Exhaled Nitric Oxide Research Articles

Early lung diffusion abnormalities and airways' inflammation in children with type 1 diabetes.

Type 1 diabetes (T1D) impacts lung function and exercise capacity in adults, but limited information is available in children. We hypothesize that T1D causes alterations in pulmonary function and cardiorespiratory fitness, i.e., exercise capacity, at early stages of the disease, due to the presence of inflammation and vascular damage. Therefore, we aim to investigate pulmonary function before and after exercise in children with T1D as compared to age matched healthy controls. Twenty-four children with T1D and twenty healthy controls underwent body plethysmography, diffusion lung capacity for carbon monoxide and fractional exhaled nitric oxide at rest and after cardio-pulmonary exercise test. In children with T1D, baseline total lung capacity and diffusion lung capacity for carbon monoxide were reduced as compared to healthy controls. Children with T1D also showed a reduced exercise capacity associated with poor aerobic fitness. Accordingly, diffusion lung capacity for carbon monoxide tended to increase with exercise in healthy controls, while no change was observed in children with T1D. Fractional exhaled nitric oxide was significantly higher at baseline and tended to increase with exercise in children with T1D, while no changes were observed in healthy controls. Altered diffusion lung capacity for carbon monoxide, increased fractional exhaled nitric oxide and a poor aerobic fitness to exercise suggests the presence of early pulmonary abnormalities in children with T1D.

Dupilumab Efficacy in Patients with Type 2 Asthma with and without Elevated Blood Neutrophils.

Elevated neutrophil counts in blood, sputum, or lung have been associated with poor clinical outcomes and more severe disease in patients with type 2 asthma. In the phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks compared with matched placebo significantly reduced severe asthma exacerbations and improved forced expiratory volume in 1 s (FEV1) in patients with uncontrolled, moderate-to-severe asthma. This post hoc analysis explored the efficacy of dupilumab in patients with type 2 asthma enrolled in QUEST with or without elevated blood neutrophil counts. Annualized severe exacerbation rates during the 52-week treatment period and least-squares mean change from baseline in FEV1 over time were evaluated for patients with elevated type 2 biomarkers at baseline (blood eosinophils ≥ 150 cells/µL or fractional exhaled nitric oxide (FeNO) ≥ 20 ppb; and eosinophils ≥ 300 cells/µL or FeNO ≥ 50 ppb) and low (<4,000 cells/µL) or high (≥4,000 cells/µL) neutrophil counts. Dupilumab significantly reduced annualized severe exacerbation rates compared with placebo during the 52-week treatment period in patients with elevated type 2 biomarkers, irrespective of baseline neutrophil count (P < 0.0001 for all comparisons). Significant improvements in FEV1 versus placebo were observed as early as Week 2 and over the 52-week treatment period, irrespective of baseline neutrophil count (P < 0.001 for all comparisons). Safety findings were similar across all subgroups, regardless of neutrophil counts at baseline. Dupilumab treatment significantly reduced annualized severe exacerbation rates and improved lung function in patients with uncontrolled, moderate-to-severe, type 2 asthma, irrespective of baseline blood neutrophil count. This trial is registered with NCT02414854.

Alveolar nitric oxide concentration plays an important role in identifying cough variant asthma and assessing asthma control in children

Objective To study the value of alveolar nitric oxide concentration (CaNO) in the identification and disease control of cough variant asthma. Methods A retrospective study was conducted on cough variant asthma (CVA-Group), nonasthmatic cough (NAC-Group) and healthy control children (C-Group) aged 5–12 years. The exhaled nitric oxide and spirometry test results of the three groups were collected and compared. Results A total of 410 children were included in this study, including 190 in the CVA-Group, 183 in the NAC-Group, and 37 in the C-Group. The CaNO values of the CVA-Group [11.40 ppb (8.48–14.25)] were significantly higher than those of the NAC-Group and C-Group (all p values <.05). The MMEF %pred values of the CVA-Group [63.65 (56.28–73.58)] were significantly lower than those of the NAC-Group and C-Group (all p values <.05). FeNO50, JawNO and other spirometry indices (FVC %pred, FEV1%pred, FEV1/FVC %pred) showed no significant difference among the three groups. ROC curve analysis showed that the optimal cutoff point value of CaNO was 9.45 ppb, corresponding to 0.816 sensitivity and 0.736 specificity. Spearman correlation analysis showed a significant negative correlation between the CaNO measurement and CVA control score. Conclusions CaNO can not only help identify CVA early in children aged 5–12 years with chronic cough but is also significantly negatively correlated with the CVA control score.

