Introduction: A hypercoagulable condition was described in patients with COVID-19 and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim: We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods: In a retrospective observational study, 2,574 unselected patients hospitalised in 30 clinical centres in Italy from February 19, 2020 to May 23, 2020 with laboratory-confirmed SARS-CoV-2 infection, were analysed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results: Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (HR=0.60; 95%CI: 0.49 to 0.74; E-value=2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusions: In-hospital heparin treatment was associated with lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomised clinical trials are eagerly awaited to provide clear-cut recommendations.

Background: Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested. Methods: We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters. Results: We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV. Conclusions: HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations. Trial registration: NCT04411459. 15D score 3 months -mean ± SD 0.857 ± 0.133 0.927 ± 0.061 0.800 ± 0.135 0.853 ± 0.114 0.637 ± 0.204 < 0.001 15D score 1 year -mean ± SD 0.880 ± 0.115 0.964 ± 0.033 0.820 ± 0.068 0.866 ± 0.088 0.572 ± 0.112 < 0.001 Mobility -mean ± SD 0.876 ± 0.207 0.963 ± 0.104 0.828 ± 0.191 0.901 ± 0.166 0.375 ± 0.298 < 0.001 Vision -mean ± SD 0.953 ± 0.119 0.992 ± 0.040 0.942 ± 0.108 0.949 ± 0.094 0.681 ± 0.280 < 0.001 Hearing -mean ± SD 0.968 ± 0.098 1.000 ± 0.000 1.000 ± 0.000 0.745 ± 0.135 0.857 ± 0.192 < 0.001 Breathing -mean ± SD 0.746 ± 0.238 0.879 ± 0.154 0.620 ± 0.227 0.753 ± 0.223 0.438 ± 0.238 < 0.001 Sleeping -mean ± SD 0.838 ± 0.238 0.940 ± 0.135 0.716 ± 0.274 0.929 ± 0.142 0.632 ± 0.312 < 0.001 Eating -mean ± SD 0.979 ± 0.102 1.000 ± 0.000 1 .000 ± 0.000 1.000 ± 0.000 0.587 ± 0.221 < 0.001 Speech -mean ± SD 0.980 ± 0.090 0.996 ± 0.032 0.996 ± 0.036 0.948 ± 0.117 0.777 ± 0.276 < 0.001 Excretion -mean ± SD 0.974 ± 0.110 1.000 ± 0.000 1.000 ± 0.000 0.872 ± 0.191 0.720 ± 0.292

Background A large proportion of patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure requiring admission to the intensive care unit (ICU) and about 80% of them need mechanical ventilation (MV). These patients show great complexity due to multiple organ involvement and a dynamic evolution over time; moreover, few information is available about the risk factors that may contribute to increase the time course of mechanical ventilation. The primary objective of this study is to investigate the risk factors associated with the inability to liberate COVID-19 patients from mechanical ventilation. Due to the complex evolution of the disease, we analyzed both pulmonary variables and occurrence of non-pulmonary complications during mechanical ventilation. The secondary objective of this study was the evaluation of risk factors for ICU mortality. Methods This multicenter prospective observational study enrolled 391 patients from fifteen COVID-19 dedicated Italian ICUs which underwent invasive mechanical ventilation for COVID-19 pneumonia. Clinical and laboratory data, ventilator parameters, occurrence of organ dysfunction, and outcome were recorded. The primary outcome measure was 28 days ventilator-free days and the liberation from MV at 28 days was studied by performing a competing risks regression model on data, according to the method of Fine and Gray; the event death was considered as a competing risk. Results Liberation from mechanical ventilation was achieved in 53.2% of the patients (208/391). Competing risks analysis, considering death as a competing event, demonstrated a decreased sub-hazard ratio for liberation from mechanical ventilation (MV) with increasing age and SOFA score at ICU admission, low values of PaO2/FiO2 ratio during the first 5 days of MV, respiratory system compliance (CRS) lower than 40 mL/cmH2O during the first 5 days of MV, need for renal replacement therapy (RRT), late-onset ventilator-associated pneumonia (VAP), and cardiovascular complications. ICU mortality during the observation period was 36.1% (141/391). Similar results were obtained by the multivariate logistic regression analysis using mortality as a dependent variable. Conclusions Age, SOFA score at ICU admission, CRS, PaO2/FiO2, renal and cardiovascular complications, and late-onset VAP were all independent risk factors for prolonged mechanical ventilation in patients with COVID-19. Trial registration NCT04411459

Background: The pathogenetic steps leading to Covid-19 interstitial pneumonia remain to be clarified. Most postmortem studies to date reveal diffuse alveolar damage as the most relevant histologic pattern. Antemortem lung biopsy may however provide more precise data regarding the earlier stages of the disease, providing a basis for novel treatment approaches. Objectives: To ascertain the morphological and immunohistochemical features of lung samples obtained in patients with moderate Covid-19 pneumonia. Methods: Transbronchial lung cryobiopsy was carried out in 12 Covid-19 patients within 20 days of symptom onset. Results: Histopathologic changes included spots of patchy acute lung injury with alveolar type II cell hyperplasia, with no evidence of hyaline membranes. Strong nuclear expression of phosphorylated STAT3 was observed in >50% of AECII. Interalveolar capillaries showed enlarged lumen and were in part arranged in superposed rows. Pulmonary venules were characterized by luminal enlargement, thickened walls, and perivascular CD4+ T-cell infiltration. A strong nuclear expression of phosphorylated STAT3, associated with PD-L1 and IDO expression, was observed in endothelial cells of venules and interstitial capillaries. Alveolar spaces macrophages exhibited a peculiar phenotype (CD68, CD11c, CD14, CD205, CD206, CD123/IL3AR, and PD-L1). Conclusions: Morphologically distinct features were identified in early stages of Covid-19 pneumonia, with epithelial and endothelial cell abnormalities different from either classical interstitial lung diseases or diffuse alveolar damage. Alveolar type II cell hyperplasia was a prominent event in the majority of cases. Inflammatory cells expressed peculiar phenotypes. No evidence of hyaline membranes and endothelial changes characterized by IDO expression might in part explain the compliance and the characteristic pulmonary vasoplegia observed in less-advanced Covid-19 pneumonia.

