Association of Asthma Education with Asthma Control Evaluated by Asthma Control Test,FEV1, and Fractional Exhaled Nitric Oxide

Background. Asthma education is an important adjunct for asthma control although the way asthma education affects asthma outcomes is poorly understood. The asthma control test (ACT), forced expiratory volume in 1 s (FEV₁), and fractional exhaled nitric oxide (FeNO) have all been used as markers of asthma control. However, the use of FeNO as a surrogate marker remains controversial. Objectives. (i) To examine whether asthma education is associated with asthma control; (ii) to compare absolute levels and changes of ACT, FEV₁, and FeNO over a year; and (iii) to evaluate whether FeNO can be used as an additional marker of asthma control. Methods. Fifty asthmatics with poor adherence (12 mild, 21 moderate, and 17 severe) received asthma education at study entry. Medications were unchanged for the first 3 months, and ACT, FEV₁, and FeNO measurements were recorded at entry, 3, 6, and 12 months. Asthma control was assessed at each visit and patients were categorized as either “stable” or “unstable” asthmatics according to the global initiative for asthma (GINA) guidelines. Results. A significant decrease in FeNO and increase in ACT score were noted in the stable asthmatic group at 3 months (p < .001), and this persisted over 12 months. Significant correlations were seen between changes (Δ) in FeNO, ACT, and FEV₁ over time. However, significant correlations between the absolute levels were not maintained over 12 months. A decrease of ≥18.6% in FeNO and a ≥3-point increase in ACT score (sensitivity: 80% and 73.3% and specificity: 83.3% and 87.5%, respectively) were associated with stable asthma control although the absolute levels were not. Conclusions. Asthma education may be useful to achieve stable control. In addition, changes rather than absolute levels of FeNO and ACT may be better markers of asthma control.     

Correlation of Exhaled Nitric Oxide, Spirometry and Asthma Symptoms

Asthma is the most common chronic disease of childhood. Asthma severity is monitored by spirometry. However, this does not directly measure airway inflammation. Exhaled nitric oxide (FeNO) is a proposed method to measure airway inflammation non-invasively. Previous studies have shown that FeNO correlates with endobronchial biopsies and symptoms in patients with asthma. We monitored daily asthma symptoms compared to monthly spirometry and FeNO. Total monthly symptom scores correlated with both forced expiratory volume at 1 sec (FEV₁) and FeNO. FeNO had a strong correlation than FEV₁. FeNO and FEV₁ were not correlated. We propose that FeNO should be used as an additional monitoring tool for asthma.     

Correlation of Exhaled Nitric Oxide,Spirometry and Asthma Symptoms

Asthma is the most common chronic disease of childhood. Asthma severity is monitored by spirometry. However, this does not directly measure airway inflammation. Exhaled nitric oxide (FeNO) is a proposed method to measure airway inflammation non-invasively. Previous studies have shown that FeNO correlates with endobronchial biopsies and symptoms in patients with asthma. We monitored daily asthma symptoms compared to monthly spirometry and FeNO. Total monthly symptom scores correlated with both forced expiratory volume at 1 sec (FEV₁) and FeNO. FeNO had a strong correlation than FEV₁. FeNO and FEV₁ were not correlated. We propose that FeNO should be used as an additional monitoring tool for asthma.     

The Use of Exhaled Nitric Oxide in the Management of Asthma

It has recently become clear that airways disease associated with eosinophilic airway inflammation, but not other patterns of inflammation, is closely associated with favourable short-and long-term responses to corticosteroid therapy, irrespective of the clinical context in which it occurs. Moreover, a raised exhaled nitric oxide (FE_NO) is a reasonable marker of eosinophilic airway inflammation, which has a number of advantages as a diagnostic and monitoring tool. In this review we outline essential background information on the use of FE_NO in clinical practice and discuss some recent work evaluating the clinical value of this technique.     

