Exhaled Nitric Oxide Research Articles

Impact of exacerbation history on long-term efficacy of dupilumab in patients with asthma.

The phase 3 QUEST (NCT02414854) and TRAVERSE (NCT02134028) studies demonstrated the efficacy of dupilumab 200/300 mg versus placebo every 2 weeks for 52 weeks (QUEST) and dupilumab 300 mg up to an additional 96 weeks (TRAVERSE) in patients ≥12 years of age with uncontrolled, moderate-to-severe asthma. Overall, safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed long-term dupilumab efficacy for up to 3 years by exacerbation history. Unadjusted annualised severe exacerbation rates (AER) and change from parent study baseline (PSBL) in pre-bronchodilator forced expiratory volume in 1 s (FEV1) and 5-item Asthma Control Questionnaire (ACQ-5) score were assessed in patients with PSBL eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥20 ppb and 1 (n=624), 2 (n=344), or ≥3 (n=311) exacerbations in the year before enrolment in QUEST. In all three groups, dupilumab treatment progressively reduced AER range to 0.17-0.30 during TRAVERSE (Weeks 48-96), increased pre-bronchodilator FEV1 range by 0.28-0.49 L by Week 96 and improved asthma control (reduced ACQ-5 score range by 1.51-2.03 by Week 48). For patients who first received dupilumab upon TRAVERSE enrolment, AER decreased, and lung function and asthma control improved rapidly, as was observed upon initiation of dupilumab in QUEST. Dupilumab was efficacious regardless of exacerbation history. For patients with uncontrolled, moderate-to-severe asthma with elevation of at least one type 2 biomarker, dupilumab treatment provides sustained, long-term reduction of exacerbation rates and improvements in lung function and asthma control irrespective of exacerbation history.

High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children

Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P< .0001), C-reactive protein level (P= .0006), and blood neutrophil count (P= .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio= 1.74 [95% CI= 1.10-2.77]; P= .0187) or low (incidence rate ratio=1.83 [95% CI= 1.21-2.77]; P= .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (β= -0.0044 [95% CI= -0.0073 to -0.0015]; pairwise interaction P= .0028) or low IL-6 levels (β= -0.0042 [95% CI= - 0.0070 to -0.0013]; pairwise interaction P= .0039). Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

A miniaturized photodiode-based chemiluminescence sensor for measurement of fractional exhaled nitric oxide

Fractional exhaled nitric oxide (FENO) measurement is a valuable tool in diagnosing and monitoring certain respiratory diseases, low cost and miniaturized NO sensor is highly demanded for FENO home healthcare self-monitoring. In this work, a miniature photodiode-based chemiluminescence sensor is presented for the sensitive measurement of NO concentration. Effects of various reflective film materials including stainless-steel, aluminum and silver for coating the inner surface of the optical cell were investigated for higher photon collection efficiency, and the silver reflective film displayed the best sensitivity. As the oxidation and pollution of silver film led to dramatical decay of signal, a quartz inner chamber with reflectance film layer coated on its outer surface was developed to achieve high stability and sensitivity simultaneously. The limit of detection for FENO was 6.6 ppb, the linear range of 10–100 ppb with a response time of 6.8 s was reached, which was satisfied the requirements for FENO measurement. The weight of the sensor is 96 g with a size of only 6.5 × 3 × 2 cm3, and the cost is estimated less than $1 K, which is suit for on-site monitoring of FENO. FENO50 was obtained the response difference of room air and breath air measured successively with a switching valve, the beath air was sampled into a bag at flow rate of 50 ml/s by offline sampling device, and multiple measurements were executed for better accuracy. The potential usage of the sensor was further illustrated by studying the FENO50 levels of individuals before and after consuming nitrate-rich sports drinks.

Assessment of Fraction of Exhaled Nitric Oxide and Soluble Receptor for Advanced Glycation End Products Biomarkers for Jordanian Asthmatic Children.