A Comprehensive Epidemiological and Clinical Study of Chronic Rhinosinusitis: First Report from an Iranian Sinusitis Registry Center

Background &amp; Objective: Chronic rhinosinusitis (CRS) is a high prevalent disease throughout the world. The aim of this study was to investigate the epidemiological and clinical characteristics of the CRS patients.&#x0D; Materials &amp; Methods: A total of 241 CRS patients aged 15-70 years were recruited. The prevalence of allergic diseases and its association with CRS, disease severity, and quality of life (QoL) were assessed using GA2LEN and SNOT-22 questionnaires, respectively. Patients' clinical diagnoses and allergic comorbidities were evaluated using paranasal sinus computed tomography (CT), nasal endoscopy, and paraclinical tests (smell identification test, fractional exhaled nitric oxide (FeNO), skin prick test (SPT), pulmonary function test (PFT)).&#x0D; Results: The mean (±SD) age of all participants was 40.1±11.1 years, with a gender distribution of 56% male and 44% female. Nasal polyps (NP) were diagnosed in 42.4% of patients. The total mean SNOT-22 scores and the mean scores of the nasal symptoms category were significantly higher in CRS patients with NP (CRSwNP) compared to CRS without NP (CRSsNP) (OR = 2.3, 95%CI = 9.6–0.55, P = 0.028). Furthermore, there was a significant association between CRSwNP and persistent allergic rhinitis comorbidity (P = 0.006). Finally, a significant association was found between CRSwNP and severe SPT reactivity to Dermatophagoides farina and date palm pollen (P = 0.04 and P &lt; 0.001, respectively).&#x0D; Conclusion: This study suggests that higher SNOT-22 scores may impact QoL in CRSwNP patients. Additionally, a significant association was found between CRS and respiratory allergic diseases.

Association between fractional exhaled nitric oxide and therapeutic adherence to controller management in pediatric asthma patients.

Guidelines for asthma management recommend, before establishing additional therapeutic behaviors, to confirm correct use and adequate therapeutic adherence to treatment. Evidence exists on the use of fractional exhaled nitric oxide (FeNO) values for monitoring therapeutic adherence in adults. It is important to establish whether there is a correlation between FeNO and therapeutic adherence in children. This study aims to provide new knowledge about the relationship between FeNO and therapeutic adherence in asthmatic children. Analytical cross-sectional study including asthma patients 5-18 years of age, attending follow-up at Hospital Militar Central (HMC) between May and November 2022 in Colombia. A sociodemographic survey was carried out, followed by the Pediatric Inhaler Adherence Questionnaire (PIAQ), and asthma control test (ACT) or childhood asthma control test (cACT). We defined adequate therapeutic adherence as not missing a single application of inhaled steroids in the last 15 days according to PIAQ. A poisson regression model was carried out including relevant predictors for therapeutic adherence such as FeNO values, age, tobacco exposure at home, atopy, and time since initiation of use of inhaled controller. Eighty-two children with a median age of 10 years (interquartile range: 7-12 years) were included. Adequate therapeutic adherence was reported by 68.3%. After adjusting for age, sex, exposure to cigarette smoke, duration of controller therapy, and atopy, FeNO < 20 ppb was independently associated with adequate therapeutic adherence (RR = 1.5, p = .04, 95% confidence interval: 1.03-2.19). FeNO values seem to be useful to identify pediatric patients with asthma who have adequate adherence to inhaled steroids in a MIC.

