Exhaled and nasal NO measurement: NO in your breath doesn't imply a negative attitude!

Measurement of exhaled nitric oxide (NO) and nasal nitric oxide commenced in the 1990s shortly after the scientific world learned about the endogenous production of NO and its multiple roles in physiologic and pathologic processes. Exhaled NO is an established approved clinical test in asthma that can cast light on eosinophilic airway inflammation and the response to anti-inflammatory medications e.g., inhaled corticosteroids. Nasal NO which is extremely low in primary ciliary dyskinesia is an established screening test for this condition. This review is a high-level practical guide for those wishing to use exhaled and nasal NO for research and clinical application.

Concordance for changes in allergic asthma domain variables after short-term corticosteroid therapy.

BACKGROUND: Asthma is a complex syndrome with multiple domains including symptoms, lung function, asthma control, and airway inflammation. A study of Fenom PRO™, a novel monitor for exhaled nitric oxide (FeNO), provided an opportunity to look at concordance/discordance (C/D) for changes in multiple asthma domains over a 2-week period after corticosteroid therapy. METHODS: Non-steroid-treated adults and children with uncontrolled asthma had asthma domain measures, (FeNO), forced expired volume in 1 s (FEV1), the 6-item Asthma Control Questionnaire scores (ACQ6), and daily asthma symptoms, assessed before and after a 2-week course of corticosteroids. Asthma symptoms were assessed using a custom novel twice-daily symptom scale (ASX). C/D bidirectional changes in all domains were calculated around both the zero point, and around the minimal important difference (MID) in relevant subjects. RESULTS: There was a highly significant fall in mean FeNO of 51.7% over 2 weeks (p < 0.0001) accompanied by significant improvements in mean FEV1, ACQ6 and ASX scores. However, C/D between individual domains varied considerably between subjects. The C/D between parameters for any change around zero for the combined adults and pediatric population was best for FeNO and ACQ6, 79.3/20.7% while FEV1 was more discordant than other parameters in general. When considering changes around the minimal important difference (MID) in a subset, the level of concordance increased in general, with FeNO and ACQ6 demonstrating a C/D of 93.5/6.6%. CONCLUSION: This data demonstrates that the concordance between changes in the asthma domains is often substantially less than 100%. Reasons for this may include different time courses for change of the separate domains, the degree of abnormality for each domain at baseline, as well as intrinsic limitations of each parameter.

Patterns and determinants of exhaled nitric oxide trajectories in schoolchildren over a 7-year period.

Fractional exhaled nitric oxide (F ENO50 ), a marker of allergic airway inflammation, is used in respiratory research and asthma clinical care; however, its trajectory with increasing age during childhood has not been well characterised. We examined F ENO50 longitudinally during a period of important somatic growth to describe trajectories across childhood and adolescence in healthy participants and evaluate clinical factors as potential determinants of trajectories.F ENO50 was collected at six visits over 8 years in a population-based cohort of 1791 schoolchildren without asthma (median age at entry 8.4 years). Smooth sex-specific F ENO50 trajectories were estimated using generalised additive mixed models, with participant-level random effects. We evaluated whether sex-specific trajectories were influenced by race/ethnicity, body mass index (BMI) percentile, allergic rhinitis or puberty.Different F ENO50 patterns were observed by sex in later childhood and several factors were associated with either F ENO50 level or change in F ENO50 as participants aged. F ENO50 -age trajectories were similar by sex until age ∼11.5 years, after which males had greater F ENO50 change than females. This divergence in F ENO50 -age trajectories coincides with puberty. Males with higher starting BMI percentile had attenuated F ENO50 -age slopes. Among males, F ENO50 levels were lower in non-Hispanic white subjects. Among both sexes, participants with rhinitis had higher F ENO50 F ENO50 levels within individuals tracked over time; however, there was considerable variation in F ENO50 patterns across participants.F ENO50 trajectories from longitudinal data provide evidence of sex differences coinciding with puberty, suggesting potential hormone link. Improved understanding of determinants of F ENO50 trajectories is needed to realise the potential for using individualised predicted F ENO50 trajectories.

