Exhaled and Systemic Biomarkers to Aid the Diagnosis of Bronchial Asthma in Elite Water Sports Athletes.

PURPOSE: Our aim was to evaluate the accuracy of a combined airway inflammatory biomarker assessment in diagnosing asthma in elite water sports athletes. METHODS: Members of the Hungarian Olympic and Junior Swim Team and elite athletes from other aquatic disciplines were assessed for asthma by objective lung function measurements, and blood eosinophil count (BEC), serum total IgE, FENO measurements, and skin prick testing were performed. A scoring system from BEC, FENO, serum IgE, and skin test positivity was constructed by dichotomising the variables and assigning a score of 1 if the variable is elevated. These scores were summed to produce a final composite score ranging from 0 to 4. RESULTS: A total of 48 participants were enrolled (age 21 ± 4 years, 42% male), of which 22 were diagnosed with asthma. Serum total IgE and FENO levels were higher in asthmatic individuals (68 [27-176] vs. 24 ([1-44], p = 0.01; 20 [17-26] vs. 15 [11-22], p = 0.02), and positive prick test was also more frequent (55% vs. 8%, p < 0.01). Asthmatic participants had higher composite variable scores (2 ([1-3] vs. 1 [0-1], p = 0.02). ROC analysis showed that total IgE, FENO, and the composite variable were suitable for identifying asthmatic participants (AUC 0.72, p = 0.01; 0.70, p = 0.02, and 0.69, p = 0.03). A composite score of >2 reached a specificity of 96.2%, sensitivity of 36.4%, and likelihood ratio of 9.5. Logistic regression model revealed a strong association between the composite variable and the asthma diagnosis (OR 2.71 (95% CI 1.17-6.23), p = 0.02). CONCLUSIONS: Our data highlight the diagnostic value of combined assessment of Th2-type inflammation in elite water sports athletes. The proposed scoring system may be helpful in ruling in asthma in this population upon clinical suspicion.

Platelet count and platelet-to-lymphocyte ratio at the onset of a severe COPD exacerbation are unrelated to the time till the next moderate or severe relapse.

PURPOSE: Acute exacerbations (AE) are severe complications of chronic obstructive pulmonary disease (COPD); however, the need for biomarkers which predict them is still unmet. High platelet count (PLC) and platelet-to-lymphocyte ratio (PLR) are associated with higher mortality in patients with COPD. We investigated if PLC and PLR at the onset of a severe AE could predict the time of the next relapse. METHODS: In a prospective observational cohort study, data of 152 patients hospitalized with AECOPD were collected, and patients were divided into PLC-low (<239 â€‹× â€‹109/L, n â€‹= â€‹51), PLC-medium (239-297 â€‹× â€‹109/L, n â€‹= â€‹51) and PLC-high (>297 â€‹× â€‹109/L, n â€‹= â€‹50) or PLR-low (<147, N â€‹= â€‹51), PLR-medium (147-295, n â€‹= â€‹51) and PLR high (>295, n â€‹= â€‹50) groups based on PLC and PLR tertiles using admission laboratory results. Clinical characteristics and the time to the next severe or moderate AE within 52 weeks were compared among subgroups using log-rank test. RESULTS: PLC and PLR tertiles did not differ in clinical characteristics or the time till the next AE (p â€‹> â€‹0.05). PLC and PLR showed a direct weak correlation to neutrophil count (Pearson r â€‹= â€‹0.26, p â€‹< â€‹0.01 and r â€‹= â€‹0.20, p â€‹= â€‹0.01) and PLC also demonstrated a weak relationship to white blood cell counts (Pearson r â€‹= â€‹0.29, p â€‹< â€‹0.001). However, PLR presented an inverse relationship to monocyte and eosinophil counts (r â€‹= â€‹-0.32, p â€‹< â€‹0.001 and r â€‹= â€‹-0.17, p â€‹= â€‹0.03). CONCLUSION: PLC and PLR do not predict the time till the next relapse; however, they may reflect on neutrophilic inflammatory response during an exacerbation of COPD.

Assessment of bronchodilator responsiveness to salbutamol or ipratropium using different criteria in treatment-naïve patients with asthma and COPD.

