Higher Exhaled Nitric Oxide Research Articles

Predictors of Low and High Exhaled Nitric Oxide Values in Asthma: A Real-World Study

Background: In asthma, exhaled nitric oxide (F_ENO) is a clinically established biomarker of airway T2 inflammation and an indicator for anti-inflammatory therapy. Objectives: The aim of the study was to identify, in an observational real-world cross-sectional study, the main characteristics of patients with asthma as classified by their F_ENO level. Method: We stratified 398 patients with stable mild-to-severe asthma according to F_ENO level as low (≤25 ppb) versus elevated (>25 ppb), subdividing the latter into two subgroups: moderately elevated (26–50 ppb) versus very high F_ENO (>50 ppb). Clinical, functional, and blood parameters were extrapolated from patients’ chart data and compared with the F_ENO stratification. Predictors of low and elevated F_ENO asthma were detected by logistic regression model. Results: Low BMI, higher blood eosinophilia, allergen poly-sensitization, the severest airflow obstruction (FEV₁/FVC), and anti-leukotriene use are predictors of elevated F_ENO values in asthma, as well as persistent rhinitis and chronic rhinosinusitis with or without nasal polyps. Beyond these, younger age, more than 2 asthma exacerbations/year, higher airflow reversibility (post-bronchodilator ∆FEV₁), and oral corticosteroid dependence are predictors of very high F_ENO values. In contrast, obesity, obstructive sleep apnoea syndrome, gastroesophageal reflux disease, arterial hypertension, and myocardial infarction are predictors of low F_ENO asthma. In our population, F_ENO correlated with blood eosinophils, airflow obstruction, and reversibility and negatively correlated with age and BMI. Conclusions: Stratifying patients by F_ENO level can identify specific asthma phenotypes with distinct clinical features and predictors useful in clinical practice to tailor treatment and improve asthmatic patients’ outcomes.

Higher exhaled nitric oxide at 6 weeks of age is associated with less bronchiolitis and wheeze in the first 12 months of age

BackgroundNitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and...

Exhaled nitric oxide detection for diagnosis of COVID-19 in critically ill patients.

COVID-19 may present with a variety of clinical syndromes, however, the upper airway and the lower respiratory tract are the principle sites of infection. Previous work on respiratory viral infections demonstrated that airway inflammation results in the release of volatile organic compounds as well as nitric oxide. The detection of these gases from patients' exhaled breath offers a novel potential diagnostic target for COVID-19 that would offer real-time screening of patients for COVID-19 infection. We present here a breath tester utilizing a catalytically active material, which allows for the temporal manifestation of the gaseous biomarkers' interactions with the sensor, thus giving a distinct breath print of the disease. A total of 46 Intensive Care Unit (ICU) patients on mechanical ventilation participated in the study, 23 with active COVID-19 respiratory infection and 23 non-COVID-19 controls. Exhaled breath bags were collected on ICU days 1, 3, 7, and 10 or until liberation from mechanical ventilation. The breathalyzer detected high exhaled nitric oxide (NO) concentration with a distinctive pattern for patients with active COVID-19 pneumonia. The COVID-19 "breath print" has the pattern of the small Greek letter omega (). The "breath print" identified patients with COVID-19 pneumonia with 88% accuracy upon their admission to the ICU. Furthermore, the sensitivity index of the breath print (which scales with the concentration of the key biomarker ammonia) appears to correlate with duration of COVID-19 infection. The implication of this breath tester technology for the rapid screening for COVID-19 and potentially detection of other infectious diseases in the future.

Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis.