Fraction of exhaled nitric oxide (FeNO) and soluble advanced glycation end-product receptor (sRAGE) are proposed as biomarkers of asthma, therefore we sought to assess their use in asthmatic children of Jordan. We conducted a case-control study at The University of Jordan Hospital. A total of 141 asthmatic children followed by respiratory pediatricians and 118 healthy children aged 4-18 years were recruited. FeNO was measured by NObreath device and serum sRAGE by ELISA that detect endogenously soluble isoform (esRAGE) and total soluble RAGE (sRAGE). sRAGE in asthmatic was half of the control (p <0.001). In addition, ratio of esRAGE/sRAGE was two-fold higher in asthmatic (p = <0.001). Neither FeNO nor esRAGE levels were significantly different between groups. FeNO and asthma control test (ACT) score were negatively correlated corrected for age and body mass index (BMI), (r = -0.180, p= 0.034). For the uncontrolled asthma group, esRAGE/sRAGE negatively correlated with ACT score (r = -.329, p = 0.038). Receiver operating curve (ROC) analysis revealed significant predictive value (PV) for sRAGE and esRAGE/sRAGE in asthma detection with area under the curve (AUC) of (0.751 ± 0.031) and (0.711±.033), consequently. However, no biomarker had a significant PV for lack of control. The current study supports utilizing sRAGE as a marker for asthma and present a potential therapeutic target. However, our results indicate that both FeNO and sRAGE have a limited role in the management of asthmatic children or assessment of asthma control.

Association between Childhood Asthma Control Test scores and lung pathophysiologic indicators in longitudinal measurements.

Childhood Asthma Control Test (C-ACT) is a well-validated questionnaire for asthma controls among 4-11 years old children. This study aims to examine if longitudinal C-ACT score changes could also reflect lung pathophysiologic changes. Thirty-seven children (43% female) aged 5 to 10 years old with mild or moderate asthma were followed up for 6 weeks with bi-weekly assessments of C-ACT, airway mechanics, lung function and respiratory inflammation. Associations of longitudinal changes in C-ACT score with lung pathophysiologic indicators were evaluated using linear mixed-effects models. A two-point worsening of total C-ACT score (sum of child and caregiver-reported) was associated with significant decreases in forced expiratory volume during the 1st second (FEV1) by 1.7% (P=0.04) and forced vital capacity (FVC) by 1.6% (P=0.01) and increased total airway resistance [airway resistance at 5 Hz (R5)] by 3.8% (P=0.05). A two-point worsening in child-reported score was significantly associated with 3.1% and 2.5% reductions in FEV1 and FVC, respectively, and with increases in R5 by 6.5% and large airway resistance [airway resistance at 20 Hz (R20)] by 5.5%. In contrast, a two-point worsening of caregiver-reported score was associated with none of the concurrent lung pathophysiologic measurements. Worsening of total C-ACT score was significantly associated with increased respiratory inflammation [fractional exhaled nitric oxide (FeNO)] in a subset (n=23) of children without eosinophilic airway inflammation. C-ACT scores were associated with none of the small airway measures. In children with mild or moderate asthma, longitudinal C-ACT score changes could reflect acute changes in large airway resistance and lung function. Measures of small airway physiology would provide valuable complementary information for asthma control. Asthma phenotype may affect whether C-ACT score could reflect respiratory inflammation.

Fractured Exhaled Nitric Oxide and Biologic Therapies for Paediatric Asthma

Abstract Bronchial asthma is the most frequently diagnosed chronic respiratory disease in children. Treatment approaches should aim to achieve the disease control, reduce limiting symptoms, and improve the quality of life. Routine treatment of patients with asthma relies on assessment of symptoms and spirometry results. These diagnostic and therapeutic strategies do not consider the level of inflammation in the airways as a fundamental pathognomonic feature of the disease. The use of biomarkers is increasing in the context of efforts to better understand individual asthma pathways (asthma endotyping), with the potential for personalized treatment with innovative biologics. Elevated levels of exhaled nitric oxide (FENO) represent an indirect marker of T2 inflammation in airways. FENO is one of the few biomarkers that have been applied in routine clinical practice. High levels predict a good therapeutic response to treatment with corticosteroids and selected biologics (Omalizumab, Dupilumab, Mepolizumab, Tezepelumab), or an increased risk of asthma exacerbation. The aim of this review is to evaluate the advantages, disadvantages, and potential applications of this test in relation to new treatment options using biologics for asthma.

Effect of infant viral respiratory disease on childhood asthma in a non-industrialized setting.