Exposure to Forest Air Monoterpenes with Pulmonary Function Tests in Adolescents with Asthma: A Cohort Study

Increasing evidence supports the direct healing effects of forests, partly attributed to the exposure to plant-emitted monoterpenes available in the forest atmosphere. The potential benefits on respiratory functions from inhaling monoterpenes have gained attention, especially due to the global rise in respiratory diseases. This study involved 42 asthmatic adolescents attending a summer rehabilitation camp at an Altitude Pediatric Asthma Center within a densely forested area in the Eastern Italian Alps. Volatile organic compound measurements indicated a pristine atmosphere, enabling the modeling of continuous hourly monoterpene concentration. The monoterpene concentration exposure and total inhaled dose were assessed over a 14-day stay, during which spirometry, lung oscillometry, and fractional exhaled nitric oxide were measured. Statistically significant correlations were observed between modifications in lung function parameters among asthmatic adolescents and monoterpene exposure. These findings suggest a potential localized airway effect that is specific to monoterpenes. This pilot cohort study might pave the way for further investigations into the therapeutic effects of forest monoterpenes on lung function tests, asthma, and the broader healing potential of forest environments.

SNPs in FAM13A and IL2RB genes are associated with FeNO in adult subjects with asthma

Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008–2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming an a priori genetic model: step (1) a machine learning technique [gradient boosting machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step (2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A (FAM13A) and SNP rs3218258 in interleukin 2 receptor subunit beta (IL2RB) gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses (FAM13A), or in immune response processes (IL2RB). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation.

Novel insights into the whole-blood DNA methylome of asthma in ethnically diverse children and youth.

The epigenetic mechanisms of asthma remain largely understudied in African Americans and Hispanics/Latinos, two populations disproportionately affected by asthma. We aimed to identify markers, regions and processes with differential patterns of DNA methylation (DNAm) in whole blood by asthma status in ethnically diverse children and youth, and to assess their functional consequences. DNAm levels were profiled with the Infinium MethylationEPIC or HumanMethylation450 BeadChip arrays among 1226 African Americans or Hispanics/Latinos and assessed for differential methylation per asthma status at the CpG and region (differentially methylated region (DMR)) level. Novel associations were validated in blood and/or nasal epithelium from ethnically diverse children and youth. The functional and biological implications of the markers identified were investigated by combining epigenomics with transcriptomics from study participants. 128 CpGs and 196 DMRs were differentially methylated after multiple testing corrections, including 92.3% and 92.8% novel associations, respectively. 41 CpGs were replicated in other Hispanics/Latinos, prioritising cg17647904 (NCOR2) and cg16412914 (AXIN1) as asthma DNAm markers. Significant DNAm markers were enriched in previous associations for asthma, fractional exhaled nitric oxide, bacterial infections, immune regulation or eosinophilia. Functional annotation highlighted epigenetically regulated gene networks involved in corticosteroid response, host defence and immune regulation. Several implicated genes are targets for approved or experimental drugs, including TNNC1 and NDUFA12. Many differentially methylated loci previously associated with asthma were validated in our study. We report novel whole-blood DNAm markers for asthma underlying key processes of the disease pathophysiology and confirm the transferability of previous asthma DNAm associations to ethnically diverse populations.

Efficacy of Bhramari pranayama and Om chanting on asthma control, quality of life, and airway inflammation in asthmatic children: an open-label randomized controlled trial

Objectives To explore the efficacy of combination of Bhramari pranayama and om chanting as an adjunct to standard pharmacological treatment on asthma control, quality of life, pulmonary function, and airway inflammation in asthmatic children. Methods Children (n = 110; 8–15 years) with uncontrolled or partly controlled asthma were recruited from the Pediatric Chest Clinic of All India Institute of Medical Sciences, New Delhi. Eligible participants were randomized to either home-based online Bhramari pranayama and om chanting plus standard treatment (YI + ST) group, or standard treatment (ST) alone group. Primary outcome measures were 12-week change in level of asthma symptom control; asthma control questionnaire (ACQ) score, spirometry indices, impulse oscillometry parameters, and pediatric asthma quality of life questionnaire (PAQLQ) score. Secondary outcome was a change in fractional exhaled nitric oxide (FeNO) levels at 12 weeks. Beginning from the enrollment, every participant was evaluated at 0, 2, 6, and 12 weeks. Results After 12 weeks of intervention, higher proportion (68.2%) of children were found to have controlled asthma symptoms in the YI + ST group as compared to ST group (38.5%) according to per protocol analysis (p = 0.03). When compared to ST group, children in YI + ST group showed significantly lower ACQ score, higher PAQLQ score and reduced FeNO levels. No significant changes were observed for the lung function parameters. Conclusion Children practicing Bhramari pranayama and om chanting for 12 weeks have better asthma symptom control, quality of life, and reduced airway inflammation than those taking standard pharmacotherapy alone.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Biomarker-guided withdrawal of inhaled corticosteroids in asthma patients with a non-T2 inflammatory phenotype – a randomized controlled trial study protocol

