Exploring the link between a novel approach for computer aided lung sound analysis and imaging biomarkers: a cross-sectional study.

BACKGROUND: Computer Aided Lung Sound Analysis (CALSA) aims to overcome limitations associated with standard lung auscultation by removing the subjective component and allowing quantification of sound characteristics. In this proof-of-concept study, a novel automated approach was evaluated in real patient data by comparing lung sound characteristics to structural and functional imaging biomarkers. METHODS: Patients with cystic fibrosis (CF) aged > 5y were recruited in a prospective cross-sectional study. CT scans were analyzed by the CF-CT scoring method and Functional Respiratory Imaging (FRI). A digital stethoscope was used to record lung sounds at six chest locations. Following sound characteristics were determined: expiration-to-inspiration (E/I) signal power ratios within different frequency ranges, number of crackles per respiratory phase and wheeze parameters. Linear mixed-effects models were computed to relate CALSA parameters to imaging biomarkers on a lobar level. RESULTS: 222 recordings from 25 CF patients were included. Significant associations were found between E/I ratios and structural abnormalities, of which the ratio between 200 and 400 Hz appeared to be most clinically relevant due to its relation with bronchiectasis, mucus plugging, bronchial wall thickening and air trapping on CT. The number of crackles was also associated with multiple structural abnormalities as well as regional airway resistance determined by FRI. Wheeze parameters were not considered in the statistical analysis, since wheezing was detected in only one recording. CONCLUSIONS: The present study is the first to investigate associations between auscultatory findings and imaging biomarkers, which are considered the gold standard to evaluate the respiratory system. Despite the exploratory nature of this study, the results showed various meaningful associations that highlight the potential value of automated CALSA as a novel non-invasive outcome measure in future research and clinical practice.

The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

The effect of posture on airflow distribution, airway geometry and air velocity in healthy subjects.

BACKGROUND: Gravity, and thus body position, can affect the regional distribution of lung ventilation and blood flow. Therefore, body positioning is a potential tool to improve regional ventilation, thereby possibly enhancing the effect of respiratory physiotherapy interventions. In this proof-of-concept study, functional respiratory imaging (FRI) was used to objectively assess effects of body position on regional airflow distribution in the lungs. METHODS: Five healthy volunteers were recruited. The participants were asked during FRI first to lie in supine position, afterwards in standardized right lateral position. RESULTS: In right lateral position there was significantly more regional ventilation also described as Imaging Airflow Distribution in the right lung than in the left lung (P < 0.001). Air velocity was significantly higher in the left lung (P < 0.05). In right lateral position there was significantly more airflow distribution in the right lung than in the left lung (P < 0.001). Significant changes were observed in airway geometry resulting in a decrease in imaged airway volume (P = 0.024) and a higher imaged airway resistance (P = 0.029) in the dependent lung. In general, the effect of right lateral position caused a significant increase in regional ventilation (P < 0.001) in the dependent lung when compared with the supine position. CONCLUSIONS: Changing body position leads to significant changes in regional lung ventilation, objectively assessed by FRI The volume based on the imaging parameters in the dependent lung is smaller in the lateral position than in the supine position. In right lateral decubitus position, airflow distribution is greater in dependent lung compared to the nondependent lung. TRIAL REGISTRATION: The trial has been submitted to www. CLINICALTRIALS: gov with identification number NCT01893697 on 07/02/2013.

Functional respiratory imaging identifies redistribution of pulmonary blood flow in patients with COVID-19.

An increasing observation is that some patients with COVID-19 have normal lung compliance but significant hypoxaemia different from typical acute respiratory distress syndrome (ARDS). We hypothesised that changes in pulmonary blood distribution may be partially responsible and used functional respiratory imaging on CT scans to calculate pulmonary blood volume. We found that patients with COVID-19 had significantly reduced blood volume in the smaller calibre blood vessels (here defined as <5 mm2 cross-sectional area) compared with matched ARDS patients and healthy controls. This suggests that using high levels of PEEP may not alone be enough to oxygenate these patients and that additional management strategies may be needed.

