Post-acute sequelae of SARS-CoV-2 infection: relationship of central nervous system manifestations with physical disability and systemic inflammation.

BACKGROUND: Despite the multitude of clinical manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC), studies applying statistical methods to directly investigate patterns of symptom co-occurrence and their biological correlates are scarce. METHODS: We assessed 30 symptoms pertaining to different organ systems in 749 adults (age = 55 ± 14 years; 47% female) during in-person visits conducted at 6-11 months after hospitalization due to coronavirus disease 2019 (COVID-19), including six psychiatric and cognitive manifestations. Symptom co-occurrence was initially investigated using exploratory factor analysis (EFA), and latent variable modeling was then conducted using Item Response Theory (IRT). We investigated associations of latent variable severity with objective indices of persistent physical disability, pulmonary and kidney dysfunction, and C-reactive protein and D-dimer blood levels, measured at the same follow-up assessment. RESULTS: The EFA extracted one factor, explaining 64.8% of variance; loadings were positive for all symptoms, and above 0.35 for 16 of them. The latent trait generated using IRT placed fatigue, psychiatric, and cognitive manifestations as the most discriminative symptoms (coefficients > 1.5, p < 0.001). Latent trait severity was associated with decreased body weight and poorer physical performance (coefficients > 0.240; p ⩽ 0.003), and elevated blood levels of C-reactive protein (coefficient = 0.378; 95% CI 0.215-0.541; p < 0.001) and D-dimer (coefficient = 0.412; 95% CI 0.123-0.702; p = 0.005). Results were similar after excluding subjects with pro-inflammatory comorbidities. CONCLUSIONS: Different symptoms that persist for several months after moderate or severe COVID-19 may unite within one latent trait of PASC. This trait is dominated by fatigue and psychiatric symptoms, and is associated with objective signs of physical disability and persistent systemic inflammation.

Ventilatory Variables and Mechanical Power in Patients with Acute Respiratory Distress Syndrome.

Rationale: Mortality in acute respiratory distress syndrome (ARDS) has decreased after the adoption of lung-protective strategies. Lower Vt, lower driving pressure (ΔP), lower respiratory rates (RR), and higher end-expiratory pressure have all been suggested as key components of lung protection strategies. A unifying theoretical explanation has been proposed that attributes lung injury to the energy transfer rate (mechanical power) from the ventilator to the patient, calculated from a combination of several ventilator variables.Objectives: To assess the impact of mechanical power on mortality in patients with ARDS as compared with that of primary ventilator variables such as the ΔP, Vt, and RR.Methods: We obtained data on ventilatory variables and mechanical power from a pooled database of patients with ARDS who had participated in six randomized clinical trials of protective mechanical ventilation and one large observational cohort of patients with ARDS. The primary outcome was mortality at 28 days or 60 days.Measurements and Main Results: We included 4,549 patients (38% women; mean age, 55 ± 23 yr). The average mechanical power was 0.32 ± 0.14 J · min-1 · kg-1 of predicted body weight, the ΔP was 15.0 ± 5.8 cm H2O, and the RR was 25.7 ± 7.4 breaths/min. The driving pressure, RR, and mechanical power were significant predictors of mortality in adjusted analyses. The impact of the ΔP on mortality was four times as large as that of the RR.Conclusions: Mechanical power was associated with mortality during controlled mechanical ventilation in ARDS, but a simpler model using only the ΔP and RR was equivalent.

A comparison of endotracheal tube compensation techniques for the measurement of respiratory mechanical impedance at low frequencies.