There are limited data from non-industrialized settings on the effects of early life viral respiratory disease on childhood respiratory illness. We followed a birth cohort in tropical Ecuador to understand how early viral respiratory disease, in the context of exposures affecting airway inflammation including ascariasis, affect wheezing illness, asthma, and rhinoconjunctivitis in later childhood. A surveillance cohort nested within a birth cohort was monitored for respiratory infections during the first 2years in rural Ecuador and followed for 8years for the development of wheeze and rhinoconjunctivitis. Nasal swabs were examined for viruses by polymerase chain reaction and respiratory symptom data on recent wheeze and rhinoconjunctivitis were collected by periodic questionnaires at 3, 5, and 8years. Stools from pregnant mothers and periodically from children aged 2years were examined microscopically for soil-transmitted helminths. Atopy was measured by allergen skin prick testing at 2years. Spirometry, fractional exhaled nitric oxide measurement, and nasal washes were performed at 8years. Associations between clinically significant respiratory disease (CSRD) and wheezing or rhinoconjunctivitis at 3, 5, and 8years were estimated using multivariable logistic regression. Four hundred and twenty six children were followed of which 67.7% had at least one CSRD episode; 12% had respiratory syncytial virus (RSV)+CSRD and 36% had rhinovirus (RHV)+CSRD. All-cause CSRD was associated with increased wheeze at 3 (OR 2.33 [95% confidence intervals (CI) 1.23-4.40]) and 5 (OR: 2.12 [95% CI 1.12-4.01]) years. RHV+CSRD was more strongly associated with wheeze at 3years in STH-infected (STH-infected [OR 13.41, 95% CI 1.56-115.64] vs. uninfected [OR 1.68, 95% CI 0.73-3.84]) and SPT+ (SPT+ [OR 9.42, 95% CI 1.88-47.15] versus SPT- [OR 1.92, 95% CI 0.84-4.38]) children. No associations were observed between CSRD and rhinoconjunctivitis. CSRD was significantly associated with childhood wheeze with stronger associations observed for RHV+CSRD in SPT+ and STH-infected children.

Sputum Neurturin Levels in Adult Asthmatic Subjects.

Neurturin (NRTN) is a neurotrophic factor that was originally identified in the development and maintenance of neural cells. Recent studies involving NRTN knockout mice have reported its anti-inflammatory effects in allergic airway conditions. However, the role of NRTN in human asthma has not yet been identified. The purposes of the present study were to confirm the presence of NRTN in the airways and to investigate the clinical and pathogenetic roles of NRTN in asthma. The NRTN levels in the induced sputum were measured by enzyme-linked immunosorbent assay (ELISA). Relationships between NRTN and clinical characteristics, asthma control status, and airway inflammation were assessed. Sixty-four asthmatic subjects were enrolled in the study. All asthmatic subjects had detectable sputum NRTN levels, with a mean (SD) level of 2.03 (1.29) ng/mL. The sputum NRTN levels had significant positive correlations with sputum eosinophil and exhaled nitric oxide levels and were significantly higher in the atopic subjects than in the non-atopic subjects. No significant difference in sputum NRTN levels were observed for asthma control status and asthma exacerbation. In sputum inflammatory analyses, sputum NRTN level was positively correlated with interleukin (IL)-5 and IL-13 levels, and negatively correlated with matrix metalloproteinase (MMP)-9 level. It is plausible that sputum NRTN could serve as a new marker for Type 2 airway inflammation, implicating its role in the process of airway remodeling in asthma. Future studies should investigate the clinical relevance of sputum NRTN level in prospective analyses.

Can Fractional Exhaled Nitric Oxide (FeNO) Serve as a Clinical Indicator for Patients Hospitalized with Crimean-Congo Hemorrhagic Fever?

Crimean-Congo hemorrhagic fever (CCHF), a zoonotic disease spread by infected viruses, can be a significant cause of morbidity and mortality in endemic areas. This prospective study aimed to establish the relationship between fractional exhaled nitric oxide (FeNO) levels and clinical prognosis of CCHF. The study included 85 participants: 55 patients followed up for CCHF from May to August 2022, and 30 healthy controls. FeNO levels were measured upon hospital admission and were 7.6 ± 3.3 parts per billion (ppb) in patients with mild/moderate CCHF, 2.5 ± 2.1 ppb in patients with severe CCHF, and 6.7 ± 1.7 ppb in the healthy control group. There was no statistically significant difference in FeNO levels between the control group and patients with mild/moderate CCHF (P = 0.09), whereas patients with severe CCHF had lower FeNO levels than those in the control group and patients with mild/moderate CCHF (P < 0.001 for both). FeNO measurement may offer a noninvasive and easily applied approach for predicting the clinical course and prognosis of CCHF in the early stages of the disease.