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids.

BACKGROUND: For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. METHODS: Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 µg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 µg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. RESULTS: A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. CONCLUSIONS: As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component's contribution in patients with moderate-to-severe COPD. TRIAL REGISTRATION:  ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677.

Economic Evaluation of Vaccines: Belgian Reflections on the Need for a Broader Perspective.

OBJECTIVES: The standard framework of economic evaluation of health programs, which is increasingly used for policy funding decisions, is insufficiently equipped to reflect the full range of health and economic benefits conferred by vaccines and thus undervalues vaccination. METHODS: In 2019, a group of Belgian health economic and clinical experts, supported by 2 senior international vaccination experts (1 American, 1 Belgian), convened 4 roundtable meetings to highlight which particular value elements of vaccination remain neglected in economic evaluations. RESULTS: They concluded that the standard economic evaluation framework fails to reflect the full value of vaccination with respect to prevention of complications linked to some vaccine-preventable diseases, health gains for caregivers, herd effects, changes in exposure to and distribution of serotypes, the effect on antimicrobial resistance, productivity gains for caregivers and patients, and the distributive implications of vaccination programs. CONCLUSIONS: Here, suggestions are made regarding how these shortcomings can be addressed in future economic evaluations of vaccines and how a more level playing field between vaccines and other health programs can be created.

Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional study.

BACKGROUND: Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. METHODS: CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. RESULTS: 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. CONCLUSIONS: Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.

Clinical Predictors of Residual Sleep Apnea after Weight Loss Therapy in Obese Adolescents.

OBJECTIVE: To investigate clinical factors that could predict residual sleep-disordered breathing (SDB) after weight loss. STUDY DESIGN: Obese subjects between 10 and 19 years of age were recruited while entering an in-patient weight loss treatment program. All subjects underwent anthropometry and sleep screening using a portable device at baseline and after 4-6 months of therapy. Sleep and International Study of Asthma and Allergies in Childhood questionnaires were completed at baseline. RESULTS: A total of 339 patients were included. Median age was 15.4 years (10.1-19.1). Body mass index z score at baseline was 2.75 ± 0.42, and 35% of subjects were boys. SDB was present in 32%. After a mean decrease in body mass index z score of 32%, residual SDB was found in 20% of subjects with SDB at baseline. Subjects with more severe SDB (OR 1.18; CI 1.01-1.34; P = .02) and respiratory allergies (OR 7.85; CI 1.20-51.39; P = .03) were at higher risk of developing residual SDB, unlike age, sex, and anthropometric variables. CONCLUSIONS: Weight loss was successful for treating SDB in 80% of patients. More severe SDB and the presence of respiratory allergies at baseline were associated with a higher risk of residual SDB after weight loss.

Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

A promising concept of combination therapy for positional obstructive sleep apnea.

PURPOSE: The objective of this randomized controlled trial was to assess the additional effect of a chest-worn sleep position trainer (SPT) in patients with residual supine-dependent obstructive sleep apnea (sdOSA) under mandibular advancement device (MAD) therapy. METHODS: Baseline and follow-up polysomnography with MAD were performed. Twenty patients with sdOSA under MAD therapy underwent two consecutive randomized polysomnographies: one with SPT and one with combination of SPT + MAD. Data are presented as median (quartile 1, quartile 3). RESULTS: The SPT reduced the time spent in supine sleeping position compared to baseline and MAD therapy. Both MAD and SPT were individually effective in reducing the overall apnea/hypopnea index (AHI) significantly when compared to baseline from 20.8 (15.1; 33.6)/h at baseline to 11.0 (6.7; 13.8)/h and to 11.1 (3.5; 17.7)/h with MAD or SPT, respectively. The combination of SPT + MAD further reduced the overall AHI to 5.7 (3.6; 7.4), which was significantly lower than with MAD alone (p < 0.001) and SPT alone (p < 0.008), respectively. CONCLUSIONS: The results of this study indicate that combination of SPT + MAD leads to a higher therapeutic efficacy in patients with sdOSA under MAD therapy when compared to one of the treatment modalities alone.

