Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis. OBJECTIVES: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission. RESULTS: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels. CONCLUSION: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.

Synthesis methods used to combine observational studies and randomised trials in published meta-analyses.

BACKGROUND: This study examined the synthesis methods used in meta-analyses pooling data from observational studies (OSs) and randomised controlled trials (RCTs) from various medical disciplines. METHODS: We searched Medline via PubMed to identify reports of systematic reviews of interventions, including and pooling data from RCTs and OSs published in 110 high-impact factor general and specialised journals between 2015 and 2019. Screening and data extraction were performed in duplicate. To describe the synthesis methods used in the meta-analyses, we considered the first meta-analysis presented in each article. RESULTS: Overall, 132 reports were identified with a median number of included studies of 14 [9-26]. The median number of OSs was 6.5 [3-12] and that of RCTs was 3 [1-6]. The effect estimates recorded from OSs (i.e., adjusted or unadjusted) were not specified in 82% (n = 108) of the meta-analyses. An inverse-variance common-effect model was used in 2% (n = 3) of the meta-analyses, a random-effects model was used in 55% (n = 73), and both models were used in 40% (n = 53). A Poisson regression model was used in 1 meta-analysis, and 2 meta-analyses did not report the model they used. The mean total weight of OSs in the studied meta-analyses was 57.3% (standard deviation, ± 30.3%). Only 44 (33%) meta-analyses reported results stratified by study design. Of them, the results between OSs and RCTs had a consistent direction of effect in 70% (n = 31). Study design was explored as a potential source of heterogeneity in 79% of the meta-analyses, and confounding factors were investigated in only 10% (n = 13). Publication bias was assessed in 70% (n = 92) of the meta-analyses. Tau-square was reported in 32 meta-analyses with a median of 0.07 [0-0.30]. CONCLUSION: The inclusion of OSs in a meta-analysis on interventions could provide useful information. However, considerations of several methodological and conceptual aspects of OSs, that are required to avoid misleading findings, were often absent or insufficiently reported in our sample.

Machine-learning-derived sepsis bundle of care.

PURPOSE: Compliance to the Surviving Sepsis Campaign (SSC) guidelines is limited. This is known to be associated with increased mortality. The aim of this retrospective cohort study was to identify among the SCC guidelines the optimal bundle of recommendations that minimize 28-day mortality. METHODS: We used a training cohort to identify, using a least absolute shrinkage and selection operator penalized machine learning model, this bundle. Patients with sepsis/septic shock admitted to the intensive care unit (ICU) were extracted from two US databases, the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database (training and internal validation cohorts) and the eICU Collaborative Research Database (eICU-CRD) (external validation cohort). In the validation cohorts, we defined a bundle group that includes patients who were treated with at least all the recommendations selected in our bundle and a no-bundle group that includes patients in whom at least one recommendation from our bundle was omitted. RESULTS: All-cause 28-day mortality was the primary outcome measure. A total of 42,735 patients were included. Six recommendations (antimicrobials, balanced crystalloid, insulin therapy, corticosteroids, vasopressin, and bicarbonate therapy) were identified from the training cohort to be included in our bundle. In the propensity score-(PS)-matched internal validation cohort, the bundle group was associated with a lower mortality (OR 0.41 [0.33-0.53]; p < 0.001) compared to the no-bundle group. This was confirmed in the PS-matched external validation cohort (OR 0.75 [0.60-0.94]; p 0.02). CONCLUSION: Our bundle of six recommendations is associated with a dramatic reduction in mortality in sepsis and septic shock. This bundle needs to be evaluated prospectively.

Empirical evaluation of the methods used in systematic reviews including observational studies and randomized trials.