Purpose The onset of the coronavirus disease 19 (COVID-19) pandemic in Italy induced a dramatic increase in the need for intensive care unit (ICU) beds for a large proportion of patients affected by COVID-19-related acute respiratory distress syndrome (ARDS). The aim of the present study was to describe the health-related quality of life (HRQoL) at 90 days after ICU discharge in a cohort of COVID-19 patients undergoing invasive mechanical ventilation and to compare it with an age and sex-matched sample from the general Italian and Finnish populations. Moreover, the possible associations between clinical, demographic, social factors, and HRQoL were investigated. Methods COVID-19 ARDS survivors from 16 participating ICUs were followed up until 90 days after ICU discharge and the HRQoL was evaluated with the 15D instrument. A parallel cohort of age and sex-matched Italian population from the same geographic areas was interviewed and a third group of matched Finnish population was extracted from the Finnish 2011 National Health survey. A linear regression analysis was performed to evaluate potential associations between the evaluated factors and HRQoL. Results 205 patients answered to the questionnaire. HRQoL of the COVID-19 ARDS patients was significantly lower than the matched populations in both physical and mental dimensions. Age, sex, number of comorbidities, ARDS class, duration of invasive mechanical ventilation, and occupational status were found to be significant determinants of the 90 days HRQoL. Clinical severity at ICU admission was poorly correlated to HRQoL. Conclusion COVID-19-related ARDS survivors at 90 days after ICU discharge present a significant reduction both on physical and psychological dimensions of HRQoL measured with the 15D instrument. Trial Registration: NCT04411459. Supplementary Information The online version contains supplementary material available at 10.1007/s11136-021-02865-7.

The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity. We setup a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACEeI) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results: Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association. Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients.

Drug-Induced Sedation Endoscopy (DISE) consists of the direct observation of the upper airways during sedative-induced sleep, allowing the identification of the sites of pharyngeal collapse, which is the main pathological event in Obstructive Sleep Apnea (OSA). The Authors have compared Target Controlled Infusion (TCI) sedation endoscopy (TCI-DISE) technique to conventional DISE (CDISE), performed by a manual bolus injection of sedative agent, to recreate accurately and safely snoring and apnea patterns comparable to natural sleep. The authors conducted a prospective, randomized, long-term study and a retrospective analysis of surgical outcomes. The apnea-event observation and its correlation with pharyngeal collapse patterns is the primary endpoint; secondary endpoints are defined as stability and safety of sedation plan of DISE-TCI technique. From January 2009 to January 2011, OSA patients were included in the study and randomly allocated into two groups: the bolus injection conventional DISE group and the TCI-DISE group. Third endpoint is to compare the surgical outcomes enrolling OSA patients from January 2009 to June 2015. We recorded the complete apnea-event at oropharynx and hypopharynx levels in 15/50 pts in conventional DISE group (30%) and in 99/123 pts in TCI-DISE group (81%) (p < 0.0001). Four pts needed oxygen in conventional DISE group because a severe desaturation occurred during the first bolus of propofol (1 mg/kg) (p = 0.4872 ns). We recorded instability of the sedation plan in 13 patients of conventional DISE group (65%) and 1 patient of the TCI-DISE group (5%) (p = 0.0001). In 37 TCI-DISE group surgical patients we reported a significant reduction of postoperative AHI (from 42.7 ± 20.2 to 11.4 ± 10.3) in comparison with postoperative AHI in 15 C-DISE group surgical patients (from 41.3 ± 23.4 to 20.4 ± 15.5) (p = 0.05). Our results suggest the DISE-TCI technique as first choice in performing sleep-endoscopy because of its increased accuracy, stability and safety. However, it is mandatory an accurate assessment of PSG/PM, which allows us to differentiate OSA patients in whom UA anatomical abnormalities are predominant in comparison with not-anatomical pathophysiologic factors, achieving good surgical patient's selection and outcomes as a consequence.

Background A Covid-19 outbreak developed in Lombardy, Veneto and Emilia-Romagna (Italy) at the end of February 2020. Fear of an imminent saturation of available ICU beds generated the notion that rationing of intensive care resources could have been necessary. Results In order to evaluate the impact of Covid-19 on the ICU capacity to manage critically ill patients, we performed a retrospective analysis of the first 2 weeks of the outbreak (February 24–March 8). Data were collected from regional registries and from a case report form sent to participating sites. ICU beds increased from 1545 to 1989 (28.7%), and patients receiving respiratory support outside the ICU increased from 4 (0.6%) to 260 (37.0%). Patients receiving respiratory support outside the ICU were significantly older [65 vs. 77 years], had more cerebrovascular (5.8 vs. 13.1%) and renal (5.3 vs. 10.0%) comorbidities and less obesity (31.4 vs. 15.5%) than patients admitted to the ICU. PaO2/FiO2 ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO2 and base excess were lower [34 vs. 42 mmHg; 0.60 vs. 1.30] in patients receiving respiratory support outside the ICU than in patients admitted to the ICU, respectively. Conclusions Increase in ICU beds and use of out-of-ICU respiratory support allowed effective management of the first 14 days of the Covid-19 outbreak, avoiding resource rationing.