Non-invasive Assessment Of Airway Inflammation Research Articles

Phénotypage de l’asthme professionnel par la réalisation d’expectoration induite après test d’exposition spécifique

RationaleAlthough the non-invasive assessment of airway inflammation through the induced sputum (IS) technique identified distinct asthma phenotypes, there is few information on the determinants of airway inflammatory pattern in sensitizer-induced occupational asthma (OA). AimTo investigate whether the pattern of airway inflammation in IS is associated with distinct clinical phenotypes of OA. MethodsThis retrospective multicentric study was conducted among 372 patients with OA confirmed by a positive specific inhalation challenge (SIC) who were recruited in the European network for the Phenotyping of OCupational Asthma cohort (2006–2018). Each patient underwent an analysis of IS before and 24 hours after the SIC. Sputum eosinophilia and neutrophilia were defined by the presence of≥3% eosinophils and≥76% neutrophils in sputum samples collected after the SIC. ResultsIn total, 268 (72%) and 42 patients (11%) exhibited sputum eosinophilia and neutrophilia, respectively. Multivariate logistic regression analysis revealed that eosinophilia was associated with exposure to a high molecular weight agent (odds ratio [OR], 1.89; 95% CI, 1.18–3.04), moderate asthma (OR, 3.17; 95% CI, 1,43–7.0) and severe asthma (OR, 2.39; 95% CI, 1.06–5.43). Sputum neutrophilia was associated with age (OR for each additional year, 1.04; 95% CI, 1.01–1.08), male gender (OR, 2.74; 95% CI, 1,21–6.8), mild asthma (OR, 3.26; 95% CI, 1.24–8.88), and dysphonia (OR, 2.83; 95% CI, 1.14–6.87). ConclusionsSputum eosinophilia post-SIC was predominant in OA patients. Sputum eosinophilia and neutrophilia were associated with distinct clinical phenotypes of OA, especially in terms of causal agents and asthma severity.

Tidal‐breathing measurement of exhaled breath temperature (EBT) in schoolchildren

Non-invasive assessment of airway inflammation is particularly useful in children. The exhaled breath temperature (EBT) may reflect inflammatory vasodilation and serve to assess respiratory symptoms and therapy with inhaled corticosteroids (ICs). To compare EBT with other non-invasive measurements in unselected schoolchildren in relation to respiratory symptoms and IC-therapy, as well as to assess reproducibility, and potentially influencing factors. In 298 Italian schoolchildren, we assessed tidal-EBT, FE(NO), spirometry, skin-prick tests, questionnaires on chronic respiratory symptoms, and medication. Subjects were divided as follows: reported wheeze, respiratory symptoms other than wheeze, and without symptoms. Subjects with reported wheeze (n = 30) more frequently presented atopy, respiratory symptoms, higher FE(NO), lower lung function than subjects with symptoms other than wheeze (n = 141) and those without symptoms (n = 127), but had a similar EBT. IC-treated children (5 wheeze, 9 respiratory symptoms other than wheeze, 4 without chronic symptoms) had lower median (interquartile range) EBT levels than IC-untreated children (n = 280) [EBT: 31.7 (30.1-32.5) vs. 32.6 (31.4-33.4), P = 0.027]. Duplicate EBT measurements were highly reproducible (ICC = 0.94). In a multiple linear-regression model, EBT was explained by age, weight, duration of EBT measurement, FE(NO), and ambient temperature (r = 0.63, P < 0.001). Tidal-EBT measurements are easy to perform, reproducible, though symptom misclassification may affect the results obtained regarding the effect of IC therapy. Factors influencing EBT should be addressed in further epidemiological studies.

Exhaled breath temperature in healthy children is influenced by room temperature and lung volume