High exhaled nitric oxide fraction (F ENO) levels are associated with greater risk of asthma exacerbation. However, it is not clear how F ENO can be used to guide safe reductions in inhaled corticosteroid (ICS) doses in asthma patients. This study assesses the ability of F ENO to guide ICS reductions. Systematic searching of electronic databases identified prospective observational studies and randomised controlled trials which recruited participants with mild-to-moderate asthma aged ≥12 years and measured F ENO before reducing ICS. We performed multilevel mixed-effects logistic regression in relation to acute exacerbations and estimated each participant's exacerbation risk using our logistic regression model. We included data from seven out of eight eligible studies, representing 384 participants. ICS doses were halved in four studies and withdrawn in three studies. A baseline F ENO measurement of ≥50 ppb was associated with increased risk of exacerbations (crude OR 3.14, 95% CI 1.41-7.00, p=0.005; adjusted OR 3.08, 95% CI 1.36-6.98, p=0.007) and corresponded to an estimated exacerbation risk cut-off of 15%. Reducing ICS when estimated exacerbation risk was <15% versus <10% would result in fewer patients remaining on the same ICS dose (40 (10.4%) out of 384 versus 141 (36.7%) out of 384), but similar proportions of patients avoiding exacerbations (222 (91.4%) out of 243, 95% CI 87.1-94.6% versus 311 (90.4%) out of 344, 95% CI 86.8-93.3%). In patients with mild-to-moderate asthma, gradual ICS reduction when F ENO is <50 ppb may help decrease ICS use without increasing exacerbations. Future research should aim to validate these findings in larger populations.

Beetroot juice supplementation for the prevention of cold symptoms associated with stress: A proof-of-concept study

ObjectivesPsychological stress has been linked to common cold symptoms. Nitric oxide (NO) is part of the first line of epithelial defense against pathogens, and beetroot juice is a source of dietary nitrate that increases NO availability. We therefore tested whether beetroot juice protects against cold symptoms in a period of sustained acute stress. DesignSeventy-six students, 16 of these with asthma, were randomly assigned to seven daily doses of beetroot juice or no supplementation control during their final exams. MethodsParticipants completed stress ratings, a cold symptom questionnaire, and exhaled NO measurements at a low-stress period and two periods during their final exams, with one questionnaire follow-up assessment seven days after finals. ResultsBeetroot juice was associated with reduced symptoms of cold and sickness during and following finals. Those with asthma showed the greatest benefits. Higher exhaled NO was concurrently and prospectively associated with reduced symptomatology. ConclusionBeetroot juice during periods of psychological stress protects against cold symptoms. Preliminary evidence suggests particular benefits in asthma, which could translate into reduced asthma exacerbations due to respiratory infections.Clinical Trial ID: NCT03159273

High exhaled nitric oxide levels correlate with nonadherence in acute asthmatic children

High exhaled nitric oxide levels correlate with nonadherence in acute asthmatic children

Lung function and dust in climbing halls: two pilot studies.

In climbing halls, high levels of dust are found because magnesia powder is used to dry hands. Concerns have been raised about possible health effects after reports from asthmatics experiencing worsening of symptoms while or after climbing. We investigated acute and sub-acute effects of climbing in dusty halls on lung function in two pilot studies. The first study examined 109 climbers before and after a climbing activity that lasted at least 1 h. In the second study, 25 climbers from different age classes participated in a 2-day climbing competition. Of these, 24 agreed to take part in our investigation, but only 22 provided valid lung function tests on both days. The climbers underwent lung function tests before the first round of the competition (in the morning), after the second round approximately 3 h later and in the morning of the second day before the competition started again. In the first study, we found acute effects, a decline in lung function immediately after the exposure, likely due to protective reflexes of the bronchial muscles and stronger declines in persons with higher exhaled nitric oxide (NO) pre-climbing. In the second study, we also expected sub-acute effects on the next day due to inflammation. On the first day of the competition (second study), dust levels at a central monitor increased over time in a linear manner. Most of the dust was in the size range between 2.5 and 10 μm and dust levels of particulate matter (PM10) reached 0.5 mg/m3. There was a decline in lung function over 24 h in persons with higher exhaled NO levels pre-exposure. All spirometric parameters were affected though the effects were not statistically significant in all cases. Younger age classes started earlier in the morning. Because of the increasing trend in dust levels we expected stronger effects with higher numbers but for the acute effects the reverse was true, possibly because younger climbers use magnesia more or with less experience thus causing higher individual exposure. No differences by age or by time of the first climb were observed for the 24-h lung function change.