Mediterranean Diet and Airway Inflammation in School-Aged Children.

There seems to exist an intricate relationship between airway inflammation, body mass index (BMI), and diet. The intake of specific foods or food groups has been suggested to suppress the oxidative stress and inflammatory processes that characterize airway inflammation, but little is known about dietary patterns and their complex interplay with BMI and airway inflammation. Therefore, this cross-sectional study aimed to explore the association between adherence to the Mediterranean diet (MD), a characteristic European diet, and levels of airway inflammation in school-aged children, taking into account their BMI. This cross-sectional analysis comprised 660 children: 49.1% females, 7-12 years old. Adherence to the MD was assessed through the alternate Mediterranean score (aMED). Higher scores represent a healthier diet (0-8). Airway inflammation was assessed measuring exhaled fractional nitric oxide (eNO). Two categories of BMI were considered: non-overweight/non-obese (p < 85th) and overweight/obese (p ≥ 85th). The associations between diet and airway inflammation were estimated using logistic regression models. Higher scores of the aMED were associated with decreased odds of having eNO ≥ 35 ppb, but only in non-overweight/non-obese children (OR = 0.77; 95% CI, 0.61-0.97). For overweight/obese children, the previous association was not significant (OR = 1.57, 95% CI, 0.88-2.79). Our findings suggest that adherence to the MD is associated with lower levels of airway inflammation among non-overweight/non-obese children.

Exacerbations Among Patients With Asthma Are Largely Dependent on the Presence of Multimorbidity.

Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Managing Asthma During Pregnancy and the Postpartum Period

Asthma is one of the most common chronic diseases in pregnancy and is associated with adverse perinatal outcomes. Asthma symptoms worsen in approximately 40% of women, and exacerbations requiring medical intervention occur in at least 20% of women. Factors associated with exacerbation and worsening asthma include multiparity, obesity, black race, exacerbations prior to pregnancy and poor asthma control. Exacerbations are associated with further increased risks for poor perinatal outcomes including low birth weight, preterm birth and small for gestational age, as well as an increase in the development of asthma in early childhood. Common medications used for asthma, including short acting beta agonists and inhaled corticosteroids are considered safe to use in pregnancy. While guidelines generally suggest traditional step therapy for the management of asthma in pregnancy, there are alternative models of care and management approaches which may be effective in pregnancy, but require more research. These include single inhaler maintenance and reliever (SMART) therapy, treatment adjustment with fractional exhaled nitric oxide (FeNO), treatable traits personalised medicine approaches and telemedicine. Little is known about changes to asthma in the postpartum period, however, low adherence to medication, and potential effects of postpartum depression on asthma exacerbation risk warrant further research.

Characterization and Factors Associated with Poor Asthma Control in Adults with Severe Eosinophilic Asthma.

A study was conducted in 98 adult patients diagnosed with severe eosinophilic asthma (73.5% women, mean age 47.2 years) and followed prospectively for 1 year. The aim of the study was to characterize this population and to identify factors associated with poor prognosis at 1 year of follow-up. At the initial visit, uncontrolled severe asthma was diagnosed in 87.7% of patients. Allergic sensitization was observed in 81.7% (polysensitization in 17.3%), with clinically significant allergic asthma in 45%. The mean percentage of sputum eosinophils was 4.7% (standard deviation(SD) 6.3%) and the mean (SD) blood eosinophil count 467 (225) cells/µL. Almost half of the patients (48.3%) had sputum eosinophilia (>3% eosinophils). Sputum eosinophils correlated significantly with peripheral eosinophilia (p = 0.004) and, to a lesser extent, with fractional exhaled nitric oxide (FeNO) (p = 0.04). After 1 year, 48 patients (49%) had uncontrolled asthma in all visits, and 50 (51%) had controlled asthma in some visits. Airway obstruction (FEV1 < 80% predicted) was the main reason for uncontrolled asthma. In the multivariate analysis, an obstructive pattern (odds ratio (OR) 7.45, 95% confidence interval (CI) 2.41-23.03, p < 0.0001) and the patient's age (OR 1.045, 95% CI 1.005-1.086, p = 0.026) were independent predictors of poor asthma control. In adult-onset and long-standing asthma, serum interleukin (IL) IL-17 was higher in the uncontrolled asthma group. This study contributes to characterizing patients with severe eosinophilic asthma in real-world clinical practice.

