A Transcriptomic Severity Classifier IMX-SEV-3b to Predict Mortality in Intensive Care Unit Patients with COVID-19: A Prospective Observational Pilot Study.

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.

Soluble urokinase plasminogen activator receptor and procalcitonin for risk stratification in patients with a suspected infection in the emergency department: a prospective cohort study.

BACKGROUND AND IMPORTANCE: Early identification of patients at risk of clinical deterioration may improve prognosis of infected patients in the emergency department (ED). Combining clinical scoring systems with biomarkers may result in a more accurate prediction of mortality than a clinical scoring system or biomarker alone. OBJECTIVE: The objective of this study is to investigate the performance of the combination of National Early Warning Score-2 (NEWS2) and quick Sequential Organ Failure Assessment (qSOFA) score with soluble urokinase plasminogen activator receptor (suPAR) and procalcitonin to predict 30-day mortality in patients with a suspected infection in the ED. DESIGN, SETTINGS AND PARTICIPANTS: This was a single-center prospective observational study, conducted in the Netherlands. Patients with suspected infection in the ED were included in this study and followed-up for 30 days. The primary outcome of this study was all cause 30-day mortality. The association between suPAR and procalcitonin with mortality was assessed in subgroups of patients with low and high qSOFA (<1 and ≥1) and low and high NEWS2 (<7 and ≥7). MAIN RESULTS: Between March 2019 and December 2020, 958 patients were included. A total of 43 (4.5%) patients died within 30 days after ED visit. A suPAR ≥ 6 ng/ml was associated with an increased mortality risk: 5.5 vs. 0.9% ( P  < 0.01) in patients with qSOFA = 0 and 10.7 vs. 2.1% ( P  = 0.02) in patients with qSOFA ≥ 1. There was also an association between procalcitonin ≥0.25 ng/ml and mortality: 5.5 vs. 1.9% ( P  = 0.02) for qSOFA = 0 and 11.9 vs. 4.1% ( P  = 0.03) for qSOFA ≥ 1. Similar associations were found within patients with a NEWS < 7 (5.9 vs. 1.2% for suPAR and 7.0 vs. 1.7% for procalcitonin, P  < 0.001). CONCLUSION: In this prospective cohort study, suPAR and procalcitonin were associated with increased mortality in patients with either a low or high qSOFA and patients with low NEWS2.

Performance of the FebriDx Rapid Point-of-Care Test for Differentiating Bacterial and Viral Respiratory Tract Infections in Patients with a Suspected Respiratory Tract Infection in the Emergency Department.

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.

Joint Modeling of Repeated Measurements of Different Biomarkers Predicts Mortality in COVID-19 Patients in the Intensive Care Unit.

Introduction: Predicting disease severity is important for treatment decisions in patients with COVID-19 in the intensive care unit (ICU). Different biomarkers have been investigated in COVID-19 as predictor of mortality, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and soluble urokinase-type plasminogen activator receptor (suPAR). Using repeated measurements in a prediction model may result in a more accurate risk prediction than the use of single point measurements. The goal of this study is to investigate the predictive value of trends in repeated measurements of CRP, PCT, IL-6, and suPAR on mortality in patients admitted to the ICU with COVID-19. Methods: This was a retrospective single center cohort study. Patients were included if they tested positive for SARS-CoV-2 by PCR test and if IL-6, PCT, suPAR was measured during any of the ICU admission days. There were no exclusion criteria for this study. We used joint models to predict ICU-mortality. This analysis was done using the framework of joint models for longitudinal and survival data. The reported hazard ratios express the relative change in the risk of death resulting from a doubling or 20% increase of the biomarker's value in a day compared to no change in the same period. Results: A total of 107 patients were included, of which 26 died during ICU admission. Adjusted for sex and age, a doubling in the next day in either levels of PCT, IL-6, and suPAR were significantly predictive of in-hospital mortality with HRs of 1.523 (1.012-6.540), 75.25 (1.116-6247), and 24.45 (1.696-1057) respectively. With a 20% increase in biomarker value in a subsequent day, the HR of PCT, IL-6, and suPAR were 1.117 (1.03-1.639), 3.116 (1.029-9.963), and 2.319 (1.149-6.243) respectively. Conclusion: Joint models for the analysis of repeated measurements of PCT, suPAR, and IL-6 are a useful method for predicting mortality in COVID-19 patients in the ICU. Patients with an increasing trend of biomarker levels in consecutive days are at increased risk for mortality.

Blood myxovirus resistance protein-1 measurement in the diagnostic work-up of suspected COVID-19 infection in the emergency department.

INTRODUCTION: Myxovirus resistance protein 1 (MxA) is a biomarker that is elevated in patients with viral infections. The goal of this study was to evaluate the diagnostic value of MxA in diagnosing COVID-19 infections in the emergency department (ED) patients. METHODS: This was a single-center prospective observational cohort study including patients with a suspected COVID-19 infection. The primary outcome of this study was a confirmed COVID-19 infection by RT-PCR test. MxA was assessed using an enzyme immunoassay on whole blood and receiver operating chart and area under the curve (AUC) analysis was conducted. Sensitivity, specificity, negative predictive value, and positive predictive value of MxA on diagnosing COVID-19 at the optimal cut-off of MxA was determined. RESULTS: In 2021, 100 patients were included. Of these patients, 77 patients had COVID-19 infection and 23 were non-COVID-19. Median MxA level was significantly higher (p < .001) in COVID-19 patients compared to non-COVID-19 patients, respectively 1933 and 0.1 ng/ml. The AUC of MxA on a confirmed COVID-19 infection was 0.941 (95% CI: 0.867-1.000). The optimal cut-off point of MxA was 252 ng/ml. At this cut-off point, the sensitivity of MxA on a confirmed COVID-19 infection was 94% (95% CI: 85%-98%) and the specificity was 91% (95% CI: 72%-99%). CONCLUSION: MxA accurately distinguishes COVID-19 infections from bacterial infections and noninfectious diagnoses in the ED in patients with a suspected COVID-19 infection. If the results can be validated, MxA could improve the diagnostic workup and patient flow in the ED.

