Potential Diaphragm Muscle Weakness-related Dyspnea Persists Two Years after COVID-19 and Could Be Improved by Inspiratory Muscle Training: Results of an Observational and an Interventional Trial.

RATIONALE: Diaphragm muscle weakness might underly persistent exertional dyspnea despite normal lung/cardiac function in individuals previously hospitalized for acute COVID-19 illness. OBJECTIVES: Firstly, to determine the persistence and pathophysiological nature of diaphragm muscle weakness and its association with exertional dyspnea two years after hospitalization for COVID-19, and secondly to investigate the impact of inspiratory muscle training (IMT) on diaphragm and inspiratory muscle weakness and exertional dyspnea in individuals with long COVID. METHODS: ~2 years after hospitalization for COVID-19, 30 individuals (11 female, median age 58 [interquartile range (IQR) 51-63] years) underwent comprehensive (invasive) respiratory muscle assessment and evaluation of dyspnea. Eighteen with persistent diaphragm muscle weakness and exertional dyspnea were randomized to 6 weeks of IMT or sham training; assessments were repeated immediately after and 6 weeks after IMT completion. The primary endpoint was change in inspiratory muscle fatiguability immediately after IMT. RESULTS: At median 31 [IQR 23-32] months after hospitalization, 21/30 individuals reported relevant persistent exertional dyspnea. Diaphragm muscle weakness on exertion and reduced diaphragm cortical activation were potentially related to exertional dyspnea. Compared with sham control, IMT improved diaphragm and inspiratory muscle function (sniff transdiaphragmatic pressure 83 [IQR 75-91] vs. 100 [IQR 81-113] cmH2O; p=0.02), inspiratory muscle fatiguability (time to task failure 365 [IQR 284-701] vs. 983 [IQR 551-1494] sec; p=0.05), diaphragm voluntary activation index (79 [IQR 63-92] vs 89 [IQR 75-94]%; p=0.03), and dyspnea (Borg score 7 [IQR 5.5-8] vs. 6 [IQR 4-7]; p=0.03); improvements persisted for 6 weeks after IMT completion. CONCLUSIONS: This study is the first to identify a potential treatment for persisting exertional dyspnea in long COVID, and provide a possible pathophysiological explanation for the treatment benefit. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Supplemental oxygen therapy in chronic obstructive pulmonary disease: is less is more? How much is too much?

PURPOSE OF REVIEW: Currently available evidence supporting the use of supplemental oxygen therapy (SOT) in chronic obstructive pulmonary disease (COPD) is complex, and data on the mortality reduction associated with SOT usage in patients with severe daytime resting hypoxemia have not been updated since the development of other treatments. RECENT FINDINGS: No reduction in mortality was found when SOT was used in patients with moderate resting daytime, isolated nocturnal, or exercise-induced hypoxemia. However, some of these patients obtain other significant benefits during SOT, including increased exercise endurance, and a mortality reduction is possible in these 'responders'. The adverse effects of long-term oxygen therapy also need to be considered, such as reduced mobility and social stigma. Furthermore, conservative SOT could improve outcomes in the setting of COPD exacerbations compared with higher concentration oxygen regimens. Compared with usual fixed-dose SOT, automated oxygen administration devices might reduce dyspnea during exercise and COPD exacerbations. SUMMARY: Current recommendations for SOT need to be revised to focus on patients who respond best and benefit most from this therapy. A conservative approach to SOT can reduce side effects compared with higher concentration oxygen regimens, and automated oxygen administration devices may help to optimize SOT.

Definition of the Post-COVID syndrome using a symptom-based Post-COVID score in a prospective, multi-center, cross-sectoral cohort of the German National Pandemic Cohort Network (NAPKON).