BackgroundNon-T2 asthma is characterized by the absence of elevated type 2 inflammatory biomarkers such as blood-eosinophils, total and allergen-specific Immunoglobulin E and Fractional exhaled Nitric Oxide (FeNO). According to guidelines, inhaled corticosteroids (ICS) are the cornerstone of asthma management. However, ICS treatment is associated with a risk of local side effects, including hoarseness and thrush, and long-term high-dose therapy may cause systemic adverse effects. Furthermore, whereas treatment with ICS is highly effective in T2 asthma, studies have shown a markedly reduced ICS efficacy in patients with a lower degree of T2 inflammation, thus posing a clinical challenge in this subgroup of patients. Hence, owing to the ICS dosage step-up approach in current clinical guidelines, patients with low T2 biomarkers are at risk of being exposed to high doses of ICS, and by that at risk of side effects. Thus, an ICS-treatment regime guided by biomarkers that reflects the inflammatory phenotype is warranted in order to reduce the corticosteroid burden in patients with non-T2 asthma. This study combines a panel of non-T2 inflammatory markers (low periostin, low blood-eosinophils, and low FeNO), to determine if this group of patients can maintain asthma control during ICS withdrawal.MethodsThis is an ongoing prospective multicenter open-label randomized, controlled trial aiming to assess if ICS can be safely tapered in patients with non-T2 asthma. The patients are randomized 1:1 to either standard of care or an ICS tapering regimen (n = 55 in each group) where the initial ICS dose is reduced by 50% for 8 weeks followed by total ICS removal. The primary endpoint is change in asthma control questionnaire (ACQ) from baseline to post-tapered ICS. The secondary endpoints are time from baseline to drop-out caused by loss of asthma control, changes in serum-periostin, blood-eosinophils, FeNO, Forced Expiratory Volume in 1 s (FEV1) and in sputum-eosinophils.DiscussionThis study aims to provide data on ICS tapering in non-T2 asthma patients and to contribute to a more individualized and corticosteroid-sparing treatment regime in this group of patients.Trial registrationClinicaltrials.gov Identifier: NCT03141424. Registration date: May 5th, 2017.

Is fractional exhaled nitric oxide a treatable trait in chronic cough: a narrative review.

Current management of chronic cough is largely based on sequential therapeutic trials. The concept of treatable traits was first introduced for individualized treatment of chronic airway diseases; however, it has emerged as a potentially useful strategy in revising the management of chronic cough. This narrative review aimed to analyze the literature to determine if fractional exhaled nitric oxide (FeNO) is a treatable trait in chronic cough, compared to other type 2 biomarkers, and to summarize current knowledge and gaps in the clinical application. An online electronic search was performed on PubMed, Web of Science, and Scopus of English-language literature with following keywords: cough, nitric oxide (NO), eosinophils, biomarker, and treatable trait. Relevance and eligibility of each article were assessed by one or more of the authors and a narrative review was composed. Eosinophilic or type 2 airway inflammation is a major treatable trait in patients with chronic cough. Induced sputum tests are regarded as the gold standard for defining inflammatory phenotype, however, technically demanding and cannot be widely applied in clinical practice. FeNO, a practical biomarker, has emerged as an alternative to induced sputum analyses. Mechanistic and clinical evidence indicated that FeNO had a potential for diagnostic utility and treatment response predictability. FeNO measurement may help to identify patients with chronic cough that will benefit from corticosteroid treatment. Further studies are warranted to determine the diagnostic roles of FeNO in the management of patients with chronic cough.

