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Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027

Treatment modalities and reported adverse events by quartile of period of inclusion.

Example of the first severe ICI-myocarditis case treated with abatacept guided by real-time immune-monitoring assessment of CD86RO (CD86 receptor occupancy) on circulating monocytes.

Methods concerning Immune-checkpoint proteins profiling on peripheral blood mononuclear cells and Circulating immune checkpoint agents drug monitoring

Immune-checkpoint-inhibitor (ICI)–associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation.Significance:Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis.See related commentary by Dougan, p. 1040.This article is highlighted in the In This Issue feature, p. 1027

BACKGROUND: SARS-CoV-2 aerosolization during noninvasive positive-pressure ventilation may endanger health care professionals. Various circuit setups have been described to reduce virus aerosolization. However, these setups may alter ventilator performance. RESEARCH QUESTION: What are the consequences of the various suggested circuit setups on ventilator efficacy during CPAP and noninvasive ventilation (NIV)? STUDY DESIGN AND METHODS: Eight circuit setups were evaluated on a bench test model that consisted of a three-dimensional printed head and an artificial lung. Setups included a dual-limb circuit with an oronasal mask, a dual-limb circuit with a helmet interface, a single-limb circuit with a passive exhalation valve, three single-limb circuits with custom-made additional leaks, and two single-limb circuits with active exhalation valves. All setups were evaluated during NIV and CPAP. The following variables were recorded: the inspiratory flow preceding triggering of the ventilator, the inspiratory effort required to trigger the ventilator, the triggering delay, the maximal inspiratory pressure delivered by the ventilator, the tidal volume generated to the artificial lung, the total work of breathing, and the pressure-time product needed to trigger the ventilator. RESULTS: With NIV, the type of circuit setup had a significant impact on inspiratory flow preceding triggering of the ventilator (P < .0001), the inspiratory effort required to trigger the ventilator (P < .0001), the triggering delay (P < .0001), the maximal inspiratory pressure (P < .0001), the tidal volume (P = .0008), the work of breathing (P < .0001), and the pressure-time product needed to trigger the ventilator (P < .0001). Similar differences and consequences were seen with CPAP as well as with the addition of bacterial filters. Best performance was achieved with a dual-limb circuit with an oronasal mask. Worst performance was achieved with a dual-limb circuit with a helmet interface. INTERPRETATION: Ventilator performance is significantly impacted by the circuit setup. A dual-limb circuit with oronasal mask should be used preferentially.

Highlights • Pre workshop international survey on MPV • Best practice guidline on the provision of MPV in NMD's by reviewing and recommend the most appropriate monitoring, mode, settings and equipment required for MPV. • Best practice algorithm on MPV for daytime ventilatory support (see Figure 1 ).Figure 1Figure 1 shows the best practice algorithm for the initiation of mouthpiece ventilation (MPV) in the long-term setting. For each stage of the algorithm there is a description to assist in the provision of this service.Figure 1 • Future studies in MPV.

To describe health-related quality of life (HRQoL) and dyspnea of COVID-19, 2 and 12 months after an intensive care unit (ICU) stay.Patients discharged from the ICU between April and June 2020 and subsequently transferred to an inpatient rehabilitation facility were assessed 2 months and 12 months after ICU admission. HRQoL was assessed by the EuroQoL EQ-5D-3L (visual analog scale and time trade-off normalized to the French population algorithm) and dyspnea was assessed by the modified Medical Research Council (mMRC) dyspnea scale.We enrolled 94 patients. Median EQ-5D-3L time trade-off was 0.80 (interquartile range, 0.36-0.91) at 2 months and 0.91 (0.52-1.00) at 12 months (P = 0.12). EQ-5D-3L visual analog scale was 70 (60-85) at 2 months and 70 (60-85) at 12 months (P = 0.07). The mMRC dyspnea scale was 3 (2-4) at ICU discharge, 1 (0-2), P 0.001 at 2 months and 1 (1-2) at 12 months. At 12 months, 68 (76%) patients reported at least one symptom that was not present prior to ICU admission and 27 (61%) of the 44 patients who were previously working had returned to work. On multiple linear regression, factors associated with EQ-5D-3L were body mass index on ICU admission, tracheostomy, male gender and active smoking.Twelve months after ICU admission for COVID-19 and subsequent rehabilitation, a substantial proportion of patients reported alterations of HRQoL, dyspnea and symptoms that were not present prior to admission and a substantial proportion of these patients had not returned to work. Factors associated with a risk of poorer 12-month quality of life, may help to identify at-risk patients.

