Assessing airway inflammation: from guessing to quantitative measurements

Diagnosing asthma and following the response to treatment have relied on lung function measurements. Improved knowledge of the cellular events leading to airflow limitation has led to new clinical methods to assess the inflammatory component of the disease. Induced sputum analysis and exhaled nitric oxide (NO) measurements are already tools for clinical practice. New cell-specific inflammatory markers and further innovations in the testing of exhaled air, e.g. breath condensates and technical development of simple methods and devices, will also benefit the busy practitioner in near future. Assessing airway inflammation by quantitative measurements, instead of guessing, will also strengthen the role of anti-inflammatory medication as first-line treatment of asthma, even in its mildest forms.     

护理干预在呼出气一氧化氮测定哮喘患者气道炎性反应评估中的作用

目的探讨规范化护理干预在呼出气一氧化氮（FENO）测定哮喘患者气道炎性反应评估中的作用。方法将62例哮喘患者随机分为干预组32例和对照组30例,2组均在治疗前后行呼出气一氧化氮测定。对照组给予常规方法测定,干预组在常规方法基础上给予护理干预。对2组患者的测定舒适状况、满意度、治疗疗效进行对比分析。结果测定舒适度、满意度交及治疗的疗效干预组明显优于对照组,差异有统计学意义。结论规范化护理干预在呼出气一氧化氮测定中可排除检测中的不良干扰,提高测定水平的准确性,对于改善哮喘患者临床症状、缓解气道炎性反应有—定的的临床指导意义,值得推荐使用。     

Traditional and new approaches to asthma monitoring

Once the diagnosis of asthma is established, monitoring must be implemented to achieve asthma control. Because of the variability of asthma, monitoring is a long-term commitment to effectively adjust treatment and assure that therapy goals are met. This paper reviews the definition of asthma control, including the dimensions of impairment and risk, and the 2007 National Asthma Education and Prevention Program's Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma, recommendations for periodic assessment and monitoring of effective control. New approaches to asthma monitoring, such as airway hyperresponsiveness, sputum eosinophils, exhaled nitric oxide, and pharmacogenetic measurements, will be critiqued.     

Markers of lung disease in exhaled breath: nitric oxide

Management of airway inflammation requires proper monitoring and treatment to improve long-term outcomes. However, achieving this goal is difficult, as current methods have limitations. Although nitric oxide (NO) was first identified 200 years ago, its physiological importance was not recognized until the early 1980s. Many studies have established the role of NO as an essential messenger molecule in body systems. In addition, studies have demonstrated a significant relationship between changes in exhaled NO levels and other markers of airway inflammation. The technique used to measure NO in exhaled breath is noninvasive, reproducible, sensitive, and easy to perform. Consequently, there is growing interest in the use of exhaled NO in the management of asthma and other pulmonary conditions. The purpose of this review is to promote a basic understanding of the physiologic actions of NO, measurement techniques, and ways that research findings might translate to future application in clinical practice. Specifically, the article will review the role of exhaled NO in regard to its historical background, mechanisms of action, measurement techniques, and implications for clinical practice and research.     

DASH for asthma: A pilot study of the DASH diet in not-well-controlled adult asthma

This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n = 90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months, followed by at least monthly phone consultations for another 3 months. Follow-up assessments will occur at 3 and 6 months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1 second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management.     

Solving insomnia electronically: Sleep treatment for asthma (SIESTA): A study protocol for a randomized controlled trial

BackgroundChronic insomnia is associated with poor asthma control. Cognitive-behavioral treatment for insomnia (CBT-I) is an efficacious and durable treatment for comorbid insomnia in medical and psychiatric disorders. However, the efficacy and potential accompanying mechanisms of CBT-I have not been examined in asthma. The purpose of this study is to test the efficacy of a CBT-I intervention on sleep and asthma control in adults with insomnia and asthma. We will also explore airway inflammation (i.e., exhaled nitric oxide, blood eosinophils) as a potential biological mechanism linking improvements in sleep with improvements in asthma control.MethodsThe study is a single center, parallel group, randomized controlled trial. Two hundred and ten adults with insomnia and asthma that is not well-controlled will be randomized to either a 9-week Internet-based CBT-I program (Sleep Healthy Using the Internet (SHUTi)) or an enhanced usual care condition which utilizes an online educational video about insomnia. The primary sleep outcome is insomnia severity measured by the Insomnia Severity Index. Secondary sleep outcomes are sleep quality and wrist actigraph-recorded sleep parameters. Asthma control will be assessed by the Asthma Control Test, Asthma Quality of Life Questionnaire, pulmonary function testing, and self-report of asthma exacerbations and asthma-related healthcare utilization. Treatment outcomes will be measured at baseline, 9 weeks, and 6 months.DiscussionThis trial has the potential to identify a novel strategy for improving asthma control. Findings may advocate for the inclusion of treatment of comorbid insomnia into current asthma management practice guidelines.     

