Effect of fluticasone propionate/formoterol and fluticasone furoate/vilanterol on adolescents with chronic bronchial obstruction.

Background: The combination of an inhaled corticosteroid (ICS) and long-acting ß-agonist (LABA) (ICS/LABA) has shown superiority in improving lung function (FEV1) compared with an ICS alone. The clinical effect of a ICS/LABA combination depends on the fine-particle fraction and the pulmonary deposition. Objective: We sought to compare the efficacy of 2 combinations of an ICS and LABA, namely, fluticasone propionate (FP) and formoterol (FORM) (FP/FORM) and fluticasone furoate (FF) and vilanterol (VI) (FF/VI), in asthmatic adolescents with chronic bronchial obstruction. Methods: FP/FORM (125 µg/5 µg, 2 doses twice daily via the k-haler [Mundipharma, Cambridge, UK]) and FF/VI (92 µg/22 µg, once daily via the Ellipta inhaler [GlaxoSmithKline]) were administered to adolescents aged 12 to 17 years who required regular antiasthmatic medication and had a ratio of FEV1 to forced vital capacity (FEV1/FVC) less than -1.65 SD in a 2-sequence, 16-week crossover trial. The primary efficacy end point was change in FEV1 compared with baseline. Secondary end points were FEV1/FVC ratio, maximal expiratory flow at 50% of the FVC, impulse oscillometry indices respiratory resistance at 5 Hz (R5), difference between R5 and respiratory resistance at 20 Hz (R20), area of reactance, and Asthma Control Test score. Results: Both ICS/LABA combinations resulted in a significant improvement in FEV1 and maximal expiratory flow at 50% of the FVC z scores without any significant difference between FP/FORM and FF/VI, with 40% of patients with either treatment achieving a normal prebronchodilator FEV1/FVC z score. Neither area of reactance nor difference between R5 and R20 improved significantly with either treatment. Conclusion: Both ICS/LABA combinations demonstrated significant improvements in FEV1z score. More than one-third of the asthmatic adolescents with prolonged bronchial obstruction achieved a normal prebronchodilator FEV1/FVC ratio.

Small airway function in Finnish COVID-19 survivors.

Follow-up studies of COVID-19 patients have found lung function impairment up to six months after initial infection, but small airway function has not previously been studied. Patients (n = 20) hospitalised for a severe SARS-CoV-2 infection underwent spirometry, impulse oscillometry, and multiple measurements of alveolar nitric oxide three to six months after acute infection. None of the patients had small airway obstruction, nor increased nitric oxide concentration in the alveolar level. None of the patients had a reduced FEV1/FVC or significant bronchodilator responses in IOS or spirometry. In conclusion, we found no evidence of inflammation or dysfunction in the small airways.

Impulse oscillometry and free-running tests for diagnosing asthma and monitoring lung function in young children.

BACKGROUND: Separating individuals with viral-induced wheezing from those with asthma is challenging, and there are no guidelines for children under 6 years of age. Impulse oscillometry, however, is feasible in 4-year-old children. OBJECTIVE: To explore the use of impulse oscillometry in diagnosing and monitoring asthma in young children and evaluating treatment response to inhaled corticosteroid (ICS). METHODS: A total of 42 children (median age 5.3 years, range 4.0-7.9 years) with physician-diagnosed asthma and lability in oscillometry were followed for 6 months after initiation of ICS treatment. All children performed the 6-minute free-running test and impulse oscillometry at 3 time points. After the baseline, they attended a second visit when they had achieved good asthma control and a third visit approximately 60 days after the second visit. A positive ICS response was defined as having greater than 19 points in asthma control test and no hyperreactivity on the third visit. RESULTS: In total, 38 of 42 children responded to ICS treatment. Exercise-induced increases of resistance at 5 Hz decreased after ICS treatment (61% vs 18% vs 13.5%, P < .001), and running distance during the 6-minute test was lengthened (800 m vs 850 m vs 850 m, P = .001). Significant improvements in childhood asthma control scores occurred between the baseline and subsequent visits (21 vs 24 vs 24, P < .001) and acute physicians' visits for respiratory symptoms (1, (0-6) vs 0, (0-2), P = .001). Similar profiles were observed in children without aeroallergen sensitization and among those under 5 years of age. CONCLUSION: Impulse oscillometry is a useful tool in diagnosing asthma and monitoring lung function in young children.

