Longitudinal Assessment of Systemic Steroid Therapy on Hyperinflammatory Endothelial Biomarker Profiles and Serology Responses of COVID-19 Patients (preprint)

This first of its kind study provides objective context to the potential mechanism of action of corticosteroid use in COVID-19 patients from 3 separate European medical centers by connecting inflammatory biomarkers to IgG levels for the SARS-CoV-2 spike protein antigens and neutralization of ACE2 binding within infected individuals. CXCL9 is described herein as an important COVID-19 biomarker connecting disease severity with inflammatory biomarker and serology response profiles in corticosteroid-treated patients.

Clinical Characteristics and Risk Factors for Myocardial Injury and Arrhythmia in COVID-19 patients (preprint)

Background: Patients with COVID-19 can develop myocardial injury and arrhythmia during the course of their illness. However, the underlying risk factors for the development of cardiovascular related manifestations are unclear. Methods: Using a register-based multi-center cross-sectional design, we analyzed 80 patients with myocardial injury and 401 controls, as well as 71 patients with arrhythmia and 409 controls, all admitted with COVID-19. Putative risk factors for myocardial injury and arrhythmia were evaluated with logistic regression with adjustment for potential confounders. Results: COVID-19 patients with myocardial injury had fatigue (66.2%) and dyspnea (63.7%), while those with arrhythmia had dyspnea (71.8%). Patients with myocardial injury and arrhythmia had a significant mortality of 92.5% and 94.4%, respectively. A history of chronic obstructive pulmonary disease (COPD) or heart diseases was associated with an increased risk of myocardial injury (odds ratio [OR] = 1.94, 95% confidence interval [CI]: 1.01-3.71; OR = 7.43, 95% CI: 3.99-13.83) and arrhythmia (OR = 1.94, 95% CI: 1.00-3.75; OR = 13.16, 95% CI: 6.75-25.68). In addition, we found that gamma glutamyltranspeptidase (GGT) >50U/L (OR = 2.14, 95% CI: 1.37-3.32; OR = 1.85, 95% CI: 1.19-2.85), serum creatinine >111mol/L (OR = 8.96, 95% CI: 4.4-18.23; OR = 3.71, 95% CI: 2.01-6.85), serum sodium <136 mmol/L (OR = 4.68, 95% CI: 2.46-8.91; OR = 2.06; 95% CI: 1.06-4.00) were all associated with increased risk of myocardial injury and arrhythmia, respectively. Conclusion: Our reported clinical characteristics and identified risk factors are important for clinical study of COVID-19 patients developing myocardial injury and arrhythmia.

Risk Factors for ICU Admission, Mechanical Ventilation and Mortality in Hospitalized Patients with COVID-19 in Hubei, China. (preprint)

Purpose: To examine the risk factors for Intensive Care Unit (ICU) admission, mechanical ventilation and mortality in hospitalized patients with COVID-19. Methods: This was a retrospective cohort study including 432 patients with laboratory-confirmed COVID-19 who were admitted to three medical centers in Hubei province from January 1st to April 10th 2020. Primary outcomes included ICU admission, mechanical ventilation and death occurring while hospitalized or within 30 days. Results: Of the 432 confirmed patients, 9.5% were admitted to the ICU, 27.3% required mechanical ventilation, and 33.1% died. Total leukocyte count was higher in survivors compared with those who died (8.9 vs 4.8 x 109/l), but lymphocyte counts were lower (0.6 vs 1.0 x 109/l). D-dimer was significantly higher in patients who died compared to survivors (6.0ug/l vs 1.0ug/l, p<0.0001. This was also seen when comparing mechanically versus non-mechanically-ventilated patients. Other significant differences were seen in AST, ALT, LDH, total bilirubin and creating kinase. The following were associated with increased odds of death: age > 65 years (adjusted hazard ratio (HR 2.09, 95% CI 1.02-4.05), severe disease at baseline (5.02, 2.05-12.29), current smoker (1.67, 1.37-2.02), temperature >39o C at baseline (2.68, 1.88-4.23), more than one comorbidity (2.12, 1.62-3.09), bilateral patchy shadowing on chest CT or X-ray (3.74, 1.78-9.62) and organ failure (6.47, 1.97-26.23). The following interventions were associated with higher CFR: glucocorticoids (1.60, 1.04-2.30), ICU admission (4.92, 1.37-17.64) and mechanical ventilation (2.35, 1.14-4.82). Conclusion: Demographics, including age over 65 years, current smoker, diabetes, hypertension, and cerebrovascular disease, were associated with increased risk of mortality. Mortality was also associated with glucocorticoid use, mechanical ventilation and ICU admission. Take-Home Message: COVID-19 patients with risk factors were more likely to be admitted into ICU and more likely to require mechanical ventilation.

Point-of-care serological assays for SARS-CoV-2 in a UK hospital population: potential for enhanced case finding (preprint)

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Case identification is currently made by real-time polymerase chain reaction (PCR) during the acute phase and largely restricted to healthcare laboratories. Serological assays are emerging but independent validation is urgently required to assess their utility.We evaluated five different point-of-care (POC) SARS-CoV-2 antibody test kits against PCR, finding concordance across the assays (n=15). We subsequently tested 200 patients using the OrientGene COVID-19 IgG/IgM Rapid Test Cassette and find a sensitivity of 74% in the early infection period (day 5-9 post symptom onset), with 100% sensitivity not seen until day 13. Specificity was 96%, but in validating the serological tests uncovered potential false-negatives from PCR testing late-presenting cases. A positive predictive value (PPV) of 37% in the general population precludes any use for general screening. Where a case definition is applied however, the PPV is substantially improved (95·4%), supporting use of serology testing in carefully targeted populations. Larger studies in specific patient cohorts, including those with mild infection are urgently required to inform on the applicability of POC serological assays to help control the spread of SARS-CoV-2 and improve case finding of patients that may experience late complications. 

Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients (preprint)

Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently hypothesized, using artificial intelligence (AI)-algorithms, to be useful for the treatment of COVID-19 infection via a proposed anti-cytokine effects and as an inhibitor of host cell viral propagation1,2. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids, which express hAAK1 and hGAK. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. This represents an important example of an AI-predicted treatment showing scientific and clinical promise during a global health crisis. Collectively, these data support further evaluation of the AI-derived hypothesis on anti-cytokine and anti-viral activity and supports its assessment in randomized trials in hospitalized COVID-19 patients.