Exhaled breath temperature (EBT) has been proposed for the non-invasive assessment of airway inflammation. Previous studies have not examined the influence of room temperature or lung size on the EBT. This study aimed to address these issues in healthy children. We assessed the effects of room temperature and lung volume in 60 healthy children aged 9-11 years (mean age 10.3 years, 33 male). Static lung volumes were assessed using multiple breath nitrogen washout. Questionnaire and skin prick tests were also used to establish respiratory health in the children. We obtained the EBT parameters of slope, end plateau temperature (PLET) and normalized plateau temperature (nPLET; plateau temperature minus inspired air temperature), and ascertained physiological factors influencing EBT. End plateau temperature was shown to be proportionally affected by room temperature (r = 0.532, P < 0.001) whereas slope and nPLET decreased with increasing room temperature (r = -0.392 P < 0.02 and r = -0.507 P = 0.002). After adjusting for room temperature, height and age, the total lung capacity (r(2) = 0.435, P = 0.006) and slow vital capacity (SVC; r(2) = 0.44, P = 0.005) were found to be the strongest predictors of end PLET in healthy children. When all factors were included in a multiple regression model, SVC and room temperature were the only predictors of plateau and nPLET. Slope was only influenced by room temperature. Exhaled breath temperature measurements are highly feasible in children with a 95% success rate in this healthy population. Room temperature and SVC significantly influence EBT variables in healthy children. Further studies are required to investigate the ability of EBT to assess airway inflammation in children with respiratory disease. Pediatr. Pulmonol. 2011; 46:1062-1068. © 2011 Wiley Periodicals, Inc.

Exhaled Breath Condensate in Asthma: From Bench to Bedside

The need for non-invasive assessment of airway inflammation is imperative, since inflammatory airway diseases, such as asthma and COPD, are characterized by variation in their clinical presentation throughout their course. Exhaled breath condensate (EBC) collection represents a rather appealing method that can be used to conveniently and noninvasively collect a wide range of volatile and non-volatile molecules from the respiratory tract, without affecting airway function or inflammation. Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values. A large number of mediators of inflammation, oxidative and nitrosative stress, including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, prostanoids, nitrogen oxides, peptides and cytokines, have been studied in EBC. This review focuses mainly on the presentation of the above biomarkers in asthma as well as on the effect of various factors on their concentrations. Concentrations of such mediators have been shown to be related to the underlying asthma and its severity and to be modulated by therapeutic interventions. Despite the encouraging positive results up-to-date, the introduction of EBC in everyday clinical practice requires the work-out of some methodological pitfalls, the standardization of EBC collection, and finally the identification of a reliable biomarker which is reproducible, has normal values and provides information for the underlying inflammatory process and the response to treatment. So far none of the parameters studied in EBC fulfils the aforementioned requirements.

696 Study of Some Inflammatory Markers in Children with Moderate Persistent Bronchial Asthma Before and After Therapy with Inhaled Corticosteroids

Inhaled corticosteroids is the mainstay of bronchial asthma therapy (BA) because it targets the underlying airway inflammation. This study included 30 children aged 5-15 years with moderate persistent asthma. The aim was to study some inflammatory markers (sputum eosinophils SE, AEC, eosinophilic cationic protein ECP, and TNF- ∼) and measurement FEV1/FVC as an indicator of obstructive airway disease. The measurements were done 3 times for the patients and once for 20 age and sex matched healthy children (control group). The first sample was taken in both groups before start of therapy. The second was done for the patients after 3 months of ICS and the third was taken with reappearance of symptoms of BA during or after complete withdrawal of ICS over 4 months. Our patients in the pretreatment sample had significantly higher levels of sputum eosinophis, AEC, ECP, TNF- ∼, and FEV1/FVC compared to the control Compared to the pretreatment values these values except AEC decreased significantly after 3 months of ICS. Relapse occurred in 25 patients during withdrawal of the ICS therapy and only 5 patients remained asymptomatic after complete stoppage of the treatment. Relapse was associated with significant increase in the levels of TNF-∼ and SE in the third sample compared to the second sample. We conclude that non-invasive assessment of airway inflammation is enough to monitor children with BA. ICS is an effective tool against this inflammation. TNF-∼ followed by sputum eosinophils are sensitive predictors of relapse in the children withBA.

Exhaled carbon monoxide in asthmatics: a meta-analysis

BackgroundThe non-invasive assessment of airway inflammation is potentially advantageous in asthma management. Exhaled carbon monoxide (eCO) measurement is cheap and has been proposed to reflect airway inflammation and oxidative stress but current data are conflicting. The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control.MethodsA systematic search for English language articles published between 1997 and 2009 was performed using Medline, Embase and Cochrane databases. Observational studies comparing eCO in non-smoking asthmatics and healthy subjects or asthmatics before and after steroid treatment were included. Data were independently extracted by two investigators and analyzed to generate weighted mean differences using either a fixed or random effects meta-analysis depending upon the degree of heterogeneity.Results18 studies were included in the meta-analysis. The eCO level was significantly higher in asthmatics as compared to healthy subjects and in intermittent asthma as compared to persistent asthma. However, eCO could not distinguish between steroid-treated asthmatics and steroid-free patients nor separate controlled and partly-controlled asthma from uncontrolled asthma in cross-sectional studies. In contrast, eCO was significantly reduced following a course of corticosteroid treatment.ConclusionseCO is elevated in asthmatics but levels only partially reflect disease severity and control. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics.