Pneumococcal lower respiratory tract infections in adults: an observational case-control study in primary care in Belgium.

BACKGROUND: Serious lower respiratory tract infections (SLRTIs), especially Streptococcus pneumoniae (SP)-related pneumonia cause considerable morbidity and mortality. Chest imaging, sputum and blood culture are not routinely obtained by general practitioners (GPs). Antibiotic therapy is usually started empirically. The BinaxNOW® and Urine Antigen Detection (UAD) assays have been developed respectively to detect a common antigen from all pneumococcal strains and the 13 pneumococcal serotypes present in the vaccine Prevenar 13® (PCV13). METHODS: OPUS-B was a multicentre, prospective, case-control, observational study of patients with SLRTI in primary care in Belgium, conducted during two winter seasons (2011-2013). A urine sample was collected at baseline for the urine assays. GPs were blinded to the results. All patients with a positive BinaxNOW® test and twice as much randomly selected BinaxNOW® negative patients were followed up. Recorded data included: socio-demographics, medical history, vaccination history, clinical symptoms, CRB-65 score, treatments, hospitalization, blood cultures, healthcare use, EQ-5D score. The objectives were to evaluate the percentage of SP SLRTI within the total number of SLRTIs, to assess the percentage of SP serotypes and to compare the burden of disease between pneumococcal and non-pneumococcal SLRTIs. RESULTS: There were 26 patients with a BinaxNOW® positive test and 518 patients with a BinaxNOW® negative test. The proportion of pneumococcal SLRTI was 4.8 % (95 % CI: 3.1 %-7.2 %). Sixty-eight percent of positive cases showed serotypes represented in PCV13. In the BinaxNOW-positive patients, women were more numerous, there was less exposure to young children, seasonal influenza vaccination was less frequent, COPD was more frequent, the body temperature and the number of breaths per minute were higher, the systolic blood pressure was lower, the frequency of sputum, infiltrate, chest pain, muscle ache, confusion/disorientation, diarrhoea, pneumonia and exacerbations of COPD was more frequent, EQ-5D index and VAS scale were lower, the number of visits to the GP, of working days lost and of days patients needed assistance were higher. CONCLUSIONS: SP was responsible for approximately 5 % of SLRTIs observed in primary care in Belgium. Pneumococcal infection was associated with a significant increase in morbidity. Sixty-eight percent of serotypes causing SLRTI were potentially preventable by PCV13.

A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD.

Fluticasone furoate/vilanterol trifenatate (FF/VI) is a once-daily inhaled corticosteroid/long-acting ß2-agonist combination in development for chronic obstructive pulmonary disease (COPD) treatment. We compared the efficacy and safety of FF/VI versus fluticasone propionate/salmeterol (FP/SAL) twice daily over 12 weeks. Moderate to very severe COPD patients received FF/VI 100/25 µg once daily in the morning (n=266) or FP/SAL 500/50 µg twice daily (n=262). The primary end-point was a change from baseline in 0-24 h weighted mean forced expiratory volume in 1 s (wmFEV1) at 12 weeks. Additional end-points included time to 100 mL improvement from baseline on day 1 and a change from baseline in St George's Respiratory Questionnaire (SGRQ). Safety was also assessed. wmFEV1 (mean 130 mL) was greater and time to 100 mL improvement shorter (median 16 min) with FF/VI than FP/SAL (weighted mean 108 mL, median 28 min). Health status (SGRQ total score) improved in both groups (FF/VI -4.3 units, FP/SAL -3.0 units). Differences between treatments were not statistically significant. Six patients in the FF/VI (2%) and three in the FP/SAL (1%) arm experienced serious adverse events, none of which were considered to be drug related. Improvements in lung function and health status were not significantly different between FF/VI 100/25 µg once daily and FP/SAL 500/50 µg twice daily; there was no apparent difference between the safety profiles of either therapy.