Bruxism Relieved Under CPAP Treatment in a Patient With OSA Syndrome.

Bruxism is a heterogeneous condition related to various underlying mechanisms, including the presence of OSA. This case report illustrates that sleep mandibular movement monitoring and analysis could provide a useful opportunity for detection of both sleep bruxism and respiratory effort. The current case suggests that tracking of respiratory effort could enable evaluation of bruxism and its potential interactions. Successful treatment of sleep-related respiratory effort may lead to improved or resolution of bruxism in cases where such a causal relationship does exist.

Three Major Efforts to Phenotype Asthma: Severe Asthma Research Program, Asthma Disease Endotyping for Personalized Therapeutics, and Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome.

The SARP, ADEPT, and U-BIOPRED programs are all significant efforts in characterizing asthma and reporting clusters that will assist in designing personalized therapies for asthma, and especially severe asthma. Key aspects of the design of these programs are summarized and major findings are reported in this review.

Clinical precision, accuracy, number and durations of exhalations for a novel electrochemical monitor for exhaled nitric oxide.

BACKGROUND: Exhaled nitric oxide (FeNO) is a validated marker of eosinophilic inflammation. Fenom ProTM is a novel FDA-cleared monitor for FeNO. The American Thoracic Guidelines from 2005 recommend at least 6 s exhalation for adults and in some cases up to 10 s, and 4 s for children, and that the average of the first two valid exhalations is taken as the FeNO value. METHODS: Clinical precision, 6 versus 10 s exhalations, the first versus the average of the first two valid exhalation methods comparison were evaluated for Fenom ProTM, as well as a methods comparison to the NIOX VERO® monitor. RESULTS: The intent-to-treat population (n = 126) consisted of 83 adults, and 43 pediatric subjects with 16 subjects under 12 years of age. Clinical precision for 10 s exhalations on Fenom ProTM was excellent with a within-subject standard deviation (SD) range of 0.57-3.73 ppb and mean coefficient of variation (CV) range of 4.21% to 9.65%. The clinical precision for the separate adult and pediatric groups as well as for the 6 s exhalations were similar. The 10 and 6 s exhalation comparisons and one versus the average of two valid exhalations showed a high level of agreement. The Fenom ProTM and the NIOX VERO® monitors also demonstrated a high level of agreement with the values from the latter slightly lower (mean bias of -3.2 ppb). CONCLUSION: Fenom ProTM demonstrated eminently acceptable performance supporting its clinical utility. The data suggests that 6 s exhalations can be used in adults and children, and that one exhalation is adequate rather than obtaining the average of two exhalations on Fenom ProTM.

Mandibular Movement Analysis to Assess Efficacy of Oral Appliance Therapy in OSA.

RATIONALE: The respiratory effort index derived from vertical mandibular movements (MM-REI) is a potential marker of increased respiratory effort during sleep. We evaluated the effectiveness of mandibular advancement splint therapy using MM-REI, in comparison with the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). METHODS: Fifty-six subjects (median age, 47 years) with OSA treated with a custom mandibular advancement splint (Herbst appliance) were evaluated at the end of the titration procedure when snoring was reported absent by the sleep partner. We employed a magnetometer to capture mandibular movements (Brizzy; Nomics). Mandibular advancement splint efficacy was assessed as the percent change from baseline, using Bayesian multilevel models. RESULTS: At the end of titration, all indices of OSA severity decreased compared with baseline: AHI (-48.9% to -71.1%), ODI (-49.5% to -77.2%), with obstructive hypopnea index and MM-REI showing the largest responses (-70.6% to -88.5% and -69.5% to -96.3%, respectively). MM-REI normalization via reductions in both mandibular movement event rate and duration accurately reflected efficacy of the appliance. CONCLUSIONS: The reduction of vertical respiratory mandibular movements estimated by MM-REI and sleep respiratory effort duration accompanied the decrease in obstructive hypopneas, AHI, and ODI when snoring resolved in subjects with OSA treated with an optimally titrated mandibular advancement splint.

A phase 2a study of toreforant, a histamine H4 receptor antagonist, in eosinophilic asthma.