Inhaled Mannitol in the Diagnosis and the Management of Asthma

The need for a diagnostic test for asthma was established when it was realized that asthma symptoms could not be relied upon to predict the presence, or not, of airway hyper-responsiveness and inflammation, the hallmarks of asthma. A need to identify asthmatic patients who were overtreated or undertreated with inhaled corticosteroids (ICS) has also been recognized. Dry-powder mannitol, given by inhalation, is used as a bronchial provocation test to meet this need. Mannitol is an osmotic agent and causes the release of mediators that provoke the airways to narrow. This airway response to mannitol is dependent on the presence of inflammatory cells, and it is reduced or even completely inhibited by treatment with ICS. Studies in large populations have shown that mannitol has a high specificity (95%) for identifying asthma and can be used to monitor treatment with ICS. Importantly, when mannitol responsiveness is reduced by treatment with ICS, all other indices of airway inflammation are reduced, in association with improvements in clinical symptoms. The responsiveness to mannitol is more frequent than the responsiveness to exercise in both adults and children. Mannitol responsiveness is not necessarily associated with other markers of airway inflammation such as a high exhaled nitric oxide and/or a sputum eosinophilia. This may be due to mast cells being the important cell for the mannitol response. In adults, a negative mannitol test result is common in asthmatic patients taking ICS, and consideration should be given to the back titration of the dose to confirm the diagnosis and reduce risks from overtreatment.

Persistently high exhaled nitric oxide and loss of lung function in controlled asthma

BackgroundsIt remains unclear whether a persistently high exhaled nitric oxide fraction (FeNO) in patients with controlled asthma is associated with the progressive loss of lung function. MethodsThis was a 3-year prospective study. We examined the changes in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) and FeNO in 140 patients with controlled asthma. We initially determined the FeNO cut-off point for identifying patients with a rapid decline in FEV1 (>40 mL/yr). Next, a total of 122 patients who maintained high or non-high FeNO were selected, and the associations between the FeNO trend and changes in FEV1 and bronchodilator response (BDR) were investigated. ResultsA FeNO level >40.3 ppb yielded 43% sensitivity and 86% specificity for identifying patients with a rapid decline in FEV1. Patients with persistently high FeNO had higher rates of decline in FEV1 (42.7 ± 37.5 mL/yr) than patients with non-high FeNO (16.7 ± 31.5 mL/yr) (p < 0.0005). The changes in BDR from baseline to the end of the study, in patients who had high or non-high levels of FeNO were −0.8% and 0.1%, respectively (p < 0.01). In a multivariate analysis adjusted by age, body mass index, asthma control, blood eosinophil numbers, and FEV1% of predicted, a FeNO level of ≥40 ppb was independently associated with an accelerated decline in FEV1 (p < 0.05). ConclusionsThis study suggests that FeNO is potentially valuable tool for identifying individuals who are at risk of a progressive loss of lung function among patients with controlled asthma.

Clinical Implications of Having Reduced Mid Forced Expiratory Flow Rates (FEF25-75), Independently of FEV1, in Adult Patients with Asthma.

IntroductionFEF25-75 is one of the standard results provided in spirometry reports; however, in adult asthmatics there is limited information on how this physiological measure relates to clinical or biological outcomes independently of the FEV1 or the FEV1/FVC ratio.PurposeTo determine the association between Hankinson’s percent-predicted FEF25-75 (FEF25-75%) levels with changes in healthcare utilization, respiratory symptom frequency, and biomarkers of distal airway inflammation.MethodsIn participants enrolled in the Severe Asthma Research Program 1–2, we compared outcomes across FEF25-75% quartiles. Multivariable analyses were done to avoid confounding by demographic characteristics, FEV1, and the FEV1/FVC ratio. In a sensitivity analysis, we also compared outcomes across participants with FEF25-75% below the lower limit of normal (LLN) and FEV1/FVC above LLN.ResultsSubjects in the lowest FEF25-75% quartile had greater rates of healthcare utilization and higher exhaled nitric oxide and sputum eosinophils. In multivariable analysis, being in the lowest FEF25-75% quartile remained significantly associated with nocturnal symptoms (OR 3.0 [95%CI 1.3–6.9]), persistent symptoms (OR 3.3 [95%CI 1–11], ICU admission for asthma (3.7 [1.3–10.8]) and blood eosinophil % (0.18 [0.07, 0.29]). In the sensitivity analysis, those with FEF25-75% <LLN had significantly more nocturnal and persistent symptoms, emergency room visits, higher serum eosinophil levels and increased methacholine responsiveness.ConclusionsAfter controlling for demographic variables, FEV1 and FEV1/FVC, a reduced FEF25-75% is independently associated with previous ICU admission, persistent symptoms, nocturnal symptoms, blood eosinophilia and bronchial hyperreactivity. This suggests that in some asthmatics, a reduced FEF25-75% is an independent biomarker for more severe asthma.

