Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Assessment of respiratory function and exercise tolerance at 4-6 months after COVID-19 infection in patients with pneumonia of different severity.

BACKGROUND: The evaluation of COVID-19 systemic consequences is a wide research field in which respiratory function assessment has a pivotal role. However, the available data in the literature are still sparse and need further strengthening. AIM: To assess respiratory function 4-6 months after hospital discharge based on lung disease severity in patients who overcome COVID-19 pneumonia. METHODS: Patients hospitalised either in the Internal Medicine Department (IMD) for moderate to severe disease or in the Intensive Care Unit (ICU) for critical disease underwent spirometry with maximal flow-volume curve, lung volumes, lung diffusion capacity (DLCO ) and six-minute walking test (6-MWT). RESULTS: Eighty-eight patients were analysed: 40 from the IMD and 48 from the ICU. In both cohorts, there was a greater prevalence of male patients. In the IMD cohort, 38% of patients showed at least one altered respiratory parameter, while 62% in the ICU cohort did so (P < 0.05). Total lung capacity (TLC) and DLCO were the most frequently altered parameters: 15% and 33% from IMD versus 33% and 56% from ICU, respectively (P < 0.05). In IMD patients, 5% had only restrictive deficit, 22% had only lung diffusion impairment and 10% had both. In ICU patients, 6% had only restrictive deficit, 29% had only lung diffusion impairment and 27% had both (P < 0.05). ICU patients showed a higher frequency of abnormal 6-MWT (P < 0.05). CONCLUSION: Lung function tests and 6-MWT are highly informative tools for monitoring the negative consequences of COVID-19 pneumonia, which were more frequent and more complex in patients discharged from ICU.

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation.

Alpha1-antitrypsin (AAT) is one of the major inhibitors involved in protease/antiprotease homeostasis, and it is mainly produced by hepatocytes and pulmonary epithelial cells. Its deficiency, called alpha1-antitrypsin deficit (AATD), leads to severe hepatic and respiratory issues. Also, AAT is released into the bloodstream providing systemic anti-inflammatory effects. Apart from acting as an acute-phase anti-inflammatory protein, it can be a biomarker for monitoring disease evolution. A reduced or defective production leads to a loss of anti-inflammatory function, protease-antiprotease imbalance and cellular engorgement due to polymers deposition, with system-wide repercussions. This review aims to evaluate AATD condition in the major vessels of the head and neck, thoracic and abdominal districts. Also, a dedicated focus on autoimmune vascular diseases will be provided. A critical revision of the main literature findings starting from the 1980s until now has been performed. Studies conducted over the years have provided several contradictory pieces of evidence. Most authors acknowledge the protective and anti-inflammatory AAT role on the vascular endothelium. However, correlations between AATD and major arteries, cerebral and cardiovascular conditions, and autoimmune diseases remain unclear. Most studies recognize the role of AATD in vascular diseases but only as a cofactor inducing cellular and tissue structure impairments. However, this condition alone is not enough to determine new disease onset. Due to the opposing results reported over the years, there is still a considerable lack of knowledge on the role covered by AATD in vascular diseases. A renewed interest in this research field should be encouraged to grant new solid evidence and validate the putative role of AATD screening and replacement therapy as useful diagnostic and treatment tools.

Acute Effect of Bronchodilator on Intrathoracic Airway Wall Compliance in COPD Patients.