Patient Inspiratory Maneuver Performance; Peak Lungpower, Acceleration and Volume.

Background: Use of drug delivery devices between nebulizers, dry powder inhalers (DPIs), or metered dose inhalers (MDIs), for treating patients with asthma and chronic obstructive pulmonary disease (COPD), is based on patients' capability of coordinating the inhalation maneuver and achieving sufficient airflow. There are limited data available with regard to how patients meet the requirements of successful inhalation performance, and how the concept of inspiratory lungpower could be applied. The aim of this work was to study the patient inspiratory airflow profile performance in large data sets. We analyzed how the Kamin-Haidl inhalation criteria were met by patients with DPIs such as Easyhaler for combination therapy (EH-combi), Easyhaler for monotherapy (EH-mono), Diskus, and Turbuhaler (TH), and applied peak lungpower instead of peak inspiratory flow rate as an indicator of patient performance. Materials and Methods: Data sets gathered in two previous studies for DPIs, that is, EH-combi, EH-mono, Diskus, and TH, were used to analyze how inspiratory lungpower representing inspiratory muscle power, flow acceleration, and volume after peak met the inhalation criteria. The measured patient airflow profiles through inhalers were assessed for patients with asthma or COPD. Results: Based on the Kamin-Haidl inhalation criteria, successful inhalation requirements were met with EH-combi in 96.1% and with EH-mono in 92.6% of patients. The success rates were 89.5% and 84.6% with Diskus and TH, respectively, (p < 0.0001 between devices). In patients with asthma or COPD, the mean lungpower was 7.51 and 6.15 W for EH-combi, 8.79 and 6.88 W for EH-mono, 7.18 and 4.36 W for Diskus, and 9.65 and 6.86 W for TH, respectively, when patients followed the manufacturer's written instructions. Conclusions: Lungpower applied to the Kamin-Haidl inhalation criteria concept could be an applicable method for reviewing patient performance for different DPIs despite DPIs' characteristic differences in airflow resistance. In light of these results, DPIs provide a feasible treatment option for a large majority of respiratory patients.

Airway hyperresponsiveness, remodeling and inflammation in infants with wheeze.

BACKGROUND: The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear. OBJECTIVE: To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing. METHODS: Inclusion criteria were as follows: full-term, 3-23 months of age; doctor -diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body plethysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analysed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed. RESULTS: Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function was correlated with AHR (P = .047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (P = .057 and 0.056, respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (P = .031). CONCLUSIONS AND CLINICAL RELEVANCE: These findings do not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed.

Predictive value of childhood airway hyper-responsiveness to indirect stimuli: 10-year longitudinal study.

BACKGROUND: Airway hyper-responsiveness (AHR) is a common feature in asthma. The use of AHR in predicting active asthma or the persistence of AHR in childhood is poorly understood. By analyzing longitudinal connections including different measures of AHR, lung function, and inflammation markers, we sought to identify the best available method for predicting persistence of AHR and identification of later active asthma. METHODS: We tested 105 asthmatic children aged 3-7 years with fractional exhaled nitric oxide (FeNO), impulse oscillometry (IOS), and AHR evaluated by indirect methods (hypertonic saline and exercise challenge). Ten years later, 64 children participated in the follow-up visit and were tested with FeNO, IOS, spirometry, and methacholine challenge. At both study visits, blood samples were collected, and a questionnaire was completed. RESULTS: Asthma was in remission in 66% of patients at adolescence. AHR measured by hypertonic saline challenge at preschool age was associated with asthma symptoms (OR 10.2; 95% CI 2.8, 37.3) but not with AHR estimated with methacholine challenge 10 years later. AHR measured by exercise challenge was not associated with AHR or recent asthma symptoms in adolescence. Preschool eosinophilia continued until adolescence in 87% of patients but was not associated with AHR or subjective signs of asthma 10 years later. Wheezy preschoolers with atopy had a higher risk for AHR in adolescence (OR 4.1; 95% CI 1.0, 16.2). CONCLUSION: Results from hypertonic saline challenge are associated with persistent asthma symptoms even after a decade. AHR measured by indirect methods at preschool age did not predict AHR in adolescence.

Inspiratory and Expiratory Flow Changes, Voice Symptoms and Laryngeal Findings during Histamine Challenge Tests.

