Katrijn Daenen

Background: Treatment guidelines for acute respiratory distress syndrome (ARDS) recommend the use of high‐dose corticosteroids based on their anti‐inflammatory effects, yet the efficacy of this therapeutic strategy in patients with COVID‐19 related ARDS is inconclusive. To more thoroughly understand the mechanism of action for high‐dose corticosteroids in patients with COVID‐19‐related ARDS, we hypothesized that the reduction of inflammatory markers induced by high‐dose corticosteroids would reduce mortality (i.e., inflammation as a mediator). Design and Methods: In this retrospective cohort study, we included patients with COVID‐19‐related ARDS admitted to the intensive care unit (ICU) of an academic hospital in Rotterdam, the Netherlands between March 2020 and June 2022. High‐dose corticosteroids were defined as > 6 mg of dexamethasone/day or equivalent. Biomarkers included C‐reactive protein (CRP), d ‐dimer, ferritin, leukocyte count, interleukin‐6 (IL‐6), lactate dehydrogenase, and neutrophil‐to‐lymphocyte ratio (NLR). Using a causal mediation framework, we estimated the average mediation effect (AME) and % mediation for each biomarker, allowing to quantify the degree to which continuous levels of inflammatory markers mediate the association between receiving high‐dose corticosteroids and mortality. The models used in this framework accounted for time‐varying treatment/mediation with inverse probability of treatment weights, determined from the covariates PaO ₂ /FiO ₂ ratio, sex at birth, age, NLR, and ICU length of stay. Results: Of the 327 patients included, 122 (37.3%) received high‐dose corticosteroids. The risk of death was higher in patients who did vs. did not receive high‐dose corticosteroids [incidence rate = 0.54, 95% confidence interval (CI) = 0.42–0.71 and 0.21, 95% CI = 0.15–0.29/person‐month, respectively; p < 0.001]. This effect remained in most analyses accounting for time‐varying treatment/mediation. The association between high‐dose corticosteroids and mortality was reduced (i.e., mediated) with lower levels of CRP (AME = −0.006, 95% CI = −0.011, −0.002; %‐mediation = −82.0%), d ‐dimer (AME = −0.002, 95% CI = −0.005, −0.001; %‐mediation = −33.1%), and IL‐6 (AME = −0.002, 95% CI = −0.004, −0.001; %‐mediation = −25.5%). There was no evidence of mediation for other biomarkers. Conclusion: CRP, d ‐dimer, and IL‐6 mediated the association between high‐dose corticosteroids and mortality. When inflammation was reduced, the deleterious effect of high‐dose corticosteroids was eliminated.

Predicting mortality in COVID-19 ARDS may support ICU clinical decision-making. Biomarkers of innate immunity, coagulation, endothelial injury, and fibroproliferation have been studied as predictors. We aimed to examine whether trends in plasma biomarkers predict ICU mortality and to explore underlying biological processes through pathway analysis. Additionally, we explored whether HDS changes biomarker trajectories in COVID-19 ARDS. In this observational study, we included patients with COVID-19 ARDS admitted to the ICU of an academic hospital in Rotterdam between February 2020 and February 2022. In repeated plasma samples, 64 biomarkers were measured. Joint modeling assessed the association between biomarker changes and ICU mortality, adjusting for age, sex, BMI, and HDS. Protein–protein interaction and gene ontology enrichment analyses were performed using STRING, Cytoscape, and DAVID EASE. Biomarker trajectories were compared between HDS-treated and non-treated patients, adjusting for timing, SOFA score, and tocilizumab. One hundred and sixty-two patients were included and 43 died during ICU stay. A doubling in the values of 26 biomarkers over the next day was predictive of ICU mortality (HRs 0.16–8.56; q < 0.05). Gene ontology enrichment analysis identified 19 overrepresented biological processes (FDR ≤ 0.05), with highest fold enrichment for macrophage chemotaxis, negative regulation of bone resorption, and leukocyte cell–cell adhesion. Forty-eight patients received HDS at a median of 6 ICU days. HDS significantly changed the trajectories of four mortality-associated biomarkers: Albumin and lactoferrin decreased, while CRP and VEGF increased. In COVID-19 ARDS, repeated biomarker measurements demonstrate a systemic inflammatory state associated with mortality. HDS changed trends of several biomarkers, but did not reduce those associated with fatal outcomes. Trial registration : ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359