PURPOSE: In patients with chronic obstructive pulmonary disease (COPD), bronchial responsiveness after acute administration of short acting bronchodilators is conventionally assessed by measuring the improvement of forced expiratory volume in the first second (FEV1) during a maximal forced expiratory maneuver. This study aimed to measure the variation of intrathoracic airway wall compliance (AWC) after acute administration of short acting beta-2 agonist in COPD patients since this might influence the final modification of airway caliber during maximal expiratory effort and the resulting bronchodilation as inferred by FEV1 changes. METHODS: In a group of 10 patients suffering from COPD, intrathoracic AWC was measured at middle (50% of Forced Vital Capacity (FVC) and low (75% of FVC) lung volumes using the interrupter method during forced expiratory maneuver in basal conditions and after acute inhalation of albuterol (salbutamol) (400 mcg by MDI). Ten healthy subjects were examined similarly as a control group. RESULTS: Lower values of baseline intrathoracic AWC at both lung volumes were found in COPD patients (1.72 ± 0.20 ml/cmH2O and 1.08 ± 0.20 ml/cmH2O, respectively) as compared to controls (2.28 ± 0.27 ml/cmH2O and 1.44 ± 0.22 ml/cmH2O, respectively) (p < 0.001). In COPD patients, AWC increased significantly at both lung volumes after salbutamol, amounting to 1.81 ± 0.38 ml/cmH2O and 1.31 ± 0.39 ml/cmH2O, respectively (p < 0.01), but the relative change was not different from that observed in controls. CONCLUSION: In COPD patients, AWC is reduced compared to controls, but after bronchodilator, the intrathoracic airways become more compliant. The consequent increased collapsibility under high positive pleural pressure could limit the airway caliber improvement seen after bronchodilator, as assessed by the FEV1 changes during the forced expiratory maneuver, underestimating the effective bronchodilation achieved in these patients.

Effects of short-term exposure to particulate matter on emergency department admission and hospitalization for asthma exacerbations in Brescia district.

BACKGROUND: Rising pollution plays a crucial role in worsening several respiratory diseases. Particulate Matter (PM)-induced asthma exacerbations are one of the most dangerous events. OBJECTIVES: To assess the correlation between progressive particulate matter short-term exposure and asthma exacerbations, we investigated the role of PM levels on Emergency Department (ED) admissions and hospitalizations for these events in Brescia, an important industrial city located in northern Italy with high yearly levels of air pollution. METHODS: We analyzed 1050 clinical records of ED admissions for suspected asthma exacerbation, starting from January 2014 to December 2017. Daily PM levels were collected from the Environmental Protection Regional Agency. We performed a time-series analysis using a Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ERR) of severe asthma exacerbation over a 10 µg/m3 increase in PM10 and PM2.5 concentration. RESULTS: We selected and focused our analysis on 543 admissions for indisputable asthma exacerbation in ED and hospital. The time-series study showed an increase of the RR (CI95%) for asthma exacerbation-related ED admissions of 1.24 with an ERR of 24.2% for PM2.5 at lag0-1 (p < 0.05). We also estimated for PM2.5 a RR (CI95%) of 1.12 with an ERR of 12.5% at lag0-5 (p ≤ 0.05). Again, for PM2.5, an increase of the RR (CI95%) for asthma exacerbation-related hospitalizations of 1.31 with an ERR of 30.7% at lag0-1 (p < 0.05) has been documented. These findings were confirmed and even reinforced considering only the population living in the city. CONCLUSIONS: Short-term PM exposure, especially for PM2.5, plays a critical role in inducing asthma exacerbation events leading to ED admission or hospitalization.

Z-alpha1-antitrypsin polymers and small airways disease: a new paradigm in alfa-1 anti-trypsin deficiency-related COPD development?

The presence of Alpha1-Antitrypsin (AAT) polymers, known to promote a sustained pro-inflammatory activity, has been previously demonstrated in bronchial biopsies of subjects with Z-AAT deficiency (AATD) suggesting a possible role in the development of COPD through a small airway disease impairment. The study aimed to assess the presence of small airways dysfunction and the potential correlation with the presence of Z-AAT polymers obtained by Exhaled Breath Condensate (EBC) collection in PiZZ subjects, as compared with matched healthy PiMM subjects. We enrolled 19 asymptomatic, never smoker subjects: 9 PiZZ and 10 PiMM as controls, without obstructive ventilatory defect (i.e., normal FEV1/VC% ratio). All subjects underwent complete pulmonary function tests (PFT). EBC was collected in all subjects. ELISA test was applied to search for Z-AAT polymers. The PiZZ subjects showed normal lung volumes and DLCO values. However, in comparison with PiMM subjects, the single breath test N2 wash-out revealed significant differences regarding the phase III slope (1.45±0.35 N2/L vs. 0.96±0.40 N2/L) (p<0.02) in the PiZZ subjects, while the closing volume/vital capacity ratio (14.3±4.5 % vs. 11.3±6.3 %) was not significantly increased. The ELISA test detected the presence of Z-AAT polymers in 44% of PiZZ patients. Asymptomatic, never smoker PiZZ subjects with normal spirometry and lung diffusion capacity showed airways impairment when compared to PiMM subjects. Although Z-AAT polymers were found only in 44% of PiZZ subjects, these findings suggest the possibility that chronic bronchiolitis can develop as a result of the long-term pro-inflammatory activity of Z-AAT polymers in subjects with Z-related AATD.