Background: The criteria for significant bronchodilator responsiveness (BDR) were published in 2005 by the European Respiratory Society/American Thoracic Society, which were revised in 2021, however, data on the agreement between these two recommendations in untreated patients with airflow limitation are missing. Aims: We aimed to study BDR to salbutamol (SABA) or ipratropium bromide (SAMA) in patients with suspected bronchial asthma or COPD at initial clinical presentation using the 2005 and 2021 criteria and explore clinical factors associated with BDR+. Methods: Symptomatic, treatment-naïve patients with expiratory airflow limitation (n = 105, 57 men, age (mean ± standard deviation): 65 ± 10 years) underwent BDR testing with 400 mcg salbutamol (day 1) or 80 mcg ipratropium bromide (day 2) and BDR was measured after 15 and 30 minutes. Clinical factors with risk for BDR+ were assessed with binomial logistic regression analysis. Results: We found a good agreement between the number of 2005-BDR+ and 2021-BDR+ patients at 15 and 30 minutes post-salbutamol and post-ipratropium (88.6-94.8%). More patients showed BDR+ after 30 minutes than following 15 minutes using either criterion. When results at 30 minutes are considered, the number of patients with 2005-BDR+ (82%) was higher than that of 2021-BDR+ (75%), with the proportion of SAMA+ patients being higher than that of SABA+ (2005: 70% vs. 49%, Fisher exact p < 0.01; 2021: 64% vs. 41%, p = 0.001). 2005-BDR+ and 2021-BDR+ to SABA were associated with decreasing pre-BD FEV1% predicted and the presence of cough. More patients with asthma were in the SABA+ group compared to the SAMA+ group (2005: 71% vs. 53%, Fischer exact p = 0.04; 2021: 77% vs. 52%, p = 0.02). Conclusions: Fewer patients show BDR+ according to the 2021 criteria in comparison with the 2005 recommendations, and protocols for BDR testing may consider the assessment of response to both SABA and SAMA after 30 minutes.

Circulating apelin, IL22RA2 and VEGF in pre-capillary pulmonary hypertension.

Cytokines can modulate vascular remodelling and the adaptation of the right ventricle in pre-capillary pulmonary hypertension (PH). However, detailed data on the circulating levels of cytokines in patients are limited. We measured blood cytokine concentration in 39 treatment-naïve patients (pulmonary arterial hypertension: N = 16, chronic thromboembolic PH: N = 15, PH due to lung disease: N = 8) and 12 control subjects using enzyme-linked immunoassays. Apelin concentration >1,261 ng/mL identified patients with PH (66% sensitivity and 82% specificity), and in patients it was related to systolic pulmonary arterial pressure (PAP) (r = 0.33, P = 0.04), right atrial pressure (r = 0.38, P = 0.02), cardiac index (r = -0.34, P = 0.04), and right ventricular stroke work index (r = -0.47, P = 0.003). IL22RA2 concentration correlated with mean PAP (r = -0.32, P = 0.04) and serum N-terminal pro B-type natriuretic peptide level (r = -0.42, P = 0.01). VEGF concentration increased in patients upon clinical improvement (N = 16, P = 0.02). Circulating apelin is a novel biomarker of pre-capillary PH. Apelin and IL22RA2 levels are related to right ventricular function upon diagnosis of PH.

The Role of the Circadian Rhythm in Dyslipidaemia and Vascular Inflammation Leading to Atherosclerosis.

Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Many lines of evidence suggest that the disturbances in circadian rhythm are responsible for the development of CVDs; however, circadian misalignment is not yet a treatable trait in clinical practice. The circadian rhythm is controlled by the central clock located in the suprachiasmatic nucleus and clock genes (molecular clock) located in all cells. Dyslipidaemia and vascular inflammation are two hallmarks of atherosclerosis and numerous experimental studies conclude that they are under direct influence by both central and molecular clocks. This review will summarise the results of experimental studies on lipid metabolism, vascular inflammation and circadian rhythm, and translate them into the pathophysiology of atherosclerosis and cardiovascular disease. We discuss the effect of time-respected administration of medications in cardiovascular medicine. We review the evidence on the effect of bright light and melatonin on cardiovascular health, lipid metabolism and vascular inflammation. Finally, we suggest an agenda for future research and recommend on clinical practice.

The Role of Gut Bacteriome in Asthma, Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnoea.

The human body contains a very complex and dynamic ecosystem of bacteria. The bacteriome interacts with the host bi-directionally, and changes in either factor impact the entire system. It has long been known that chronic airway diseases are associated with disturbances in the lung bacteriome. However, less is known about the role of gut bacteriome in the most common respiratory diseases. Here, we aim to summarise the evidence concerning the role of the intestinal bacteriome in the pathogenesis and disease course of bronchial asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea. Furthermore, we discuss the consequences of an altered gut bacteriome on the most common comorbidities of these lung diseases. Lastly, we also reflect on the therapeutic potential of influencing the gut microbiome to improve disease outcomes.

Clinical Predictors of Lung-Function Decline in Systemic-Sclerosis-Associated Interstitial Lung Disease Patients with Normal Spirometry.

Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients and compare disease behavior to that in idiopathic pulmonary fibrosis (IPF) patients. Patients with normal forced vital capacity (FVC > 80% predicted; SSc-ILD: n = 31; IPF: n = 53) were followed for at least 1 year. Predictors of functional decline including clinical symptoms, comorbidities, lung-function values, high-resolution CT pattern, and treatment data were analyzed. SSc-ILD patents were significantly younger (59.8 ± 13.1) and more often women (93 %) than IPF patients. The median yearly FVC decline was similar in both groups (SSc-ILD = −67.5 and IPF = −65.3 mL/year). A total of 11 SSc-ILD patients met the PPF criteria for functional deterioration, presenting an FVC decline of −153.9 mL/year. Cough and pulmonary hypertension were significant prognostic factors for SSc-ILD functional progression. SSc-ILD patients with normal initial spirometry presenting with cough and PH are at higher risk for showing progressive functional decline.

Hypercapnia in COPD: Causes, Consequences, and Therapy.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder that may lead to gas exchange abnormalities, including hypercapnia. Chronic hypercapnia is an independent risk factor of mortality in COPD, leading to epithelial dysfunction and impaired lung immunity. Moreover, chronic hypercapnia affects the cardiovascular physiology, increases the risk of cardiovascular morbidity and mortality, and promotes muscle wasting and musculoskeletal abnormalities. Noninvasive ventilation is a widely used technique to remove carbon dioxide, and several studies have investigated its role in COPD. In the present review, we aim to summarize the causes and effects of chronic hypercapnia in COPD. Furthermore, we discuss the use of domiciliary noninvasive ventilation as a treatment option for hypercapnia while highlighting the controversies within the evidence. Finally, we provide some insightful clinical recommendations and draw attention to possible future research areas.

Postoperative respiratory complications in children with obstructive sleep apnoea syndrome.

Objective: We aimed to prospectively assess the effect of comorbidities on the occurrence of postoperative respiratory complications (PoRCs) after adenotonsillectomy in children with obstructive sleep apnoea syndrome (OSA) and whether otherwise healthy children need a higher level of postoperative monitoring. Methods: 577 children who had OSA and underwent adenotonsillectomy were enrolled. The effects of demographics, comorbidities and OSA on PoRCs were investigated with logistic regression analysis. Results: The PoRC rate was 4.3%. Postoperative oxygen desaturations were more marked in patients with comorbidities (p = 0.005). The presence of comorbidity increased the risk of PoRCs (odds ratio 4.234/3.226-5.241, 95% confidence intervals, p < 0.001). There was no difference in apnoea-hypopnoea index (AHI) values between comorbid patients with and without PoRCs [8.2 (3.8-50.2) vs 14.3 (11.7-23.3)]. (p = 0.37). In the group of patients without comorbidities, PoRCs were associated with a higher AHI [14.7 (3.4-51.3) vs 3.9 (2.0- 8.0), p < 0.001]. Conclusions: Comorbidities are more closely linked with PoRCs than OSA severity. In patients without comorbidity, PoRCs are associated with OSA severity and usually occur within the first 2 hours after the intervention.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Assessing Treatment Success or Failure as an Outcome in Randomised Clinical Trials of COPD Exacerbations. A Meta-Epidemiological Study.

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or "cure" of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006-2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required.

Measurements of upper and lower airway nitric oxide in healthy adults.

Introduction.Nasal nitric oxide (NO) measurement can be a useful tool for monitoring upper airway diseases. However, there is a considerable lack of validation data.Aims.To evaluate the repeatability and intra-subject variations of nasal NO output (nVNO) in healthy adults and to study its correlation with lower airway NO parameters.Methods.nVNOwas measured in healthy non-smokers at baseline (N= 31, age: 28 ± 6 years), after 1 h (N= 15), 1 d (N= 15), 1 week (N= 17), and compared using the Bland-Altman method. At baseline, lower airway NO parameters (FENO, flux of NO in the conducting airways and alveolar NO concentration) were also measured and correlated tonVNO(Spearman correlation). Multivariate regression analysis was used to assess the factors influencingnVNO.Results.Baseline mediannVNOwas 465 (interquartile range (IQR) = 404-536) nL min-1. The mean differences between the baseline and repeated measurements were not significant (p> 0.05). The coefficient of repeatability (mean: 118, IQR = 88-181 nL min-1) and coefficient of variation (mean: 9.1%) were low. We found no correlation betweennVNOand lower airway NO parameters (p> 0.05). Sex (ß= -0.52,p= 0.02) and body weight (ß= -0.65,p= 0.03) influencednVNO(model:p= 0.04,R2= 0.31).Conclusion.nasal NO output has good repeatability in healthy adults. The NO productions of lower and upper airways are not related in health, but nasal NO output seems to be affected by sex and body weight.