OBJECTIVE: The aim of this study was to analyse the associations between the spirometry parameter changes in relation to laryngeal finding changes and self-reported voice and throat symptom changes among patients undergoing a histamine challenge test. PATIENTS AND METHODS: Thirty adult patients with a chronic cough underwent a histamine challenge test. Videolaryngostroboscopy and voice and throat symptoms were assessed using a visual analogue scale immediately before and after the challenge test. Correlations between the relative changes in spirometry values in relation to the change in vocal fold oedema and redness and self-reported voice and throat symptom changes during the challenge test were assessed. RESULTS: A correlation between the relative change in inspiratory and expiratory air flow values and the change in voice and throat symptoms during the histamine challenge test was found. The vocal fold oedema, visible on videolaryngostroboscopy, caused by the histamine challenge did not significantly affect the spirometry air flow values. CONCLUSION: The relative changes in inspiratory and expiratory air flow and voice and throat symptoms during the histamine challenge test correlated. The vocal fold oedema caused by the histamine challenge, visible on videolaryngostroboscopy, did not significantly affect the spirometry air flow values.

Serum chitinase-like protein YKL-40 is linked to small airway function in children with asthmatic symptoms.

BACKGROUND: Lung function impairment among asthmatic children begins in early life, and biomarkers for identifying this impairment are needed. The chitinase-like protein YKL-40 has been associated with asthma and lung function in adults, but studies in children have yielded conflicting results. We evaluated the potential of YKL-40 and other systemic biomarkers for identifying lung function deficits in children with asthmatic symptoms. METHODS: We determined the levels of serum YKL-40, periostin, and high-sensitivity C-reactive protein (hs-CRP) from the blood samples of 49 children with asthmatic symptoms. Lung function was assessed with impulse oscillometry (IOS) and spirometry, combined with an exercise challenge and a bronchodilator test. Fractional exhaled nitric oxide was measured at multiple flow rates. RESULTS: Serum levels of YKL-40 showed significant correlations with most IOS indices at baseline (P = .008-.039), but there was no association between YKL-40 and spirometry parameters. Neither periostin nor hs-CRP were associated with baseline lung function. Children with a significant response in either the exercise challenge or the bronchodilator test had increased serum levels of YKL-40 (P = .003) and periostin (P = .035). YKL-40 correlated significantly with the blood neutrophil count (rs  = .397, P = .005) but was not associated with biomarkers of eosinophilic inflammation. CONCLUSION: Serum YKL-40 is a potential biomarker for lung function deficits in children with asthmatic symptoms. These deficits appear to be focused on small airways and may remain undetected with spirometry.

Converting FENO by different flows to standard flow FENO.

In clinical practice, assessment of expiratory nitric oxide (FENO ) may reveal eosinophilic airway inflammation in asthmatic and other pulmonary diseases. Currently, measuring of FENO is standardized to exhaled flow level of 50 ml s-1 , since the expiratory flow rate affects the FENO results. To enable the comparison of FENO measured with different expiratory flows, we firstly aimed to establish a conversion model to estimate FENO at the standard flow level, and secondly, validate it in five external populations. FENO measurements were obtained from 30 volunteers (mixed adult population) at the following multiple expiratory flow rates: 50, 30, 100 and 300 ml s-1 , after different mouthwash settings, and a conversion model was developed. We tested the conversion model in five populations: healthy adults, healthy children, and patients with COPD, asthma and alveolitis. FENO conversions in the mixed adult population, in healthy adults and in children, showed the lowest deviation between estimated F ^ ENO from 100 ml s-1 and measured FENO at 50 mL s-1 : -0·28 ppb, -0·44 ppb and 0·27 ppb, respectively. In patients with COPD, asthma and alveolitis, the deviation was -1·16 ppb, -1·68 ppb and 1·47 ppb, respectively. We proposed a valid model to convert FENO in healthy or mixed populations, as well as in subjects with obstructive pulmonary diseases and found it suitable for converting FENO measured with different expiratory flows to the standard flow in large epidemiological data, but not on individual level. In conclusion, a model to convert FENO from different flows to the standard flow was established and validated.

Standardizing dose in dosimetric bronchial challenge tests.