Exhaled Nitric Oxide Decreases in Association with Attendance at an Asthma Summer Camp

Attendance at a summer asthma camp has been associated with improved outcomes in children with asthma. We hypothesized that one mechanism involved in improved asthma outcomes is reduction in airway inflammation. To investigate this, we measured the fractional concentration of exhaled nitric oxide (FeNO), lung function (forced expiratory volume in 1 sec, FEV₁) and asthma control (Juniper Asthma Control Questionnaire, ACQ) from children at the beginning and end of a 1-week asthma summer camp. We also obtained a symptoms-only ACQ at 1 and 6 months after the end of camp. We enrolled 10 girls, 17 boys, mean (± SD) age = 9.6 ± 1.3 years. At baseline, FeNO (ppb), median (25–75 IQR) = 11.4 (7.2–21.3); ACQ = 0.86 (0.43–1.21); FEV₁ (%pred, mean ± SD) = 87 ± 10. At the end of camp, FeNO = 6.2 (4.4–8.4), a change of ?45%, p < 0.0001; ACQ = 0.71 (0.43–1.14), a fall of 14%, p = 0.72; and mean FEV₁% predicted remained unchanged. There were no significant changes in the follow-up symptoms-only ACQ at 1 and 6 months. We conclude that airway inflammation, as measured by FeNO, improved during 1 week of asthma camp, but there were no significant changes in lung function or asthma control. Since no child had a change in anti-inflammatory therapy during camp, these findings suggest that airway inflammation was reduced because of improved adherence to therapy and/or reduced exposure to pro-inflammatory stimuli in the home environment. The finding of reduced inflammation following attendance at an asthma summer camp should motivate the child, the parents and the clinician to focus their efforts on improving adherence to therapy and reducing exposures at home.     

Validation Study of Fractional Exhaled Nitric Oxide Measurements Using a Handheld Monitoring Device

We tested reproducibility of exhaled nitric oxide (FE_NO) and inter-operator handling when measured with a handheld device, NIOX MINO®. We enrolled 20 volunteers using a priori goals of acceptable reproducibility to be mean within-subject standard deviation less than 3 parts per billion (ppb) for FE_NO measurements less than 30 ppb, and mean coefficient of variation less than 10% for FE_NO measurements more than 30 ppb. Seventeen subjects with measurements less than 30 ppb displayed a mean standard deviation of 1.15, and 3 subjects with FE_NO more than 30 ppb had a mean coefficient of variation of 2.4%. We conclude that NIOX MINO demonstrates excellent reproducibility for all ranges of FE_NO.     

Validation Study of Fractional Exhaled Nitric Oxide Measurements Using a Handheld Monitoring Device

We tested reproducibility of exhaled nitric oxide (FE_NO) and inter-operator handling when measured with a handheld device, NIOX MINO®. We enrolled 20 volunteers using a priori goals of acceptable reproducibility to be mean within-subject standard deviation less than 3 parts per billion (ppb) for FE_NO measurements less than 30 ppb, and mean coefficient of variation less than 10% for FE_NO measurements more than 30 ppb. Seventeen subjects with measurements less than 30 ppb displayed a mean standard deviation of 1.15, and 3 subjects with FE_NO more than 30 ppb had a mean coefficient of variation of 2.4%. We conclude that NIOX MINO demonstrates excellent reproducibility for all ranges of FE_NO.     

Measurement of Fractional Exhaled Nitric Oxide by a New Portable Device: Comparison with the Standard Technique

Background. Fractional exhaled nitric oxide (FeNO) measurement is a reliable, noninvasive marker of airway inflammation. The use of portable FeNO analyzers may enable the assessment of airway inflammation in primary care. Objective. The authors compared FeNO values obtained by a new portable device (NObreath, Bedfont, UK) to those of the standard stationary analyzer (NIOX, Aerocrine, Sweden) in a large cohort of asthmatic patients. Methods. One hundred and fifty-four (age range: 14–83 years, forced expiratory volume in one second [FEV₁] range: 48–134% predicted, asthma control test [ACT] range: 7–25) out of 168 recruited patients completed the study. Each patient performed at least two valid FeNO measurements at a constant flow rate of 50 ml/s on each of the two analyzers. Results. A significant relationship between the FeNO values obtained by the two devices (r = .95, p < .001) was found. Altman-Bland plot confirmed this agreement. Within-patient repeatability was excellent in both devices. Intraclass correlation coefficients for NIOX and NObreath values were .925 and .967, respectively. By means of receiver operating characteristic curve analysis, the FeNO cutoff points that better identified patients with ACT ≥ 20 were 15 ppb (0.84 sensitivity and 0.42 specificity) by NIOX and 25 ppb (0.53 sensitivity and 0.69 specificity) by NObreath. Easiness to use of both devices, assessed by visual analogue scale was not different. Conclusion. FeNO measurements obtained by the new portable FeNO analyzer are reliable because they are directly comparable with those obtained by the stationary standard device. The use of portable instruments may facilitate the FeNO measurement in primary care.     