OBJECTIVES: To examine the methodological characteristics of systematic reviews and meta-analyses including observational studies (OSs) and randomized controlled trials (RCTs), in various medical disciplines. STUDY DESIGN AND SETTING: We searched Medline via PubMed to identify systematic reviews of interventions including RCTs and OSs published in 110 journals from 2015 to 2019. We extracted in duplicate general and methodological characteristics of the systematic review. RESULTS: We identified 402 systematic reviews. Only 39% (n = 160) of them reported the availability of a pre-established protocol. A rationale for including observational data in the systematic review was clearly reported in 25% (n = 102) of the systematic reviews. Thirty two percent (n = 130) of the reviews reported a search strategy intending to identify published and unpublished data for RCTs and OSs. The risk of bias of the individual studies was assessed in 89% (n = 359) of the systematic reviews. In 74% (n = 266) it was assessed for both RCTs and OSs; 180 (50%) used different tools. Information about confounding factors was reported in only 11% of systematic reviews and the type of effect estimates (crude or adjusted) used was specified in only 22% of the systematic reviews. Among the 385 systematic reviews that performed data synthesis, only 132 (33%) pooled OSs and RCTs in the same meta-analysis. CONCLUSION: Including OSs in systematic reviews of interventions could provide useful information but such an approach could also be misleading; thus, several methodological details are needed to ensure appropriate handling of OS and valid results. Our study revealed, although, that substantial methodological information is missing in reports published in high-impact factor general and specialty journals.

Outcomes and predictors of delayed endoscopic biliary drainage for severe acute cholangitis due to choledocholithiasis in an intensive care unit.

BACKGROUND: Acute cholangitis (AC) is an infection of the biliary tract secondary to biliary obstruction requiring biliary drainage through endoscopic retrograde cholangiopancreatography. This study aims to compare the outcome between the early and delayed ERCP in patients with severe AC. METHODS: Patient with severe AC due to choledocholithiasis admitted to intensive care unit were included. Early ERCP was defined was as ERCP performed within 24 h following hospital admission. Propensity-score matching was used to reduce the imbalance between groups. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay, onset or persistent organ failure. RESULTS: The delayed ERCP group had a higher mortality rate at 30 days (45,5 versus 13%, <0.001) and at 1 year (59,7% versus 15,6%, p <0.001). Delayed ERCP had also a higher rate of respiratory adverse events (54,5 versus 27,8%, p = 0,002), longer ICU (7.41 versus 4.61, p = 0,004) and hospital (11,88 versus 9,22, p = 0,042) length of stay. Predictors of delayed ERCP were cardiac arrythmias, liver disease, creatinine value and white blood cell count at baseline. CONCLUSIONS: Delays in ERCP for patients with severe AC appear to be associated with higher mortality rate and prolonged ICU and hospital stays.

Sample size considerations for studies comparing intubating conditions using quantitative monitoring versus a fixed interval during onset of neuromuscular blockade.

INTRODUCTION: Data in the literature are still scarce to establish any recommendations on the use of quantitative monitoring during tracheal intubation. PATIENTS AND METHODS: In this monocentric study, non-morbidly obese adult female patients without risk factors for difficult tracheal intubation were prospectively included. After 0.5 mg.kg-1 atracurium during propofol-sufentanil anaesthesia, intubation conditions were evaluated using the Copenhague and Cormack-Lehane classification at the complete twitch suppression at the TOF to the AP (monitor group) or after a fixed 3 min waiting time after atracurium injection (3-min group). We also examined sample size for future studies. RESULTS: We included 102 (monitor group) and 97 (3-min group) adult non-obese female patients without different characteristics. Intubation conditions were acceptable in 96/102 (94%) in the monitor group vs. 84/97 (87%) in the 3-min group, p = 0.07. The presence of a Cormack and Lehane view of 1 was marginally better in the monitor group as compared to the 3-min group, p = 0.041. We propose two possibility of sample size based on a difference of observed events based on acceptable intubation conditions, n = 602, or on excellent intubation conditions, n = 550. DISCUSSION: This observational study shows that the use of a neuromuscular TOF monitoring of the ulnar nerve as compared to a fixed 3-min waiting time after atracurium injection could improve laryngoscopic view and show a tendency to better intubation conditions without conclusive statistical significance. We suggest that researchers consider our recommendations in terms of the sample size to include in their future research, keeping in mind the limitations of our study.