PURPOSE: The objective examination of the Post-COVID syndrome (PCS) remains difficult due to heterogeneous definitions and clinical phenotypes. The aim of the study was to verify the functionality and correlates of a recently developed PCS score. METHODS: The PCS score was applied to the prospective, multi-center cross-sectoral cohort (in- and outpatients with SARS-CoV-2 infection) of the "National Pandemic Cohort Network (NAPKON, Germany)". Symptom assessment and patient-reported outcome measure questionnaires were analyzed at 3 and 12 months (3/12MFU) after diagnosis. Scores indicative of PCS severity were compared and correlated to demographic and clinical characteristics as well as quality of life (QoL, EQ-5D-5L). RESULTS: Six hundred three patients (mean 54.0 years, 60.6% male, 82.0% hospitalized) were included. Among those, 35.7% (215) had no and 64.3% (388) had mild, moderate, or severe PCS. PCS severity groups differed considering sex and pre-existing respiratory diseases. 3MFU PCS worsened with clinical severity of acute infection (p = .011), and number of comorbidities (p = .004). PCS severity was associated with poor QoL at the 3MFU and 12MFU (p < .001). CONCLUSION: The PCS score correlated with patients' QoL and demonstrated to be instructive for clinical characterization and stratification across health care settings. Further studies should critically address the high prevalence, clinical relevance, and the role of comorbidities. TRAIL REGISTRATION NUMBER: The cohort is registered at www. CLINICALTRIALS: gov under NCT04768998.

Effective non-invasive ventilation reduces muscle sympathetic nerve activity in patients with stable hypercapnic COPD.

Increased sympathetic drive is of prognostic significance in chronic obstructive pulmonary disease (COPD) but its determinants remain poorly understood. One potential mechanism may be chemoreflex-mediated adrenergic stimulation caused by sustained hypercapnia. This study determined the impact of non-invasive ventilation (NIV) on muscle sympathetic nerve activity (MSNA) in patients with stable hypercapnic COPD. Ten patients (age 70 ± 7 years, GOLD stage 3-4) receiving long-term NIV (mean inspiratory positive airway pressure 21 ± 7 cmH2O) underwent invasive MSNA measurement via the peroneal nerve during spontaneous breathing and NIV. Compared with spontaneous breathing, NIV significantly reduced hypercapnia (PaCO2 51.5 ± 6.9 vs 42.6 ± 6.1 mmHg, p < 0.0001) along with the burst rate (64.4 ± 20.9 vs 59.2 ± 19.9 bursts/min, p = 0.03) and burst incidence (81.7 ± 29.3 vs 74.1 ± 26.9 bursts/100 heartbeats, p = 0.04) of MSNA. This shows for the first time that correcting hypercapnia with NIV decreases MSNA in COPD.

Diaphragm Muscle Weakness Might Explain Exertional Dyspnea 15 Months after Hospitalization for COVID-19.

Rationale: Dyspnea is often a persistent symptom after acute coronavirus disease (COVID-19), even if cardiac and pulmonary function are normal. Objectives: This study investigated diaphragm muscle strength in patients after COVID-19 and its relationship to unexplained dyspnea on exertion. Methods: Fifty patients previously hospitalized with COVID-19 (14 female, age 58 ± 12 yr, half of whom were treated with mechanical ventilation, and half of whom were treated outside the ICU) were evaluated using pulmonary function testing, 6-minute-walk test, echocardiography, twitch transdiaphragmatic pressure after cervical magnetic stimulation of the phrenic nerve roots, and diaphragm ultrasound. Diaphragm function data were compared with values from a healthy control group. Measurements and Main Results: Moderate or severe dyspnea on exertion was present at 15 months after hospital discharge in approximately two-thirds of patients. No significant pulmonary function or echocardiography abnormalities were detected. Twitch transdiaphragmatic pressure was significantly impaired in patients previously hospitalized with COVID-19 compared with control subjects, independent of initial disease severity (14 ± 8 vs. 21 ± 3 cm H2O in mechanically ventilated patients vs. control subjects [P = 0.02], and 15 ± 8 vs. 21 ± 3 cm H2O in nonventilated patients vs. control subjects [P = 0.04]). There was a significant association between twitch transdiaphragmatic pressure and the severity of dyspnea on exertion (P = 0.03). Conclusions: Diaphragm muscle weakness was present 15 months after hospitalization for COVID-19 even in patients who did not require mechanical ventilation, and this weakness was associated with dyspnea on exertion. The current study, therefore, identifies diaphragm muscle weakness as a correlate for persistent dyspnea in patients after COVID-19 in whom lung and cardiac function are normal. Clinical trial registered with www.clinicaltrials.gov (NCT04854863).