Measurement of respiratory impedance ([Formula: see text]) in intubated patients requires accurate compensation for pressure losses across the endotracheal tube (ETT). In this study, we compared time-domain (TD), frequency-domain (FD) and combined time-/frequency-domain (FT) methods for ETT compensation. We measured total impedance ([Formula: see text]) of a test lung in series with three different ETT sizes, as well as in three intubated porcine subjects. Pressure measurement at the distal end of the ETT was used to determine the true [Formula: see text]. For TD compensation, pressure distal to the ETT was obtained based on its resistive and inertial properties, and the corresponding [Formula: see text] was estimated. For FD compensation, impedance of the isolated ETT was obtained from oscillatory flow and pressure waveforms, and then subtracted from [Formula: see text]. For TF compensation, the nonlinear resistive properties of the ETT were subtracted from the proximal pressure measurement, from which the linear resistive and inertial ETT properties were removed in the frequency-domain to obtain [Formula: see text]. The relative root mean square error between the actual and estimated [Formula: see text] ([Formula: see text]) showed that TD compensation yielded the least accurate estimates of [Formula: see text] for the in vitro experiments, with small deviations observed at higher frequencies. The FD and TF compensations yielded estimates of [Formula: see text] with similar accuracies. For the porcine subjects, no significant differences were observed in [Formula: see text] across compensation methods. FD and TF compensation of the ETT may allow for accurate oscillometric estimates of [Formula: see text] in intubated subjects, while avoiding the difficulties associated with direct tracheal pressure measurement.

Heterogeneous effects of alveolar recruitment in acute respiratory distress syndrome: a machine learning reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.

BACKGROUND: Despite a robust physiological rationale, recruitment manoeuvres with PEEP titration were associated with harm in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). We sought to investigate the potential heterogeneity in treatment effects in patients enrolled in the ART, using a machine learning approach. METHODS: The primary outcome was hospital mortality. Patients were clustered using baseline clinical and physiological data using the k-means for mixed large data method. The heterogeneity in treatment effect between clusters was investigated using Bayesian methods. We further investigated whether baseline driving pressure could modulate the association between treatment arm, cluster, and mortality. RESULTS: Data from all 1010 patients enrolled in the ART were analysed. Partitioning suggested that three clusters were present in the ART population. The largest cluster (Cluster 1) was characterised by patients with pneumonia and requiring vasopressor support. Recruitment manoeuvres with PEEP titration were associated with higher mortality in Cluster 1 (probability of harm of >98%), but this association was absent in Clusters 2 and 3 (probability of harm of 45% and 68%, respectively). Higher baseline driving pressure was associated with a progressive reduction in the association between alveolar recruitment with PEEP titration and mortality. CONCLUSIONS: Recruitment manoeuvre with PEEP titration may be harmful in acute respiratory distress syndrome (ARDS) patients with pneumonia or requiring vasopressor support. Driving pressure appears to modulate the association between the ART study intervention, aetiology of ARDS, and mortality. This machine learning approach may help tailor future RCTs. CLINICAL TRIAL REGISTRATION: NCT01374022.

Driving pressure and survival in the acute respiratory distress syndrome.

BACKGROUND: Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) can improve survival in patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (ΔP=VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing. METHODS: Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined ΔP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease. RESULTS: Among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval [CI], 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, P=0.004 and P=0.001, respectively). CONCLUSIONS: We found that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundação de Amparo e Pesquisa do Estado de São Paulo and others.).

Neurally Adjusted Ventilatory Assist (NAVA) or Pressure Support Ventilation (PSV) during spontaneous breathing trials in critically ill patients: a crossover trial.

