Clinical Significance of the Increased Peak Levels of Exhaled Nitric Oxide in Patients with Bronchial Asthma.
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Abstract:
We measured exhaled nitric oxide (NO) with a chemiluminescence method to elucidate the clinical significance of the increased concentration of exhaled NO in patients with bronchial asthma. Exhaled NO was measured in 25 patients with bronchial asthma and in 10 healthy control subjects. The concentration of exhaled NO in asthmatics was significantly higher than in the controls (250.4 +/- 30.4,59.9 +/- 9.6 ppb, respectively, p < 0.01). Symptomatic patients (unstable asthmatics) had a higher exhaled NO concentration than did the asymptomatic patients (stable asthmatics) (384.2 +/- 32.5,143.6 +/- 18.8 ppb, respectively, p < 0.01). The exhaled NO concentration was significantly correlated with the peak expiratory flow rate (r = 0.671, p < 0.01) and eosinophil ratio in induced sputum (r = 0.772, p < 0.05), but it was not correlated with the parameters of bronchial hyperactivity (Dmin and PD35 Grs). We conclude that the increased concentration of exhaled NO in patients with bronchial asthma reflects the state of airway inflammation, and we suggest that the measurement of exhaled NO is a useful, non-invasive and simple method for the management of bronchial asthma.Keywords:
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小児気管支喘息における気道炎症レベルの有力なモニター法として呼気中一酸化窒素（Fractional exhaled nitric oxide；FeNO）分析，呼気凝集液（Exhaled Breath Condensate；以下EBCと略）分析に期待が集まる．近年，ポータブル型FeNO測定機が医療機器として承認され，その使用が容易となった．FeNOは喘息の診断のみならず，重症度判定，治反応性等にも応用可能である．EBCに関しては，過酸化水素等酸化ストレスマーカー，ロイコトリエン等エイコサノイド，サイトカイン等の測定が可能である．臨床所見・呼吸機能にFeNO, EBC等のデータを加味して診療を進めることが最良と考える．
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Exhaled NO and nitrite as potential biomarkers in asthma
The measurement of exhaled biomarkers has gained increasing interest in recent years, mainly driven by the unmet clinical need to monitor airway inflammation and the response to anti-inflammatory treatment. The current issue of Thorax contains two important publications in this rapidly growing field. The study by Pijnenburg et al shows how exhaled nitric oxide (NO) measurement can serve clinical practice,1 while the investigation by Marteus et al draws attention to the potential pitfalls of measuring nitrite in exhaled breath condensate (EBC).2
It was hardly more than a decade between the discovery by Gustaffson et al in 1991 that the exhaled breath contains NO and the approval of such a measurement for clinical practice to monitor the effect of anti-inflammatory treatment in asthma.3,4 The road has been paved by approximately 2000 publications on the measurement of the fractional concentration of exhaled nitric oxide (FENO) in health and disease, including three guidelines which provide methodological recommendations by internationally known experts in the field and endorsed by the European Respiratory Society (ERS) and/or the American Thoracic Society (ATS).5–7 By using these recommendations, exhaled NO can be …
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The use of sputum eosinophil count in asthma clinics is rapidly expanding as it has been reported as being a useful indicator of the worsening of asthma symptoms and that its normalisation reduces asthma exacerbations and admissions. Without additional steroids, levels of sputum eosinophils have been shown to be highly variable in severe asthmatic patients. Furthermore, precise patient phenotyping is increasingly becoming important as our understanding of the physiopathology of severe asthma widens. We introduced sputum differential cell counting in our severe asthma clinic, with a view to first reducing sputum eosinophils below 3% by augmenting anti-inflammatory therapy, and attempting steroid withdrawal once patients became sputum eosinophil negative (E−). To date, 264 patients have been investigated for sputum eosinophils, using induction with nebulised sodium chloride if necessary and suitable. This paper presents our yearly update of the anti-inflammatory (steroid) therapy of the first successive patients with at least two successful sputum counts (current n=71), specifically investigating patients’ management in the light of their positive sputum eosinophil levels at baseline assessment. Twenty patients were sputum eosinophil positive (E+) on their initial visit and 25 had reduced eosinophil levels (p=0.001) on a subsequent visit, including 14 becoming E−. Nineteen were offered a trial of steroid augmentation: 11 patients with a trial of IM triamcinolone (all patients had subsequent reduced eosinophils levels, 9 becoming E−, p=0.003); 5 patients with increased oral prednisolone treatment (four patients with reduced eosinophils levels, one becoming E−); 3 with increased inhaled steroid therapy (all with reduced eosinophil levels, 1 becoming E−). 66% of patients with uncontrolled sputum eosinophilia were treated with an increase in anti-inflammatory maintenance therapy. Sputum eosinophil levels decreased for 95% of these as already reported, but only 11/19 achieved full control of sputum eosinophilia with 2/11 failing to normalise eosinophils despite IM triamcinolone (representing a population of confirmed steroid resistance. Sputum eosinophil negativity used as a surrogate marker for asthma control has been shown to be an essential tool in identification and management of patients with asthma at risk of deterioration and admission.