Inhalation therapies in COPD - adverse drug reactions impact on emergency department presentations.

PURPOSE: Inhaled drugs have been cornerstones in the treatment of chronic obstructive pulmonary disease (COPD) for decades and show a high prescription volume. Due to the local application, drug safety issues of these therapies are often underestimated by professionals and patients. Data about adverse drug reactions (ADRs) caused by inhaled therapy in patients with COPD and polypharmacy are rare. We aimed to analyze the use and relevance of inhaled therapies in those patients in relation to ADR complaints, which were severe enough to warrant presentation to the emergency department. METHODS: Emergency department cases due to suspected ADRs of the ADRED database (n = 2939, "Adverse Drug Reactions in Emergency Departments"; DRKS-ID: DRKS00008979, registration date 01/11/2017) were analyzed for inhaled drugs in patients with COPD. ADRs in cases with overdosed inhaled drugs were compared to non-overdosed cases. ADRs, potentially caused by inhaled drugs, were evaluated, clustered into complexes, and assessed for association with inhaled drug classes. RESULTS: Of the 269 included COPD cases, 67% (n = 180) received inhaled therapy. In 16% (n = 28), these therapies were overdosed. Overdosed cases presented the complexes of malaise and local symptoms more frequently. Related to the use of inhaled anticholinergics, local (dysphagia-like) and related to inhaled beta-2 agonists, local (dysphagia-like) and sympathomimetic-like ADRs presented more frequently. CONCLUSION: Overdosed inhaled therapies in patients with COPD lead to relevant ADRs and impact on emergency room presentations. These are rarely associated to inhaled therapy by healthcare professionals or patients. Due to the high volume of inhaled drug prescriptions, pharmacovigilance and patient education should be more focused in patients with COPD. German Clinical Trial Register: DRKS-ID: DRKS00008979.

State-of-the-Art Opinion Article on Ventilator-Induced Diaphragm Dysfunction: Update on Diagnosis, Clinical Course, and Future Treatment Options.

Evidence from both animal and human studies now supports the development of ventilator-induced diaphragm dysfunction (VIDD) starting as early as 24 h after initiation of mechanical ventilation in the intensive care unit (ICU). However, although the concept of VIDD is now widely accepted, there remain several unanswered questions regarding its pathophysiology, rate of development, and (potentially) recovery after mechanical ventilation.This state-of-the-art opinion article briefly explains VIDD and provides an update on its clinical and prognostic relevance. It then focusses on state-of-the-art diagnostic approaches to determine diaphragm function, strength, and control (neural and peripheral), highlights knowledge gaps relevant to VIDD, and discusses the use of diaphragm pacing for VIDD prevention. It is suggested that future research projects in mechanically ventilated patients would ideally use both cortical and cervical phrenic nerve stimulation studies over time (including also diaphragm electromyography) as the gold standard techniques. This approach has not yet been utilized in a longitudinally designed study in the ICU. Application of these gold standard techniques would allow better understanding of the true pathophysiology and rate of development of VIDD. Notably, these techniques would be superior to diaphragm ultrasound, which yields surrogate markers of diaphragm function only without any direct measure of diaphragm strength or control. It is also suggested that such translational research would further advance understanding of diaphragm pacing as a very promising treatment option for VIDD.

Bioimpedance based determination of cardiac index does not show enough trueness for point of care use in patients with systolic heart failure.

Cardiac output (CO) is a key parameter in diagnostics and therapy of heart failure (HF). The thermodilution method (TD) as gold standard for CO determination is an invasive procedure with corresponding risks. As an alternative, thoracic bioimpedance (TBI) has gained popularity for CO estimation as it is non-invasive. However, systolic heart failure (HF) itself might worsen its validity. The present study validated TBI against TD. In patients with and without systolic HF (LVEF ≤ 50% or > 50% and NT-pro-BNP < 125 pg/ml, respectively) right heart catheterization including TD was performed. TBI (Task Force Monitor©, CNSystems, Graz, Austria) was conducted semi-simultaneously. 14 patients with and 17 patients without systolic HF were prospectively enrolled in this study. In all participants, TBI was obtainable. Bland-Altman analysis indicated a mean bias of 0.3 L/min (limits of agreement ± 2.0 L/min, percentage error or PE 43.3%) for CO and a bias of -7.3 ml (limits of agreement ± 34 ml) for cardiac stroke volume (SV). PE was markedly higher in patients with compared to patients without systolic HF (54% vs. 35% for CO). Underlying systolic HF substantially decreases the validity of TBI for estimation of CO and SV. In patients with systolic HF, TBI clearly lacks diagnostic accuracy and cannot be recommended for point-of-care decision making. Depending on the definition of an acceptable PE, TBI may be considered sufficient when systolic HF is absent.Trial registration number: DRKS00018964 (German Clinical Trial Register, retrospectively registered).