BACKGROUND: Neurally Adjusted Ventilatory Assist (NAVA) is a proportional ventilatory mode that uses the electrical activity of the diaphragm (EAdi) to offer ventilatory assistance in proportion to patient effort. NAVA has been increasingly used for critically ill patients, but it has not been evaluated during spontaneous breathing trials (SBT). We designed a pilot trial to assess the feasibility of using NAVA during SBTs, and to compare the breathing pattern and patient-ventilator asynchrony of NAVA with Pressure Support (PSV) during SBTs. METHODS: We conducted a crossover trial in the ICU of a university hospital in Brazil and included mechanically ventilated patients considered ready to undergo an SBT on the day of the study. Patients underwent two SBTs in randomized order: 30 min in PSV of 5 cmH2O or NAVA titrated to generate equivalent peak airway pressure (Paw), with a positive end-expiratory pressure of 5 cmH2O. The ICU team, blinded to ventilatory mode, evaluated whether patients passed each SBT. We captured flow, Paw and electrical activity of the diaphragm (EAdi) from the ventilator and used it to calculate respiratory rate (RR), tidal volume (VT), and EAdi. Detection of asynchrony events used waveform analysis and we calculated the asynchrony index as the number of asynchrony events divided by the number of neural cycles. RESULTS: We included 20 patients in the study. All patients passed the SBT in PSV, and three failed the SBT in NAVA. Five patients were reintubated and the extubation failure rate was 25% (95% CI 9-49%). Respiratory parameters were similar in the two modes: VT = 6.1 (5.5-6.5) mL/Kg in NAVA vs. 5.5 (4.8-6.1) mL/Kg in PSV (p = 0.076) and RR = 27 (17-30) rpm in NAVA vs. 26 (20-30) rpm in PSV, p = 0.55. NAVA reduced AI, with a median of 11.5% (4.2-19.7) compared to 24.3% (6.3-34.3) in PSV (p = 0.033). CONCLUSIONS: NAVA reduces patient-ventilator asynchrony index and generates a respiratory pattern similar to PSV during SBTs. Patients considered ready for mechanical ventilation liberation may be submitted to an SBT in NAVA using the same objective criteria used for SBTs in PSV. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01337271 ), registered April 12, 2011.

The impact of being homeless on the unsuccessful outcome of treatment of pulmonary TB in São Paulo State, Brazil.

BACKGROUND: Tuberculosis (TB) is a major public health problem requiring complex treatment, the success of which depends on biological, social, and institutional factors. São Paulo State (SPS), in Brazil, has a high TB burden. Because of high socioeconomic heterogeneity and chaotic urbanisation, homelessness might play an important role in the TB burden in SPS. Our aim was to determine the association between homelessness and outcome of treatment of pulmonary TB (PTB) in SPS. METHODS: A historical cohort from the routine SPS TB database for 2009-2013 was analysed. The study population was newly diagnosed adult patients with PTB. Homelessness was ascertained at notification or when treatment started. Our outcome was unsuccessful outcome of treatment. We used logistic regression to adjust for potential confounders and multiple imputation for missing data. RESULTS: We analysed 61,817 patients; 1726 (2.8 %, 95%CI 2.7-2.9 %) were homeless. Homeless patients were concentrated in bigger cities, were more frequently middle-aged males, had black/brown skin colour, and had received less education (P < 0.001, for all). Alcohol and drug use was three times more frequent in homeless patients (43.2 % vs 14.4 %, 30.2 % vs. 9.4 %, P < 0.001, respectively). HIV testing was less common among the homeless, of whom 17.3 % were HIV positive compared with 8.5 % among the not homeless population (P < 0.001). Microbiologic confirmation was more frequent among the homeless (91.6 % vs. 84.8 %, P < 0.001). Unsuccessful outcome of treatment was 57.3 % among the homeless and 17.5 % among the not homeless (OR = 6.32, 95%CI 5.73-6.97, P < 0.001), mainly due to loss to follow-up (39 %) and death (10.5 %). After full-adjustment for potential confounders, homelessness remained strongly associated with lower treatment success (aOR = 4.96, 95 % CI 4.27-5.76, P < 0.001). HIV status interacted with homelessness: among HIV-infected patients, the aOR was 2.45 (95%CI 1.90-3.16, Pinteraction < 0.001). The population attributable fraction for the joint effect of homelessness, alcohol and drug use was almost 20 %. CONCLUSIONS: Confirming our hypothesis, homelessness led to a marked reduction in the successful treatment of newly diagnosed pulmonary tuberculosis. Homelessness and associated conditions were important contributors to lack of treatment success in pulmonary tuberculosis in São Paulo. A multifaceted intervention must be implemented to target this vulnerable population.