Biomarkers in the Exhaled Breath Condensate of Healthy Adults: Mapping the Path Towards Reference Values

The need for non-invasive assessment of airway inflammation is imperative, since inflammatory airway diseases, such as asthma and COPD, are characterized by variation in their clinical presentation throughout their course. Exhaled breath condensate (EBC) collection represents a rather appealing method that can be used to conveniently and noninvasively collect a wide range of volatile and non-volatile molecules from the respiratory tract, without affecting airway function or inflammation. Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values. The large number of measurable biomarkers and the diversity of the used methodologies are some of the points that hamper its wide clinical application. This review focuses mainly on the presentation of normal values of the most widely studied EBC markers as reported by investigators that have used healthy subjects as controls or as a basic study population. These biomarkers include hydrogen peroxide, NO-related products, arachidonic acid metabolites and pH. From those biomarkers, the only one with established reference values in healthy subjects is EBC pH, whereas the majority of the rest need further refinement and standardization of the methodologies used. Different subpopulations and the effect of various factors on healthy subjects are also reported, in an effort to delineate future directions that may lead to the establishment of reference values.

Non-Invasive Assessment of Airway Inflammation in Ship-Engine Workers

Smoking is harmful for respiratory function. In young to middle-aged men the damage is insidious and difficult to demonstrate. The respiratory impairment could increase under specific stressful conditions in the professional environment. On the hypothesis that exhaled markers are useful for assessing airway susceptibility to inhaled irritants, we measured exhaled markers and lung function in smoking and non-smoking engine-driver military coastguards before and after a patrol at sea. Eighteen men, mean age 39 yrs (range 23-58 yrs), 8 smokers, underwent spirometry, exhaled and nasal nitric oxide (eNO, nNO), exhaled carbon monoxide (CO) and exhaled breath condensate (EBC) for measures of hydrogen peroxide (H2O2), leukotriene B4 (LTB4), proteins (Prots), 8-isoprostanes (8-IsoPs), nitrite (NO2-) and nitrosothiols (RS-NOs) at baseline and after an 8-hour patrol navigation on board small, high-speed diesel-powered ships. At baseline, the smokers showed higher middle flows and CO levels, lower eNO and nNO than non-smokers, but similar levels of EBC markers; geometric means (95% confidence interval), CO: 23.6 (14.5 to 38.3) vs. 3.5 (2.5 to 5.3) ppm; eNO: 7.9 (4.8 to 12.9) vs. 26.7 (15.7 to 45.5) ppb, p=0.000. After navigation, Prots, 8-IsoPs and RS-NOs (but not lung function variables or other markers) significantly increased only in smokers; baseline vs post-navigation RS-NOs: 0.27 (0.11 to 0.65) vs. 1.30 (0.58 to 2.89) micromol, p=0.012. The respiratory consequences of a stressing environment in engine-driver military coastguards who actively smoke are better assessed by measuring EBC markers than by eNO, nNO or lung function. By increasing airway inflammation from oxidative-stress, tobacco smoking appears to interact with other chemical or physical factors elicited during sea navigation. Precisely what these factors are deserves further investigation.