Investigating the Link between Alpha-1 Antitrypsin Deficiency and Abdominal Aortic Aneurysms.

BACKGROUND: Alpha-1-Antitrypsin (AAT) is one of the major plasmatic protease inhibitors. In the last decade, an association between Alpha-1-Antitrypsin Deficiency (AATD) and Abdominal Aortic Aneurysms (AAA) has been hypothesized. Multiple factors may be involved in AAA's etiopathogenesis, and an underlying structural defect of the extracellular matrix (ECM) is always present. AATD could be a reasonable risk factor for AAA because it is related to protease/antiprotease imbalance and enhanced ECM degradation of the vessel wall. METHODS: We performed genotyping of 138 patients hospitalized in the Vascular Surgery Division of the ASST-Spedali Civili di Brescia, Italy, for nontraumatic rupture of AAA. The second purpose was to observe the distribution of main nongenetic risk factors for AAA between patients with and without AATD. RESULTS: Out of 138 patients, 22 were found with AATD: 16 MS, 1 SS, 3 MZ, and 2 with a new rare AAT variant. When compared to the general Italian population, our cohort's frequency of deficient S allele was significantly higher (7.8 vs. 2.2% respectively, P < 0.01), whereas the deficient Z allele was similar (1.1 vs. 1.3% respectively, P > 0.05). Although we found no differences in age, gender, hypertension, diabetes, and smoke habits between AAA patients with and without AATD, hyperlipidemia was significantly less frequent in patients with AATD (46.4 vs. 12.5% respectively, P < 0.05). CONCLUSIONS: In our AAA patients' cohort, the S allele frequency was higher than in the general Italian population. Our results support the hypothesis that AATD might be a risk factor for AAA.

Predictors of exercise-induced bronchoconstriction in subjects with mild asthma.

BACKGROUND: Physical effort is capable of triggering airway obstruction in asthmatics, the so-called exercise-induced bronchoconstriction in asthma (EIBa). This study was performed in subjects with mild persistent asthma, aiming to find predictors for developing EIBa. METHODS: In 20 subjects with mild asthma, measurements of baseline functional respiratory parameters and airways responsiveness by a methacholine challenge were obtained on the first day. A maximal, symptom-limited incremental cardiopulmonary exercise test (CPExT) was performed the day after, with subsequent, repeated maneuvers of maximal full forced expiration to monitor the FEV1 change at 1,3,5,7,10 and 15 min after the end of the exercise. RESULTS: 19 subjects completed the two-days protocol. No functional parameters both at rest and during effort were useful to predict EIBa after stopping exercise. In asthmatics with EIBa, mean Inspiratory Capacity (IC) did not increase with increasing ventilatory requirements during CPExT because 6 of them (50%) displayed dynamic pulmonary hyperinflation (DH), as documented by their progressive increase of end-expiratory lung volume. This subgroup, showing earlier post-exercise FEV1 fall, had significantly lower forced mean expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%) at rest (p < 0.05) and higher airways responsiveness, expressed as PD20FEV1 (p < 0.05) as compared with other asthmatics with EIBa. CONCLUSIONS: No functional respiratory parameters seem to predict EIBa in mild asthmatics. However, in those with EIBa, a subgroup developed DH during exercise, and this was associated with a baseline reduced forced expiratory flow rates at lower lung volumes and higher airway hyperresponsiveness, suggesting a prominent small airways impairment.

A prospective evaluation of lung function at three and six months in patients with previous SARS-COV-2 pneumonia.