La ventilation par embout buccal dans les maladies neuromusculaires.Le document qui suit est la traduction intégrale du compte rendu établi à l’occasion du 252

Ineffective efforts (IEs) are among the most common types of patient-ventilator asynchrony. The objective of this study is to validate IE detection during expiration using pressure and flow signals, with respiratory effort detection by esophageal pressure (Pes) measurement as the reference, in patients with neuromuscular diseases (NMDs). We included 10 patients diagnosed with chronic respiratory failure related to NMD. Twenty-eight 5-minute recordings of daytime ventilation were studied for IE detection. Standard formulas were used to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of IE detection using pressure and flow signals compared to Pes measurement. Mean sensitivity and specificity of flow and pressure signal-based IE detection versus Pes measurement were 97.5% ± 5.3% and 91.4% ± 13.7%, respectively. NPV was 98.1% ± 8.2% and PPV was 67.6% ± 33.8%. Spearman's rank correlation coefficient indicated a moderately significant correlation between frequencies of IEs and controlled cycles ( ρ = 0.50 and p = 0.01). Among respiratory cycles, 311 (11.2%) were false-positive IEs overall. Separating false-positive IEs according to their mechanisms, we observed premature cycling in 1.2% of cycles, delayed ventilator triggering in 0.1%, cardiac contraction in 9.2%, and upper airway instability during expiration in 0.3%. Using flow and pressure signals to detect IEs is a simple and rapid method that produces adequate data to support clinical decisions.

Introduction: Hypoxaemia, tachypnea and tachycardia are frequent in obese patients and may lead to suspect an undiagnosed pulmonary embolism (PE). Hypoxaemia in obese subjects is mostly due to the intrapulmonary shunt resulting from the atelectasis of the lung bases common with obesity. Reversal of this intrapulmonary shunt with Continuous positive airway pressure (CPAP) and improving hypoxaemia, could help to rule out PE in obese patients. Objective: Investigate with a new algorithm the role of CPAP to exclude PE suspected in hypoxaemic obese patients. Methods: This study was undertaken at the department of nutrition at the Pitie salpetriere hospital in Paris, France. Obese patients with a BMI > 30 kg/m 2 underwent spirometry and Arterial Blood Gases (ABG) analysis. If the ABG showed an increase in the alveolar arterial oxygen gradient {P(A-a)O 2 }, CPAP was applied at 10 cmH 2 O for 30 minutes and the outcome was assessed by another ABG sample. If the P(A-a)O 2 was not normalized, D-dimers and CT Pulmonary Angiography (CTPA) were evaluated to exclude or confirm the suspected PE. Results: Three hundred and fifty obese patients were studied and 33% of the patients were found to have an increased P(A-a) O 2 with mean PaO 2 and P(A-a)O 2 values of 72.2±6.3 and 27.8±5.4 mmHg respectively. CPAP normalized the P(A-a)O 2 in 64 patients (∼60%) with no evidence of PE during the 2 years follow up period. In the remaining patients, D-dimers and CTPA confirmed PE in only 3 cases. Conclusion: CPAP is a simple, non invasive measure to reverse the intrapulmonary shunt observed with obesity and may play a role to exclude PE suspected in obese subjects.

Background. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non invasive ventilation (NIV) alleviates respiratory symptoms and prolongs life but delaying NIV in ALS is therefore desirable. We aimed to establish whether early diaphragm pacing could achieve this objective. Methods. Multicenter randomized controlled trial involving 12 French multidisciplinary ALS centers. Eligible patients had moderate ALS-related respiratory involvement (forced vital capacity 60-80 % predicted). All patients were operated laparoscopically and received an intradiaphragmatic phrenic nerve stimulator (NeuRxRA4®, Synapse Biomedical, USA). They were then randomly assigned to active or sham stimulation. The primary outcome was NIV free survival. Investigators and patients were blinded to treatment. NIV was decided by an external allocation panel (triple blind design). Results. we randomly assigned 74 participants to active (n=37) or sham (n=37) stimulation. The median NIV free survival since randomization was 6.0 months in the active stimulation group, vs. 8.8 months in the sham stimulation group (p = 0.02). Sixty-five percent of the patients in the active group experienced severe adverse events, vs. 59%. Median overall survival from randomization was 15.6 months (95%CI 9-27) in the active group, vs. more than 33 months (p = 0.007). Conclusions. Early diaphragm pacing in ALS patients with incipient respiratory involvement did not delay NIV and was associated with decreased survival.