A Potential Association between Ribonuclease 1 Dynamics in the Blood and the Outcome in COVID-19 Patients.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.

[Weaning from prolonged mechanical ventilation on a specialised weaning unit: a retrospective comparison of patients with and without SARS-CoV-2 infection]. / Entwöhnung von der Langzeitbeatmung nach ARDS auf einer spezialisierten Weaning-Einheit ­ ein retrospektiver Vergleich von Patienten mit und ohne SARS-CoV-2 Infektion.

BACKGROUND: Available data on patients requiring prolonged mechanical ventilation due to severe COVID-19 are sparse. Here we compare patients with ARDS related or not related to SARS-CoV-2 infection treated in a specialised weaning unit. METHODS: A retrospective analysis of all patients with prolonged mechanical ventilation associated with an ARDS admitted from the 21st November 2013 to the 23rd July 2021 to the weaning unit of the University Hospital RWTH Aachen was performed. ARDS patients with COVID-19 (cARDS) were compared to patients with ARDS not related to COVID-19 (ncARDS). RESULTS: In total, n=129 patients in prolonged need for mechanical ventilation after ARDS were treated in the weaning unit, of whom n=38 had been suffering from ARDS related to COVID-19. Both patients groups were similar in terms of demographic parameters, underlying chronic illnesses, severity of ARDS and the duration of mechanical ventilation before being admitted to the weaning unit. During ICU stay, prone positioning and therapy with systemic corticosteroids was used more frequently in cARDS patients. Furthermore, therapy with vasoconstrictors was needed more often (cARDS: 42.1% vs. ncARDS 12.1%; p=0.0003) and urinary output was lower (cARDS: 1980 ml vs. ncARDS: 2600 ml; p=0.0037) in this patient group. The clinical course of the weaning process was similar in patients with cARDS and ncARDS, there were no significant differences in the occurrence of complications and the duration of mechanical ventilation. There were n=5 deaths (13.2%) in the cARDS and n=15 deaths (16.5%) in the ncARDS group. After hospital discharge, n=4 patients required non-invasive ventilation whereas out-of-hospital invasive ventilation was only necessary in one patient (all in the ncARDS group). CONCLUSION: After having survived the acute phase, the disease prognosis of patients with severe COVID-19 is favourable and most patients can be successfully weaned from mechanical ventilation. In addition, there were only minor differences compared to patients with ARDS unrelated to COVID-19.

[Non-invasive Mechanical Ventilation in Acute Respiratory Failure. Clinical Practice Guidelines - on behalf of the German Society of Pneumology and Ventilatory Medicine]. / S2k-Leitlinie Nichtinvasive Beatmung als Therapie der akuten respiratorischen Insuffizienz.

The guideline update outlines the advantages as well as the limitations of NIV in the treatment of acute respiratory failure in daily clinical practice and in different indications.Non-invasive ventilation (NIV) has a high value in therapy of hypercapnic acute respiratory failure, as it significantly reduces the length of ICU stay and hospitalization as well as mortality.Patients with cardiopulmonary edema and acute respiratory failure should be treated with continuous positive airway pressure (CPAP) and oxygen in addition to necessary cardiological interventions. This should be done already prehospital and in the emergency department.In case of other forms of acute hypoxaemic respiratory failure with only mild or moderately disturbed gas exchange (PaO2/FiO2 > 150 mmHg) there is no significant advantage or disadvantage compared to high flow nasal oxygen (HFNO). In severe forms of ARDS NIV is associated with high rates of treatment failure and mortality, especially in cases with NIV-failure and delayed intubation.NIV should be used for preoxygenation before intubation. In patients at risk, NIV is recommended to reduce extubation failure. In the weaning process from invasive ventilation NIV essentially reduces the risk of reintubation in hypercapnic patients. NIV is regarded useful within palliative care for reduction of dyspnea and improving quality of life, but here in concurrence to HFNO, which is regarded as more comfortable. Meanwhile NIV is also recommended in prehospital setting, especially in hypercapnic respiratory failure and pulmonary edema.With appropriate monitoring in an intensive care unit NIV can also be successfully applied in pediatric patients with acute respiratory insufficiency.