OBJECTIVE: This study investigated the consequences of Coronavirus Disease 2019 (COVID-19) pneumonia on lung function in the first 6 months after hospital discharge. METHODS: A prospective lung function assessment in SARS-CoV2 patients with COVID-19 pneumonia, hospitalized between March and April 2020, was conducted with spirometry measurements including lung volumes, mainly total lung capacity (TLC), lung diffusion capacity for carbon monoxide (DLCO) collected at 3 months after hospital discharge. Patients with restrictive ventilatory defect or impaired DLCO or both were re-evaluated at 6 months with global spirometry and chest HRCT scan. RESULTS: Among 40 consecutive patients, 19 (48%) had normal pulmonary functional tests (group A), and 21 (52%) showed residual lung function abnormalities at 3 months after hospital discharge (group B). In group B, 4 patients (19%) had only loss of lung volume as shown by TLC reduction (group 1), 13 patients (62%) had decreased both TLC and DLCO (group 2), and 4 patients (19%) had isolated reduction in DLCO (group 3). At 6-month follow-up in group 1, although all patients improved, only one normalized total lung capacity (TLC). In group 2, TLC and DLCO increased significantly (p < 0.01), but only 3 patients reached normal values. In group 3, DLCO improved for most patients, normalizing in 50% of them. At 6-months significant correlations between an internal-built chest HRCT scan severity score and TLC (r2 = 0.33; p < 0.01) and DLCO (r2 = 0.32; p < 0.01) were found. CONCLUSIONS: Nearly 50% of patients recovered in the post-critical phase. Most of those with abnormal pulmonary function tests at 3 months improved subsequently, but only another 29% (6 out of 21) reached normal values at 6 months. These results indicate that lung function spontaneous recovery is faster at first and occurs more slowly thereafter, leaving more than one third (15 out of 40) of patients with abnormal lung function tests at 6 months.

Single-breath oxygen dilution for the measurement of total lung capacity: technical description and preliminary results in healthy subjects.

Objective. Total lung capacity (TLC) assessment outside of a research laboratory is challenging. We describe a novel method for measuring TLC that is both simple and based only on portable equipment, and report preliminary data in healthy subjects.Approach. We developed an open circuit system to administer a known amount of oxygen to a subject in a single maximal inspiratory maneuver. Oxygen fraction, expired and inspired flows were continuously monitored to allow a precise computation of the mass balance. Values of TLC and functional residual capacity (FRC) were compared with standard methods (body plethysmography and multiple-breath helium dilution). Twenty healthy subjects participated to the study, eleven of which performed the maneuver twice to assess test-retest reliability.Main results.There was high agreement in TLC between the proposed method and the two standard methods (R2 > 0.98, bias not different from 0, and 95% limits of agreements <± 0.4 l for both). Test-retest reliability was high (intraclass correlation coefficient >0.99 and no bias). Results were similar for FRC, with a slightly higher variability due its sensitivity to changes in posture or breathing pattern.Significance.Single-breath oxygen dilution is accurate and reliable in assessing TLC and FRC in healthy subjects. The technique is appealing for time- or resource-limited settings, such as field physiological research expeditions or mass screenings.

Emergency department admission and hospitalization for COPD exacerbation and particulate matter short-term exposure in Brescia, a highly polluted town in northern Italy.

BACKGROUND: Short-term exposure to high Particulate Matter (PM) concentrations worsens several respiratory conditions. OBJECTIVES: We evaluated the relationship between short-term exposure to Particulate Matter and fine Particulate Matter (PM10 - PM2.5) and Emergency Department (ED) admissions and hospitalizations for COPD exacerbation observed at the University Hospital, Spedali Civili of Brescia, a city with some of the highest yearly levels of air pollution in Italy. METHODS: We collected data from patients admitted to the ED with a COPD exacerbation diagnosis, starting from January 2014 to January 2016. Daily PM levels were collected from the Environmental Protection Regional Agency (ARPA). We performed a time-series analysis using the Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ER) for COPD exacerbation-related ED admissions and hospitalizations, over a 10µg/m3 increase in PM concentration. RESULTS: We collected data from 431 COPD patients. Both PM10 and PM2.5 were significantly associated with the risk of COPD exacerbation-related ED admission and hospitalization. Each increase of 10µg/m3 of PM10 and PM2.5 corresponded respectively to a RR for ED admissions of 1.06 and 1.08 at lag0-1; 1.06 and 1.09 at lag0-5 (p < 0.05). Similar results for COPD Exacerbation-related hospitalizations were found, with a RR of 1.07 and 1.10 at lag0-1 and 1.07 and 1.11 at lag0-5 for each increase of 10µg/m3 PM10 and PM2.5, respectively. CONCLUSIONS: Our findings show that in a highly polluted city of Northern Italy, short-term increase in exposure to PM10-PM2.5 is associated with a higher risk of ED admission and hospitalization due to COPD exacerbation with a greater incidence during the winter season.