Non-Invasive Assessment of Airway Inflammation in Asthma: An Overview

The goals of asthma management are the accurate diagnosis and effective control of symptoms, prevention of exacerbations and the achievement and preservation of best pulmonary function. Despite improvements in asthma care patients are still misdiagnosed or undertreated. The reason for this is simple, asthma is a heterogeneous disease, but in most primary and secondary care settings only one facet, variable airflow obstruction, is addressed. The two other main aspects of asthma, airway inflammation and airway hyperresponsiveness, remain under-utilized in both diagnosis and treatment of asthma. Treatment algorithms based on airway hyperresponsiveness have been successfully used to reduce asthma exacerbations but at the expense of more corticosteroid use. Using a non-invasive marker of airway inflammation has also been shown to reduce exacerbations compared with a control group following current guidelines, but with similar steroid dose between both groups and with comparative symptom and quality of life measures. There are various non-invasive markers of airway inflammation (as opposed to bronchial biopsy and bronchoalveolar lavage). This article will concentrate on the use of the two most clinically important methods of assessing airway inflammation, namely induced sputum and exhaled nitric oxide. It will evaluate the indications, practicalities and use for each method and discuss future areas for research. Keywords: corticosteroid, sputum eosinophilia, NO synthases (NOS), airway hyper responsiveness, bronchodilators

Ion trap liquid chromatography/tandem mass spectrometry analysis of leukotriene B4 in exhaled breath condensate

The objective of this study is the measurement of leukotriene B7 (LTB4), a potent inflammatory mediator, in exhaled breath condensate by using liquid chromatography/mass spectrometry (LC/MS and LC/MS/MS). Condensation of exhaled breath is a non-invasive method to collect airway secretions. Deuterated (d4)-LTB4 was used as internal standard. The MS and MS/MS behavior of LTB4 and LTB4-d4 was studied by electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) in both positive and negative ion polarity mode. Preliminary results show that monitoring negative ions in ESI mode has the best sensitivity for both LTB4 and LTB4-d4. Therefore, negative ESI was chosen, and the [M-H]- ions at m/z 335 and 339 were selected for quantification. The lower limit of quantification for LTB4, expressed as the lowest point of the calibration curve, was 100 pg/mL. Using this technique, we measured LTB4 in exhaled breath condensate in two healthy subjects, four asthmatic patients on anti-inflammatory treatment, and four asthmatic patients who were not on anti-inflammatory drugs. Exhaled LTB4 concentrations were detected only in asthmatic patients who were not on anti-inflammatory therapy. This method is potentially useful for non-invasive assessment of airway inflammation, but the sensitivity of the technique needs to be improved.

The Relationship of Induced-Sputum Inflammatory Cells to BAL and Biopsy

Airway inflammation in severe asthma may indicate prognosis and guide therapy. Noninvasive assessment of airway inflammation using induced sputum (IS) could allow monitoring of response to therapy. The late fraction of IS has been reported to sample the distal lung more than the early fraction.1 We examined whether early IS collection (E-IS; first 10 min) and late IS collection (L-IS; second 10 min) of differentials correlated with BAL and endobronchial biopsy inflammatory cells in normal subjects, and subjects with mild, moderate, and severe asthma.

Non-invasive assessment of airway inflammation in occupational lung diseases.

The clinical investigation of occupational asthma is currently based on the demonstration of functional changes after exposure to occupational agents, but it does not yet include any monitoring of airway inflammation, one of the hallmarks of this disease. Methods permitting a non-invasive assessment of airway inflammation, such as induced sputum and exhaled nitric oxide, are currently under investigation for research purposes in occupational asthma. Their role in clinical practice has not yet been established. The advantages and limitations of these methods for occupational airway diseases, and more particularly occupational asthma, are discussed in this review.

Noninvasive assessment of airway inflammation in children: induced sputum, exhaled nitric oxide, and breath condensate

Noninvasive markers of airway inflammation are needed for use in research and clinical practice in childhood asthma. Induced sputum and exhaled nitric oxide are well established as direct markers of inflammation for use in asthma research. Sputum can be induced from children of &gt;6 yrs using inhalation of hypertonic saline, and, if appropriate, can be combined with an assessment of airway responsiveness to hypertonic saline. The success rate of sputum induction in children is 68-100%. Most studies have processed sputum using the plug selection method, and show that the dominant cell in sputum from normal children is the macrophage, and that the upper normal limit for sputum eosinophils in children is 2.5%. The inflammatory response in childhood asthma is characterized by elevated numbers of sputum eosinophils, and eosinophil cationic protein concentration, as well as increased nitric oxide and hydrogen peroxide levels in exhaled breath. Sputum eosinophils correlate with objective markers of disease severity in steroid-naive children with asthma, and in severe asthma. Inflammatory marker levels are lower in children using glucocorticosteroids. Induced sputum and exhaled gases are important markers of inflammation in childhood asthma. The clinical utility of these markers warrants further study.