BACKGROUND: Data from preclinical and clinical studies support the evaluation of histamine 4 receptor antagonists in the treatment of asthma. Toreforant is a selective histamine 4 receptor antagonist that could be effective in patients with eosinophilic asthma. OBJECTIVE: To evaluate the efficacy and safety of toreforant in patients with eosinophilic, persistent asthma that was inadequately controlled despite current treatment. METHODS: In this phase 2a, multicenter, randomized, double-blinded, parallel-group, placebo-controlled, proof-of-concept study, 162 eligible patients were randomized (1:1) to placebo or 30 mg of toreforant once daily through week 24 and followed for 4 weeks. The primary end point was change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16. Secondary end points included change from baseline at week 16 in postbronchodilator percent-predicted forced expiratory volume in 1 second, Asthma Control Questionnaire scores, weekly averages of Daytime and Nighttime Asthma Diary Symptom Scores, and weekly average of number of puffs in a day that rescue medication was used. RESULTS: There was no significant difference between groups in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at week 16 (difference in least-square means -0.19%; 95% confidence interval -3.01 to 2.64; P = .90). Similarly, there were no significant differences between groups at week 16 in changes from baseline in the secondary end points (P ≥ .30). Toreforant was generally well tolerated. No deaths or serious adverse events were reported at any time point. CONCLUSION: Toreforant, at the dose tested, failed to provide therapeutic benefit in this population of patients with uncontrolled, eosinophilic, persistent asthma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01823016.

Persistent respiratory effort after adenotonsillectomy in children with sleep-disordered breathing.

OBJECTIVES: Adenotonsillectomy (AT) markedly improves but does not necessarily normalize polysomnographic findings in children with adenotonsillar hypertrophy and related sleep-disordered breathing (SDB). Adenotonsillectomy efficacy should be evaluated by follow-up polysomnography (PSG), but this method may underestimate persistent respiratory effort (RE). Mandibular movement (MMas) monitoring is an innovative measurement that readily identifies RE during upper airway obstruction. We hypothesized that MMas indices would decrease in parallel of PSG indices and that children with persistent RE more reliably could be identified with MMas. METHODS: Twenty-five children (3-12 years of age) with SDB were enrolled in this individual prospective-cohort study. Polysomnography was supplemented with a midsagittal movement magnetic sensor that measured MMas during each respiratory cycle before and > 3 months after AT. RESULTS: Adenotonsillectomy significantly improved PSG indices, except for RE-related arousals (RERA). Mandibular movement index changes after AT significantly were correlated with corresponding decreases in sleep apnea-hypopnea index (AHI) and O2 desaturation index (ODI) (Spearman's rho = 0.978 and 0.922, respectively), whereas changes in MMas duration significantly were associated with both RERA duration (rho = 0.475, P = 0.017) and index (rho = 0.564, P = 0.003). Conditional multivariate analysis showed that both AHI and RERA significantly contributed to the variance of MMas index after AT (P = 0.0003 and 0.0005, respectively), whereas MMas duration consistently was related to the duration of RERA regardless of AT. CONCLUSION: Adenotonsillectomy significantly reduced AHI. However, persistent RERA were apparent in a significant proportion of children, and this was reflected by the remaining abnormal MMas pattern. Follow-up of children after AT can be recommended and readily achieved by monitoring MMas to identify persistent RE. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1230-1237, 2018.

Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study.

BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. CONCLUSION: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.