Recent technical recommendations on bronchial challenge testing aim at standardized assessment of provocative dose of causing 20% decrease in FEV1 (PD20). The aim of this study was to investigate the effect of mode of nebulization on the output of a computerized dosimeter (APS) and to compare PD20 obtained by two different dosimetric systems in vivo. The output of the APS system was tested during continuous nebulization, and using simulated breaths, for intermittent actuations with four different durations. Using output data, a modified methacholine challenge protocol was applied for APS and compared with a standard set-up using Spira dosimeter in 14 asthmatic patients attending duplicate methacholine challenges using both systems, within median (range) 3 (1-6) days apart. The calculated output (mg min-1 ) with all the intermittent mode settings was significantly higher (P<0·001) than in the continuous mode, and in the intermittent mode, the output was dependent of the pulse duration. The PD20 values assessed with the APS and Spira systems were significantly correlated (r = 0·69; P<0·007), without systematic difference in the geometric means (P = 0·10). A moderate to good agreement was found for assessment of significant hyperresponsiveness. The results suggest that in dosimetric systems for bronchial challenge tests, the output of the nebulizer is dependent on the mode of nebulization, and this should be considered when standardizing the dose between devices and protocols. As long as the delivered dose is determined for the specified nebulization mode of the protocol, it may be possible to obtain comparable results between different devices.

Small airway oscillometry indices: Repeatability and bronchodilator responsiveness in young children.

INTRODUCTION: The impulse oscillometry (IOS) indices absolute and relative difference between respiratory resistance at 5 and 20 Hz (R5-20 and R5-20%, respectively) and the area under the reactance curve (AX) are postulated to reflect small airway function. Data on their cutoff values to evaluate bronchodilator responsiveness (BDR) or between-visit changes after interventions are limited in young children. METHODS: We evaluated the BDR of 103 healthy children aged 2-7 years, who received either salbutamol (n = 84) or placebo (n = 19) in order to determine cutoff values for BDR of R5-20, R5-20%, and AX. We then determined the repeatability within and between two IOS measurements 7-14 days apart in young children aged 4-8 years with asthmatic symptoms (n = 43), including cutoff values for significant between-visit changes. RESULTS: The investigated IOS parameters showed marked BDR (fifth percentile cutoff of 75-110% of the baseline value) in healthy children, whereas no significant changes were seen after inhalation of placebo. The agreement within the triplicate IOS measurement was excellent (ICC > 0.80), and the agreement of results between visits was good (ICC > 0.60). A change in R5-20, R5-20%, and AX of 0.65, 1.08, and 0.84 z-scores, respectively, would exceed 95% confidence intervals for between-visit variability. CONCLUSION: We introduce cutoff values for BDR of R5-20, R5-20%, and AX, and their repeatability indices and cutoff limits for significant between-visit changes. These IOS parameters may show greater variability than the conventional IOS indices during follow-up, but the between-visit agreement remains good, providing potentially useful endpoints for monitoring lung function in young children.

Measurement of tidal breathing flows in infants using impedance pneumography.

Tidal breathing flow volume (TBFV) profiles have been used to characterise altered lung function. Impedance pneumography (IP) is a novel option for assessing TBFV curves noninvasively. The aim of this study was to extend the application of IP for infants and to estimate the agreement between IP and direct pneumotachograph (PNT) measurements in assessing tidal airflow and flow-derived indices.Tidal flow profiles were recorded for 1 min simultaneously with PNT and uncalibrated IP at baseline in 44 symptomatic infants, and after methacholine-induced bronchoconstriction in a subgroup (n=20).The agreement expressed as the mean deviation from linearity ranged between 3.9 and 4.3% of tidal peak inspiratory flow, but was associated with specific airway conductance (p=0.002) and maximal flow at functional residual capacity (V'maxFRC) (p=0.004) at baseline. Acute bronchoconstriction induced by methacholine did not significantly affect the agreement of IP with PNT. TBFV indices derived from IP were slightly underestimated compared to PNT, but were equally well repeatable and associated with baseline V'maxFRC (p=0.012 and p=0.013, respectively).TBFV profiles were consistent between IP and PNT in most infants, but the agreement was affected by reduced lung function. TBFV parameters were not interchangeable between IP and PNT, but had a similar association with lung function in infants.

Laryngeal Mucosal Reaction during Bronchial Histamine Challenge Test Visualized by Videolaryngostroboscopy.