Targeted omics and systems medicine: personalising care

A key problem in the management of respiratory diseases is that subsets of patients do not respond to available treatments. Ideally, clinicians should have access to diagnostic markers to personalise drugs for patients with respiratory diseases before starting treatment. Although such markers do not exist in clinical settings, 1 Chung KF Wenzel SE Brozek JL et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43: 343-373 Crossref PubMed Scopus (2337) Google Scholar some markers for personalised medicine could reach the clinic in the near future. For example, in asthma, biomarkers such as airway eosinophilia, high exhaled nitric oxide, 2 Chung KF New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med. 2013; 1: 639-652 Summary Full Text Full Text PDF Scopus (74) Google Scholar and transcriptional signatures from bronchial brushings might potentially stratify patients for available and novel biological drugs. 3 Wenzel S Ford L Pearlman D et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013; 368: 2455-2466 Crossref PubMed Scopus (986) Google Scholar However, high-throughput (omics technologies) studies of patients with seasonal allergic rhinitis show the complexity of identification of biomarkers for treatment response. 4 Nestor CE Barrenäs F Wang H et al. DNA methylation changes separate allergic patients from healthy controls and may reflect altered CD4+ T-cell population structure. PLoS Genet. 2014; 10: e1004059 Crossref PubMed Scopus (55) Google Scholar Thousands of genes change expression in nasal fluids, nasal fluid cells, nasal mucosa, and allergen-challenged blood T cells in patients with seasonal allergic rhinitis compared with controls. 4 Nestor CE Barrenäs F Wang H et al. DNA methylation changes separate allergic patients from healthy controls and may reflect altered CD4+ T-cell population structure. PLoS Genet. 2014; 10: e1004059 Crossref PubMed Scopus (55) Google Scholar The involvement of different cell types and external triggers suggests that similar numbers of genes might change in expression in airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). This complexity indicates that single biomarkers might not suffice to stratify accurately patients for personalised medicine. 5 Barabási A-L Gulbahce N Loscalzo J Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011; 12: 56-68 Crossref PubMed Scopus (2960) Google Scholar Instead, a change of scale to omics-based diagnostics might be needed. Diagnostic kits that measure transcriptional signatures are now used to stratify patients with breast cancer. 6 Ward S Scope A Rafia R et al. Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2013; 17: 1-302 PubMed Google Scholar But will this technique be achievable in the respiratory clinic? Achievement of this goal can be broken into three parts—one, measurement and validation of human genes, gene products, and metabolites on a genome-wide scale; two, extraction of parts of the genome-wide data with potential diagnostic value, ideally based on functional understanding or so-called targeted omics; and third, such biomarkers being clinically useful at a reasonable cost.

Oscillatory shear stress-induced arginase activity may explain reduced exhaled nitric oxide levels after vest chest physiotherapy in cystic fibrosis.