Inhaled Steroids and Active Smoking Drive Chronic Obstructive Pulmonary Disease Symptoms and Biomarkers to a Greater Degree Than Airflow Limitation.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. OBJECTIVES: The purpose of the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study was to correlate clinical features and biomarkers with molecular characteristics in a well-profiled COPD cohort. METHODS: A total of 67 COPD subjects (forced expiratory volume in the first second of expiration [FEV1]: 45%-80% predicted) and 63 healthy smoking and nonsmoking controls underwent multiple assessments including patient questionnaires, lung function, and clinical biomarkers including fractional exhaled nitric oxide (FENO), induced sputum, and blood. MEASUREMENTS AND MAIN RESULTS: The impact of inhaled corticosteroids (ICSs), and to a lesser extent current smoking, was more associated with symptom control, exacerbation rates, and clinical biomarkers, than severity by FEV1. The ICS-treated smoking subjects were most symptomatic, with significantly elevated scores on patient-reported outcomes and more annual exacerbations (P < .05). Inhaled corticosteroid users had greater airflow obstruction and air trapping compared with non-ICS users, regardless of smoking status. Smoking, regardless of ICS use, was associated with significantly lower FENO (P < .05). Smoking, in non-ICS users, was associated with an elevated proportion of sputum neutrophils and reduced sputum macrophages. Increased serum C-reactive protein was observed in smokers but not in ICS and nonsmoking ICS users (P < .05). In contrast, only air trapping and neutrophilic inflammation increased with severity, defined by postbronchodilator FEV1. CONCLUSIONS: Compared with COPD severity by FEV1, ICS use and current smoking were better determinants of clinical characteristics and biomarkers. Use of the ADEPT COPD data promises to prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches.

Mandibular Movements As Accurate Reporters of Respiratory Effort during Sleep: Validation against Diaphragmatic Electromyography.

CONTEXT: Mandibular movements (MM) are considered as reliable reporters of respiratory effort (RE) during sleep and sleep disordered breathing (SDB), but MM accuracy has never been validated against the gold standard diaphragmatic electromyography (EMG-d). OBJECTIVES: To assess the degree of agreement between MM and EMG-d signals during different sleep stages and abnormal respiratory events. METHODS: Twenty-five consecutive adult patients with SDB were studied by polysomnography (PSG) that also included multipair esophageal diaphragm electromyography and a magnetometer to record MM. EMG-d activity (microvolt) and MM (millimeter) amplitudes were extracted by envelope processing. Agreement between signals amplitudes was evaluated by mixed linear regression and cross-correlation function and in segments of PSG including event-free and SDB periods. RESULTS: The average total sleep time was 370 ± 18 min and the apnea hypopnea index was 24.8 ± 5.2 events/h. MM and EMG-d amplitudes were significantly cross-correlated: median r (95% CI): 0.67 (0.23-0.96). A mixed linear model showed that for each 10 µV of increase in EMG-d activity, MM amplitude increased by 0.28 mm. The variations in MM amplitudes (median range: 0.11-0.84 mm) between normal breathing, respiratory effort-related arousal, obstructive, mixed, and central apnea periods closely corresponded to those observed with EMG-d activity (median range: 2.11-8.23 µV). CONCLUSION: MM amplitudes change proportionally to diaphragmatic EMG activity and accurately identify variations of RE during normal sleep and SDB.

Perspectives on exhaled nitric oxide.

The history of nitric oxide (NO) in the respiratory field dates back to the beginning of the 1990s with the pioneering study by Lars Gustafsson et al describing the presence of endogenous NO in the exhaled breath of human beings. Soon after, independent studies showed that exhaled NO concentrations (FENO) is higher in asthmatics than in normal subjects. Not all asthmatics demonstrate a high FENO, reflecting the heterogeneity of asthma. High values of FENO are associated with over-expression of corticosteroid-sensitive iNOS isoform and allergic/eosinophilic inflammation. A major feature of elevated FENO in asthma is the prediction of inhaled corticosteroid (ICS) response, and FENO more than 50 ppb in adults is a strong indicator of likely ICS sensitivity. In addition, FENO values are elevated in asthma when asthma control deteriorates, identifying patients at risk of exacerbations, and, on the other hand, FENO reductions during ICS therapy precede improvement in respiratory symptoms and lung function, suggesting that FENO is a sensitive predictor of loss of asthma control. FENO also predicts the response to biological therapy (anti-IgE, -IL-5 and -IL-13 antibodies) in severe asthma but, interestingly, FENO values fall only after treatment with anti-IL-13 and -IL-4/IL-13 receptor antibodies. The use of FENO as a Type-2 inflammatory biomarker, in constellation with other Type-2 markers, could help to determine who might benefit from ICS and biological treatment. It remains to find out more precise cut-off values of FENO to identify potential ICS responders in specific phenotypes.

Monitoring mandibular movements to detect Cheyne-Stokes Breathing.