Long-term non-invasive ventilation (NIV) has become a widespread modality of treatment in chronic obstructive pulmonary disease (COPD) patients with chronic respiratory failure. However, benefits in terms of patient-related outcomes are still under debate. Both NIV adherence and heterogeneous responses in different COPD phenotypes may contribute to the difficulty of demonstrating NIV benefits. Our aim was to assess the impact of NIV adherence on the rate of hospitalization for acute exacerbation and death.This is a prospective multi-centre cohort study of COPD patients treated by long-term NIV. Comorbidities, anthropometrics, respiratory parameters were collected at inclusion in the study. Follow-up data included vital status, NIV adherence and hospitalizations. The influence of NIV adherence on prognosis was tested using an adjusted Cox model. Sensitivity analyses for obese and non-obese COPD subtypes were also conducted.Two hundred thirteen patients (48% obese) were included with 45.5% died during 47.7 [interquartile range = 27.8; 73] months' follow-up. Survival was better in obese COPD than non-obese COPD. The use of NIV 9 h/day was associated with an increased risk of death or hospitalization for acute exacerbation [HR = 1.6; 95CI: 1.1-2.4]. In obese COPD, this risk described a U-shaped curve from1 to9 h/day NIV usage with an improvement in prognosis when NIV adherence was5 h/day [HR = 0.5; 95CI: 0.2-0.9].Adherence to NIV was associated with better prognosis only in obese COPD. NIV use9 h/day predicted poor outcomes.

Endobronchial valve (EBV) therapy may be associated with improvements in chronic obstructive pulmonary disease-related outcomes and may therefore be linked to improvements in the body mass index, airflow obstruction, dyspnoea, exercise capacity (BODE) index. Data from 416 patients with advanced emphysema and hyperinflation across Europe and USA, who were randomised to EBV (n=284) or conservative therapy (n=132) were analysed. Quantitative image analysis was used to compare the volume of the targeted lobe at baseline and at 6 months to determine target lobe volume reduction (TLVR). 44% of patients receiving EBV therapy (versus 24.7% of controls) had clinically significant improvements in the BODE index (p0.001). BODE index was significantly reduced by mean ± sd 1.4 ± 1.8, 0.2 ± 1.3 and 0.1 ± 1.3 points in patients with TLVR50%, 20%-50% and20%, respectively (intergroup differences p0.001), but increased by 0.3 ± 1.2 points in controls. Changes in BODE were predicted by baseline BODE and correlated significantly with lobar exclusion and lung volumes at 6 months. A greater proportion of patients in the treatment group than in the control group achieved a clinically meaningful improvement in BODE index; however, the likelihood of benefit was less than half in both groups. Patients in whom TLVR was obtained had greater improvements in clinical outcomes.

Open studies suggest that treatment of obesity hypoventilation syndrome (OHS) by noninvasive ventilation (NIV) restores sleep quality and daytime vigilance and reduces cardiovascular morbidity. However, to our knowledge no randomized controlled trial (RCT) comparing NIV to conservative measures is available in the field. The goal of this study was to assess in patients with OHS, during an RCT, effects of 1-month NIV compared with lifestyle counseling on blood gas measurements, sleep quality, vigilance, and cardiovascular, metabolic, and inflammatory parameters.Thirty-five patients in whom OHS was newly diagnosed were randomized either to the NIV group or the control group represented by lifestyle counseling. Assessments included blood gas levels, subjective daytime sleepiness, metabolic parameters, inflammatory (hsCRP, leptin, regulated upon activation normal T-cell express and secreted [RANTES], monocyte chemoattractant protein-1, IL-6, IL-8, tumor necrosis factor-α, resistin) and antiinflammatory (adiponectin, IL-1-RA) cytokines, sleep studies, endothelial function (reactive hyperemia measured by peripheral arterial tonometry [RH-PAT]), and arterial stiffness.Despite randomization, NIV group patients (n = 18) were older (58 ± 11 years vs 54 ± 6 years) with a higher baseline Paco(2) (47.9 ± 4.2 mm Hg vs 45.2 ± 3 mm Hg). In intention-to-treat analysis, compared with control group, NIV treatment significantly reduced daytime Paco(2) (difference between treatments: -3.5 mm Hg; 95% CI, -6.2 to -0.8) and apnea-hypopnea index (-40.3/h; 95% CI, -62.4 to -18.2). Sleep architecture was restored, although nonrespiratory microarousals increased (+9.4/h of sleep; 95% CI, 1.9-16.9), and daytime sleepiness was not completely normalized. Despite a dramatic improvement in sleep hypoxemia, glucidic and lipidic metabolism parameters as well as cytokine profiles did not vary significantly. Accordingly, neither RH-PAT (+0.02; 95% CI, -0.24 to 0.29) nor arterial stiffness (+0.22 m/s; 95% CI, -1.47 to 1.92) improved.One month of NIV treatment, although improving sleep and blood gas measurements dramatically, did not change inflammatory, metabolic, and cardiovascular markers.ClinicalTrials.gov; No.: NCT00603096; URL: www.clinicaltrials.gov.