Exposure to polycyclic aromatic hydrocarbons (PAHs) in outdoor air and respiratory health, inflammation and oxidative stress biomarkers: A panel study in healthy young adults

Exposure to polycyclic aromatic hydrocarbons (PAHs) can be associated with different types of health effects. However, the systemic changes of health effects between fluctuations of PAHs exposure have not been established. In this study, urinary hydroxylated PAHs (OH-PAHs) and 12 biomarkers were determined among 36 students from the urban to the suburb in Taiyuan in 2019. The concentration of Σ12OH-PAHs in urban areas (28.2 and 21.4 μg/g Cr) was significantly higher than that in suburban area (16.8 μg/g Cr). The regression showed that hydroxy-phenanthrene (OH-Phe, 1/2/3/4/9-OH-Phe) was significantly positively correlated with lung function (PEF25 and PEF50), 8-hydroxydeoxyguanosine (8-OHdG), interleukin-8 (IL-8), and fractional exhaled nitric oxide (FeNO). Moreover, there were negative associations of 2-hydroxyfluorene (2-OH-Flu) with FVC and FEV1. 1 unit increase of 1-hydroxypyrene (1-OH-Pyr) was negatively associated with 18.8% FVC, 17.3% FEV1, and 26.4% PEF25 in the suburban location, respectively. During urban2, each unit change of 2-OH-Flu was associated with 10.9% FVC and 10.5% FEV1 decrease, which were higher than those in suburban location. 8-OHdG decreased by 32.0% with each unit increase in 3-hydroxyfluorene (3-OH-Flu) during urban2 (p < 0.05), while 1.9% in the suburban location. During the suburban period, the increase in OH-Phe was correlated with the decrease in malondialdehyde (MDA). The respiratory damage caused by PAHs in the urban disappeared after backing to the urban from the suburban area. Notably, despite the total significant liner mixed regression association of FeNO with multiple OH-PAHs, the association of FeNO with OH-PAHs was not significant during different periods except for 2-OH-Flu. Our findings suggested that short-term exposure to different concentrations of PAHs might cause changes in health effects and called for further research to investigate possible alterations between health effects and PAH exposure.

Use of fractional exhaled nitric oxide as a potential predictor of bronchodilator response.

Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV1): positive (BD+) and negative (BD-). Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count (BD+, P = .03; BD-, P = .04) and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127 (95% confidence interval,-0.269 to -0.486) and 0.696 (95% confidence interval, 0.246-0.899; P = .007), respectively. Measuring FENO levels may be useful for identifying patients with BD+.

Type 2 Low Biomarker Stability and Exacerbations in Severe Uncontrolled Asthma.

We investigated the stability of T2 low status, based on low levels of T2 biomarkers, and exacerbation rates in T2 low and non-T2 low asthma from clinical retrospective data of severe uncontrolled asthma patients. Knowledge of the T2 low biomarker profile is sparse and biomarker stability is uncharted. Secondary care patients with severe uncontrolled asthma and at least two blood eosinophil counts (BEC) and fractional exhaled nitric oxide (FeNO) measured for determination of type 2 inflammation status were evaluated from a follow-up period of 4 years. Patients were stratified into four groups: T2 low150 (n = 31; BEC < 150 cells/µL and FeNO < 25 ppb), non-T2 low150 (n = 138; BEC > 150 cells/µL and/or FeNO > 25 ppb), T2 low300 (n = 66; BEC < 300 cells/µL and FeNO < 25 ppb), and non-T2 low300 (n = 103; BEC > 300 cells/µL and/or FeNO > 25 ppb). Exacerbation rates requiring hospital care, stability of biomarker status, and cumulative OCS and ICS doses were assessed during follow-up. Among patients with severe uncontrolled asthma, 18% (n = 31) were identified as T2 low150, and 39% (n = 66) as T2 low300. In these groups, the low biomarker profile was stable in 55% (n = 11) and 72% (n = 33) of patients with follow-up measures. Exacerbation rates were different between the T2 low and non-T2 low groups: 19.7 [95% CI: 4.3-45.6] in T2 low150 vs. 8.4 [4.7-13.0] in non-T2 low150 per 100 patient-years. BEC and FeNO are useful biomarkers in identifying T2 low severe uncontrolled asthma, showing a stable follow-up biomarker profile in up to 72% of patients. Repeated monitoring of these biomarkers is essential in identifying and treating patients with T2 low asthma.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of ICS dose.

Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

Using the 6-min walk test to assess the clinical response to mepolizumab and conventional therapy in severe eosinophilic asthma.

Severe asthma limits exercise to avoid respiratory symptoms. The objective of the present study was to investigate the role of the 6-min walk test (6MWT) in severe asthma. Consecutive patients with severe eosinophilic asthma were enrolled. A 6MWT was performed before and after 12 months. Inhaled therapy dose, oral corticosteroids dose, pulmonary function tests, eosinophil blood count, fractional exhaled nitric oxide (FeNO), Asthma Control Test (ACT) score and responses to the Asthma Quality of Life Questionnaire (AQLQ) were also recorded. Of the 22 patients enrolled, 13 were treated with mepolizumab 100 mg every 4 weeks in addition to conventional therapy and nine with conventional therapy only. The majority of the patients were treated with high-dose inhaled corticosteroids/long-acting β-agonists/long-acting muscarinic receptor antagonists, while approximately half were on continuous oral corticosteroids. After 12 months, the mepolizumab group only showed a significant improvement in pulmonary function tests (percentage forced expiratory volume in 1 s and percentage forced expiratory flow at 25-75% forced vital capacity (FEF25-75%), both p<0.001; percentage forced vital capacity, p<0.01) and clinical laboratory parameters (eosinophil count, FeNO measured at a flow rate of 50 mL·s-1, ACT and AQLQ, p<0.001). No significant changes in the proportion of patients using continuous oral corticosteroids and high-dose inhaled corticosteroids/long-acting β-agonists/long-acting muscarinic receptor antagonists were observed in either group (p>0.05). By paired comparisons, statistically significant improvements of the mean 6-min walk distance (6MWD) were observed in the mepolizumab (p<0.001) and conventional therapy (p<0.01) groups, while no improvement was seen in dyspnoea Borg scale, heart rate, percentage oxygen saturation or systolic and diastolic blood pressure. 6MWD showed significant direct correlations with ACT (r=0.5998, p<0.001), AQLQ (r=0.3978, p=0.009) and FEF25-75% (r=0.3589, p=0.017). The 6MWT could complement severe asthma assessment and be relevant in evaluating the objective response to treatment, including biological therapies like mepolizumab.

Pulmonary function testing in patients with liver cirrhosis (Review).

Liver cirrhosis is a common long-term outcome of chronic hepatic inflammation. Patients with liver cirrhosis may also have pulmonary complications. There are several reasons for pulmonary dysfunction in liver cirrhosis, including intrinsic cardiopulmonary dysfunction unrelated to liver disease and specific disorders related to the presence of liver cirrhosis and/or portal hypertension. The most prevalent and clinically significant pulmonary complications are hepatic hydrothorax, hepatopulmonary syndrome, spontaneous pulmonary empyema and portopulmonary hypertension. Pulmonary function tests (PFTs) have traditionally been used to assess the lung function of patients with liver cirrhosis. To the best of our knowledge, the present review is the first to detail all types of PFTs performed in patients with liver cirrhosis and discuss their clinical significance. Patients with liver cirrhosis have reduced values of spirometric parameters, diffusion capacity for carbon monoxide (DLCO), lung volumes, maximal inspiratory pressure and maximal expiratory pressure. Furthermore, they have a higher closing volume, a greater airway occlusion pressure 0.1 sec after the onset of inspiratory flow and greater exhaled nitric oxide values. In order to improve pulmonary function, patients with ascites may require therapeutic paracentesis. Such findings should be considered when evaluating individuals with liver disease, particularly those who may require surgery. Poor lung function, particularly restrictive lung disease, can have an impact on post-transplant outcomes, such as ventilator time, length of hospital duration and post-operative pulmonary complications; thus, the transplant care team needs to be aware of its prevalence and relevance.

High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.