Infection of lung megakaryocytes and platelets by SARS-CoV-2 anticipate fatal COVID-19.

SARS-CoV-2, although not being a circulatory virus, spread from the respiratory tract resulting in multiorgan failures and thrombotic complications, the hallmarks of fatal COVID-19. A convergent contributor could be platelets that beyond hemostatic functions can carry infectious viruses. Here, we profiled 52 patients with severe COVID-19 and demonstrated that circulating platelets of 19 out 20 non-survivor patients contain SARS-CoV-2 in robust correlation with fatal outcome. Platelets containing SARS-CoV-2 might originate from bone marrow and lung megakaryocytes (MKs), the platelet precursors, which were found infected by SARS-CoV-2 in COVID-19 autopsies. Accordingly, MKs undergoing shortened differentiation and expressing anti-viral IFITM1 and IFITM3 RNA as a sign of viral sensing were enriched in the circulation of deadly COVID-19. Infected MKs reach the lung concomitant with a specific MK-related cytokine storm rich in VEGF, PDGF and inflammatory molecules, anticipating fatal outcome. Lung macrophages capture SARS-CoV-2-containing platelets in vivo. The virus contained by platelets is infectious as capture of platelets carrying SARS-CoV-2 propagates infection to macrophages in vitro, in a process blocked by an anti-GPIIbIIIa drug. Altogether, platelets containing infectious SARS-CoV-2  alter COVID-19 pathogenesis and provide a powerful fatality marker. Clinical targeting of platelets might prevent viral spread, thrombus formation and exacerbated inflammation at once and increase survival in COVID-19.

The Prognostic Role of Early Postoperative Troponin I in Lung Transplantation-A Retrospective 7-Year Analysis.

OBJECTIVES: Postoperative cardiac troponin I concentration is predictive of worsened outcomes in cardiac surgery. Lung transplantation (LT) surgery shares common features with cardiac surgery, but postoperative troponin has yet to be investigated. The authors aimed to evaluate the association between early postoperative troponin concentration and the 1-year mortality after transplantation. DESIGN: A retrospective, observational, single-center study. SETTING: At a tertiary care, university hospital. PARTICIPANTS: Patients who underwent lung transplantation from January 2011 to December 2017 INTERVENTIONS: For each patient, preoperative, intraoperative, and postoperative data were collected, as well as the troponin I measurement at the moment of postoperative intensive care unit admission. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty LT procedures were analyzed. Troponin I was elevated in all LT patients, with a median of 3.82 ng/mL-1 (2-6.42) ng/mL-1 significantly higher in non-survivors than in survivors with 5.39 (2.88-7.44) v 3.50 ng/mL (1.74-5.76), p = 0.005. In the multivariate analysis, the authors found that only the Simplified Acute Physiology Score II score (hazard ratio [HR] 1.03; 95% confidence interval [CI] [1.001; 1.05]; p = 0.007) and the need to maintain extracorporeal life support at the end of surgery (HR 2.54; 95% CI [1.36; 4.73]; p = 0.003) were independently associated with the 1-year mortality. The multiple linear regression model found that troponin levels were associated with the need for extracorporeal life support (ECLS) (p = 0.014), the amount of transfused packed red blood cells (p = 0.008), and bilateral LT (p < 0.001). CONCLUSION: Early postoperative troponin serum levels were not independently associated with 1-year mortality. Early postoperative troponin I levels were correlated to bilateral LT, the need for ECLS, and intraoperative blood transfusion.

Prognostic value of the PaO2 /FiO2 ratio determined at the end-surgery stage of a double-lung transplantation.