Pulmonary rehabilitation in lymphangioleiomyomatosis: a controlled clinical trial.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease frequently associated with reduced exercise capacity. The aim of this study was to assess safety and efficacy of pulmonary rehabilitation in LAM.This controlled clinical trial included 40 patients with LAM and a low physical activity level. The pulmonary rehabilitation programme comprised 24 aerobic and muscle strength training sessions and education. The primary outcome was exercise capacity (endurance time during a constant work rate exercise test). Secondary outcomes included health-related quality of life (St George's Respiratory Questionnaire (SGRQ)), 6-min walking distance (6MWD), dyspnoea, peak oxygen consumption (V'O2 ), daily physical activity (pedometer), symptoms of anxiety and depression, lung function and peripheral muscle strength (one-repetition maximum).The baseline characteristics were well balanced between the groups. The pulmonary rehabilitation group exhibited improvements in the following outcomes versus controls: endurance time (median (interquartile range) 169 (2-303) s versus -33 (-129-39) s; p=0.001), SGRQ (median (interquartile range) -8 (-16-2) versus 2 (-4-5); p=0.002) and 6MWD (median (interquartile range) 59 (13-81) m versus 20 (-12-30) m; p=0.002). Dyspnoea, peak V'O2 , daily physical activity and muscle strength also improved significantly. No serious adverse events were observed.Pulmonary rehabilitation is a safe intervention and improves exercise capacity, dyspnoea, daily physical activity, quality of life and muscle strength in LAM.

Pulmonary involvement in long-term mixed connective tissue disease: functional trends and image findings after 10 years.

OBJECTIVES: Interstitial lung disease (ILD) is highly prevalent in patients with mixed connective tissue disease (MCTD). However, little is known about the long-term progression of ILD in MCTD. The aims of this study were to describe pulmonary function test (PFT) and high-resolution computed tomography (HRCT) results in long-term MCTD patients, to measure changes in PFT and HRCT results over a 10-year period, and to ascertain correlations in functional and imaging data. METHODS: In this retrospective cohort study, comparison between baseline and follow-up PFT and HRCT data was performed for 39 unselected consecutive MCTD patients. RESULTS: At baseline, 51% of the patients had abnormal PFTs. Forced vital capacity (FVC) was slightly reduced at baseline (77% of predicted), but remained stable after 10 years. A relative decrease of 15% in the diffusion capacity for carbon monoxide (DLCO) was detected (from 84% to 71% of predicted, p<0.001). The median lower lobes ILD-HRCT score progressed from 7.5% at baseline to 11.2% at follow-up (p=0.02), and findings of traction bronchiolectasis and honeycombing increased (p<0.05). A moderate negative correlation was observed between functional parameters and quantification of image findings. CONCLUSIONS: Functional and radiologic alterations suggestive of ILD in long-term MCTD patients are prevalent, mild, and progressed slightly over time. The most sensitive parameters for detecting subtle progression of ILD in MCTD patients are trends in DLCO, quantification of lower-lobes disease by HRCT (lower-lobes %ILD-HRCT score), and qualitative analysis of HRCT imaging.

Impact of extended lung protection during mechanical ventilation on lung recovery in patients with COVID-19 ARDS: a phase II randomized controlled trial.

