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Most published prediction models for Coronavirus Disease 2019 (COVID-19) were poorly reported, at high risk of bias, and heterogeneous in model performance. To tackle methodological challenges faced in previous prediction studies, we investigated whether model updating and extending improves mortality prediction, using the Intensive Care Unit (ICU) as a proxy. All COVID-19 patients admitted to seven ICUs in the Euregio-Meuse Rhine during the first pandemic wave were included. The 4C Mortality and SEIMC scores were selected as promising prognostic models from an external validation study. Five predictors could be estimated based on cohort size. TRIPOD guidelines were followed and logistic regression analyses with the linear predictor, APACHE II score, and country were performed. Bootstrapping with backward selection was applied to select variables for the final model. Additionally, shrinkage was performed. Model discrimination was displayed as optimism-corrected areas under the ROC curve and calibration by calibration slopes and plots. The mortality rate of the 551 included patients was 36%. Discrimination of the 4C Mortality and SEIMC scores increased from 0.70 to 0.74 and 0.70 to 0.73 and calibration plots improved compared to the original models after updating and extending. Mortality prediction can be improved after updating and extending of promising models., (© 2024. The Author(s).)

Introduction: We aimed to identify risk factors associated with ICU mortality in critically ill patients with COVID-19 pneumonia treated with Extracorporeal membrane oxygenation (ECMO). We also aimed to assess protocol violations of the local eligibility criteria of ECMO initiation., Methods: All 31 consecutive adult patients with confirmed COVID-19 pneumonia admitted to ICU and treated with ECMO from March 13th 2020 to 8 December 2021 were enrolled. Eligibility criteria for ECMO initiation were: P/F-ratio<50 mmHg >3 hours, P/F-ratio<80 mmHg >6 hours or pH<7.25 + PaCO2>60 mmHg >6 hours, despite maximal protective invasive ventilation. Primary outcome was ICU mortality. Univariate logistic regression analyses were performed to identify predictors of ICU mortality., Results: 12 out of 31 patients (38.7%) did not survive ECMO treatment in ICU. Half of the non-survivors suffered from acute kidney failure compared to 3 out of 19 survivors (15.79%) ( p = .04). Half of the non-survivors required CRRT treatment versus 1 patient in the survivor group (5.3%) ( p < .01). Higher age (2.45 (0.97-6.18), p = .05), the development of AKI (5.33 (1.00-28.43), p = .05), need of CRRT during ICU stay (18.00 (1.79-181.31), p = .01) and major bleeding during ECMO therapy (0.51 (0.19-0.89), p < .01) were identified to be predictors of ICU mortality., Conclusion: Almost 60% of patients could be treated successfully with ECMO with sustained results at 3 months. Predictors for ICU mortality were development of AKI and need of CRRT during ICU stay, higher age category and major bleeding. Inadvertent ECMO allocation was noted in almost one in five patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and is linked to disease severity and mortality. However, antibody and cytokine responses in the early disease stage and their association with disease course and outcome are still not completely understood. In this large, multi-centre cohort study, blood samples of 434 Belgian COVID-19 hospitalized patients with different disease severities (ranging from asymptomatic/mild to critically ill) from the first wave of the COVID-19 pandemic were obtained. Baseline antibody and cytokine responses were characterized and associations with several clinical outcome parameters were determined. Anti-spike immunoglobulin (Ig)G and IgM levels were elevated in patients with a more severe disease course. This increased baseline antibody response however was associated with decreased odds for hospital mortality. Levels of the pro-inflammatory cytokines IL-6, IP-10 and IL-8, the anti-inflammatory cytokine IL-10 and the antiviral cytokines IFN-α, IFN-β and IFN-λ1 were increased with disease severity. Remarkably, we found significantly lower levels of IFN-λ2,3 in critically ill patients compared to patients of the moderate and severe disease category. Finally, levels of IL-8, IL-6, IP-10, IL-10, IFN-α, IFN-β, IFN-γ and IFN-λ1 at baseline were positively associated with mortality, whereas higher IFN-λ2,3 levels were negatively associated with mortality., (© 2023. The Author(s).)