Respiratory function, autonomic dysfunction, and systemic inflammation are closely linked in patients with COPD and tidal flow limitation: An exploratory study.

RATIONALE: The study aimed to investigate the interplay among respiratory function, autonomic dysfunction, and systemic inflammation in COPD patients. METHODS: In 19 COPD patients, functional respiratory parameters, heart rate variability (HRV), and plasma high-sensitivity-C-reactive-protein (hs-CRP) were assessed. Forced oscillation technique (FOT) was used to detect the absence (NFL) or presence (FL) of resting tidal expiratory flow limitation. Subsequently, patients underwent an incremental shuttle walking test (ISWT). Twenty healthy subjects were also shown as controls. RESULTS: FEV1, DLCO, and lung volumes displayed significant correlations with LH/FH ratio (0.56 < r2<0.27,p < 0.01). A significant relationship was found between LH/FH ratio with IC/TLC ratio% (r2 = 0.29,p < 0.05) and hs-CRP (r2 = 0.26,p < 0.05). Patients with FL had greater hs-CRP plasma levels (p < 0.05), lower IC/TLC% (p < 0.05), and higher LH/FH ratio (p<0.001). CONCLUSIONS: Worse airflow obstruction was associated with a higher LH/HF ratio, directly related, to hs-CRP and indices of dynamic hyperinflation. The presence of resting tidal FL with dynamic pulmonary hyperinflation is a strong driver of systemic inflammation and autonomic dysfunction.

Alpha1-antitrypsin deficiency and asthma.

PURPOSE OF REVIEW: The aim of the article is to highlight the association between α1-antitrypsin deficiency (AATD) and asthma. RECENT FINDINGS: AATD is one of the most common and underrecognized autosomal disorders associated with an increased risk of developing liver and lung diseases. An association between α1-antitrypsin and asthma has been suggested, especially with severe forms of this disease. Many studies have shown an increased prevalence of asthma in the α1-antitrypsin-deficient population overtime (4-38%). The biological mechanism underlying these two conditions and able to bind them has not yet been well investigated. As α1-antitrypsin is the main inhibitor of the serine proteinase and it is an important anti-inflammatory protein with pronounced immunomodulatory activities, it can be hypothesized that the link between AATD and asthma might be represented by the elastase/antielastase imbalance and the proinflammatory effect that occurs because of the reduction of this protein. SUMMARY: There is a strong need for further researches to better understand the molecular mechanisms binding AATD and asthma. It is also recommendable to screen for AATD, late-onset asthma patients, and/or those with not fully reversible airways obstruction.

Assessment and treatment of airflow obstruction in patients with chronic obstructive pulmonary disorder: a guide for the clinician.

Introduction: Chronic obstructive pulmonary disorder (COPD) is a common cause of disability, morbidity and mortality worldwide. Early diagnosis and adequate treatment maintained over time are crucial to reducing these harmful consequences.Areas covered Persistent, not reversible and naturally progressive airflow obstruction is the functional hallmark of COPD. Therefore, in the presence of individual and environmental risk factors, with or without reported suggestive symptoms, simple spirometry must be performed enough quickly to objectify an obstructive ventilatory defect and assist physicians in making a diagnosis of COPD. Then, to cope with the heterogeneity of COPD patients, more specific functional tests and imaging techniques should be implemented to better define the underlying prevalent disease and its severity. That is necessary to decide whether to introduce ICS and establish the initial level of the treatment with just one or two bronchodilators, to control and freeze, when possible, the underlying pathological process.Expert opinion: The objective assessment of airflow obstruction is mandatory to make a diagnosis of COPD, but the prevalent disease sustaining the disorder should also be investigated to select a targeted therapy, because main determinants of airflow obstruction can be different in COPD patients and may differently respond to treatment.