The well-executed study by Sisson et al. [1] demonstrates the potential of vest chest physiotherapy (VCPT) in improving airway clearance in cystic fibrosis (CF) patients. The authors point out that they observed a nonsignificant tendency towards higher exhaled nitric oxide (NOx) levels in CF compared to healthy control subjects which is at odds with previous findings of lower NOx in CF [2, 3]. Contrary to Sisson et al.'s hypothesis, VCPT in CF patients reduced rather than increased NOx. The authors discuss this unexpected finding with regard to increased cellular NO utilisation and distal airway mucous barriers to NO diffusion. An alternative explanation involves NO synthetase (NOS) and arginase activity in airway epithelial cells. Both enzymes compete for L-arginine as substrate and imbalances in activity levels are believed to be important in the pathogenesis of airway inflammation and hyperreactivity [4]. Arginase converts L-arginine into L-ornithine and urea, effectively modulating NOS activity, proinflammatory oxidant species generation, and airway remodelling [5]. Impaired lung function in CF is likely associated with reduced NO-mediated bronchodilation arising from low levels of L-arginine, impaired NOS expression, and increased arginase activity [6, 7]. Elevated systemic arginase and concomitantly reduced L-arginine levels were observed in acutely hospitalised CF patients and normalised after successful treatment [8]. Increased arginase activity, in addition to limiting NO production, also contributes to CF lung pathology through downstream products [9], is associated with Pseudomonas infection, and inversely related to lung function [10]. Arginase is moreover thought to play a role in the pathogenesis of other lung diseases like asthma and chronic obstructive pulmonary diseases [11, 12]. Recently, inhaled L-arginine was demonstrated to be a safe and potentially beneficial treatment approach in CF [13]. A possible mechanism to explain Sisson et al.'s [1] surprising finding of lower NOx after VCPT may be an increase in arginase activity through oscillatory mechanical stimulation of lung epithelial cells. Several studies in animal and cell models have demonstrated that specific patterns of mechanical stimulation can induce vascular endothelial arginase expression and activity. For instance, oscillatory shear stress induced stronger arginase activation than application of unidirectional shear force in porcine [14] and ApoE-deficient murine carotid artery segments [15]. An in vitro study showed that cyclic stretching of vascular smooth muscle cells upregulated arginase mRNA expression and enzyme activity whilst inhibiting NOS [16]. The VCPT device used in Sisson et al.'s [1] study produced oscillatory inflation/deflation cycles at a rate of 10–15 Hz throughout 20-minute treatment sessions. Thus, a possible explanation for reduced exhaled NO could be oscillatory shear stress-induced upregulation of arginase activity and associated inhibition of NOS. Whilst the observed vascular endothelial response in arginase activity to shear forces remains to be demonstrated for airway epithelial cells, the suggested link provides a plausible theory to account for Sisson et al.'s intriguing findings.

Reassessment of Omalizumab-Dosing Strategies and Pharmacodynamics in Inner-City Children and Adolescents

Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment. Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers. Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks. Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy. A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.

Cough Triggers and Their Pathophysiology in Patients with Prolonged or Chronic Cough

The character or timing of chronic cough is considered to be unpredictable for diagnosing its cause. However, the associations of cough triggers with cough pathophysiology remains unknown. We developed a closed questionnaire listing 18 triggers that were reported by ≥1% of 213 patients in a retrospective survey. Using this questionnaire, patients with cough-predominant or cough-variant asthma (n = 140) and those with non-asthmatic cough (54) were asked whether their cough was induced by the listed triggers. Associations of triggers with causes of cough, airway sensitivity to inhaled methacholine, exhaled nitric oxide (NO) levels, number of sensitizing allergens, and scores from gastroesophageal reflux (GER) questionnaires were examined. Factor analysis was used to categorize variables, including the 12 most common cough triggers, diagnosis of asthmatic cough, airway sensitivity, and exhaled NO levels. "Cold air" and "fatigue/stress" induced cough more often in asthmatic coughers than in non-asthmatic coughers. "Spices" and "meals" induced cough more frequently in GER-coughers (n = 19). Patients who marked "cold air" as the trigger were more sensitive to inhaled methacholine and showed higher exhaled NO levels than those who did not mark this trigger. The "post-nasal drip" trigger was associated with elevated exhaled NO levels, and this association was mainly exhibited by patients with cough-predominant asthma. The triggers "pollen" and "mold smell" were associated with a number of sensitizing allergens. The number of triggers was weakly associated with GER scores. By factor analysis, "cold air," "fatigue/stress," asthmatic cough, airway hypersensitivity, and elevated NO levels were categorized into the same factor. Several cough triggers may reflect the pathophysiology of prolonged or chronic cough.