OBJECTIVES/HYPOTHESIS: To examine the changes in the larynx, as well as self-reported voice and throat symptoms, among patients undergoing a histamine challenge test. Thus, to understand the possible clinical effects of histamine on the larynx. STUDY DESIGN: Controlled, open prospective study. METHODS: Thirty adult patients with prolonged cough and suspicion of bronchial asthma underwent a histamine challenge test. Videolaryngostroboscopy was performed immediately before and after the challenge. Voice and throat symptoms immediately before and after the challenge test were assessed using a visual analog scale. RESULTS: Videolaryngostroboscopy after exposure showed significant increases in edema (P < 0.001) as well as redness (P < 0.001) of the vocal folds after the exposure. Self-reported voice complaints increased significantly for 8 of 11 symptoms. A moderate positive correlation was found between the increase in edema of the vocal folds and reported heartburn/regurgitation symptoms (r = 0.42, P < 0.05). Atopy, asthma, nasal symptoms, or bronchial hyperreactivity during the histamine challenge test were not associated with laryngeal reactions. CONCLUSIONS: According to the results, the laryngeal mucosal reaction during a histamine challenge test can be objectively visualized. Videolaryngostroboscopy findings, together with an increase in self-reported voice and throat symptoms, show that histamine has potential effects on vocal folds. The mucosal reaction seems to be pronounced among patients with reflux symptoms, probably reflecting the permeability features of the vocal folds.

Double-blind placebo-controlled challenge showed that peanut oral immunotherapy was effective for severe allergy without negative effects on airway inflammation.

AIM: This study examined the efficacy and the safety of peanut oral immunotherapy (OIT). METHODS: We recruited 60 patients aged six years to 18 years who had a moderate-to-severe reaction to a double-blind placebo-controlled peanut challenge: 39 received OIT during an eight-month build-up phase and maintenance phase and 21 controls avoided peanuts. We measured specific immunoglobulin E and G4 (IgE and IgG4) to peanuts and to Ara h 1, 2, 3, 8 and 9 and monitored adverse events, bronchial hyper-responsiveness (BHR) to methacholine and fractional concentrations of exhaled nitric oxide (FeNO). The median follow-up period was 30 months. RESULTS: Most (85%) of the OIT patients passed the build-up phase and 67% tolerated 5 g of peanuts during the post-treatment challenge. No controls were desensitised, with a risk ratio of 29 and 95% confidence interval of 1.9-455. During OIT, IgE to peanut, Ara h 1, 2 and 3 decreased and IgG4 increased. Consuming peanuts had no harmful effects on BHR or FeNO. The annual incidence rate of emergency visits during the follow-up period was 11% or 3.0 per 10 000 patient-days. CONCLUSION: Peanut OIT was efficacious in severe allergies without negative effects on airway inflammation, but unpredictable long-term reactions might occur.

Exhaled nitric oxide indicates poorly athlete's asthma.

INTRODUCTION: In athletes, exercise-induced respiratory symptoms are common and their assessment is time and resource consuming. OBJECTIVE: The objective was to evaluate fractional concentration of exhaled nitric oxide (FENO) as a predictor of bronchial hyperresponsiveness (BHR) and of asthma. MATERIALS AND METHODS: Eighty-seven elite athletes and a control group of 87 sedentary patients with symptoms suggesting asthma underwent measurements of FENO and of BHR by using methacholine provocation test (MCH) and eucapnic voluntary hyperpnoea (EVH) (athletes) or histamine provocation test (HIST) (controls). RESULTS: In athletes, elevated FENO (>30 ppb) was not associated with lung function-confirmed asthma or with MCH positivity, but receiver operating characteristics (ROC) analysis showed some predictive value for EVH positivity [Area Under Curve (AUC) 0.652, 95% confidence interval (CI): 0.53 to 0.78, P = 0.020]. However, the sensitivity (55%) and the specificity (71%) were poor. In sedentary patients, FENO was significantly associated with both confirmed asthma and HIST positivity, ROC analysis showing FENO to be significantly predictive for HIST positivity (AUC 0.83, 95% CI: 0.70 to 0.96, P = 0.001) and for asthma (AUC 0.74, 95% CI: 0.63 to 0.85, P < 0.001). CONCLUSION: The results suggest that in contrast to sedentary patients, FENO seems to be a poor predictor of BHR and of clinical asthma in elite athletes. We find it unlikely that FENO could be a useful screening tool in athletes with exercise-induced respiratory symptoms.