BACKGROUND: Protective ventilation seems crucial during early Acute Respiratory Distress Syndrome (ARDS), but the optimal duration of lung protection remains undefined. High driving pressures (ΔP) and excessive patient ventilatory drive may hinder lung recovery, resulting in self-inflicted lung injury. The hidden nature of the ΔP generated by patient effort complicates the situation further. Our study aimed to assess the feasibility of an extended lung protection strategy that includes a stepwise protocol to control the patient ventilatory drive, assessing its impact on lung recovery. METHODS: We conducted a single-center randomized study on patients with moderate/severe COVID-19-ARDS with low respiratory system compliance (CRS < 0.6 (mL/Kg)/cmH2O). The intervention group received a ventilation strategy guided by Electrical Impedance Tomography aimed at minimizing ΔP and patient ventilatory drive. The control group received the ARDSNet low-PEEP strategy. The primary outcome was the modified lung injury score (mLIS), a composite measure that integrated daily measurements of CRS, along with oxygen requirements, oxygenation, and X-rays up to day 28. The mLIS score was also hierarchically adjusted for survival and extubation rates. RESULTS: The study ended prematurely after three consecutive months without patient enrollment, attributed to the pandemic subsiding. The intention-to-treat analysis included 76 patients, with 37 randomized to the intervention group. The average mLIS score up to 28 days was not different between groups (P = 0.95, primary outcome). However, the intervention group showed a faster improvement in the mLIS (1.4 vs. 7.2 days to reach 63% of maximum improvement; P < 0.001), driven by oxygenation and sustained improvement of X-ray (P = 0.001). The intervention group demonstrated a sustained increase in CRS up to day 28 (P = 0.009) and also experienced a shorter time from randomization to room-air breathing (P = 0.02). Survival at 28 days and time until liberation from the ventilator were not different between groups. CONCLUSIONS: The implementation of an individualized PEEP strategy alongside extended lung protection appears viable. Promising secondary outcomes suggested a faster lung recovery, endorsing further examination of this strategy in a larger trial. Clinical trial registration This trial was registered with ClinicalTrials.gov (number NCT04497454) on August 04, 2020.

Post-COVID-19 condition: systemic inflammation and low functional exercise capacity.

Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported. Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment. Results: SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1ß serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.

Environmental triggers of autoimmunity in anti-synthetase syndrome: the lungs under the spot light.

The prevalence of interstitial lung involvement in anti-synthetase syndrome (anti-SS) may be as high as 70% and is a major contributor to morbidity and mortality. Histidyl-tRNA synthetase (Jo-1) is the most common autoantigenic target among the aminoacyl-tRNA synthetases. We report two well documented anti-SS cases where it was observed significant exposure to a known inhaled offending antigen, development of a lymphocytic interstitial lung disease (ILD) and negative auto-antibodies, interpreted at first as hypersensitivity pneumonitis. Only after 14 and 30 months, respectively, the development of systemic symptoms compatible with anti-SS and anti-Jo-1 was observed. A growing body of evidence suggests that the lungs are the environment in which Jo-1 autoimmunity may be initiated and propagated. The description of the clinical and laboratorial evolution of these patients together with accumulated evidence of biological plausibility support the hypothesis that anti-SS can follow an episode of lung inflammation secondary to inhaled antigen exposure.

Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis (LAM) is characterized by exercise performance impairment. Although airflow limitation is common, no previous studies have evaluated the prevalence and impact of dynamic hyperinflation (DH) in LAM. OBJECTIVES: To investigate the dynamic responses during maximal exercise and the prevalence, predictors, and repercussions of DH in LAM. METHODS: Forty-two patients with LAM performed symptom-limited incremental cycle exercise and pulmonary functions tests (PFTs) and were compared with 10 age-matched healthy women. Dyspnea intensity, inspiratory capacity, oxygen saturation, and cardiac, metabolic, and respiratory variables were assessed during exercise. Patients with LAM also performed a 6-minute walk test (6MWT). MEASUREMENTS AND MAIN RESULTS: Patients with LAM had higher baseline dyspnea, poorer quality of life, obstructive pattern, air trapping, and reduced diffusing capacity of carbon monoxide in PFTs. Although they had the same level of regular physical activity, their maximal exercise performance was reduced and was associated with ventilatory limitation, greater desaturation, and dyspnea. The prevalence of DH was high in LAM (55%), even in patients with mild spirometric abnormalities, and was correlated with airflow obstruction, air trapping, and diffusing capacity of carbon monoxide. Compared with the non-DH subgroup, the patients who developed DH had a ventilatory limitation contributing to exercise cessation on cycling and higher desaturation and dyspnea intensity during the 6MWT. CONCLUSIONS: Ventilatory limitation and gas exchange impairment are important causes of exercise limitation in LAM. DH is frequent in LAM, even in patients with mild spirometric abnormalities. DH was associated with the severity of disease, higher dyspnea, and lower oxygen saturation. In the 6MWT, desaturation and dyspnea were greater in patients with DH.

Respiratory arousal threshold among patients with isolated sleep apnea and with comorbid insomnia (COMISA).