Effect of Inhaled Steroid Therapy on Exhaled Nitric Oxide and Bronchial Responsiveness in Children with Asthma

Inhaled steroid therapy is reported to reduce the level of exhaled nitric oxide (eNO), but the effects of inhaled corticosteroids (ICS) on bronchial hyperresponsiveness (BHR) have been controversial. The aim of this study was to determine the effects of ICS on the relationship between eNO and BHR. Twenty-six children with asthma were recruited, including 14 children who were receiving ICS (ICS group) and 12 who were not (ICS-naive group). The fractional exhaled nitric oxide concentration (FENO) was examined by the recommended online method. To evaluate BHR, an acetylcholine challenge test was performed. In the ICS-naive group, FENO was significantly correlated with PC₂₀ (p < 0.05, r = ?0.70), but not in the ICS group. In conclusion, FENO was significantly correlated with BHR in the ICS-naive group, but this relationship was not present in the ICS group. Our results suggest that the use of ICS should be taken into consideration when evaluating the relation between BHR and airway inflammation.     

Development and Preliminary Validation of the Asthma Intensity Manifestations Score (AIMS) Derived from Asthma Control Test,FEV1, Fractional Exhaled Nitric Oxide,and Step Therapy Assessments

Objective. Inherent asthma severity is difficult to assess clinically. The purpose of this study was to develop an Asthma Intensity Manifestations Score (AIMS) as a surrogate for asthma severity. Methods. Three hundred and four patients treated with inhaled corticosteroids completed the Asthma Control Test (ACT), underwent spirometry, and fractional exhaled nitric oxide (FENO) testing, and reported their current medications. These parameters (defined as ACT < 16, forced expiratory volume in 1 second [FEV₁] < 80% predicted, FENO > 50 ppb, and Expert Panel Report [EPR3] step care level >3) were related to prior year outcomes to develop the AIMS and to follow-up year outcomes to validate it. Results. FENO was independently related to prior year short-acting beta agonist (SABA) ≥ 7 (odds ratio [OR] 2.9); ACT (OR 4.9), FEV₁ (OR 3.3), and step care (OR 3.9) were independently related to prior year systemic corticosteroid (SCS) ≥ 2. Thus, all the four items were chosen for the AIMS (0–4 points). AIMSs were linearly related to follow-up year SABA ≥ 7, any SCS, SCS ≥ 2, and emergency hospital care (all p < .01). Compared to patients with AIMSs <2, patients with AIMSs ≥2 were at more than a fourfold greater risk of requiring ≥2 SCS in the following year and were at a 2–2.8-fold greater risk of experiencing other adverse outcomes during that time period. Conclusions. The AIMS is linearly related to future year adverse asthma outcomes. Further studies will be necessary to confirm its utility as a surrogate for asthma severity in clinical practice and clinical research.     