Determinants of baseline lung function and bronchodilator response in 4-year-old children.

The prolonged period required for maturation of the respiratory system makes it vulnerable to environmental exposure. This study aimed to investigate the association between early-life factors and lung function in preschool children. Children aged 4 years, who were included in a prospective birth cohort, underwent lung function testing at baseline (n=535) and after bronchodilation (n=498) by forced oscillations. Information on symptoms and exposures was collected through half-yearly questionnaires. Allergen-specific serum IgE was quantified at 1 and 4 years. Multiple linear regression analysis showed that the baseline respiratory resistance and reactance area were larger in the children with previous wheeze, those with early-onset sensitisation to inhalant allergens and those who were smaller. Furthermore, children with previous lower respiratory tract infections exhibited higher baseline resistance values. The baseline resistance was the only independent determinant of the bronchodilator-induced change in resistance, whereas current height and baseline reactance area were independently associated with the change in reactance area. In conclusion, previous lower respiratory tract infections, the timing of previous wheeze, inhalant sensitisation and current height independently influence the baseline lung function of 4-year-old children, whereas baseline lung function is the principal determinant of the bronchodilator response.

Sleep-disordered breathing and C-reactive protein in obese children and adolescents.

PURPOSE: Sleep-disordered breathing (SDB) is common among overweight and obese children. It is a risk factor for several health complications, including cardiovascular disease. Inflammatory processes leading to endothelial dysfunction are a possible mechanism linking SDB and cardiovascular disease. Elevated C-reactive protein (CRP) is a risk factor for cardiovascular disease and is independently correlated with obstructive sleep apnea syndrome (OSAS) in adults. Our goal is to evaluate the relationship between CRP and OSAS in overweight and obese children and adolescents. METHODS: One hundred and twenty children were prospectively studied (85 without OSAS, 20 mild OSAS, 15 moderate-to-severe OSAS). All subjects underwent polysomnography, and a blood sample was taken to determine CRP levels. RESULTS: No significant differences were found in CRP between subjects with or without OSAS, and no correlations were found between CRP and OSAS severity, despite the relationship between CRP and BMI (r = 0.21, p = 0.015) and between CRP and fat mass (r = 0.31, p < 0.001). CONCLUSION: These results suggest that CRP levels are correlated with the level of obesity but are not influenced by SDB in obese children and adolescents; hence, this in contrast to that in adult population.

Validation of computational fluid dynamics models for airway deposition with SPECT data of the same population.

This study compared computational fluid dynamic (CFD) model predictions on aerosol deposition in six asthmatic patients to the in-vivo results of the same group. Patient-specific ventilation and internal air distribution were prescribed using inspiratory and expiratory CT scans of each patient, accounting for individual lobar air flow distribution. Moreover, the significant influence of realistic mouth and throat geometries on regional deposition is demonstrated. The in-vivo data were obtained from single photon emission computed tomography (SPECT) in 6 subjects with mild asthma selected from a database of historical clinical trials. The governing flow and particle tracking equations were solved numerically using a commercial CFD tool, and the modeled deposition results were compared to the SPECT data. Good agreement was found between the CFD model, applying k-ω SST turbulence model, and SPECT in terms of aerosol deposition. The average difference for the lobar deposition obtained from CFD model and SPECT/CT data was 2.1%. The high level of agreement is due to applying patient specific airway geometries and inspiratory/expiratory CT images, anatomical upper airways, and realistic airway trees. The results of this study show that CFD is a powerful tool to simulate patient-specific deposition if correct boundary conditions are applied and can generate similar information obtained with functional imaging tools, such as SPECT.

Personalized pulmonary rehabilitation program for patients with post-acute sequelae of COVID-19: A proof-of-concept retrospective study.