Background: High-dose corticosteroids (HDS) are established treatment for non-COVID-19 acute respiratory distress syndrome (ARDS) because of their anti-inflammatory effects. In COVID-19 patients requiring oxygen therapy or invasive mechanical ventilation, 6mg dexamethasone daily reduces mortality. In severe COVID-19 pneumonia, higher corticosteroid doses are sometimes administered in an attempt to reduce mortality. This study evaluated the effect of HDS compared to standard-dose dexamethasone on IC mortality and superinfection rates in Suriname. Methods: This retrospective cohort study included patients with PCR-confirmed severe COVID-19 pneumonia admitted to ICUs in Suriname, between June 2020 and October 2021. Data was analyzed from a random sample of patients extracted from a larger database originally collected for another ICU COVID-19 study. Patients received standard-dose corticosteroids (SDS) and/or HDS (dexamethasone > 6 mg daily or equivalent). Treatment with HDS was analyzed as a time-dependent exposure. Predictors of mortality were identified through logistic regression and incorporated as covariates in a time-updated Cox survival model. Chi-square test compared bacterial superinfections between treatment groups. Results: Of 103 included patients, 36 (35%) received HDS. Invasive mechanical ventilation, septic shock, bacterial superinfection, creatinine elevation, age, CXR score, and P/F ratios were associated with mortality in univariable analysis. In multivariable analysis, only age (OR 1.10 per year, p=0.022) and invasive mechanical ventilation (OR 8.28, p=0.046) remained significant. Time-updated survival analysis showed no significant harm or benefit with HDS (HR 1.99, 95% CI:0.78– 5.09, p=0.15) and no increased superinfection rates (p=1.00). Conclusion: This first Surinamese study of HDS in severe COVID-19 pneumonia found no improved outcomes compared to SDS, nor increased bacterial superinfections. Our findings do not support HDS escalation in this population. The identified mortality risk factors provide valuable guidance for recognizing high-risk patients.

Background: High-dose corticosteroids (HDS) are an established treatment for non-COVID-19 acute respiratory distress syndrome (ARDS) because of their anti-inflammatory effects. In COVID-19 patients requiring oxygen therapy or invasive mechanical ventilation, 6mg dexamethasone daily reduces mortality. This study evaluated the effect of HDS compared to standard-dose dexamethasone on IC mortality and superinfection rates in ICU patients with COVID-19 in Suriname. Methods: This retrospective cohort study included patients with PCR-confirmed severe COVID-19 pneumonia admitted to ICUs in Suriname, between June 2020 and October 2021. Patients received standard-dose corticosteroids (SDS) and/or HDS (dexamethasone >6 mg daily or equivalent). Treatment with HDS was analyzed as a time-dependent exposure. Predictors of mortality were identified through logistic regression and incorporated as covariates in a time-updated Cox survival model. Chi-square test compared bacterial superinfections between treatment groups. Results: Of 103 included patients, 36(35%) received HDS. In multivariable analysis, only age (OR 1.10 per year, p=0.022) and invasive mechanical ventilation (OR 8.28, p=0.046) were associated with mortality. Time-updated survival analysis showed no significant harm or benefit with HDS (HR 1.99, 95% CI:0.78-5.09, p=0.15) and no increased superinfection rates (p=1.00). Conclusion: This first Surinamese study of HDS in severe COVID-19 pneumonia found no improved outcomes compared to SDS, nor increased bacterial superinfections. These findings do not support corticosteroid dose escalation beyond standard dexamethasone therapy in severe COVID-19 pneumonia.

Purpose: Patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) who lack clinical improvement are frequently treated with high-dose corticosteroids (HDS). Since HDS is used to reduce hyperinflammation in these patients, levels of (pro-)inflammatory biomarkers after commencing HDS treatment could be useful in predicting mortality. This study aims to evaluate biomarker levels after commencing HDS over time, along with their capacity to predict mortality. Patients and Methods: This retrospective cohort study included patients with COVID-19 ARDS treated with HDS in the intensive care unit (ICU) at an academic hospital in the Netherlands between March 2020-March 2022. Inflammatory biomarkers (ie, C-reactive protein (CRP), D-dimer, ferritin, leukocyte count, interleukin-6 (IL-6), lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), and procalcitonin (PCT)) were assessed daily from start of HDS (ie baseline) until day 7. Associations between biomarker levels and all-cause-hospital-mortality were evaluated each day using logistic regression, with cut-offs identified by optimizing sensitivity (Se) and specificity (Sp). Results: Of the 122 patients included, 53 (43.4%) died during hospitalization. HDS was initiated for a median 7 days (IQR=1– 11) after ICU admission. At baseline, a moderately high predictive capacity for mortality was observed at a ferritin level > 1281 μg/L (Se=62%/Sp=64%), leukocyte count > 13.7 × 109/L (Se=42%/Sp=79%), and NLR > 12.1 (Se=61%/Sp=77%). During follow-up, CRP > 50 mg/L on day 6 (Se=50%/Sp=75%) and > 42 mg/L on day 7 (Se=50%/Sp=75%), ferritin > 1082 μg/L on day 6 (Se 63%/Sp=71%) and > 1852 μg/L on day 7 (Se=31%/Sp=79%), IL-6 > 67 mg/L on day 7 (Se=56%/Sp=79%) and LDH > 396U/L on day 6 (Se=38%/Sp=83%) and > 373 U/L on day 7 (Se=47%/Sp=72%) showed moderate capacity to predict mortality. NLR was consistently associated with mortality for all days, except day 1 (Se=36– 68%/Sp=72-92%). Conclusion: In COVID-19 ARDS patients receiving HDS, several clinically available inflammatory biomarkers moderately predicted all-cause-hospital-mortality after the start of HDS, particularly on days 6 and 7. NLR demonstrated the most consistent association with mortality over time. The use of these markers requires validation in larger cohorts.