Diaphragm dysfunction as a potential determinant of dyspnea on exertion in patients 1 year after COVID-19-related ARDS.

Some COVID-19 patients experience dyspnea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a potential correlate with exertional dyspnea after COVID-19 acute respiratory distress syndrome (ARDS) in ten patients and matched controls. One year post discharge, both pulmonary function tests and echocardiography were normal. However, six patients with persisting dyspnea on exertion showed impaired volitional diaphragm function and control based on ultrasound, magnetic stimulation and balloon catheter-based recordings. Diaphragm dysfunction with impaired voluntary activation can be present 1 year after severe COVID-19 ARDS and may relate to exertional dyspnea.This prospective case-control study was registered under the trial registration number NCT04854863 April, 22 2021.

Analysis of BNT162b2- and CVnCoV-elicited sera and of convalescent sera toward SARS-CoV-2 viruses.

BACKGROUND: The mRNA vaccine BNT162b2 (Comirnaty, BioNTech/Pfizer) and the vaccine candidate CVnCoV (Curevac) each encode a stabilized spike protein of SARS-CoV2 as antigen but differ with respect to the nature of the mRNA (modified versus unmodified nucleotides) and the mRNA amount (30 µg versus 12 µg RNA). This study characterizes antisera elicited by these two vaccines in comparison to convalescent sera. METHODS: Sera from BNT162b2 vaccinated healthcare workers, and sera from participants of a phase I trial vaccinated with 2, 4, 6, 8, or 12 µg CVnCoV and convalescent sera from hospitalized patients were analyzed by ELISA, neutralization tests, surface plasmon resonance (SPR), and peptide arrays. RESULTS: BNT162b2-elicited sera and convalescent sera have a higher titer of spike-RBD-specific antibodies and neutralizing antibodies as compared to the CVnCoV-elicited sera. For all analyzed sera a reduction in binding and neutralizing antibodies was found for the lineage B.1.351 variant of concern. SPR analyses revealed that the CVnCoV-elicited sera have a lower fraction of slow-dissociating antibodies. Accordingly, the CVnCoV sera almost fail to compete with the spike-ACE2 interaction. The significance of common VOC mutations K417N, E484K, or N501Y focused on linear epitopes was analyzed using a peptide array approach. The peptide arrays showed a strong difference between convalescent sera and vaccine-elicited sera. Specifically, the linear epitope at position N501 was affected by the mutation and elucidates the escape of viral variants to antibodies against this linear epitope. CONCLUSION: These data reveal differences in titer, neutralizing capacity, and affinity of the antibodies between BNT162b2- and CVnCoV-elicited sera, which could contribute to the apparent differences in vaccine efficacy.

Safety and efficacy of transcatheter mitral valve repair in patients with COPD; results from real-world cohort.