BACKGROUND: The patterns of mandibular movements (MM) during sleep can be used to identify increased respiratory effort periodic large-amplitude MM (LPM), and cortical arousals associated with "sharp" large-amplitude MM (SPM). We hypothesized that Cheyne Stokes breathing (CSB) may be identified by periodic abnormal MM patterns. The present study aims to evaluate prospectively the concordance between CSB detected by periodic MM and polysomnography (PSG) as gold-standard. The present study aims to evaluate prospectively the concordance between CSB detected by periodic MM and polysomnography (PSG) as gold-standard. METHODS: In 573 consecutive patients attending an in-laboratory PSG for suspected sleep disordered breathing (SDB), MM signals were acquired using magnetometry and scored manually while blinded from the PSG signal. Data analysis aimed to verify the concordance between the CSB identified by PSG and the presence of LPM or SPM. The data were randomly divided into training and validation sets (985 5-min segments/set) and concordance was evaluated using 2 classification models. RESULTS: In PSG, 22 patients (mean age ± SD: 65.9 ± 15.0 with a sex ratio M/F of 17/5) had CSB (mean central apnea hourly indice ± SD: 17.5 ± 6.2) from a total of 573 patients with suspected SDB. When tested on independent subset, the classification of CSB based on LPM and SPM is highly accurate (Balanced-accuracy = 0.922, sensitivity = 0.922, specificity = 0.921 and error-rate = 0.078). Logistic models based odds-ratios for CSB in presence of SPM or LPM were 172.43 (95% CI: 88.23-365.04; p < 0.001) and 186.79 (95% CI: 100.48-379.93; p < 0.001), respectively. CONCLUSION: CSB in patients with sleep disordered breathing could be accurately identified by a simple magnetometer device recording mandibular movements.

Exhaled Nitric Oxide in Systemic Sclerosis Lung Disease.

Background. Exhaled nitric oxide (eNO) is a potential biomarker to distinguish systemic sclerosis (SSc) associated pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We evaluated the discriminative validity, feasibility, methods of eNO measurement, and magnitude of differences across lung diseases, disease-subsets (SSc, systemic lupus erythematosus), and healthy-controls. Methods. Consecutive subjects in the UHN Pulmonary Hypertension Programme were recruited. Exhaled nitric oxide was measured at 50 mL/s intervals using chemiluminescent detection. Alveolar and conducting airway NO were partitioned using a two-compartment model of axial diffusion (CMAD) and the trumpet model of axial diffusion (TMAD). Results. Sixty subjects were evaluated. Using the CMAD model, control subjects had lower median (IQR) alveolar NO than all PAH subjects (2.0 (1.5, 2.5) versus 3.14 ppb (2.3, 4.0), p = 0.008). SSc-ILD had significantly lower median conducting airway NO compared to controls (1009.5 versus 1342.1 ml⁎ppb/s, p = 0.04). SSc-PAH had increased median (IQR) alveolar NO compared to controls (3.3 (3.0, 5.7) versus 2.0 ppb (1.5, 2.5), p = 0.01). SSc-PAH conducting airway NO inversely correlated with DLCO (r -0.88 (95% CI -0.99, -0.26)). Conclusion. We have demonstrated feasibility, identified that CMAD modeling is preferred in SSc, and reported the magnitude of differences across cases and controls. Our data supports discriminative validity of eNO in SSc lung disease.

Mandibular position and movements: Suitability for diagnosis of sleep apnoea.