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who have been admitted to the intensive care unit (ICU) often face months of physical disability after discharge. To optimize recovery, it is important to understand the role of musculoskeletal alterations in critically ill patients infected with SARS-CoV-2. The main aim of the present study was to describe the presence and morphology of nemaline bodies found in the skeletal muscle tissue from critically ill patients infected with SARS-CoV-2. In n = 7 patients infected with SARS-CoV-2, ultrastructural characteristics of vastus lateralis muscle obtained on days 1-3 and days 5-8 following ICU admission were investigated in more detail with electron microscopy. Those muscle biopsies consistently showed variable degrees of myofiber necrosis and myofibrillar disorganization. In 4/7 (57%) patients on days 5-8, the Z-line material accumulated into nemaline bodies with a typical lattice-like appearance at higher magnification, similar to that found in nemaline myopathy. This study is the first to describe the disintegration of myofibrils and the accumulation of Z-line material into nemaline bodies in the skeletal muscle tissue obtained from critically ill coronavirus disease-19 patients following ICU admission, which should be interpreted primarily as a non-specific pathological response of extreme myofibrillar disintegration associated with myofiber necrosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated prognostic models in the Euregio Intensive Care COVID (EICC) cohort., Study Design and Setting: In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results., Results: 551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between -9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration., Conclusion: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Acute kidney injury (AKI) has been reported as a frequent complication of critical COVID-19. We aimed to evaluate the occurrence of AKI and use of kidney replacement therapy (KRT) in critical COVID-19, to assess patient and kidney outcomes and risk factors for AKI and differences in outcome when the diagnosis of AKI is based on urine output (UO) or on serum creatinine (sCr)., Methods: Multicenter, retrospective cohort analysis of patients with critical COVID-19 in seven large hospitals in Belgium. AKI was defined according to KDIGO within 21 days after ICU admission. Multivariable logistic regression analysis was used to explore the risk factors for developing AKI and to assess the association between AKI and ICU mortality., Results: Of 1286 patients, 85.1% had AKI, and KRT was used in 9.8%. Older age, obesity, a higher APACHE II score and use of mechanical ventilation at day 1 of ICU stay were associated with an increased risk for AKI. After multivariable adjustment, all AKI stages were associated with ICU mortality. AKI was based on sCr in 40.1% and UO in 81.5% of patients. All AKI stages based on sCr and AKI stage 3 based on UO were associated with ICU mortality. Persistent AKI was present in 88.6% and acute kidney disease (AKD) in 87.6%. Rapid reversal of AKI yielded a better prognosis compared to persistent AKI and AKD. Kidney recovery was observed in 47.4% of surviving AKI patients., Conclusions: Over 80% of critically ill COVID-19 patients had AKI. This was driven by the high occurrence rate of AKI defined by UO criteria. All AKI stages were associated with mortality (NCT04997915)., (© 2022. The Author(s).)

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries., Design: Multicenter observational cohort study., Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany., Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave., Interventions: None., Measurements and Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications., Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Patients infected with severe acute respiratory syndrome coronavirus (SARS-CoV-2) can develop severe illness necessitating intensive care admission. Critically ill patients are susceptible for the development of secondary bacterial infections. Due to a combination of virus- and drug-induced immunosuppression, critically ill patients with corona virus disease 2019 (COVID-19) may even have a higher risk of developing a secondary infection. These secondary infections can aggravate the severity of illness and increase the risk of death. Further research on secondary infections in COVID-19 patients is essential. Therefore, the objective of this study was to investigate the incidence and associated risk factors of secondary bacterial infections and to identify the most common groups of pathogens in critically ill COVID-19 patients., Methods: This mono-center, retrospective observational cohort study was performed at the intensive care unit (ICU) of the Jessa Hospital, Hasselt, Belgium. All adult COVID-19 patients admitted to the ICU from 13th March 2020 until 17th October 2020, were eligible for inclusion in the study. Data from the resulting 116 patients were prospectively entered into a customized database. The resulting database was retrospectively reviewed to investigate three types of secondary bacterial infections (secondary pneumonia, bloodstream infections of unknown origin, catheter-related sepsis)., Results: Of 94 included patients, 68% acquired at least one of the studied secondary bacterial infections during their ICU stay. Almost two thirds of patients (65.96%, n = 62) acquired a secondary pneumonia, whereas 29.79% (n = 28) acquired a bacteremia of unknown origin and a smaller proportion of patients (14.89%, n = 14) acquired a catheter-related sepsis. Male gender (P = 0.05), diabetes mellitus (P = 0.03) and the cumulative dose of corticosteroids (P = 0.004) were associated with increased risk of secondary bacterial infection. The most common pathogens detected in the cultures of patients with secondary pneumonia were Gram-negative bacilli. Bacteremia of unknown origin and catheter-related sepsis were mostly caused by Gram-positive cocci., Conclusion: This study confirms that the incidence of secondary bacterial infections is very high in critically ill COVID-19 patients. These patients are at highest risk of developing secondary pneumonia. Male gender, a history of diabetes mellitus and the administration of corticosteroids were associated with increased risk of secondary bacterial infection., (© 2022. The Author(s).)

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies., (© 2022. The Author(s).)