High procalcitonin levels associated with increased intensive care unit admission and mortality in patients with a COVID-19 infection in the emergency department.

BACKGROUND: Patients with a severe COVID-19 infection often require admission at an intensive care unit (ICU) when they develop acute respiratory distress syndrome (ARDS). Hyperinflammation plays an important role in the development of ARDS in COVID-19. Procalcitonin (PCT) is a biomarker which may be a predictor of hyperinflammation. When patients with COVID-19 are in the emergency department (ED), elevated PCT levels could be associated with severe COVID-19 infections. The goal of this study is to investigate the association between PCT levels and severe COVID-19 infections in the ED. METHODS: This was a retrospective cohort study including patients with a confirmed COVID-19 infection who visited the ED of Erasmus Medical Center in Rotterdam, the Netherlands, between March and December 2020. The primary outcome was a severe COVID-19 infection, which was defined as patients who required ICU admission, all cause in-hospital mortality and mortality within 30 days after hospital discharge. PCT levels were measured during the ED visit. We used logistic regression to calculate the odds ratio (OR) with 95% confidence interval (95% CI) and corresponding area under the curve (AUC) of PCT on a severe COVID-19 infection, adjusting for bacterial coinfections, age, sex, comorbidities, C-reactive protein (CRP) and D-dimer. RESULTS: A total of 332 patients were included in the final analysis of this study, of which 105 patients reached the composite outcome of a severe COVID-19 infection. PCT showed an unadjusted OR of 4.19 (95%CI: 2.52-7.69) on a severe COVID-19 infection with an AUC of 0.82 (95% CI: 0.76-0.87). Corrected for bacterial coinfection, the OR of PCT was 4.05 (95% CI: 2.45-7.41). Adjusted for sex, bacterial coinfection, age any comorbidity, CRP and D-dimer, elevated PCT levels were still significantly associated with a severe COVID-19 infection with an adjusted OR of 2.11 (95% CI: 1.36-3.61). The AUC of this multivariable model was 0.85 (95%CI: 0.81-0.90). CONCLUSION: High PCT levels are associated with high rates of severe COVID-19 infections in patients with a COVID-19 infection in the ED. The routine measurement of PCT in patients with a COVID-19 infection in the ED may assist physicians in the clinical decision making process regarding ICU disposition.

Predicting mortality in adult patients with sepsis in the emergency department by using combinations of biomarkers and clinical scoring systems: a systematic review.

BACKGROUND: Sepsis can be detected in an early stage in the emergency department (ED) by biomarkers and clinical scoring systems. A combination of multiple biomarkers or biomarker with clinical scoring system might result in a higher predictive value on mortality. The goal of this systematic review is to evaluate the available literature on combinations of biomarkers and clinical scoring systems on 1-month mortality in patients with sepsis in the ED. METHODS: We performed a systematic search using MEDLINE, EMBASE and Google Scholar. Articles were included if they evaluated at least one biomarker combined with another biomarker or clinical scoring system and reported the prognostic accuracy on 28 or 30 day mortality by area under the curve (AUC) in patients with sepsis. We did not define biomarker cut-off values in advance. RESULTS: We included 18 articles in which a total of 35 combinations of biomarkers and clinical scoring systems were studied, of which 33 unique combinations. In total, seven different clinical scoring systems and 21 different biomarkers were investigated. The combination of procalcitonin (PCT), lactate, interleukin-6 (IL-6) and Simplified Acute Physiology Score-2 (SAPS-2) resulted in the highest AUC on 1-month mortality. CONCLUSION: The studies we found in this systematic review were too heterogeneous to conclude that a certain combination it should be used in the ED to predict 1-month mortality in patients with sepsis. Future studies should focus on clinical scoring systems which require a limited amount of clinical parameters, such as the qSOFA score in combination with a biomarker that is already routinely available in the ED.

Daily Observations of Nebuliser Use and Technique (DONUT) in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) caregivers focus on correct inhalation technique for nebulisers as this is essential to optimize efficacy of inhaled drugs. However, little is known on this nebuliser technique of patients at home. METHODS: Three "hidden" video registrations were made of 32 children with CF (6-18years) nebulising at home. Videos were randomly scored on inhalation technique items using nebuliser-specific checklists and a total score was calculated. RESULTS: Median nebuliser technique was 91.9% of max score. Nebuliser technique was perfect (score 100%) in 23.3% of the patients and incorrect (score 0%) in 13.3%. Most mistakes were made in the required optimal breathing pattern. CONCLUSION: Most CF patients had good nebuliser technique on a day-to-day basis. However, errors observed likely resulted in reduced treatment efficacy and, in 13%, no treatment at all. Regular "real life" evaluation by the CF-team can improve inhaled therapy substantially.