Long-COVID patients present with a decline in physical fitness. The aim of this study is to reveal the impact of pulmonary rehabilitation (PR) on physical fitness, quality of life (QoL), and parameters of quantified thorax CT. Long-COVID patients enrolled in a 3-month PR program were retrospectively studied. PR included endurance and resistance training three times a week. Assessments pre- and post-rehabilitation included quantified chest CT, pulmonary function tests (PFT), six-minute walk test (6MWT), cardiopulmonary exercise test, and questionnaires: Hospital Anxiety and Depression Scale, post-COVID-19 Functional Status scale, Borg score, and EuroQol. Seventeen subjects (5M/12F), mean age 42 ± 13 years, were included. PR improved all questionnaires' results significantly. Only significant difference in PFT parameters was correlation between baseline total lung capacity (TLC) and difference in TLC pre- and post-rehabilitation (p = 0.002). 6MWT increased from 329 to 365 m (p < 0.001), VO2max changed from 21 to 24 mL/kg/min (p = 0.007), peak load increased from 116 to 141 Watt (p < 0.001). Blood volume in small pulmonary vessels of 1.25 to 5 mm2 in cross-sectional area (BV5%) was higher than observed in patients with acute COVID-19 infection. After rehabilitation, BV5% decreased from 65% to 62% (p = 0.020). These changes correlated directly with changes in TLC (p = 0.039). Quantified CT airway volume increased after rehabilitation (p = 0.013). After rehabilitation, TLC tended to normalize due to (re)opening of small airways, with decline in air trapping and recruitment of alveoli. Furthermore, this study revealed that pulmonary rehabilitation can improve QoL and physical fitness in long-COVID patients.

Objective measurement of compliance during oral appliance therapy for sleep-disordered breathing.

BACKGROUND: Oral appliance (OA) therapy is increasingly prescribed as a non-continuous positive airway pressure treatment modality for sleep-disordered breathing (SDB). Although OA therapy is reported to be efficacious for the treatment of SDB, data on compliance remain limited to self-report. METHODS: In this 3-month prospective clinical trial, the main outcome was to assess the safety and feasibility of an objective measurement of compliance during OA therapy using an embedded microsensor thermometer with on-chip integrated readout electronics in 51 consecutive patients with an established diagnosis of SDB (AHI 18.0 ± 11.9/h; age 47 ± 10 y; BMI 26.6 ± 4.0 kg/m(2); men/women: 31/20). Patients were unaware of the purpose of the study. RESULTS: No microsensor-related adverse events were recorded. In addition, no problems were encountered during the readout of the compliance data. Out of 51 microsensors, one had a technical defect and was lost to follow-up. In this study, the overall objective mean rate of OA use was 6.6 ± 1.3 h per day with a regular OA users' rate of 82% at the 3-month follow-up. Statistical analysis revealed no significant differences between objective and self-reported OA compliance data in this study. Measurement of the objective OA compliance allowed us to calculate the mean disease alleviation (MDA) as the product of objective compliance and therapeutic efficacy. MDA serves as a measure of the overall therapeutic effectiveness, and turned out to be 51.1%. CONCLUSIONS: The results illustrate the safety and feasibility of objective measurement of OA compliance. The objective measurement of OA compliance allows for calculation of the MDA.

Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: a longitudinal, general population study.

Nocturnal gastro-oesophageal reflux (nGOR) is associated with asthma and obstructive sleep apnoea (OSA). Our aim was to investigate whether nGOR is a risk factor for onset of asthma and onset of respiratory and OSA symptoms in a prospective population-based study. We invited 2640 subjects from Iceland, Sweden and Belgium for two evaluations over a 9-year interval. They participated in structured interviews, answered questionnaires, and underwent spirometries and methacholine challenge testing. nGOR was defined by reported symptoms. Subjects with persistent nGOR (n=123) had an independent increased risk of new asthma at follow-up (OR 2.3, 95% CI 1.1-4.9). Persistent nGOR was independently related to onset of respiratory symptoms (OR 3.0, 95% CI 1.6-5.6). The risk of developing symptoms of OSA was increased in subjects with new and persistent nGOR (OR 2.2, 95% CI 1.3-1.6, and OR 2.0, 95% CI 1.0-3.7, respectively). No significant association was found between nGOR and lung function or bronchial responsiveness. Persistent symptoms of nGOR contribute to the development of asthma and respiratory symptoms. New onset of OSA symptoms is higher among subjects with symptoms of nGOR. These findings provide evidence that nGOR may play a role in the genesis of respiratory symptoms and diseases.