Association of Exhaled Nitric Oxide to Asthma Burden in Asthmatics on Inhaled Corticosteroids

Background. Fractional exhaled nitric oxide (FENO) is a marker of airway inflammation. Its role in assessing asthma burden in clinical practice needs more study. Objective. To determine whether higher FENO levels are associated with greater asthma burden. Methods. This was a multicenter cross-sectional retrospective study of atopic 12- to 56-year-old persistent asthmatics on inhaled corticosteroids (ICS). Questionnaire and 1-year retrospective administrative data were used to analyze by unadjusted and adjusted robust Poisson regression (relative risks) and negative binomial regression [incidence rate ratios (IRRs)] the associations of masked FENO levels (NIOX MINO®) to short-acting beta-agonist (SABA) dispensings and oral corticosteroid (OCS) use in the past year independent of spirometry and an asthma control tool [Asthma Control Test (ACT)]. Results. FENO levels ranged from 7–215ppb (median 28ppb) in 325 patients. Higher FENO levels significantly correlated with more SABA dispensings and OCS courses in the past year, lower FEV₁% predicted levels, but not ACT score. FENO highest (≥48ppb) versus lowest (≤19ppb) quartile values were associated independently in the past year with ≥7 SABA canisters dispensed (relative risk=2.40, 95% CI=1.25–4.62) and total number of SABA canisters dispensed (IRR=1.46, 95% CI=1.12–1.99) and with ≥1 OCS course (relative risk=1.48, 95% CI=1.06-2.07) and total number of OCS courses (IRR=1.71, 95% CI=1.09–2.66). The significant independent relationship of higher FENO levels to increasing SABA dispensings and OCS courses was confirmed by linear trend analyses. Conclusions. Independent and clinically meaningful associations between higher FENO levels and greater asthma burden during a prior year in persistent asthmatics on ICS suggest that FENO measurement may be a complementary tool to help clinicians assess asthma burden.     

Exhaled Nitric Oxide in Children with Allergic Rhinitis and/or Asthma: A Relationship with Bronchial Hyperreactivity

Background. Nowadays, the measure of the fractional concentration of exhaled nitric oxide (FeNO) enables to assess airway inflammation during an office visit and there is international consensus on this testing methodology. The aim of this study was to evaluate whether FeNO measurement is predictable for bronchial hyperreactivity (BHR) in children with allergic rhinitis, asthma, or both. Methods. Two hundred and eighty children with allergic rhinitis, allergic asthma, or both were evaluated. Bronchial function (FEV₁ and FEF_25–75), BHR (assessed by methacholine challenge), FeNO, and sensitizations were assessed. Results. Bronchial function, BHR, and FeNO were significantly different in the three groups (p < .001). A strong inverse correlation between FeNO and BHR was found in patients with asthma and with asthma and rhinitis (r?=??0.63 and r?=??0.61, respectively). A cutoff of 32 ppb of FeNO was a predictive factor for BHR. Conclusions. This study highlights the relevance of FeNO as possible marker for BHR in allergic children and underlines the close link between upper and lower airways.     

Exhaled Nitric Oxide Levels are not Correlated with Eczema Severity in Chinese Children with Atopic Dermatitis

Asthma is a common atopic disease associated with atopic dermatitis (AD) and allergic rhinitis (AR). Exhaled nitric oxide level (eNO) has been found to be an interesting noninvasive marker of disease severity in children with asthma. However, it is uncertain if eNO may be confounded by any coexisting AD or AR. In this study, eNO in Chinese children with moderate-to-severe AD and no asthma symptoms (n = 53) was measured online by a chemiluminescence analyzer. Severity of AD was assessed using the objective SCORing-Atopic-Dermatitis score and coexisting allergic rhinitis with the Allergic-Rhinitis-Score (ARS). Patients with active symptoms of asthma or inhaled/intranasal corticosteroids were excluded. There was no difference in eNO between genders and no correlation between eNO and AD severity regardless of ARS or bronchial reactivity status. ENO appears to be a noninvasive marker whose level is independent of the two atopic diseases of AD and AR in children old enough to perform exhalation maneuver.     