Insomnia and obstructive sleep apnea (OSA) are common sleep disorders and frequently coexist (COMISA). Arousals from sleep may be a common link explaining the frequent comorbidity of both disorders. Respiratory arousal threshold (AT) is a physiologic measurement of the level of respiratory effort to trigger an arousal from sleep. The impact of COMISA on AT is not known. We hypothesized that a low AT is more common among COMISA than among patients with OSA without insomnia. Participants referred for OSA diagnosis underwent a type 3 sleep study and answered the insomnia severity index (ISI) questionnaire and the Epworth sleepiness scale. Participants with an ISI score ≥ 15 were defined as having insomnia. Sleep apnea was defined as an apnea hypopnea index (AHI) ≥ 15 events/h. Low AT was determined using a previously validated score based on 3 polysomnography variables (AHI, nadir SpO2 and the frequency of hypopneas). OSA-only (n = 51) and COMISA (n = 52) participants had similar age (61[52-68] vs 60[53-65] years), body-mass index (31.3[27.7-36.2] vs 32.2[29.5-38.3] kg/m2) and OSA severity (40.2[27.5-60] vs 37.55[27.9-65.2] events/h): all p = NS. OSA-only group had significantly more males than the COMISA group (58% vs 33%, p = 0.013. The proportion of participants with a low AT among OSA-only and COMISA groups was similar (29 vs 33%, p = NS). The similar proportion of low AT among COMISA and patients with OSA suggests that the respiratory arousal threshold may not be related to the increased arousability of insomnia.

Post-acute sequelae of SARS-CoV-2 associates with physical inactivity in a cohort of COVID-19 survivors.

The aim of this study was to determine whether Post-acute Sequelae of SARS-CoV-2 Infection (PASC) are associated with physical inactivity in COVID-19 survivors. This is a cohort study of COVID-19 survivors discharged from a tertiary hospital in Sao Paulo, Brazil. Patients admitted as inpatients due to laboratory-confirmed COVID-19 between March and August 2020 were consecutively invited for a follow-up in-person visit 6 to 11 months after hospitalization. Ten symptoms of PASC were assessed using standardized scales. Physical activity was assessed by questionnaire and participants were classified according to WHO Guidelines. 614 patients were analyzed (age: 56 ± 13 years; 53% male). Frequency of physical inactivity in patients exhibiting none, at least 1, 1-4, and 5 or more symptoms of PASC was 51%, 62%, 58%, and 71%, respectively. Adjusted models showed that patients with one or more persistent PASC symptoms have greater odds of being physically inactive than those without any persistent symptoms (OR: 1.57 [95% CI 1.04-2.39], P = 0.032). Dyspnea (OR: 2.22 [1.50-3.33], P < 0.001), fatigue (OR: 2.01 [1.40-2.90], P < 0.001), insomnia (OR: 1.69 [1.16-2.49], P = 0.007), post-traumatic stress (OR: 1.53 [1.05-2.23], P = 0.028), and severe muscle/joint pain (OR: 1.53 [95% CI 1.08-2.17], P = 0.011) were associated with greater odds of being physically inactive. This study suggests that PASC is associated with physical inactivity, which itself may be considered as a persistent symptom among COVID-19 survivors. This may help in the early identification of patients who could benefit from additional interventions tailored to combat inactivity (even after treatment of PASC), with potential beneficial impacts on overall morbidity/mortality and health systems worldwide.

High flow nasal catheter therapy versus non-invasive positive pressure ventilation in acute respiratory failure (RENOVATE trial): protocol and statistical analysis plan.