Association of the 6-minute walking test ratio and difference with pulmonary function in patients with interstitial lung disease.

To examine the associations between 6-minute walk test (6MWT) and lung functions, blood gas analysis findings, fractional exhaled nitric oxide (FeNO), and hospital stay in interstitial lung disease (ILD). The present retrospective study included patients hospitalized in Beijing Hospital of Traditional Chinese Medicine, Capital Medical University between September 2018 and December 2019. The outcomes included the difference between the actual and predicted 6MWT values (6MWT difference) and the ratio of the actual to predicted 6MWT value (6MWT ratio). This study included 137 patients. The predicted 6MWT value was 519±61m and the actual 6MWT value was 449 (196.5,694)m. The 6MWT ratio was 84.7±177.6 and 6MWT difference was 73.9±95.1m. Fractional exhaled nitric oxide (FeNO) (β= -2.157, standard error [SE]=0.836, p=0.014) and diffusing capacity of the lungs for carbon monoxide (DLCO) (β= -22.528, SE=7.48, p=0.004) had independent associations with 6MWT difference. The FeNO (β=0.403, SE=0.163, p=0.018) and DLCO (β=4.355, SE=1.458, p=0.005) had independent associations with 6MWT ratio. In ILD, 6MWT difference and 6MWT ratio were associated with FeNO and DLCO. The 6MWT value was not associated with hospital stay. Therefore, the 6MWT might be a surrogate marker of pulmonary function in clinical ILD.

Investigating the Effects of a New Peptide, Derived from the Enterolobium contortisiliquum Proteinase Inhibitor (EcTI), on Inflammation, Remodeling, and Oxidative Stress in an Experimental Mouse Model of Asthma-Chronic Obstructive Pulmonary Disease Overlap (ACO).

The synthesized peptide derived from Enterolobium contortisiliquum (pep3-EcTI) has been associated with potent anti-inflammatory and antioxidant effects, and it may be a potential new treatment for asthma-COPD overlap-ACO). Purpose: To investigate the primary sequence effects of pep3-EcTI in an experimental ACO. BALB/c mice were divided into eight groups: SAL (saline), OVA (ovalbumin), ELA (elastase), ACO (ovalbumin + elastase), ACO-pep3-EcTI (treated with inhibitor), ACO-DX (treated with dexamethasone), ACO-DX-pep3-EcTI (treated with dexamethasone and inhibitor), and SAL-pep3-EcTI (saline group treated with inhibitor). We evaluated the hyperresponsiveness to methacholine, exhaled nitric oxide, bronchoalveolar lavage fluid (BALF), mean linear intercept (Lm), inflammatory markers, tumor necrosis factor (TNF-α), interferon (IFN)), matrix metalloproteinases (MMPs), growth factor (TGF-β), collagen fibers, the oxidative stress marker inducible nitric oxide synthase (iNOS), transcription factors, and the signaling pathway NF-κB in the airways (AW) and alveolar septa (AS). Statistical analysis was conducted using one-way ANOVA and t-tests, significant when p < 0.05. ACO caused alterations in the airways and alveolar septa. Compared with SAL, ACO-pep3-EcTI reversed the changes in the percentage of resistance of the respiratory system (%Rrs), the elastance of the respiratory system (%Ers), tissue resistance (%Gtis), tissue elastance (%Htis), airway resistance (%Raw), Lm, exhaled nitric oxide (ENO), lymphocytes, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, TNF-α, INF-γ, MMP-12, transforming growth factor (TGF)-β, collagen fibers, and iNOS. ACO-DX reversed the changes in %Rrs, %Ers, %Gtis, %Htis, %Raw, total cells, eosinophils, neutrophils, lymphocytes, macrophages, IL-1β, IL-6, IL-10, IL-13, IL-17, TNF-α, INF-γ, MMP-12, TGF-β, collagen fibers, and iNOS. ACO-DX-pep3-EcTI reversed the changes, as was also observed for the pep3-EcTI and the ACO-DX-pep3-EcTI. Significance: The pep3-EcTI was revealed to be a promising strategy for the treatment of ACO, asthma, and COPD.