Background: The Sequential Organ Failure Assessment (SOFA) score has been developed to score the severity of organ dysfunction in critically ill sepsis patients and has been proven to have a high predictive value for intensive care unit (ICU) mortality in severely ill patients. Our goal was to evaluate the prognostic value of the SOFA score as well as trends in SOFA score for ICU mortality in COVID-19 patients., Methods: All consecutive patients with confirmed COVID-19 pneumonia admitted to the ICU between March 13th, 2020, and October 17th, 2020 were included in this retrospective cohort study. The worst SOFA score was evaluated daily. Multiple logistic regression models were used to evaluate the predictive value of SOFA in ICU mortality., Results: 103 patients were included in this study. 30 patients (29%) died during their ICU stay and 73 (71%) patients were discharged alive. The ICU admission SOFA score was 5.2 ± 3.3 in ICU non-survivors vs. 4.3 ± 2.9 in ICU survivors (P = 0.15). The maximum SOFA score in ICU non-survivors was 11.7 ± 4.7 vs. 7.4 ± 4.3 in ICU survivors. SOFA scores increased the first week in both survivors and non-survivors, but the increase was less pronounced in survivors. In the multiple logistic regression models, neither admission SOFA score nor combination with delta SOFA in the first 48 hours was statistically significantly related to ICU mortality. Only the maximum SOFA score remained significant (OR = 1.23, 95% CI: 1.11-1.37, P < 0.001) in the multiple logistic models with an AUC of 0.91., Conclusions: Evaluation of SOFA scores in the first 48 hours after ICU admission is not a good prognostic indicator in COVID-19 patients. Only the maximum SOFA score was predictive for ICU mortality.

Background: To minimise the risk of COVID-19 transmission, an ambulant screening protocol for COVID-19 in patients before admission to the hospital was implemented, combining the SARS CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) on a nasopharyngeal swab, a chest computed tomography (CT) and assessment of clinical symptoms. The aim of this study was to evaluatethe diagnostic yield and the proportionality of this pre-procedural screeningprotocol., Methods: In this mono-centre, prospective, cross-sectional study, all patients admitted to the hospital between 22nd April 2020 until 14th May 2020 for semi-urgent surgery, haematological or oncological treatment, or electrophysiological investigationunderwent a COVID-19 screening 2 days before their procedure. At a 2-week follow-up, the presence of clinical symptoms was evaluated by telephone as a post-hoc evaluation of the screening approach.Combined positive RT-PCR assay and/or positive chest CT was used as gold standard. Post-procedural outcomes of all patients diagnosed positive for COVID-19 were assessed., Results: In total,528 patients were included of which 20 (3.8%) were diagnosed as COVID-19 positive and 508 (96.2%) as COVID-19 negative. 11 (55.0%) of COVID-19 positive patients had only a positive RT-PCR assay, 3 (15.0%) had only a positive chest CT and 6 (30%) had both a positive RT-PCR assay and chest CT. 10 out of 20 (50.0%) COVID-19 positive patients reported no single clinical symptom at the screening. At 2 week follow-up, 50% of these patients were still asymptomatic. 37.5% of all COVID-19 negative patients were symptomatic at screening. In the COVID-19 negative group without symptoms at screening, 78 (29.3%) patients developed clinical symptoms at a 2-week follow-up., Conclusion: This study suggests that routine chest CT and assessment of self-reported symptoms have limited value in the preprocedural COVID-19 screening due to low sensitivity and/or specificity.

Background: Belgium was among the first countries in Europe with confirmed coronavirus disease 2019 (COVID-19) cases. Since the first diagnosis on February 3rd, the epidemic has quickly evolved, with Belgium at the crossroads of Europe, being one of the hardest hit countries. Although risk factors for severe disease in COVID-19 patients have been described in Chinese and United States (US) cohorts, good quality studies reporting on clinical characteristics, risk factors and outcome of European COVID-19 patients are still scarce., Methods: This study describes the clinical characteristics, complications and outcomes of 319 hospitalized COVID-19 patients, admitted to a tertiary care center at the start of the pandemic in Belgium, and aims to identify the main risk factors for in-hospital mortality in a European context using univariate and multivariate logistic regression analysis., Results: Most patients were male (60%), the median age was 74 (IQR 61-83) and 20% of patients were admitted to the intensive care unit, of whom 63% needed invasive mechanical ventilation. The overall case fatality rate was 25%. The best predictors of in-hospital mortality in multivariate analysis were older age, and renal insufficiency, higher lactate dehydrogenase and thrombocytopenia. Patients admitted early in the epidemic had a higher mortality compared to patients admitted later in the epidemic. In univariate analysis, patients with obesity did have an overall increased risk of death, while overweight on the other hand showed a trend towards lower mortality., Conclusions: Most patients hospitalized with COVID-19 during the first weeks of the epidemic in Belgium were admitted with severe disease and the overall case fatality rate was high. The identified risk factors for mortality are not easily amenable at short term, underscoring the lasting need of effective therapeutic and preventative measures.