OBJECTIVE: To evaluate the safety and efficacy of transcatheter mitral valve repair (TMVR) in patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Heart failure and COPD share many clinical features and commonly coexist. Data about the safety and efficacy of TMVR in patients with COPD is not conclusive. METHODS: Three hundred and forty consecutive patients undergoing TMVR were retrospectively included. COPD diagnosis was based on pulmonary function tests (PFTs). Intra-hospital, 30-day- and 1-year outcomes were compared between both groups. RESULTS: Eighty-two patients had COPD (24%). There was no difference in intra-hospital mortality between patients with and without COPD (both 5%, p = 0.95). Among patients who had a successful procedure and survived to discharge there was a trend toward more rehospitalization due to decompensated heart failure at 30-day follow-up in patients with COPD (12.9% vs. 6.8%, p = 0.08) with no difference in mortality. At median follow-up of 1 year, New York heart association (NYHA) category was comparable among both groups and there was no significant difference in rehospitalization (COPD: 29.9% vs. non-COPD: 34%, p = 0.5). There was a trend toward increased 1-year mortality in COPD patients (31.2% vs. 20.6%, p = 0.06). However, a composite endpoint of rehospitalization or death at 1 year did not differ between both groups (48% vs. 42.5%, p = 0.4). Regression analysis showed no correlation between COPD severity and worse TMVR outcomes. CONCLUSIONS: COPD is highly prevalent among patients undergoing TMVR. However, TMVR seems to be safe and effective in COPD patients. COPD severity and PFT impairment alone should not be considered as a contraindication for TMVR.

A scoping review of mHealth monitoring of pediatric bronchial asthma before and during COVID-19 pandemic.

Mobile (m) Health technology is well-suited for Remote Patient Monitoring (RPM) in a patient's habitual environment. In recent years there have been fast-paced developments in mHealth-enabled pediatric RPM, especially during the COVID-19 pandemic, necessitating evidence synthesis. To this end, we conducted a scoping review of clinical trials that had utilized mHealth-enabled RPM of pediatric asthma. MEDLINE, Embase and Web of Science were searched from September 1, 2016 through August 31, 2021. Our scoping review identified 25 publications that utilized synchronous and asynchronous mHealth-enabled RPM in pediatric asthma, either involving mobile applications or via individual devices. The last three years has seen the development of evidence-based, multidisciplinary, and participatory mHealth interventions. The quality of the studies has been improving, such that 40% of included study reports were randomized controlled trials. In conclusion, there exists high-quality evidence on mHealth-enabled RPM in pediatric asthma, warranting future systematic reviews and/or meta-analyses of the benefits of such RPM.

[Non-invasive Home-Ventilation: Pathophysiology, Initiation and Follow-up]. / Nicht-invasive außerklinische Beatmung: Pathophysiologie, Einstellung und Kontrolle.

COPD is the most common reason for hypercapnia. However, it is - by far - not the only reason. In fact, numerous neuromuscular disorders (not only ALS) as well as restrictive thoracic disorders do also lead to clinically highly relevant hypercapnia. Early diagnosis of hypercapnic ventilatory failure usually takes place at nighttime. NIV devices work with a periodic interplay of alternating IPAP and EPAP which results in a ventilation of the lungs, thereby elimination CO2 to treat hypercapnic respiratory failure. Firstline settings for a NIV therapy to treat "stable hypercapnia" are as follows: Pressure Support Ventilation Modus, EPAP 5 cm H2O, IPAP 15 cm H2O, Back Up rate 15/Minute. The overall goal of NIV treatment is a successful reduction in CO2. This can be achieved by changing the following variables of the ventilator settings: increase in IPAP ± increase in back up respiratory rate ± use of assisted pressure controlled ventilation mode (APCV)-.

ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19.

OBJECTIVES: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19. PATIENTS AND METHODS: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19. RESULTS: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease. CONCLUSIONS: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.

Nasal versus oronasal masks for home non-invasive ventilation in patients with chronic hypercapnia: a systematic review and individual participant data meta-analysis.

BACKGROUND: The optimal interface for the delivery of home non-invasive ventilation (NIV) to treat chronic respiratory failure has not yet been determined. The aim of this individual participant data (IPD) meta-analysis was to compare the effect of nasal and oronasal masks on treatment efficacy and adherence in patients with COPD and obesity hypoventilation syndrome (OHS). METHODS: We searched Medline and Cochrane Central Register of Controlled Trials for prospective randomised controlled trials (RCTs) of at least 1 month's duration, published between January 1994 and April 2019, that assessed NIV efficacy in patients with OHS and COPD. The main outcomes were diurnal PaCO2, PaO2 and NIV adherence (PROSPERO CRD42019132398). FINDINGS: Of 1576 articles identified, 34 RCTs met the inclusion criteria and IPD were obtained for 18. Ten RCTs were excluded because only one type of mask was used, or mask data were missing. Data from 8 RCTs, including 290 IPD, underwent meta-analysis. Oronasal masks were used in 86% of cases. There were no differences between oronasal and nasal masks for PaCO2 (0.61 mm Hg (95% CI -2.15 to 3.38); p=0.68), PaO2 (-0.00 mm Hg (95% CI -4.59 to 4.58); p=1) or NIV adherence (0·29 hour/day (95% CI -0.74 to 1.32); p=0.58). There was no interaction between the underlying pathology and the effect of mask type on any outcome. INTERPRETATION: Oronasal masks are the most used interface for the delivery of home NIV in patients with OHS and COPD; however, there is no difference in the efficacy or tolerance of oronasal or nasal masks.