Dynamics of circulating calprotectin accurately predict the outcome of moderate COVID-19 patients.

BACKGROUND: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated. METHODS: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death. FINDINGS: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19. INTERPRETATION: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit. FUNDING: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation.

Serum phosphate is associated with mortality among patients admitted to ICU for acute pancreatitis.

BACKGROUND AND AIMS: Routine laboratory tests can be useful predictors in the early assessment of the severity and mortality of acute pancreatitis (AP). The aim of this study was to evaluate the accuracy of clinical and laboratory parameters for the prediction of mortality among patients admitted to the intensive care unit (ICU) for AP. METHODS: We conducted a retrospective analysis of prospectively collected data from Beth Israel Deaconess Hospital made publicly available to examine the relationship between routine clinical and laboratory parameters with respect to mortality for AP. Cox proportional hazard ratio was used to evaluate the impact of several routine laboratory markers on mortality. Receiver operation characteristic (ROC) curve was performed to determine the accuracy of diagnosis of laboratory tests by using area under curve (AUC) for the respective analysis. RESULTS: In total, 499 patients were admitted to the ICU for AP. Several factors for predicting mortality in AP at admission were identified in the multivariate analysis: alkaline phosphatase hazard ratio (HR) = 1.00 (1.00-1.00, p = 0.024), anion gap HR = 1.09 (1.00-1.20, p = 0.047), bilirubin total HR = 1.11 (1.06-1.17, p < 0.001), calcium total HR = 0.59 (0.42-0.84, p = 0.004), phosphate HR = 1.51 (1.18-1.94, p = 0.001), potassium HR = 1.91 (1.03-3.55, p = 0.041), white blood cells HR = 1.04 (1.00-1.07, p = 0.028). The AUC of serum phosphate level for mortality was 0.7 in the ROC analysis. The optimal cut-off value of serum phosphate level for prediction of mortality was 3.78 mg/dl (sensitivity, 0.58; specificity, 0.78). CONCLUSION: In this large cohort, we identified baseline serum phosphate as the most valuable single routine laboratory test for predicting mortality in AP. Future prospective studies are required to confirm these results.

Safety of different electrocautery modes for endoscopic sphincterotomy: a Bayesian network meta-analysis.

BACKGROUND AND AIMS: Post-endoscopic retrograde cholangiopancreatography acute pancreatitis (PAP) and post-sphincterotomy hemorrhage are known adverse events of post-endoscopic retrograde cholangiopancreatography. Various electrosurgical currents can be used for endoscopic sphincterotomy. The extent to which this influences adverse events remains unclear. We assessed the comparative safety of different electrosurgical currents, through a Bayesian network meta-analysis of published studies merging direct and indirect comparison of trials. METHODS: We performed a Bayesian random-effects network meta-analysis of randomized controlled trials that compared the safety of different electrocautery modes for endoscopic sphincterotomy. RESULTS: Nine studies comparing four electrocautery modes (blended cut, pure cut, endocut, and pure cut followed by blended cut) with a combined enrollment of 1615 patients were included. The pooled results of the network meta-analysis did not show a significant difference in preventing post-sphincterotomy pancreatitis when comparing electrocautery modes. However, pure cut was associated with a statistically significant increased risk of bleeding compared with endocut [relative risk = 4.30; 95% confidence interval (1.53-12.87)]. On the other hand, the pooled results of the network meta-analysis showed no significant difference in prevention of bleeding when comparing blended cut versus endocut, pure cut followed by blended cut versus endocut, pure cut followed by blended cut versus blended cut, pure cut versus blended cut, and pure cut versus pure cut followed by blended cut. The results of rank probability found that endocut was most likely to be ranked the best. CONCLUSION: No electrocautery mode was superior to another with regard to preventing PAP. Endocut was superior with respect to preventing bleeding. Therefore, we suggest performing endoscopic sphincterotomy with endocut.