Exhaled Nitric Oxide Levels are not Correlated with Eczema Severity in Chinese Children with Atopic Dermatitis

Asthma is a common atopic disease associated with atopic dermatitis (AD) and allergic rhinitis (AR). Exhaled nitric oxide level (eNO) has been found to be an interesting noninvasive marker of disease severity in children with asthma. However, it is uncertain if eNO may be confounded by any coexisting AD or AR. In this study, eNO in Chinese children with moderate-to-severe AD and no asthma symptoms (n = 53) was measured online by a chemiluminescence analyzer. Severity of AD was assessed using the objective SCORing-Atopic-Dermatitis score and coexisting allergic rhinitis with the Allergic-Rhinitis-Score (ARS). Patients with active symptoms of asthma or inhaled/intranasal corticosteroids were excluded. There was no difference in eNO between genders and no correlation between eNO and AD severity regardless of ARS or bronchial reactivity status. ENO appears to be a noninvasive marker whose level is independent of the two atopic diseases of AD and AR in children old enough to perform exhalation maneuver.     

Analysis of Single-breath Profiles of Exhaled Nitric Oxide in Children with Allergy and Asthma: Guideline-derived Plateau Concentrations Compared to Results of Automatic Evaluation by Two Analyzers

Current guidelines recommend the single-breath measurement of fractional concentration of exhaled nitric oxide (FE_NO) at the expiratory flow rate of 50 mL/s as a gold standard. The time profile of exhaled FE_NO consists of a washout phase followed by a plateau phase with a stable concentration. This study performed measurements of FE_NO using a chemiluminescence analyzer Ecomedics CLD88sp and an electrochemical monitor NIOX MINO in 82 children and adolescents (44 males) from 4.9 to 18.7 years of age with corticosteroid-treated allergic rhinitis (N = 58) and/or asthma (N = 59). Duration of exhalation was 6 seconds for children less than 12 years of age and 10 seconds for older children. The first aim was to compare the evaluation of FE_NO-time profiles from Ecomedics by its software in fixed intervals of 7 to 10 seconds (older children) and 2 to 4 seconds (younger children) since the start of exhalation (method A) with the guideline-based analysis of plateau concentrations at variable time intervals (method B). The second aim was to assess the between-analyzer agreement. In children over 12 years of age, the median ratio of FE_NO concentrations of 1.00 (95% CI: 0.99–1.02) indicated an excellent agreement between the methods A and B. Compared with NIOX MINO, the Ecomedics results were higher by 11% (95% CI: 1–22) (method A) and 14% (95% CI: 4–26) (method B), respectively. In children less than 12 years of age, the FE_NO concentrations obtained by the method B were 34% (95% CI: 21–48) higher and more reproducible (p < 0.02) compared to the method A. The Ecomedics results of the method A were 11% lower (95% CI: 2–20) than NIOX MINO concentrations while the method B gave 21% higher concentrations (95% CI: 9–35). We conclude that in children less than 12 years of age, the guideline-based analysis of FE_NO–time profiles from Ecomedics at variable times obtains FE_NO concentrations that are higher and more reproducible than those from the fixed interval of 2 to 4 seconds and higher than NIOX MINO concentrations obtained during a short exhalation (6 seconds). The Ecomedics FE_NO concentrations of children more than 12 years of age calculated in the interval of 7 to 10 seconds represent plateau values and agree well with NIOX MINO results obtained during a standard 10-second exhalation.     

Fractional Exhaled Nitric Oxide is Associated with the Severity of Stable COPD

Abstract

The value of fractional exhaled nitric oxide (FeNO) in patients with chronic obstructive pulmonary disease (COPD) remains unclear. We aimed to assess whether FeNO is a more valuable biomarker than blood eosinophil count for identifying clinical characteristics of COPD. Stable COPD patients (n?=?390) were included and stratified by FeNO and blood eosinophil counts at recruitment. The demographic characteristics, lung functions, St George Respiratory Questionnaire (SGRQ), serum inhaled allergen-specific IgE and the exacerbations in the preceding 12?months were compared. Risk factors for moderate or severe exacerbation in the preceding 12?months were examined by binary regression analysis. The cross-sectional study showed that 167 patients had high level of FeNO (≥25?ppb) and 223 in low level (<25?ppb), while 138 patients had high blood eosinophil count (≥200 cells/μL) and 252 had low (<200 cells/μL). Compared with the high FeNO group, there were higher proportion of patients with GOLD III–IV, higher SGRQ scores, more exacerbations in the preceding 12?months, and with lower positive proportion of sIgE in the low FeNO group (p?<?0.05 for all). However, these phenomena above were not associated with blood eosinophil count. Finally, high FeNO level was associated with a lower moderate or severe exacerbation in preceding 12?months (RR: 0.541 [95%CI 0.319–0.917], p?=?0.023). In stable COPD patients, FeNO, but not blood eosinophil count was associated with the COPD severity and allergic airway inflammation. However, the role of FeNO in guiding personalized treatment of COPD patients need to be further investigated.     