孟鲁司特钠联合布地奈德福莫特罗粉吸入剂治疗支气管哮喘的临床效果及其对患者炎性因子水平、肺功能、免疫功能的影响

目的探讨孟鲁司特钠联合布地奈德福莫特罗粉吸入剂治疗支气管哮喘的临床效果及其对患者炎性因子水平、肺功能、免疫功能的影响。方法将150例支气管哮喘患者根据治疗方法分为对照组和试验组,各75例。对照组在常规治疗基础上使用布地奈德福莫特罗粉吸入剂,试验组在对照组的基础上再联合孟鲁司特钠片进行治疗。比较两组的治疗效果、炎症因子水平、免疫功能、肺功能及不良反应发生情况。结果试验组的治疗总有效率高于对照组(P<0.05);治疗后,两组的TNF-α、IL-5、IgE水平均低于治疗前,IgA和IgG水平、PEF、FEV1、FEV1/FVC均高于治疗前,且试验组优于对照组(P<0.05);两组的不良反应总发生率无显著差异(P>0.05)。结论孟鲁司特钠联合布地奈德福莫特罗粉吸入剂治疗支气管哮喘患者的临床疗效显著,可以有效降低机体的炎症因子水平,改善肺功能和免疫功能,同时不会增加不良反应的发生率,值得临床推广应用。     

Exhaled Nitric Oxide Levels during Acute Asthma Exacerbation

Objectives: Fractional exhaled nitric oxide (FE_NO) has been shown in laboratory settings and trials of patients with stable asthma to correlate with the degree of airway inflammation. The authors hypothesized that the technique of measuring FE_NO would be reproducible in the setting of acute asthma in the emergency department (ED) and that the FE_NO results during ED visits would potentially predict disposition, predict relapse following discharge, and correlate with the National Institutes of Health (NIH) asthma severity scale and peak expiratory flow measurements. Methods: The authors prospectively measured FE_NO in a convenience sample of ED patients with acute exacerbations of asthma, both at the earliest possible opportunity and then one hour later. Each assessment point included triplicate measurements to assess reproducibility. The authors also performed spirometry and classified asthma severity using the NIH asthma severity scale. Discharged patients were contacted in 72 hours to determine whether their asthma had relapsed. Results: The authors discontinued the trial (n= 53) after a planned interim analysis demonstrated reproducibility (coefficient of variation, 15%) substantially worse than our a priori threshold for precision (4%). There was no association between FE_NO response and corresponding changes in spirometry or clinical scores. Areas under the receiver operating characteristic curves for the prediction of hospitalization and relapse were poor (0.579 and 0.713, respectively). Conclusions: FE_NO measurements in ED patients with acute asthma exacerbations were poorly reproducible and did not correlate with standard measures of asthma severity. These results suggest that using existing technology, FE_NO is not a useful marker for assessing severity, response to treatment, or disposition of acute asthmatic patients in the ED.     

Differences between adult and childhood asthma

During the last 2 decades, we have gained new insights into the pathogenesis of asthma; consequently, new therapeutic agents and approaches to therapy have emerged. Nevertheless, significant gaps remain in our understanding of this disease. Important new treatment issues affect childhood (the usual time of asthma onset), and researchers have recently described increases in asthma incidence in children. Yet, most clinical studies have been performed with adults, and our knowledge about major determinants of childhood asthma remains incomplete. Major challenges in pediatric asthma include methods of easily assessing lung function and noninvasive methods of assessing asthma's inflammatory nature. Research that addresses the mechanisms responsible for disease onset is also critical to decrease the prevalence of asthma. What we know about adult asthma cannot be used in the treatment of children without further study, but it is now clear that effective treatment should begin during childhood. (J Allergy Clin Immunol 2000;106:S153-7.)     

