Pathogenesis of COVID-19 – what mediates progress from mild to severe disease?

Background:

Covid-19 is usually a mild-to-moderate infection but may progress and cause acute respiratory distress syndrome (ARDS) and respiratory failure. Despite supportive care the case-fatality is high in risk groups as elderly and those with chronic cardiopulmonary diseases. The treatment with steroids and anticoagulants has improved the prognosis but there is still an urgent need for other options for therapeutic interventions.

In addition, it is not fully known what determines the progression to severe disease and long-term complications in covid-19. Aims:

We hypothesize that severe covid-19 is caused by an inability to effectively produce specific neutralizing antibodies against SARS-CoV-2, which leads to high viral loads in the respiratory tract with subsequent pulmonary inflammation and tissue damage.

The specific aims are to characterize and identify predictive markers for mild and severe disease. In addition, we will investigate pathogenetic and host factors responsible for severe covid-19 and assess lung function and quality of life after covid-19 infection and relate the long-term outcome to the severity of the acute infection.

Workplan:

Patients, with verified covid-19 will be included in a prospective study at both Umeå and Örebro University Hospitals. Samples for quantification of viral load and blood samples will be collected throughout the course of disease. We will perform time-series analysis for metabolomics and lipidomics as well as markers for inflammation, coagulation and circulating immune cells for phenotypic and functional changes using multi-parameter flow cytometry, ELISAs for cytokines, analyses of 92 inflammatory markers using an Olink proximity extension assay.

Biopsies from heart and lungs will be collected in lethal cases.

To assess the lung function, inflammation and quality of life at follow-up after covid-19, we will perform spirometry and a questionnair, and take blood samples up to five years after disease. Importance:

Our study will provide new knowledge about the pathogeneses of covid-19, what factors that mediates the progress from mild to severe disease. The identified pathogenetic mechanisms may act as a target for therapeutic intervention. Markers for severity can be used to predict disease progression or. It is important to assess the cardiopulmonary consequences of cover-19 and long-term prognosis.