Cost-effectiveness analysis of fluticasone versus montelukast in children with mild-to-moderate persistent asthma in the Pediatric Asthma Controller Trial

Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few. We sought to compare the cost-effectiveness of 2 commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial. We compared the cost-effectiveness of low-dose fluticasone with that of montelukast in a randomized, controlled, multicenter clinical trial in children with mild-to-moderate persistent asthma. Analyses were also conducted on subgroups based on phenotypic factors. Effectiveness measures included (1) the number of asthma-control days, (2) the percentage of participants with an increase over baseline of FEV(1) of 12% or greater, and (3) the number of exacerbations avoided. Costs were analyzed from both a US health care payer's perspective and a societal perspective. For all cost-effectiveness measures studied, fluticasone cost less and was more effective than montelukast. For example, fluticasone treatment cost $430 less in mean direct cost (P < .01) and resulted in 40 more asthma-control days (P < .01) during the 48-week study period. Considering sampling uncertainty, fluticasone cost less and was more effective at least 95% of the time. For the high exhaled nitric oxide (eNO) phenotypic subgroup (eNO ≥25 ppb) and more responsive PC(20) subgroup (PC(20) <2 mg/mL), fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures, whereas not all the effectiveness measures were statistically different for the other 2 phenotypic subgroups. For children with mild-to-moderate persistent asthma, low-dose fluticasone had lower cost and higher effectiveness compared with montelukast, especially in those with more airway inflammation, as indicated by increased levels of eNO and more responsivity to methacholine.

Actual Control State of Intermittent Asthma Classified on the Basis of Subjective Symptoms

Many primary care physicians begin treatment of asthma patients on the basis of their subjective symptoms. We hypothesized that patients diagnosed as having intermittent asthma on the basis of subjective symptoms by a primary care physician may have their asthma severity underestimated. We investigated 293 patients who were in their 20s and diagnosed as having asthma. Two hundred and fifteen patients with intermittent asthma diagnosed on the basis of subjective symptoms were chosen. We evaluated their asthma severity using FEV(1) (% predicted), airway hyperresponsiveness to histamine dihydrochloride, and exhaled nitric oxide level as factors that determine asthma severity. Among these patients, 27.8% were determined to have moderate or severe asthma by the pulmonary function test. History of childhood asthma was the only significant risk factor for a low pulmonary function. Among the patients, 60.9% showed moderate or severe airway hyperresponsiveness. History of childhood asthma was the only significant risk factor for the increase in airway hyperresponsiveness. Moreover, 53.8% showed a high exhaled nitric oxide level. History of childhood asthma was associated with an increased risk of a high eNO level as determined by univariate analysis, but no significant difference was observed in the comparison by multiple logistic regression analysis. The percentage of subjects classified into the mild group by all of the results of the three tests was only 20.6%. We showed that asthma severity classified on the basis of only subjective symptoms may be underestimated in young adults. We showed that the diagnosis of mild intermittent asthma needs to be determined carefully.

The role of food allergy in the atopic march

Cite this as: K. J. Allen and S. C. Dharmage, Clinical &amp; Experimental Allergy, 2010 (40) 1439–1441.