INTRODUCTION: We evaluated the prognostic role of the arterial oxygen partial pressure/fractional inspired oxygen ratio (PaO2 /FiO2 ratio) measured at the end of double-lung transplantation (DLT). METHODS: This was a monocentric cohort study of all consecutive DLT patients between January 1, 2012, and January 1, 2016, except patients with preoperative extracorporeal membrane oxygenation (ECMO), intraoperative cardiopulmonary bypass, postoperative ECMO, large patent foramen ovale, redo transplantation during the study period, and multiorgan transplantation. RESULTS: A total of 164 patients were included in the study; 45 had a PaO2 /FiO2 ratio <200, 39 a ratio in the range 200-300, and 80 a ratio >300. The risk of being in the lower ratio group is positively related to body mass index, preoperative pulmonary hypertension, and fibrosis. It is negatively related to emergency surgery, age, and intraoperative institution of ECMO. There was a trend for more grade 3 pulmonary graft dysfunction at day 3 in the worst PaO2 /FiO2 ratio group. Mortality at 1000 days was similar for all patients and even after exclusion of patients who had required intraoperative ECMO. CONCLUSION: PaO2 /FiO2 ratio measured at the end of DLT does not forecast 1000-day mortality.

Emergency bedside ultrasound-benefits as well as caution: Part 2: Echocardiography.

PURPOSE OF REVIEW: Critical care echocardiography (CCE) has become an important component of general critical care ultrasonography, and a current review of its performance is presented. RECENT FINDINGS: Basic CCE should be performed as a goal-directed examination to better identify specific signs and to answer important clinical questions concerning acute hemodynamic concerns. It has evolved in the ICU and also in the emergency department not only for improved diagnostic capability but also as an effective part of the triage process. It remains an efficacious procedure even in patients with respiratory failure when combined with lung ultrasonography. Numerous acronyms were proposed, but in all cases, CCE responds to the same rules as fundamental echocardiography. Basic CCE requires accessible and comprehensive training for physicians and is mandatory for all intensivists. Development of pocket echo devices may increase the use of basic CCE as has miniaturization of other medical technologies. Performance should be managed by guidelines, and the CCE training program should be standardized worldwide. More trials are welcome to evaluate its impact on patient outcomes. SUMMARY: Thanks to its ability to quickly obtain a diagnostic orientation at the bedside and to implement targeted therapy, basic CCE over the past decade has become an essential tool for hemodynamic assessment of the cardiopulmonary unstable patient. Its more recent incorporation into the education of trainees in medical school and residencies/fellowships has reinforced its perceived importance in critical care management, despite the relative paucity as yet of rigorous scientific evidence demonstrating positive outcome modification from its use.

Inhaled nitric oxide dependency at the end of double-lung transplantation: a boosted propensity score cohort analysis.

Inhaled nitric oxide (iNO) is usually used during lung transplantation despite controversial postoperative benefits. Our group chose to administer iNO systematically during the procedure and stop at the end of surgery. This study aims to describe the features of patients who cannot be weaned from iNO, the reasons for this and its impact on postoperative outcomes. This is a monocentric cohort study comprised all consecutive patients who underwent double-lung transplantation (DLT) between 1 January 2012 and 1 January 2016. The impact of iNO dependency on postoperative outcomes was estimated using a boosted inverse probability of treatment weighting estimator. A total of 9.8% of the 173 patients included in the study could not be weaned from iNO at end-surgery stage. Body mass index (OR = 2.03, 95% CI = 1.14-3.29, P = 0.02) and intraoperative extracorporeal membrane oxygenation (OR = 1.80, 95% CI = 1.02-2.72, P = 0.04) were risk factors for iNO dependency In the weighted population, iNO dependency was associated with an increased prevalence of grade 3 primary graft dysfunction (adjusted RR = 4.20, 95% CI = 1.75-10.09, P < 0.001) and decreased postoperative survival during the first 1500 days of follow-up (adjusted HR = 5.0, 95% CI = 1.86-13.48, P < 0.001). Inhaled nitric oxide dependency is an early marker of a poor prognosis following DLT.

Clinical characteristics and prognosis of bacteraemia during postoperative intra-abdominal infections.