Role of extracorporeal membrane oxygenation in critically Ill COVID-19 patients and predictors of mortality.

The role of extracorporeal membrane oxygenation (ECMO) in the management of critically ill COVID-19 patients remains unclear. Our study aims to analyze the outcomes and risk factors from patients treated with ECMO. This retrospective, single-center study includes 17 COVID-19 patients treated with ECMO. Univariate and multivariate parametric survival regression identified predictors of survival. Nine patients (53%) were successfully weaned from ECMO and discharged. The incidence of in-hospital mortality was 47%. In a univariate analysis, only four out of 83 pre-ECMO variables were significantly different; IL-6, PCT, and NT-proBNP were significantly higher in non-survivors than in survivors. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was significantly higher in survivors. After a multivariate parametric survival regression, IL-6, NT-proBNP and RESP scores remained significant independent predictors, with hazard ratios (HR) of 1.069 [95%-CI: 0.986-1.160], P = .016 1.001 [95%-CI: 1.000-1.001], P = .012; and .843 [95%-CI: 0.564-1.260], P = .040, respectively. A prediction model comprising IL-6, NT-proBNP, and RESP score showed an area under the curve (AUC) of 0.87, with a sensitivity of 87.5% and 77.8% specificity compared to an AUC of 0.79 for the RESP score alone. The present study suggests that ECMO is a potentially lifesaving treatment for selected critically ill COVID-19 patients. Considering IL-6 and NT-pro-BNP, in addition to the RESP score, may enhance outcome predictions.

Sleep-Disordered Breathing and Nocturnal Hypoxemia in Precapillary Pulmonary Hypertension: Prevalence, Pathophysiological Determinants, and Clinical Consequences.

BACKGROUND AND OBJECTIVE: The clinical relevance and interrelation of sleep-disordered breathing and nocturnal hypoxemia in patients with precapillary pulmonary hypertension (PH) is not fully understood. METHODS: Seventy-one patients with PH (age 63 ± 15 years, 41% male) and 35 matched controls were enrolled. Patients with PH underwent clinical examination with assessment of sleep quality, daytime sleepiness, 6-minute walk distance (6MWD), overnight cardiorespiratory polygraphy, lung function, hypercapnic ventilatory response (HCVR; by rebreathing technique), amino-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and cardiac MRI (n = 34). RESULTS: Prevalence of obstructive sleep apnea (OSA) was 68% in patients with PH (34% mild, apnea-hypopnea index [AHI] ≥5 to <15/h; 34% moderate to severe, AHI ≥15/h) versus 5% in controls (p < 0.01). Only 1 patient with PH showed predominant central sleep apnea (CSA). Nocturnal hypoxemia (mean oxygen saturation [SpO2] <90%) was present in 48% of patients with PH, independent of the presence of OSA. There were no significant differences in mean nocturnal SpO2, self-reported sleep quality, 6MWD, HCVR, and lung and cardiac function between patients with moderate to severe OSA and those with mild or no OSA (all p > 0.05). Right ventricular (RV) end-diastolic (r = -0.39; p = 0.03) and end-systolic (r = -0.36; p = 0.04) volumes were inversely correlated with mean nocturnal SpO2 but not with measures of OSA severity or daytime clinical variables. CONCLUSION: OSA, but not CSA, is highly prevalent in patients with PH, and OSA severity is not associated with nighttime SpO2, clinical and functional status. Nocturnal hypoxemia is a frequent finding and (in contrast to OSA) relates to structural RV remodeling in PH.