Mechanistic and therapeutic studies of the innate immune response in human subjects with COVID-19

Title [en]

Abstract [sv]

Background and Aim:COVID-19 in most cases causes a mild to medium severe influenza-like disease with sore throat, fever and a dry cough. In a few cases, though, the disease retakes after 9-10 days and develops into RDS, which in a few cases may need intensive care with ventilator support. About 20% of these patients succumb due to pulmonary dysfunction.The aim of this application is to find evidence that the humoral innate immune system (HIIS) involving at least the contact-, complement-, coagulation- and the fibrinolytic- systems is activated in COVID 19. The rationale for this is to recognize the mechanism of the respiratory distress syndrome associated with COVID-19, identify new targets for therapeutic intervention and to obtain support for giving already licensed therapeutic inhibitors of these systems to patients with COVID-19 RDS. Work plan:WP1. Screening of COVID-19 RDS patients admitted to the ICU longitudinally over time for HIIS biomarkers. WP2. Cross-sectional analyses of COVID-19 RDS patients at the ICU with selected HIIS biomarkers from WP1.WP3. Treatment of COVID-19 RDS patients with the complement inhibitor AMY-101 longitudinally in order to ameliorate the COVID-19 inflammation. WP4. Investigation of the contribution of the lectin pathway of complement to systemic inflammation and coagulopathy in COVID-19 patients.WP5. Characterization of the HIIS activation in the surfactant from COVID19 patients.Significance:COVID-19 RDS is a severe and life-threatening condition. The cause of the disorder is not known but disturbances in the blood cascade systems is an emerging mechanism for explaining the cause of the respiratory disease. Activation of the coagulation system is obvious in that thromboembolism is common and our prel. data in combination with recent observations in other laboratories that the complement system is involved. Prel. data from our laboratory also implicates that the contact system is activated suggesting that the whole blood cascade system is engaged and that particularly the complement system and to some degree the coagulation system, seems to be a prognostic factor that can be used immediately in the clinic. If we together with our colleagues in Italy and the US can show that complement inhibition with AMY-101 is beneficial for the COVID-19 patients, a new treatment can be developed. Also, other already licensed therapeutic are available and can if the mechanism is clarified, be used in future clinical trials.

Abstract [en]

Background and Aim:COVID-19 in most cases causes a mild to medium severe influenza-like disease with sore throat, fever and a dry cough. In a few cases, though, the disease retakes after 9-10 days and develops into RDS, which in a few cases may need intensive care with ventilator support. About 20% of these patients succumb due to pulmonary dysfunction.The aim of this application is to find evidence that the humoral innate immune system (HIIS) involving at least the contact-, complement-, coagulation- and the fibrinolytic- systems is activated in COVID 19. The rationale for this is to recognize the mechanism of the respiratory distress syndrome associated with COVID-19, identify new targets for therapeutic intervention and to obtain support for giving already licensed therapeutic inhibitors of these systems to patients with COVID-19 RDS. Work plan:WP1. Screening of COVID-19 RDS patients admitted to the ICU longitudinally over time for HIIS biomarkers. WP2. Cross-sectional analyses of COVID-19 RDS patients at the ICU with selected HIIS biomarkers from WP1.WP3. Treatment of COVID-19 RDS patients with the complement inhibitor AMY-101 longitudinally in order to ameliorate the COVID-19 inflammation. WP4. Investigation of the contribution of the lectin pathway of complement to systemic inflammation and coagulopathy in COVID-19 patients.WP5. Characterization of the HIIS activation in the surfactant from COVID19 patients.Significance:COVID-19 RDS is a severe and life-threatening condition. The cause of the disorder is not known but disturbances in the blood cascade systems is an emerging mechanism for explaining the cause of the respiratory disease. Activation of the coagulation system is obvious in that thromboembolism is common and our prel. data in combination with recent observations in other laboratories that the complement system is involved. Prel. data from our laboratory also implicates that the contact system is activated suggesting that the whole blood cascade system is engaged and that particularly the complement system and to some degree the coagulation system, seems to be a prognostic factor that can be used immediately in the clinic. If we together with our colleagues in Italy and the US can show that complement inhibition with AMY-101 is beneficial for the COVID-19 patients, a new treatment can be developed. Also, other already licensed therapeutic are available and can if the mechanism is clarified, be used in future clinical trials.

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Uppsala University

Uppsala University

Uppsala University

Uppsala University

Uppsala University

Uppsala University

Uppsala University

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Hjärt-Lungfonden

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