BACKGROUND AND OBJECTIVE: Mandibular movements (MMs) and position during sleep reflect respiratory efforts related to increases in upper airway resistance and micro-arousals. The study objective was to assess whether MM identifies sleep-disordered breathing (SDB) in patients with moderate to high pre-test probability. METHODS: This was a prospective study of 87 consecutive patients referred for an in-laboratory sleep test. Magnetometer-derived MM signals were incorporated into standard polysomnography (PSG). Respiratory events detected with MM analysis were compared with PSG for respiratory disturbance index (RDI) with a blinded scoring. All records were scored manually according to American Academy of Sleep Medicine rules. Primary outcome was to rule-in obstructive sleep apnoea syndrome (OSAS) defined as RDI cut-off value ≥5 or 15/h total sleep time (TST). RESULTS: High concordance emerged between MM and PSG-derived RDI with high temporal coincidence between events (R2 = 0.906; P < 0.001). The mean diagnostic accuracy of MM for OSAS using RDI MM cut-off values of 5.9 and 13.5 was 0.935 (0.86-0.97) and 0.913 (0.84-0.95), with a mean positive likelihood ratio (LLR+) of 3.73 (2.7-20.4) and 8.46 (2.3-31.5), respectively. Receiver operating characteristic (ROC) curves at PSG cut-off values of 5 and 15/h TST had areas under the curve (AUC) of 0.96 (95% CI: 0.89-0.99) and 0.97 (95% CI: 0.91-0.99) (P < 0.001), respectively. MM analysis accurately identified SDB at different levels of severity. CONCLUSION: RDI assessed by MM is highly concordant with PSG, suggesting a role of ambulatory MM recordings to screen for SDB in patients with moderate to high pre-test probability.

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers. METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. RESULTS: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. CONCLUSION: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study.

BACKGROUND: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. METHODS: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. RESULTS: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. CONCLUSIONS: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. TRIAL REGISTRATION: NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.

Longitudinally Stable, Clinically Defined Clusters of Patients with Asthma Independently Identified in the ADEPT and U-BIOPRED Asthma Studies.

BACKGROUND: ADEPT (Airways Disease Endotyping for Personalized Therapeutics) and U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) are independent asthma biomarker studies that aim to enable personalization of therapies. METHODS: Patients in both studies were identified by similar criteria, and similar clinical parameters and biomarkers were assessed in blood, sputum, and airway samples. Fuzzy partition-around-medoid clustering was performed on the ADEPT dataset (n = 154) and independently on the U-BIOPRED asthma dataset (n = 82), filtered to match ADEPT inclusion criteria. For both studies, the same eight easily measurable clinical variables were used, and ADEPT also included methacholine airway hyperresponsiveness. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and the full U-BIOPRED adult asthma dataset (n = 397) as independent external validation. MEASUREMENTS AND MAIN RESULTS: Four clusters were identified in the ADEPT-asthma study population with distinct clinical and biomarker profiles. In general, Cluster 1 consists of patients with mild asthma not treated with steroids and well controlled with preserved lung function and a low-inflammatory phenotype; Cluster 2 is partially controlled, with mild airflow obstruction but severe airway hyperresponsiveness and a Th2 phenotype (brittle phenotype); Cluster 3 is partially controlled with mild airflow obstruction but reduced vital capacity, less bronchodilator reversibility, and a non-Th2 phenotype with neutrophilic inflammation (chronic obstructive pulmonary disease-like); and Cluster 4 is poorly controlled, with marked airflow obstruction, marked bronchodilator reversibility, and a mixed inflammatory phenotype. Overall, the ADEPT clusters were stable over 12 months and reproduced by identifying four analogous clusters in the U-BIOPRED asthma dataset, with distributions for most clustering and nonclustering variables similar to ADEPT. CONCLUSIONS: We report four clinical clusters in ADEPT and confirmed these by external validation in U-BIOPRED. The ADEPT clusters have distinct clinical and molecular characteristics, are stable over 12 months, and present opportunities for the development of tailored therapeutics for asthma.

Utility of animal and in vivo experimental infection of humans with rhinoviruses in the development of therapeutic agents for viral exacerbations of asthma and chronic obstructive pulmonary disease.

There is an association with acute viral infection of the respiratory tract and exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Although these exacerbations are associated with several types of viruses, human rhinoviruses (HRVs) are associated with the vast majority of disease exacerbations. Due to the lack of an animal species that is naturally permissive for HRVs to use as a facile model system, and the limitations associated with animal models of asthma and COPD, studies of controlled experimental infection of humans with HRVs have been used and conducted safely for decades. This review discusses how these experimental infection studies with HRVs have provided a means of understanding the pathophysiology underlying virus-induced exacerbations of asthma and COPD with the goal of developing agents for their prevention and treatment.