Background: The best way to offer non-invasive respiratory support across several aetiologies of acute respiratory failure (ARF) is presently unclear. Both high flow nasal catheter (HFNC) therapy and non-invasive positive pressure ventilation (NIPPV) may improve outcomes in critically ill patients by avoiding the need for invasive mechanical ventilation (IMV). Objective: Describe the details of the protocol and statistical analysis plan designed to test whether HFNC therapy is non-inferior or even superior to NIPPV in patients with ARF due to different aetiologies. Methods: RENOVATE is a multicentre adaptive randomised controlled trial that is recruiting patients from adult emergency departments, wards and intensive care units (ICUs). It takes advantage of an adaptive Bayesian framework to assess the effectiveness of HFNC therapy versus NIPPV in four subgroups of ARF (hypoxaemic non-immunocompromised, hypoxaemic immunocompromised, chronic obstructive pulmonary disease exacerbations, and acute cardiogenic pulmonary oedema). The study will report the posterior probabilities of non-inferiority, superiority or futility for the comparison between HFNC therapy and NIPPV. The study assumes neutral priors and the final sample size is not fixed. The final sample size will be determined by a priori determined stopping rules for non-inferiority, superiority and futility for each subgroup or by reaching the maximum of 2000 patients. Outcomes: The primary endpoint is endotracheal intubation or death within 7 days. Secondary outcomes are 28-day and 90-day mortality, and ICU-free and IMV-free days in the first 28 days. Results and conclusions: RENOVATE is designed to provide evidence on whether HFNC therapy improves, compared with NIPPV, important patient-centred outcomes in different aetiologies of ARF. Here, we describe the rationale, design and status of the trial. Trial registration:ClinicalTrials.gov NCT03643939.

Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue.

INTRODUCTION: Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients. METHODS: We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student's t-test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test. RESULTS: Thirty-one ARDS patients (A: PaO2/FiO2 ≤200, 45 ± 14 years, 16 males) and 11 controls (C: 52 ± 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 ± 27.2%, C:76.7 ± 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 ± 35.2%, C:21.8 ± 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 ± 54.3 µm, C:86.4 ± 33.3 µm, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P ≤0.03). The extension of normal epithelium showed a positive correlation with PaO2/FiO2 (r2 = 0.34; P = 0.02) and a negative correlation with plateau pressure (r2 = 0.27; P = 0.04). The extension of denuded epithelium showed a negative correlation with PaO2/FiO2 (r2 = 0.27; P = 0.04). CONCLUSIONS: Structural changes in small airways of patients with ARDS were characterized by epithelial denudation, inflammation and airway wall thickening with ECM remodeling. These changes are likely to contribute to functional airway changes in patients with ARDS.

Unilateral diaphragmatic paralysis: inspiratory muscles, breathlessness and exercise capacity.

BACKGROUND: Patients with unilateral diaphragmatic paralysis (UDP) may present with dyspnoea without specific cause and limited ability to exercise. We aimed to investigate the diaphragm contraction mechanisms and nondiaphragmatic inspiratory muscle activation during exercise in patients with UDP, compared with healthy individuals. METHODS: Pulmonary function, as well as volitional and nonvolitional inspiratory muscle strength were evaluated in 35 patients and in 20 healthy subjects. Respiratory pressures and electromyography of scalene and sternocleidomastoid muscles were continuously recorded during incremental maximal cardiopulmonary exercise testing until symptom limitation. Dyspnoea was assessed at rest, every 2 min during exercise and at the end of exercise with a modified Borg scale. MAIN RESULTS: Inspiratory muscle strength measurements were significantly lower for patients in comparison to controls (all p<0.05). Patients achieved lower peak of exercise (lower oxygen consumption) compared to controls, with both gastric (-9.8±4.6 cmH2O versus 8.9±6.0 cmH2O) and transdiaphragmatic (6.5±5.5 cmH2O versus 26.9±10.9 cmH2O) pressures significantly lower, along with larger activation of both scalene (40±22% EMGmax versus 18±14% EMGmax) and sternocleidomastoid (34±22% EMGmax versus 14±8% EMGmax). In addition, the paralysis group presented significant differences in breathing pattern during exercise (lower tidal volume and higher respiratory rate) with more dyspnoea symptoms compared to the control group. CONCLUSION: The paralysis group presented with exercise limitation accompanied by impairment in transdiaphragmatic pressure generation and larger accessory inspiratory muscles activation compared to controls, thereby contributing to a neuromechanical dissociation and increased dyspnoea perception.