Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19 (preprint)

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including MIS-C and chilblain-like lesions (CLL), otherwise known as "COVID toes", remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients. SummaryNET formation and degradation are dysregulated in pediatric and symptomatic adult patients with various complications of COVID-19, in association with disease severity. NET degradation impairments are multifactorial and associated with natural inhibitors of DNase 1, G-actin and anti-DNase1L3 and anti-NET antibodies. Infection with the Omicron variant is associated with decreased levels of NETs when compared to other SARS-CoV-2 strains.

A Working Model to Inform Risk-Based Back to Work Strategies (preprint)

ABSTRACT Background The coronavirus disease 2019 (COVID-19) pandemic has forced many businesses to close or move to remote work to reduce the potential spread of disease. Employers desiring a return to onsite work want to understand their risk for having an infected employee on site and how best to mitigate this risk. Here, we modelled a range of key metrics to help inform return to work policies and procedures, including evaluating the benefit and optimal design of a SARS-CoV-2 employee screening program. Methods We modeled a range of input variables including prevalence of COVID-19, time infected, number of employees, test sensitivity and specificity, test turnaround time, number of times tested within the infectious period, and sample pooling. We modeled the impact of these input variables on several output variables: number of healthy employees; number of infected employees; number of test positive and test negative employees; number of true positive, false positive, true negative, and false negative employees; positive and negative predictive values; and time an infected, potentially contagious employee is on site. Results We show that an employee screening program can reduce the risk for onsite transmission across different prevalence values and group sizes. For example, at a pre-test asymptomatic community prevalence of 0.5% (5 in 1000) with an employee group size of 500, the risk for at least one infected employee on site is 91.8%, with 3 asymptomatic infected employees predicted within those 500 employees. Implementing a SARS-CoV-2 baseline screen with an 80% sensitivity and 99.5% specificity would reduce the risk of at least one infected employee on site to 39.4% and the predicted number of infected employees onsite (false negatives) to 1. Repetitive testing is required for ongoing vigilance of onsite employees. The expected number of days an infected employee is on site depends on test sensitivity, testing interval, and turnaround time. If the test interval is longer than the infectious period (∼14 days for COVID-19), testing will not detect the infected employee. Sample pooling reduces the number of tests performed, thereby reducing testing costs. However, the pooling methodology (eg, 1-stage vs 2-stage pooling, pool size) will impact the number of employees that screen positive, thereby affected the number of employees eligible to return to onsite work. Conclusions The modeling presented here can be used to help employers understand their risk for having an infected employee on site. Further, it details how an employee screening program can reduce this risk and shows how screening performance and frequency impact the effectiveness of a screening program. The primary factors determining the effectiveness of a screening program are test sensitivity and frequency of testing. Disclaimer This publication is offered to businesses/employers as a model of potential risk arising from COVID19 in the workplace. While believed to be based on reliable data, the model described herein has not been prospectively validated and should not be relied upon for any purpose other than as an aid to understand the potential impacts of a number of variables on the risk of having COVID19 positive employees on a worksite. Decisions related to workplace safety; COVID19 related workplace testing; programs and procedures should be based upon your actual data and applicable laws and public health orders.