Biological markers in diagnosing, monitoring, and treating asthma: a focus on noninvasive measurements

Asthma is a major concern for society, healthcare professionals, and individuals and families directly affected by asthma due to rising morbidity rates and costs associated with the disease. The pathological hallmark of asthma is airway inflammation that is considered to be a major cause of exacerbations and persistent structural alterations of the airways. Assessing airway inflammation is important for investigating the underlying mechanisms of the disease and possibly for following the progression and resolution of the disease. The presence and type of airway inflammation can be difficult to detect clinically, and may result in delays in initiating appropriate therapy. The purpose of this article is to review noninvasive methods for assessing biological markers of airway inflammation and their potential role in the future for diagnosing, monitoring, and treating asthma. The article reviews the noninvasive measurements of induced sputum and exhaled nitric oxide as indicators of airway inflammation.     

The alpine climatotherapy of bronchial asthma patients]

As many as 132 patients with bronchial asthma were examined for the clinical, functional and laboratory parameters before and during alpine climatotherapy at a height of 3200 m above the sea level (the Tyuya-Ashu pass, the northern Tien Shan). In addition to the improvement of the general status, the patients manifested amelioration of ventilation and decreased responsiveness of the bronchial tree by the end of alpine climatotherapy. Favourable alterations in the immune parameters together with appreciable stimulation of steroidogenesis in the adrenals were discovered. Investigation into surface activity of the exhaled air condensate revealed activation of the surfactant system. These data and endoscopy with bronchoalveolar lavage confirmed the reduction of the inflammatory lesions in the tracheobronchial tree. Therefore, alpine climatotherapy produces a favourable effect on the main mechanisms of the disease development and can be used on a wider basis for the treatment of patients suffering from bronchial asthma.     

Clinical asthma syndromes and important asthma mimics

Asthma is a heterogeneous disorder with multiple clinical phenotypes. Phenotypes can be grouped into clinical or physiological, trigger-defined, and inflammatory phenotypes. Treatment based on inflammatory phenotyping improves clinical measures of asthma morbidity. Further study of individual asthma phenotypes will improve understanding of their immunologic and pathologic characteristics and improve diagnosis and therapy. Because asthma is a common disorder with nonspecific presenting features, other disorders are often misdiagnosed as asthma. A high index of suspicion for alternative diagnoses must be maintained when evaluating a patient who presents with clinical features suggestive of asthma, particularly if the patient presents with atypical symptoms or fails to respond to therapy.     

呼出气一氧化氮测定在支气管哮喘诊断和管理中的价值

慢性气道炎症是支气管哮喘的本质。临床上急需能客观准确地反映气道炎症的炎性标志物来指导哮喘的诊断和管理,呼出气一氧化氮(FeNO)测定是一种符合临床需要的快速检测方法,现就FeNO在哮喘诊断、气道炎症监测、哮喘严重程度评级及预测哮喘发作等方面的研究进展做一综述。     

靶向Th17细胞免疫治疗中重度哮喘的作用

支气管哮喘（简称哮喘）是多种炎症细胞和炎性介质参与的慢性气道炎症性疾病。Thl/Th2免疫反应失衡是哮喘主要的发病机制,而嗜酸粒细胞性气道炎症和气道高反应性为哮喘的显著临床特征。Th17细胞通过活化和募集中性粒细胞,促进气道炎症发生发展,尤其与中重度哮喘密切相关。Th17细胞为中重度哮喘提供了潜在的治疗靶点。深入研究Th17细胞分化调控机制,有望为治疗中性粒细胞性哮喘带来新的愿景。     

Increased bronchial nitric oxide production in patients with asthma measured with a novel method of different exhalation flow rates

The concentration of nitric oxide (NO) in exhaled air is increased in patients with asthma, suggesting that measuring fractional exhaled NO concentration (FE(NO)) may be used to monitor asthmatic airway inflammation. However, increased FE(NO) is not specific for asthma, as other inflammatory lung diseases may also increase FE(NO). To augment the specificity of FE(NO) measurement, we tested a novel theoretical modelling of pulmonary NO dynamics that allows the approximation of alveolar NO concentration and bronchial NO flux separately by measuring FE(NO) at several exhalation flow rates. We measured FE(NO) at four exhalation flow rates in 10 steroid-naive asthmatics, 5 patients with extrinsic allergic alveolitis, and in 10 healthy controls. Both the asthmatics and the patients with alveolitis had significantly higher FE(NO) than the healthy controls. The increased NO concentration originated from the bronchial level in the asthmatics and from the alveolar level in the patients with alveolitis. In the second part of the study we assessed the repeatability of FE(NO) test, within-day and day-to-day (during two weeks) variation in FE(NO), and the effects of mouth pressure and cigarette smoking on FE(NO) in healthy volunteers. Repeatability of 10 subsequent measurements was high (coefficient of variation (CV) 4.6% +/- 0.4%), and no diurnal variation was found. The day-to-day variation during a 2-week period gave a CV of 10.6% +/- 1.0%. The magnitude of mouth pressure (5-20 cmH2O in adults, 5-40 cmH2O in children) during measurement had no effect on FE(NO). Smoking a cigarette caused a small and transient but statistically significant increase in FE(NO) at 1 and 5 min after smoking. In conclusion, FE(NO) measurement is highly repeatable with low day-to-day variation among healthy subjects. Our results also suggest that the present novel method of measuring FE(NO) at several exhalation flow rates can be used to approximate alveolar and bronchial contributions to FE(NO) separately and thus increase the clinical value of this test.     