BACKGROUND: Bloodstream infections of abdominal origin are usually associated with poor prognosis. We assessed the clinical and microbiological characteristics of critically ill patients admitted to the intensive care unit (ICU) for postoperative intra-abdominal infection (PIAI) and analysed the influence of bacteraemia on their outcome. METHODS: All consecutive PIAI patients admitted to the ICU between 1999 and 2014 were prospectively analysed. Bacteraemic patients (at least one positive blood culture in the 24 h preceding/following surgery) were compared with non-bacteraemic patients. Demographic characteristics, underlying disease, severity scores at the time of reoperation, microbiological results, therapeutic management, outcome, and survival were recorded. Results are expressed as median (interquartile range (IQR)) or proportions. RESULTS: Overall, 343 patients (54% male, 62 (49-73) years old) with PIAI were analysed, including 64 (19%) bacteraemic patients. Immunosuppression and cancer were more frequent in bacteraemic patients (p < 0.001 in both cases). No difference between groups was observed for the characteristics of initial surgery. Time to reoperation, site, and cause of PIAI were similar in both groups. At the time of reoperation, Sequential Organ Failure Assessment (SOFA) score was higher in bacteraemic patients (8 (6-10) versus 7 (4-10); p < 0.05). A predominance of Gram-positive (34%) and Gram-negative (47%) bacteria were recovered from blood cultures (polymicrobial bacteraemia in 9 (14%) patients and bacteraemia involving multidrug-resistant organisms in 14 (22%) patients). In multivariate analysis, risk factors for bacteraemia were immunosuppression or cancer, high SOFA score, and E. coli in peritoneal samples. Bacteraemia did not impact the management (with similar results for the adequacy of antibiotic therapy, anti-infective agents used, de-escalation or duration of therapy in both groups). Neither hospital mortality nor morbidity criteria differed between groups. Risk factors for mortality in multivariate analysis were urgent initial surgery, high Simplified Acute Physiology Score (SAPS) II score and documented antifungal therapy, but not perioperative bacteraemia. CONCLUSIONS: In this ICU population, bacteraemia did not change the overall management of patients with PIAI. Our data suggest that bacteraemic patients do not require a specific management.

Morbidity and mortality related to pneumonia and TRACHEOBRONCHITIS in ICU after lung transplantation.

BACKGROUND: Bacterial respiratory infections (BRI) are major complications contributing to increased morbidity and mortality after lung transplantation (LT). This study analyzed epidemiology and outcome of 175 consecutive patients developing BRI in ICU after LT between 2006 and 2012. METHODS: Three situations were described: colonization determined in donors and recipients, pneumonia and tracheobronchitis during the first 28 postoperative days. Severity score, demographic, bacteriologic and outcome data were collected. RESULTS: 26% of donors and 31% of recipients were colonized. 92% of recipients developed BRI, including at least one episode of pneumonia in 19% of recipients. Only 21% of recipients developed BRI with an organism cultured from the donor's samples, while 40% of recipients developed BRI with their own bacteria cultured before LT. Purulent sputum appears to be an important factor to discriminate tracheobronchitis from pneumonia. When compared to patients with tracheobronchitis, those with pneumonia had longer durations of mechanical ventilation (13 [3-27] vs 3 [29], p = 0.0005) and ICU stay (24 [16-34] vs 14 [9-22], p = 0.002). Pneumonia was associated with higher 28-day (11 (32%) vs 9 (7%), p = 0.0004) and one-year mortality rates (21 (61%) vs 24 (19%), p ≤ 0.0001). CONCLUSIONS: These data confirm the high frequency of BRI right from the early postoperative period and the poor prognosis of pneumonia after LT.

Persistent but dysfunctional mucosal SARS-CoV-2-specific IgA and low lung IL-1ß associate with COVID-19 fatal outcome: A cross-sectional analysis.

