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.

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

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.

Background: Specific vaccines are indicated for immunocompromised patients (ICPs) due to their vulnerability to infections. Recommendation of these vaccines by healthcare professionals (HCPs) is a crucial facilitator for vaccine uptake. Unfortunately, the responsibilities to recommend and administer these vaccines are not clearly allocated among HCPs involved in the care of adult ICPs. We aimed to evaluate HCPs’ opinions on directorship and their role in facilitating the uptake of medically indicated vaccines as a basis to improve vaccination practices. Methods: A cross-sectional survey was performed among in-hospital medical specialists (MSs), general practitioners (GPs), and public health specialists (PHSs) in the Netherlands to assess their opinion on directorship and the implementation of vaccination care. Additionally, perceived barriers, facilitators, and possible solutions to improve vaccine uptake were investigated. Results: In total, 306 HCPs completed the survey. HCPs almost unanimously (98%) reported that according to them, the primary treating physician is responsible for recommending medically indicated vaccines. Administering these vaccines was seen as a more shared responsibility. The most important barriers experienced by HCPs in recommending and administering were reimbursement problems, a lack of a national vaccination registration system, insufficient collaboration among HCPs, and logistical problems. MSs, GPs and PHSs all mentioned the same three solutions as important strategies to improve vaccination practices, i.e., reimbursement of vaccines, reliable and easily accessible registration of received vaccines, and arrangements for collaboration among the different HCPs that are involved in care. Conclusion: The improvement in vaccination practices in ICPs should focus on better collaboration among MSs, GPs, and PHSs, who should know each other’s expertise; clear agreement on responsibility; reimbursement for vaccines; and the availability of clear registration of vaccination history.

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.