呼出气一氧化氮对哮喘的诊断作用及与过敏原sIgE的关系

目的探讨呼出气一氧化氮(FeNO)对哮喘的诊断作用及与过敏原特异性IgE抗体(sIgE)的关系。方法选取2017年8月至2019年8月收治的98例疑似哮喘患儿进行观察,收集所有患儿的临床特征指标,检测肺功能及FeNO浓度,分析FeNO对哮喘的诊断作用及其与过敏原sIgE的关系。结果哮喘组的FeNO水平高于非哮喘组(P<0.05)。血清过敏原sIgE阳性患儿的Fe NO水平高于阴性患儿(P<0.05)。经Pearson相关性分析得出,FeNO水平与血清过敏原sIgE、血清总IgE和血清过敏原种类呈显著正相关(r=0.703、0.624、0.719,P<0.05)。结论FeNO在哮喘中具有一定的诊断价值,与过敏原sIgE存在显著的相关性,可为临床诊断与治疗哮喘提供有利参考依据。     

Noninvasive Markers of Airway Inflammation in Asthma

Background: Although airway inflammation plays a major role in the pathophysiology of asthma, quantitative markers of airway nflammation are limited in clinical practice. Objective: To determine if the levels of noninvasive markers of eosinophil‐catalyzed oxidation, lipid peroxidation, and nitric oxide (NO) production are associated with asthma. Methods: Participants were enrolled from academic medical centers participating in the Severe Asthma Research Program. Clinical characteristics, laboratory data, pulmonary function tests, and the levels of the following noninvasive markers were obtained: urinary bromotyrosine (BrTyr), a marker of eosinophil‐catalyzed oxidation, urinary F₂‐isoprostanes (F₂‐lsoPs), markers of lipid peroxidation, and exhaled NO, a marker of airway inflammation. Results: Fifty‐seven asthmatic participants and 38 healthy participants were enrolled. BrTyr, F₂‐lsoPs, and exhaled NO were each significantly increased in asthmatic participants versus controls (p < 0.01). An elevated level (greater than the median) of any marker was associated with a significant 3‐ to 6‐fold greater odds of having asthma. Participants with two or more elevated marker levels showed an 18‐fold greater odds of having asthma. Relationships were also noted with airflow obstruction and bronchodilator response. Conclusion: The findings from this pilot study indicate that urinary levels of BrTyr and F₂‐lsoPs, in addition to exhaled NO levels, are associated with asthma.     

Differentiating COPD from asthma in clinical practice

It has been recognized that features of chronic obstructive pulmonary disease (COPD) and asthma overlap, often rendering a firm diagnosis difficult to achieve for the clinical practitioner. There are hypotheses suggesting that both asthma and COPD may indeed share common origins with differences in phenotypic presentation being related to disease evolution or interaction between endogenous and exogenous factors. Others suggest that the two conditions are clinically and pathophysiologically distinct. Studies of the underlying inflammation demonstrate a difference in the preponderance of inflammatory cells and mediators in each disease, yet many shared characteristics in the inflammatory process can be found when examining the two conditions. Generally, later age of presentation favors a diagnosis of COPD; fully reversible airflow limitation on pulmonary function testing suggests a diagnosis of asthma; hyperinflation at rest makes a diagnosis of COPD likely; impaired diffusing capacity is associated with COPD whereas these measurements in patients suffering from asthma are usually normal or even elevated; reduced elastic recoil is the hallmark of COPD, particularly those who pathophysiologically demonstrate abnormal enlargement of air spaces with wall destruction seen in emphysema; and finally history of atopy favors a diagnosis of asthma, particularly if presenting at a younger age. This review reflects discussion of the differences and similarities in diagnosis and treatment.