Severity of adult-onset asthma - a matter of blood neutrophils and severe obesity

BackgroundAdult-onset asthma is associated with a poor treatment response. The aim was to study associations between clinical characteristics, asthma control and treatment in adult-onset asthma. MethodsPrevious participants within the population-based Obstructive Lung Disease in Northern Sweden studies (OLIN) were in 2019–2020 invited to clinical examinations including structured interviews, spirometry, fractional exhaled nitric oxide (FeNO), skin prick test and blood sampling. In total, n = 251 individuals with adult-onset asthma (debut >15 years of age) were identified. Uncontrolled asthma was defined according to ERS/ATS and treatment step according to GINA (2019). ResultsAmong individuals with uncontrolled asthma (34%), severe obesity (16.3% vs 7.9%, p = 0.041) and elevated levels of blood neutrophils, both regarding mean level of blood neutrophils (4.25*109/L vs 3.67*109/L, p = 0.003), and proportions with ≥4*109/L (49.4% vs 33.3%, p = 0.017) and ≥5*109/L (32.1% vs 13.7%, p < 0.001) were more common than among those with controlled asthma. Adding the dimension of GINA treatment step 1–5, individuals with uncontrolled asthma on step 4–5 treatment had the highest proportions of blood neutrophils ≥5*109/L (45.5%), severe obesity (BMI≥35, 26.1%), dyspnea (mMRC≥2) (34.8%), and most impaired lung function in terms of FEV1%<80% of predicted (42.9%), FEV1<LLN (47.6%), FVC<80% of predicted (42.9%) and FVC < LLN (38.1%). No associations between level of asthma control and treatment were found regarding blood eosinophils, FeNO or allergic sensitization. ConclusionThis study indicates that in adult-onset asthma, primarily non-type-2 characteristics such as obesity and blood neutrophils associate with poor asthma control and higher doses of inhaled corticosteroids.

Efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma with fungal sensitization.

Fungal sensitization (FS) exacerbates asthma in patients who have elevated type 2 inflammatory response. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases. This post hoc analysis, funded by the manufacturers of dupilumab, was conducted to assess dupilumab efficacy in patients from the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) and TRAVERSE open-label extension (NCT02134028) study who had uncontrolled, moderate-to-severe asthma with type 2 inflammatory phenotype (defined as blood eosinophil count ≥150 cells/μL or FeNO ≥25 ppb) and with FS (defined as IgE specific to Alternaria alternata, Aspergillus fumigatus or Cladosporium herbarum >0.35 IU/mL). We evaluated annualized rate of severe exacerbations (AER), change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1 ), asthma control (per 5-item Asthma Control Questionnaire [ACQ-5]) and biomarker levels (blood eosinophil count, fractional exhaled nitric oxide [FeNO], total IgE, fungal-specific IgEs, thymus and activation-regulated chemokine [TARC] and eotaxin-3). Dupilumab vs. placebo reduced AER, improved pre-BD FEV1 and asthma control (ACQ-5), and reduced serum IgE levels, blood eosinophil count, TARC, eotaxin-3 and FeNO in patients both with and without FS after 52 weeks of treatment in QUEST. Reductions in asthma exacerbation rates and improvements in all other variables were sustained over the TRAVERSE open-label extension study. Dupilumab demonstrated efficacy during prolonged treatment in patients with uncontrolled, moderate-to-severe asthma with FS.

The Influence of Short-Term Weather Parameters and Air Pollution on Adolescent Airway Inflammation.

Fraction of exhaled Nitric Oxide (FeNO) is a marker of airway inflammation. We examined the main effects and interactions of relative humidity (RH) and air pollution on adolescents' FeNO. Two thousand and forty-two participants from the 15-year follow-up of the German GINIplus and LISA birth cohorts were included. Daily meteorological (maximum [Tmax], minimum [Tmin] and mean [Tmean] temperatures and RH) and air pollution [Ozone (O3), nitrogen dioxide (NO2) and particulate matter < 2.5 µm (PM2.5)] were assessed. Linear models were fitted with Ln(FeNO) as the outcome. Increases in FeNO indicate an increase in lung inflammation. Increased FeNO was associated with an increase in temperature, PM2.5, O3 and NO2. A 5% increase in RH was associated with a decrease in FeNO. Interactions between RH and high (p = 0.007) and medium (p = 0.050) NO2 were associated with increases in FeNO; while interactions between RH and high (p = 0.042) and medium (p = 0.040) O3 were associated with decreases in FeNO. Adverse effects were present for male participants, participants with low SES, participants with chronic respiratory disease, and participants from Wesel. Short-term weather and air pollution have an effect on lung inflammation in German adolescents. Future research should focus on further assessing the short-term effect of multiple exposures on lung inflammation in adolescents.