Dyspnea During Night-Time and at Early Morning in Patients with Stable COPD is Associated with Supine Tidal Expiratory Flow Limitation.

Rationale: Patients with chronic obstructive pulmonary disorder (COPD) complain of various COPD-related symptoms with different daily frequencies. During the night-time and at early morning, dyspnea is often reported and may predict an increased risk of COPD exacerbation and hospitalization and all-cause mortality. The aim of the study was to assess the underlying mechanisms of this symptom, seeking functional biomarkers of its occurrence. Methods: Stable COPD patients with moderate-to-severe airflow obstruction and without confounding comorbidities underwent extensive baseline function respiratory tests. Spirometry, maximal flow-volume curves, lung volumes, and lung diffusion capacity parameters were obtained. Inspiratory capacity was also measured both in seated and supine positions. Forced oscillation technique (FOT) and negative expiratory pressure (NEP) method were used to establish the presence of tidal expiratory flow limitation (EFL) during recumbency. Questionnaires for recording COPD-related symptoms were administered. Sleep-related disturbances reported by the patients were also registered. Results: Forty-two consecutive COPD patients aged 65±9 completed the protocol. They were divided, according to the absence (NFL) or presence (FL) of supine EFL, in NFL group (n=17) and FL group (n=25). FL COPD patients had more severe airflow obstruction (FEV1= 46.4±19.4 vs 65.1±12.5% pred., p<0.01) and they showed no increase of supine IC in contrast with NFL COPD patients (ΔIC= 0.080±0.18 vs 0.390±0.28 L, p<0.01). Dyspnea either during night-time and at early morning was significantly more reported in FL COPD patients than in NFL COPD patients (p<0.05) and in those with less than 10% increase in supine IC (p<0.05). Conclusion: Supine EFL is frequently associated with both night-time and early morning dyspnea, suggesting that the development of recumbent dynamic pulmonary hyperinflation, heralded by the lack of increment of IC in supine position, is a pivotal mechanism of this symptom. No or trivial increase in supine IC may indicate the occurrence of dyspnea under these conditions.

Effects of Chronic and Acute Pulmonary Hyperinflation on Phrenic Nerve Conduction in Patients with COPD.

In patients with moderate-to-severe Chronic Obstructive Pulmonary Disorder (COPD), pulmonary hyperinflation can occur at rest and increase during episodes of exacerbation. Among other mechanical constraints, changes in position and configuration of the diaphragm are also induced by increased end-expiratory lung volume. Both descent and flattening of diaphragm might damage the phrenic nerves by stretching their fibers. The study aimed to investigate the phrenic nerve conduction in COPD patients in stable conditions and during COPD exacerbation. In a group of 11 COPD patients without relevant comorbidities in stable conditions and subsequently in another group of 10 COPD patients during in-hospital COPD exacerbation and recovery, measurements of functional respiratory parameters and assessment of phrenic nerves motor conduction by bilateral electric stimulation were performed concurrently. Significant increase in phrenic nerves latency (p < 0.05), but similar amplitude of motor compound muscle action potential (cMAP) was observed in stable COPD patients vs. matched controls (p < 0.05). However, in COPD patients with resting pulmonary hyperinflation as reliably detected by substantial Inspiratory Capacity reduction (<80% pred.), the mean bilateral latency was longer vs. COPD patients without pulmonary hyperinflation (p < 0.02). During COPD exacerbation, in contrast with mean latency, the mean amplitude of phrenic nerves cMAP improved at discharge when compared with in-hospital admission (p < 0.05). In stable COPD patients the velocity of phrenic nerve conduction was impaired mostly in the presence of pulmonary hyperinflation, while during COPD exacerbation where dynamic pulmonary hyperinflation abruptly occurs, the reversible decrease of cMAP amplitude does suggest a temporary, acute axonal damage of phrenic nerves, potentially contributing to diaphragmatic dysfunction in these circumstances.

Inhaled Corticosteroids in COPD: Trying to Make a Long Story Short.