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Exhaled breath condensate (EBC) has been increasingly studied as a noninvasive research method for sampling the alveolar and airway space and is recognized as a promising source of biomarkers of lung diseases. Substances measured in EBC include oxidative stress and inflammatory mediators, such as arachidonic acid derivatives, reactive oxygen/nitrogen species, reduced and oxidized glutathione, and inflammatory cytokines. Although EBC has great potential as a source of biomarkers in many lung diseases, the low concentrations of compounds within the EBC present challenges in sample collection and analysis. Although EBC is viewed as a noninvasive method for sampling airway lining fluid (ALF), validation is necessary to confirm that EBC truly represents the ALF. Likewise, a dilution factor for the EBC is needed in order to compare across subjects and determine changes in the ALF. The aims of this paper are to address the characteristics of EBC; strategies to standardize EBC sample collection and review available analytical techniques for EBC analysis.
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The fractional exhaled nitric oxide(FeNO)has been applied more and more widely in disorders of respiratory system, and is considered to be one of the most promising markers of expiration in monitoring the development and outcome of respiratory inflammatory airway disease.This paper is to review the application and prospect of FeNO in bronchiolitis in children.
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Fractional exhaled nitric oxide; Bronchiolitis; Children; Respiratory syncytial virus
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Asthma is a chronic condition usually characterized by underlying inflammation. The study of asthmatic inflammation is of the utmost importance for both diagnostic and monitoring purposes. The gold standard for investigating airway inflammation is bronchoscopy, with bronchoalveolar lavage and bronchial biopsy, but the invasiveness of such procedures limits their use in children. For this reason, in the last decades there has been a growing interest for the development of noninvasive methods. In the present review, we describe the most important non-invasive methods for the study of airway inflammation in children, focusing on the measure of the fractional exhaled nitric oxide (feNO), on the measure of the exhaled breath temperature (EBT) and on the analysis of both exhaled breath condensate (EBC) and exhaled air (Volatile Organic Compounds, VOCs), using targeted and untargeted approaches. We summarize what is currently known on the topic of exhaled biomarkers in childhood asthma, with a special emphasis on emerging approaches, underlining the role of exhaled biomarkers in the diagnosis, management and treatment of asthma, and their potential for the development of personalized treatments. Among non-invasive methods to study asthma, exhaled breath analysis remains one of the most interesting approaches, feNO and "-omic" sciences seem promising for the purpose of characterizing biomarkers of this disease.
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The exhaled breath condensate (EBC) approach provides a convenient and noninvasive approach for sampling the pulmonary epithelial lining fluid (ELF). Increased EBC concentrations of more than a dozen inflammatory markers and hydrogen ions have been reported in lung diseases associated with inflammation. However, the usefulness of EBC is compromised by uncertainties concerning the sources of the EBC droplets and by the extreme and variable dilution of ELF droplets with condensed water vapor ( approximately 20,000-fold). Reported increases in EBC concentrations may reflect proportionate increases in the total volume rather than the concentration of ELF droplets in the collected samples. Conclusions regarding ELF concentrations can only be made if this dilution is estimated with a dilutional indicator (e.g., conductivity of lyophilized EBC). In normal EBC samples, pH is effectively set by oral contamination with NH(3), and EBC pH cannot provide reliable information regarding ELF pH in normal subjects. Acidification of EBC observed in asthma and other conditions may reflect acidification of ELF, decreases in NH(3) added to the EBC, and/or the presence of gastric droplets in the EBC.
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Summary Background Collection of exhaled breath condensate (EBC) is a simple, non‐invasive method of obtaining samples from the airways and it can be repeated in short intervals without side effects; therefore, it provides an opportunity to monitor the changes in concentration of inflammatory mediators in the airways. However, EBC analysis still has several unresolved issues. Objective To better understand the characteristics of EBC, we compared cysteinyl leukotriene (CysLT) concentrations between bronchoalveolar lavage fluid (BALF) and EBC. We also attempted to correct CysLT concentrations in BALF and EBC diluted with saline and water vapour using biological markers. Methods EBC was collected from 14 patients with idiopathic pulmonary fibrosis before bronchoscopy. We measured CysLT concentrations and also quantified tyrosine, urea and total protein as possible biomarkers for correcting dilution. Results (1) We have validated the quantification of CysLTs in EBC. (2) Although a significant correlation was observed among tyrosine and urea concentrations in BALF, urea and total protein concentrations were below the detection limit in EBC. (3) CysLT concentrations were higher in BALF than in EBC (median, 15.96 pg/mL vs. 5.5 pg/mL; P =0.001) and there was no correlation of CysLT concentrations in BALF with those in EBC. A significant correlation of the ratio of total CysLT concentration to tyrosine concentration (CysLT/Y) in EBC with that in BALF was observed ( r =0.547, P =0.043). (4) CysLT/Y in EBC correlated with serum KL‐6 concentration and total cell count in BALF, and CysLT/Y in BALF also correlated with exhaled NO concentration and %VC. Conclusions CysLT/Y in EBC significantly correlated with that in BALF and some clinical parameters correlated with CysLT/Y. Tyrosine concentration may be used to correct the dilution error for CysLT concentrations, and CysLT/Y in EBC can be a surrogate marker for CysLT concentrations in BALF.
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Introduction: Systematic analysis of markers from exhaled breath condensate (EBC) has become a more and more interesting tool for non-invasive diagnosis of lung and airway diseases. Standardization of EBC collection with respect to collection time and breathing pattern has been achieved by the development of ECoScreen and ECoVent. However, the issues on the pulmonary site in regard to the release of different markers remains still unclear. The aim of the study was to provide the technical tool to assess whether EBC markers are released from the conducting airways or the lung periphery.
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