Computed tomography after severe COVID-19 pneumonia: findings at 6†months and beyond.

Parenchymal bands and ground-glass opacities consistent with a pattern of late organising pneumonia are frequently observed 6 months after ICU admission for #COVID19, whereas fibrotic changes of limited extent are only observed in about 1/3 of patients https://bit.ly/2UGOsbr.

Lupus Anticoagulant Single Positivity During the Acute Phase of COVID-19 Is Not Associated With Venous Thromboembolism or In-Hospital Mortality.

OBJECTIVE: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19. METHODS: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19. RESULTS: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-ß2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-ß2 -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively). CONCLUSION: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality.

Placental growth factor level in plasma predicts COVID-19 severity and in-hospital mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with vascular inflammation and endothelial injury. OBJECTIVES: To correlate circulating angiogenic markers vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), and fibroblast growth factor 2 (FGF-2) to in-hospital mortality in COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with COVID-19 infection were enrolled. VEGF-A, PlGF, and FGF-2 were measured in each patient ≤48 h following admission. RESULTS: The study enrolled 237 patients with suspected COVID-19: 208 patients had a positive diagnostic for COVID-19, of whom 23 were mild outpatients and 185 patients hospitalized after admission. Levels of VEGF-A, PlGF, and FGF-2 significantly increase with the severity of the disease (P < .001). Using a logistic regression model, we found a significant association between the increase of FGF-2 or PlGF and mortality (odds ratio [OR] 1.11, 95% confidence interval [CI; 1.07-1.16], P < .001 for FGF-2 and OR 1.07 95% CI [1.04-1.10], P < .001 for PlGF) while no association were found for VEGF-A levels. Receiver operating characteristic curve analysis was performed and we identified PlGF above 30 pg/ml as the best predictor of in-hospital mortality in COVID-19 patients. Survival analysis for PlGF confirmed its interest for in-hospital mortality prediction, by using a Kaplan-Meier survival curve (P = .001) and a Cox proportional hazard model adjusted to age, body mass index, D-dimer, and C-reactive protein (3.23 95% CI [1.29-8.11], P = .001). CONCLUSION: Angiogenic factor PlGF is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that PlGF blocking strategies could be a new interesting therapeutic approach in COVID-19.

rs2476601 polymorphism in PTPN22 is associated with Crohn's disease but not with ulcerative colitis: a meta-analysis of 16,838 cases and 13,356 controls.

BACKGROUND: Although the rs2476601 polymorphism of PTPN22 has been reported to be a susceptibility gene for Crohn's disease (CD), results from different studies vary and remain inconclusive. Also, no association has been found between rs2476601 and the risk of ulcerative colitis (UC). The aim of this meta-analysis was to investigate the association between this PTPN22 polymorphism (rs2476601) and the risk of inflammatory bowel disease, UC and CD. METHODS: We performed a meta-analysis by identifying relevant candidate gene-based studies from EMBASE and MEDLINE. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the strength of associations between rs2476601 and inflammatory bowel diseases, using a fixed effect or random effect model. Publication bias was also assessed. RESULTS: By pooling 14 different studies, 13,356 controls, 8182 patients with CD, and 8656 with UC were included. We found that the T allele of PTPN22 was not significantly associated with a higher risk of developing UC (OR 1.06, 95%CI 0.98-1.14) but was associated with a decreased risk of developing CD (OR 1.28, 95%CI 1.17-1.40). The T allele in rs2476601 lowered the risk of CD by 22%. CONCLUSION: This study shows that PTPN22 (rs2476601) is significantly associated with the risk of developing CD, but has no association with UC. This suggests that these diseases have different pathways involved in their pathophysiology.