FebriDx is a rapid point-of-care test combining qualitative measurements of C-reactive protein (CRP) and Myxovirus Resistance Protein A (MxA) using a disposable test device to detect and differentiate acute bacterial from viral respiratory tract infections. The goal of this study was to investigate the diagnostic accuracy of FebriDx in patients with suspected respiratory tract infections in the emergency department (ED). This was an observational cohort study, performed in the ED of an academic hospital. Patients were included if they had a suspected infection. The primary outcome was the presence of a bacterial or viral infection, determined by clinical adjudication by an expert panel. The sensitivity, specificity, and positive and negative predictive value of FebriDx for the presence of bacterial versus non-bacterial infections, and viral versus non-viral infections were calculated. Between March 2019 and November 2020, 244 patients were included. A bacterial infection was present in 41%, viral infection was present in 24%, and 4% of the patients had both viral and bacterial pathogens. FebriDx demonstrated high sensitivity in the detection of bacterial infection (87%), high NPV (91%) to rule out bacterial infection, and high specificity (94%) for viral infection in patients with a suspected infection in the ED.

The prediction of disease outcomes in COVID-19 patients in the ICU is of critical importance, and the examination of host gene expressions is a promising tool. The 29-host mRNA Inflam-matix-Severity-3b (IMX-SEV-3b) classifier has been reported to predict mortality in emergency department COVID-19 patients and surgical ICU patients. The accuracy of the IMX-SEV-3b in predicting mortality in COVID-19 patients admitted to the ICU is yet unknown. Our aim was to investigate the accuracy of the IMX-SEV-3b in predicting the ICU mortality of COVID-19 patients. In addition, we assessed the predictive performance of routinely measured biomarkers and the Sequential Organ Failure Assessment (SOFA) score as well. This was a prospective observational study enrolling COVID-19 patients who received mechanical ventilation on the ICU of the Erasmus MC, the Netherlands. The IMX-SEV-3b scores were generated by amplifying 29 host response genes from blood collected in PAXgene^® Blood RNA tubes. A severity score was provided, ranging from 0 to 1 for increasing disease severity. The primary outcome was the accuracy of the IMX-SEV-3b in predicting ICU mortality, and we calculated the AUROC of the IMX-SEV-3b score, the biomarkers C-reactive protein (CRP), D-dimer, ferritin, leukocyte count, interleukin-6 (IL-6), lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), procalcitonin (PCT) and the SOFA score. A total of 53 patients were included between 1 March and 30 April 2020, with 47 of them being included within 72 h of their admission to the ICU. Of these, 18 (34%) patients died during their ICU stay, and the IMX-SEV-3b scores were significantly higher in non-survivors compared to survivors (0.65 versus 0.57, p = 0.05). The Area Under the Receiver Operating Characteristic Curve (AUROC) for prediction of ICU mortality by the IMX-SEV-3b was 0.65 (0.48–0.82). The AUROCs of the biomarkers ranged from 0.52 to 0.66, and the SOFA score had an AUROC of 0.81 (0.69–0.93). The AUROC of the pooled biomarkers CRP, D-dimer, ferritin, leukocyte count, IL-6, LDH, NLR and PCT for prediction of ICU mortality was 0.81 (IQR 0.69–0.93). Further validation in a larger interventional trial of a point-of-care version of the IMX-SEV-3b classifier is warranted to determine its value for patient management.

Background: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19. Objective: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19. Methods: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand. Results: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024. Conclusions: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment. Trial Registration: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359 International Registered Report Identifier (IRRID): DERR1-10.2196/48183