Exhaled nitric oxide in intubated ICU patients on mechanical ventilation—a feasibility study

It can be a clinical challenge to distinguish inflammation from infection in critically ill patients. Therefore, valid and conclusive surrogate markers for infections are desired. Nitric oxide (NO) might be that marker since concentrations of exhaled NO have shown to change in the presence of various diseases. This observational, prospective, single-center feasibility study aimed to investigate if fractional exhaled NO (FeNO) can be measured in intubated patients with or without infection, pneumonia and septic shock in a standardized, reliable setting. 20 intubated patients in the intensive care unit (ICU) were included for analysis. FeNO mean values were measured in the endotracheal tube via the suction channel using a chemiluminescence based analyzer. We developed a pragmatic method to measure FeNO repeatedly and reliably in intubated patients using a chemiluminescence based analyzer. We found a median of 0.98 (0.59–1.44) FeNO mean (ppb) in exhaled breath from all 20 intubated patient. Intubated patient with suspected infection had a significantly lower median FeNO mean compared with the intubated patients without suspected infection. Similarly did patients with septic shock demonstrate a significantly lower median FeNO mean than without septic shock. We found no statistical difference in median FeNO mean for intubated patients with pneumonia. It was feasible to measure FeNO in intubated patients in the ICU. Our results indicate decreased levels of FeNO in infected intubated patients in the ICU. The study was not powered to provide firm conclusions, so larger trials are needed to confirm the results and to prove FeNO as a useful biomarker for distinguishment between infection and inflammation in the ICU.

Dupilumab leads to better-controlled asthma & quality of life in children: the VOYAGE study.

Dupilumab has shown long-term treatment benefits in children with uncontrolled asthma. We assessed in more detail the impact of dupilumab on asthma control and health-related quality of life (HRQoL) in children and their caregivers. Children aged 6-11 years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide [FeNO] ≥20 ppb; n=350) were treated with dupilumab or placebo for 52 weeks in the VOYAGE study. Primary outcomes of these analyses were asthma control (change from baseline in Interviewer-Administered 7-item Asthma Control Questionnaire [ACQ-7-IA] and achieving a clinically meaningful response of ≥0.5]; proportion of patients achieving well-controlled asthma or better [ACQ-7-IA ≤0.75]), effect on patients' (Standardised Paediatric Asthma Quality of Life Questionnaire [PAQLQ[S]-IA]), and caregivers' (Paediatric Asthma Caregiver's Quality of Life Questionnaire [PACQLQ] score) HRQoL; and allergic rhinitis-related QoL. Dupilumab versus placebo significantly improved children's ACQ-7-IA scores by week 4 with sustained improvements through week 52 (least-squares mean difference at week 52: -0.44, 95% CI -0.59 to -0.30; p<0.0001); a higher proportion achieved a clinically meaningful response (week 52: 86% versus 75%; p=0.0051). At weeks 24 and 52, more children who received dupilumab achieved well-controlled asthma (ACQ-7-IA ≤0.75: 61% versus 43%, p=0.0001; 70% versus 46%, p<0.0001, respectively). Significant improvements in PAQLQ[S]-IA and PACQLQ scores were observed by week 52. In children aged 6-11 years with moderate-to-severe type 2 asthma, dupilumab treatment was associated with rapid, sustained improvements in asthma control. HRQoL was significantly improved for children and their caregivers. Sanofi and Regeneron Pharmaceuticals Inc.

Tezepelumab and Mucus Plugs in Patients with Moderate-to-Severe Asthma

BackgroundMucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo.MethodsCASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores.ResultsAbsolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation.ConclusionsTezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)