Aeroallergen sensitization in asthma: Prevalence and correlation with severity

Aeroallergen sensitization occurs in most patients with asthma and is noted in a high percentage of patients with mild and moderate asthma. The percentage of those that are atopic with severe asthma appears less, but still approximates the percent seen in patients with mild and moderate asthma. The objective of this study was to review the prevalence of positive skin tests and atopic disease in patients with asthma. A review was performed of the literature with searches to include "skin test and asthma," "allergic asthma," and "allergies and asthma" in both PubMed and Ovid and selected articles that were relative to our objective. Most studies highlight the significances that allergic disease plays in asthma. However, the prevalence of allergic disease in mild to moderate asthma ranges from 50 to 95% and recent data suggest that 95% may be very accurate. In severe asthma the percentage is less, but still recent data suggest it may be as high as 90%. Patients with high IgE, high exhaled nitric oxide (eNO), low provocative concentration of methacholine causing a 20% fall in forced expiratory ventilation in 1 second (PC(20)) and minority ethnicity have a higher number of positive skin tests and presumably are hypersensitive to more aeroallergens. Patients with late-onset asthma are less likely to be allergic; nonetheless, the vast majority even >65 years of age have an allergic component to their disease. Female gender, late-onset asthma, nasal polyps, severe asthma, and, possibly, patients with a reaction to autologous serum injection increases the likelihood that asthma may be nonallergic, as defined by negative skin tests. The vast majority of patients with mild-to-moderate and even severe asthma have an allergic component to their disease. Avoidance, omalizumab, and allergen immunotherapy may be useful in all severities of asthma, even in the elderly, if indicated and not contraindicated. As many as 90-95% of patients with asthma have aeroallergen sensitization and the pattern varies with ethnicity, location of residence, and onset of asthma, but not age. Higher levels of IgE and eNO and lower values of PC(20), are noted in patients with asthma and aeroallergen sensitization.

Levels of nitric oxide oxidation products are increased in the epithelial lining fluid of children with persistent asthma

Children with severe allergic asthma have persistent airway inflammation and oxidant stress. We hypothesized that children with severe allergic asthma would have increased concentrations of the nitric oxide (NO) oxidation products nitrite, nitrate, and nitrotyrosine in the proximal and distal airway epithelial lining fluid (ELF). We further hypothesized that NO oxidation products would be associated with higher exhaled NO values (fraction of exhaled nitric oxide [F(ENO)]), greater allergic sensitization, and lower pulmonary function. Bronchoalveolar lavage fluid was obtained from 15 children with mild-to-moderate asthma, 30 children with severe allergic asthma, 5 nonasthmatic children, and 20 nonsmoking adults. The bronchoalveolar lavage fluid was divided into proximal and distal portions and nitrite, nitrate, and nitrotyrosine values were quantified. Children with mild-to-moderate and severe allergic asthma had increased concentrations of nitrite (adult control subjects, 15 +/- 3 micromol/L; pediatric control subjects, 23 +/- 4 micromol/L; subjects with mild-to-moderate asthma, 56 +/- 26 micromol/L; subjects with severe asthma, 74 +/- 18 micromol/L), nitrate (37 +/- 13 vs 145 +/- 38 vs 711 +/- 155 vs 870 +/- 168 micromol/L, respectively) and nitrotyrosine (2 +/- 1 vs 3 +/- 1 vs 9 +/- 3 vs 10 +/- 4 micromol/L, respectively) in the proximal ELF. Similar results were seen in the distal ELF, although the concentrations were significantly lower (P < .05 for each). Although univariate analyses revealed no associations between NO oxidation products and clinical features, multivariate analyses revealed F(ENO) values to be a significant predictor of NO oxidation in asthmatic children. NO oxidation products are increased in the ELF of asthmatic children. The relationship between F(ENO) values and airway nitrosative stress is complicated and requires further study.

Association of Ambient Ozone Exposure with Airway Inflammation and Allergy in Adults with Asthma

Previous studies have demonstrated associations of high ozone levels with increased epidemiologic as well as lung function measures of asthma activity. In an observational study during the summer months, we hypothesized that higher ambient ozone levels are associated with more frequent symptoms, higher airway and systemic inflammation, as well as worse lung function in asthmatics as compared with non-asthmatic individuals. Thirty-eight asthmatics and thirteen healthy control subjects residing in metropolitan Atlanta were enrolled during peak ozone season. Medical histories, quality-of-life questionnaires, spirometry, serum immunoglobulin (IgE), peripheral eosinophil counts, and exhaled nitric oxide (NO) were obtained during study visits. Personal ozone exposures over the 2 days before presentation were estimated based on location and activity surveys. Upper airway symptoms were more frequent in asthmatics. Higher levels of ozone were associated with worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatics. Finally, both asthmatics and non-asthmatics with allergies showed associations between air quality and airway inflammation. In adults with asthma but not controls studied during peak ozone season, increasing ozone exposure predicted lower lung function and increased biomarkers of respiratory and systemic inflammation. These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards.