor antagonist (oral zafirlukast, 20 mg twice daily) to inhaled corticosteroid therapy in patients with this genotype. SUBJECTS AND METHODS: We enrolled 24 patients with mild to moderate asthma who were being treated with inhaled corticosteroids. Patients were randomly assigned to receive one of three treatments (placebo, zafirlukast, or formoterol in addition to inhaled corticosteroids) for 1 week each in a crossover fashion, separated by a 1-week placebo run-in and washout period. Measurements of bronchoprotection (measured as the provocative dose of methacholine that produced a 20% decline in forced expiratory volume in 1 second [FEV 1]), exhaled nitric oxide (a surrogate marker of airway inflammation), and symptoms were made before each treatment and 12 hours after the last dose of each treatment. RESULTS: Both formoterol and zafirlukast were equally effective in maintaining asthma control compared with placebo: the geometric mean-fold difference in the methacholine provocative dose was 1.5-fold (95% confidence interval [CI]: 1.1- to 2.2-fold) for zafirlukast and 1.9-fold (95% CI: 1.2- to 2.9-fold) for formoterol. As compared with placebo, zafirlukast caused a significant suppression in exhaled nitric oxide (1.7-fold difference in geometric mean values, 95% CI: 1.1- to 2.6-fold) but formoterol did not (1.2-fold difference, 95% CI: 0.8- to 1.9-fold). Diary cards showed significant ( P <0.05) improvements in the peak flow with formoterol (morning and evening) and zafirlukast (evening) as compared with placebo. CONCLUSIONS: Formoterol and zafirlukast maintained asthma control in patients who might be genetically predisposed to fare worse with long-acting beta 2-agonists. The reduction in exhaled nitric oxide with zafirlukast suggests that it may have anti-inflammatory effects in addition to those seen with inhaled corticosteroids.

Dose–response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma

PURPOSE: Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose–response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function. SUBJECTS AND METHODS: After a 10-day placebo run-in, we evaluated the effects of 200 μg, 400 μg, and 800 μg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 ± 12 years (mean ± SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 am and after stimulation with human corticotropin releasing factor. RESULTS: For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 μg (low dose) and 800 μg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 μg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 μg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose. CONCLUSIONS: In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.