The use of inhaled corticosteroids (ICSs) in long-term treatment of COPD has been a debated topic for a long time. According to the evidence produced till now, ICSs are presently advocated in combination with long-acting bronchodilators for high-risk symptomatic COPD patients with a history of frequent COPD exacerbations. However, the heterogeneity of COPD patients in terms of prevalent underlying disease, with its associated biological and functional characteristics, and different types of exacerbation makes this recommendation highly questionable. This review aims to discuss the usefulness of ICSs in the pharmacological management of COPD and trys to detect those aspects that may likely anticipate a beneficial response following their therapeutic use related to respiratory function, functional decline, prevention of exacerbation, and quality of life. In this respect, the BERN acronym, meaning Bronchiolitis, Eosinophilia, Responsiveness to bronchodilator, and Non-smoker, may be of practical utility to select among COPD patients those that can take more advantage from ICS adoption when positive and vice versa when negative.

Lung air trapping lowers respiratory arousal threshold and contributes to sleep apnea pathogenesis in COPD patients with overlap syndrome.

STUDY OBJECTIVES: Overlap syndrome occurs when obstructive sleep apnea (OSA) and chronic obstructive pulmonary disorder (COPD) coexist in the same patient. Although several studies highlighted the importance of clinical phenotyping in OSA, the trait contribution to OSA pathogenesis in overlap syndrome has not been investigated. With this pilot study, we aimed to measure OSA determinants and their relationship with functional respiratory parameters in a sample of patients with overlap syndrome. In particular, we hypothesize that patients with COPD have in the low arousal threshold a major contributor for the development of OSA. METHODS: Ten consecutive non-hypercapnic COPD patients (body mass index<35 kg/m2) suffering from overlap syndrome with no other relevant comorbidities underwent a phenotyping polysomnography. Traits were measured with CPAP dial-downs. RESULTS: Arousal threshold was found to be inversely associated to functional measures of lung air trapping and static hyperinflation. Particularly, correlations with residual volume (r2 = 0.49, p =  0.024) and residual volume to total lung capacity ratio (r2 = 0.48, p =  0.026) were evident. Only 20% of patients showed a high upper airway passive collapsibility as single pathological trait. In contrast, among those patients with multiple altered traits (6 out of 10), all had an elevated loop gain and 4 (∼65%) a low arousal threshold. CONCLUSIONS: High loop gain and particularly low arousal threshold seem important contributors to OSA pathogenesis and severity in patients with COPD. Recognizing in COPD patients these features as key traits may open avenues for personalized medicine in the field of overlap syndrome.

Raw Bioelectrical Impedance Analysis Variables Are Independent Predictors of Early All-Cause Mortality in Patients With COPD.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a valuable method for estimating fat-free mass and fat mass in patients with COPD by using specific predictive equations. In addition, raw BIA variables such as high- to low-frequency impedance ratios (IRs) and phase angle, most likely as a result of providing information on muscle quality, have been related to disease severity and mortality in patients with several diseases but never in COPD. The aim of this study was to investigate the predictive role of raw BIA variables on 2-year survival in COPD. METHODS: Impedance (Z) at 5-10-50-100-250 kHz and phase angle at 50 kHz were determined in 210 patients with COPD. Three IRs were calculated: Z at 50 kHz/Z at 5 kHz (50/5 IR), Z at 100 kHz/Z at 5 kHz (100/5 IR), and Z at 250 kHz/Z at 5 kHz (250/5 IR). Demographic, respiratory, and body composition data at baseline were recorded. All-cause mortality was assessed during 2 years of follow-up. RESULTS: After the follow-up period, all-cause mortality was 13.8%. Statistically significant differences between nonsurvivors and survivors emerged in terms of age, weight, BMI, FEV1, inspiratory capacity, and modified Medical Research Council dyspnea score. With respect to nutritional variables, nonsurvivors had lower fat-free mass (P = .031), lower fat mass (P = .015), higher IRs (P < .001 for all the ratios), and lower phase angle (P < .001) compared with survivors. After adjustment for confounding factors, each unit increase of IRs and each unit decrease of phase angle were associated with a higher risk of death. CONCLUSIONS: IRs and phase angle, as raw BIA variables, are independent and powerful predictors of all-cause mortality in COPD and should be considered, together with inspiratory capacity and 6-min walk distance, as significant prognostic factors in the short- to middle-term.