Exhaled Nitric Oxide in Asthma: Variability,Relation to Asthma Severity,and Peripheral Blood Lymphocyte Cytokine Expression

Exhaled nitric oxide has been used as a means of indirectly measuring the underlying inflammation in asthma. The objectives of the study were to measure exhaled nitric oxide levels in asthma patients and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between exhaled nitric oxide and intracellular cytokine expression. Exhaled nitric oxide was elevated in patients with moderate to severe asthma and with treatment decreased in the first week reaching to a near normal level by 4 weeks. Elevated exhaled nitric oxide was associated with decreased IL-4 and IL-13 cytokine expression by CD8 lymphocytes.     

Exhaled Nitric Oxide in Asthma: Variability, Relation to Asthma Severity, and Peripheral Blood Lymphocyte Cytokine Expression

Exhaled nitric oxide has been used as a means of indirectly measuring the underlying inflammation in asthma. The objectives of the study were to measure exhaled nitric oxide levels in asthma patients and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between exhaled nitric oxide and intracellular cytokine expression. Exhaled nitric oxide was elevated in patients with moderate to severe asthma and with treatment decreased in the first week reaching to a near normal level by 4 weeks. Elevated exhaled nitric oxide was associated with decreased IL-4 and IL-13 cytokine expression by CD8 lymphocytes.     

Association between the Results of the Childhood Asthma Control Test and Objective Parameters in Asthmatic Children

Objective. The Childhood Asthma Control Test (C-ACT), a seven-item, self-administered questionnaire, has been used as a tool to assess the control level in children with asthma. The aim of this study was to determine whether the C-ACT reflects airflow limitation and airway inflammation in addition to clinical manifestations. Methods. Asthmatic children aged 5–11 years who were able to perform the lung function test and fractional exhaled nitric oxide (FeNO) evaluation correctly were recruited during their regular visits. Children and their parents were asked to answer the officially developed Japanese version of the C-ACT. Results. Among 258 children (176 boys, median age 9 years), there was a significant positive correlation between the C-ACT score and the percent predicted forced expiratory volume in 1 s (%FEV₁) (r = 0.317, p < .001). The accuracy of the C-ACT for identifying asthmatic subjects with normal lung function (%FEV₁ >80%) described as the area under the receiver operating characteristic curve was 71.5% (95% CI = 62.8–80.2%, p < .001), and based on the Youden index the optimal cutoff score was 23 (sensitivity of 78% and specificity of 54%). In contrast, there was no relationship between the C-ACT score and the FeNO value. Conclusions. These results suggest that a cutoff score of 23 for the C-ACT could be useful for identifying children with well-controlled asthma and normal lung function. Further studies are warranted to develop an easy-to-use questionnaire to assess the extent of airway inflammation in children.     

Off-Line Fractional Exhaled Nitric Oxide Measurement Is Useful to Screen Allergic Airway Inflammation in an Adult Population

To determine whether off-line fractional exhaled nitric oxide (FeNO) measurement is applicable to screen allergic airway inflammation for epidemiologic studies, we examined 280 adults, measuring off-line FeNO samplings, pulmonary function, and serum immunoglobulin E (IgE). Subjects with recurrent wheeze (recurrent wheezers) had significantly higher FeNO and IgE levels and significantly lower forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) than non-wheezers. Statistical analysis showed that FeNO and FEV₁/FVC were significant predictors for recurrent wheezers, independent of smoking. The cut-off FeNO level for screening allergic airway inflammation was 38 ppb in non-smokers and 32.9 ppb in smokers. Thus, off-line FeNO can be used as a good marker to screen allergic airway inflammation, regardless of smoking.