The role of the mucosal pulmonary antibody response in coronavirus disease 2019 (COVID-19) outcome remains unclear. Here, we found that in bronchoalveolar lavage (BAL) samples from 48 patients with severe COVID-19-infected with the ancestral Wuhan virus, mucosal IgG and IgA specific for S1, receptor-binding domain (RBD), S2, and nucleocapsid protein (NP) emerged in BAL containing viruses early in infection and persist after virus elimination, with more IgA than IgG for all antigens tested. Furthermore, spike-IgA and spike-IgG immune complexes were detected in BAL, especially when the lung virus has been cleared. BAL IgG and IgA recognized the four main RBD variants. BAL neutralizing titers were higher early in COVID-19 when virus replicates in the lung than later in infection after viral clearance. Patients with fatal COVID-19, in contrast to survivors, developed higher levels of mucosal spike-specific IgA than IgG but lost neutralizing activities over time and had reduced IL-1ß in the lung. Altogether, mucosal spike and NP-specific IgG and S1-specific IgA persisting after lung severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance and low pulmonary IL-1ß correlate with COVID-19 fatal outcome. Thus, mucosal SARS-CoV-2-specific antibodies may have adverse functions in addition to protective neutralization. Highlights: Mucosal pulmonary antibody response in COVID-19 outcome remains unclear. We show that in severe COVID-19 patients, mucosal pulmonary non-neutralizing SARS-CoV-2 IgA persit after viral clearance in the lung. Furthermore, low lung IL-1ß correlate with fatal COVID-19. Altogether, mucosal IgA may exert harmful functions beside protective neutralization.

Neutrophil Extracellular Traps in SARS-CoV2 Related Pneumonia in ICU Patients: The NETCOV2 Study.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poorly understood disease involving a high inflammatory status. Neutrophil extracellular traps (NETs) have been described as a new pathway to contain infectious diseases but can also participate in the imbalance of the inflammatory and the coagulation systems. NETs could be a therapeutic target in COVID-19 patients. Methods: Consecutive patients with SARS-CoV2 related pneumonia admitted to the intensive care unit were included in a prospective bicentric study. Neutrophil extracellular trap concentrations were quantified in whole blood samples at day-1 and day-3 by flow cytometry. The primary outcome was the association between the blood NET quantification at ICU admission and the number of days with refractory hypoxemia defined by a PaO2/FIO2 ratio ≤100 mmHg. Results: Among 181 patients admitted to the ICUs for acute respiratory failure related to SARS-CoV2 pneumonia, 58 were included in the analysis. Patients were 62 [54, 69] years old in median, mostly male (75.9%). The median number of days with severe hypoxemia was 4 [2, 6] days and day-28 mortality was 27.6% (n = 16). The blood level of NETs significantly decreased between day-1 and day-3 in patients who survived (59.5 [30.5, 116.6] to 47 [33.2, 62.4] p = 0.006; 8.6 [3.4, 18.0] to 4 [1.4, 10.7] p = 0.001 and 7.4 [4.0, 16.7] to 2.6 [1.0, 8.3] p = 0.001 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively) while it remained stable in patients who died (38.4 [26.0, 54.8] to 44.5 [36.4, 77.7] p = 0.542; 4.9 [1.3, 13.0] to 5.5 [2.8, 6.9] p = 0.839 and 4 [1.3, 13.6] to 2.7 [1.4, 4.5] p = 0.421 for MPO+, Cit-H3+, and MPO+ Cit-H3+ NETs, respectively). In multivariable negative binomial regression, the blood level of MPO+ NETs was negatively associated with the number of days with severe hypoxemia within 7 days (0.84 [0.73, 0.97]), while neither Cit-H3+ NETs nor double-positive NETs were significantly associated with the primary outcome. Conclusion: The whole blood level of NETs at day-1 was negatively associated with the number of days with severe hypoxemia in patients admitted to the intensive care unit for SARS-CoV2 related pneumonia. The lack of decrease of the blood level of NETs between day-1 and day-3 discriminated patients who died within day-28.