Blood eosinophils on hospital admission for COPD exacerbation do not predict the recurrence of moderate and severe relapses.

BACKGROUND AND OBJECTIVE: The relationship between hospitalisation with an eosinophilic acute exacerbation of COPD (AE-COPD) and future relapses is unclear. We aimed to explore this association by following 152 patients for 12 months after hospital discharge or until their first moderate or severe flare-up. METHODS: Patients hospitalised with AE-COPD were divided into eosinophilic and non-eosinophilic groups based on full blood count results on admission. All patients were treated with a course of systemic corticosteroid. The Cox proportional hazards model was used to study the association with the time to first re-exacerbation; a generalised linear regression model was applied to identify clinical variables related to the recurrence of relapses. RESULTS: We did not find a difference in the time to the next moderate or severe exacerbation between the eosinophilic (≥2% of total leukocytes and/or ≥200 eosinophils·µL-1, n=51, median (interquartile range): 21 (10-36) weeks) and non-eosinophilic groups (n=101, 17 (9-36) weeks, log-rank test: p=0.63). No association was found when other cut-off values (≥3% of total leukocytes and/or ≥300 eosinophils·µL-1) were used for the eosinophilic phenotype. However, the higher number of past severe exacerbations, a lower forced expiratory volume in 1 s (FEV1) at discharge and higher pack-years were related to shorter exacerbation-free time. According to a subgroup analysis (n=73), 48.1% of patients with initial eosinophilic exacerbations had non-eosinophilic relapses on readmission. CONCLUSIONS: Our data do not support an increased risk of earlier recurring moderate or severe relapses in patients hospitalised with eosinophilic exacerbations of COPD. Eosinophilic severe exacerbations present a variable phenotype.

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is related to endothelial dysfunction and the impaired generation of nitric oxide (NO) from L-arginine by the endothelial NO synthase (eNOS). The relationship between eNOS dysfunctionality and airway inflammation is unknown. We assessed serum asymmetric and symmetric dimethylarginine (ADMA and SDMA) and nitrite/nitrate concentrations, indicators of eNOS function, in patients with COPD and correlated them with markers of inflammation. METHODS: We recruited 15 control smokers, 29 patients with stable and 32 patients with exacerbated COPD requiring hospitalization (20 of them were measured both at admission and discharge). Serum L-arginine, ADMA, SDMA, nitrite and nitrate were measured and correlated with airway inflammatory markers (fractional exhaled nitric oxide concentration - FENO, sputum nitrite and nitrate, sputum cellularity), serum C-reactive protein - CRP, white blood cell count, lung function and blood gases. ANOVA, t-tests and Pearson correlation were used (mean ± SD or geometric mean ± geometric SD for nitrite/nitrate). RESULTS: Serum L-arginine/ADMA, a marker of substrate availability for eNOS, was lower in stable (214 ± 58, p < 0.01) and exacerbated COPD (231 ± 68, p < 0.05) than in controls (287 ± 64). The serum concentration of SDMA, a competitor of L-arginine transport, was elevated during an exacerbation (0.78 ± 0.39 µM) compared to stable patients (0.53 ± 0.14 µM, p < 0.01) and controls (0.45 ± 0.14 µM, p < 0.001). ADMA correlated with blood neutrophil percentage (r = 0.36, p < 0.01), FENO (r = 0.42, p < 0.01) and a tendency for positive association was observed to sputum neutrophil count (r = 0.33, p = 0.07). SDMA correlated with total sputum inflammatory cell count (r = 0.61, p < 0.01) and sputum neutrophil count (r = 0.62, p < 0.01). Markers were not related to lung function, blood gases or CRP. L-arginine/ADMA was unchanged, but serum SDMA level decreased (0.57 ± 0.42 µM, p < 0.05) after systemic steroid treatment of the exacerbation. Serum nitrite level increased in stable and exacerbated disease (4.11 ± 2.12 and 4.03 ± 1.77 vs. control: 1.61 ± 1.84 µM, both p < 0.001). CONCLUSIONS: Our data suggest impaired eNOS function in stable COPD, which is transiently aggravated during an exacerbation and partly reversed by systemic steroid treatment. Serum ADMA and SDMA correlate with airway inflammatory markers implying a possible effect of anti-inflammatory therapy on endothelial dysfunction. Serum nitrite can serve as a compensatory pool for impaired endothelial NO generation.