Novel functional imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol.

BACKGROUND: Inhaled formulations using extrafine particles of long-acting ß2-agonists and corticosteroids were developed to optimize asthma treatment. Findings that these combinations reach and treat smaller airways more effectively are predominantly based on general non-specific outcomes with little information on regional characteristics. OBJECTIVES: This study aims to assess long-term effects of extrafine beclomethasone/formoterol on small airways of asthmatic patients using novel functional imaging methods. METHODS: Twenty-four stable asthma patients were subdivided into three groups (steroid naive, n = 7; partially controlled, n = 6; well controlled, n = 11). Current treatment was switched to a fixed combination of extrafine beclomethasone/formoterol (Foster®; Chiesi Pharmaceuticals, Parma, Italy). Patients underwent lung function evaluation and thorax high-resolution computerized tomography (HRCT) scan. Local airway resistance was obtained from computational fluid dynamics (CFD). RESULTS: After 6 months, the entire population showed improvement in pre-bronchodilation imaging parameters, including small airway volume (p = 0.0007), resistance (p = 0.011), and asthma control score (p = 0.016). Changes in small airway volume correlated with changes in asthma control score (p = 0.004). Forced expiratory volume in 1 s (p = 0.044) and exhaled nitric oxide (p = 0.040) also improved. Functional imaging provided more detail and clinical relevance compared to lung function tests, especially in the well-controlled group where only functional imaging parameters showed significant improvement, while the correlation with asthma control score remained. CONCLUSIONS: Extrafine beclomethasone/formoterol results in a significant reduction of small airway obstruction, detectable by functional imaging (HRCT/CFD). Changes in imaging parameters correlated significantly with clinically relevant improvements. This indicates that functional imaging is a useful tool for sensitive assessment of changes in the respiratory system after asthma treatment.

Unraveling pathophysiologic mechanisms contributing to symptoms in patients with post-acute sequelae of COVID-19 (PASC): A retrospective study.

Patients with post-acute sequelae of COVID-19 (PASC) present with a decrease in physical fitness. The aim of this paper is to reveal the relations between the remaining symptoms, blood volume distribution, exercise tolerance, static and dynamic lung volumes, and overall functioning. Patients with PASC were retrospectively studied. Pulmonary function tests (PFT), 6-minute walk test (6MWT), and cardiopulmonary exercise test were performed. Chest CT was taken and quantified. Patients were divided into two groups: minor functional limitations (MFL) and severe functional limitations (SFL) based on the completed Post-COVID-19 Functional Status scale (PCFS). Twenty one patients (3 M; 18 FM), mean age 44 (IQR 21) were studied. Eighteen completed the PCFS (8 MFL; 10 SFL). VO2 max was suboptimal in both groups (not significant). 6MWT was significantly higher in MFL-group (p = 0.043). Subjects with SFL, had significant lower TLC (p = 0.029). The MFL-group had more air trapping (p = 0.036). Throughout the sample, air trapping correlated significantly with residual volume (RV) in L (p < 0.001). An increase in air trapping was related to an increase in BV5 (p < 0.001). Mean BV5 was 65% (IQR 5%). BV5% in patients with PASC was higher than in patients with acute COVID-19 infection. This increase in BV5% in patients with PASC is thought to be driven by the air trapping in the lobes. This study reveals that symptoms are more driven by occlusion of the small airways. Patients with more physical complaints have significantly lower TLC. All subjects encounter physical limitations as indicated by suboptimal VO2 max. Treatment should focus on opening or re-opening of small airways by recruiting alveoli.