Complement C3 activation in the ICU: Disease and therapy as Bonnie and Clyde

Patients in the intensive care unit (ICU) often straddle the divide between life and death. Understanding the complex underlying pathomechanisms relevant to such situations may help intensivists select broadly acting treatment options that can improve the outcome for these patients. As one of the most important defense mechanisms of the innate immune system, the complement system plays a crucial role in a diverse spectrum of diseases that can necessitate ICU admission. Among others, myocardial infarction, acute lung injury/acute respiratory distress syndrome (ARDS), organ failure, and sepsis are characterized by an inadequate complement response, which can potentially be addressed via promising intervention options. Often, ICU monitoring and existing treatment options rely on massive intervention strategies to maintain the function of vital organs, and these approaches can further contribute to an unbalanced complement response. Artificial surfaces of extracorporeal organ support devices, transfusion of blood products, and the application of anticoagulants can all trigger or amplify undesired complement activation. It is, therefore, worth pursuing the evaluation of complement inhibition strategies in the setting of ICU treatment. Recently, clinical studies in COVID-19-related ARDS have shown promising effects of central inhibition at the level of C3 and paved the way for prospective investigation of this approach. In this review, we highlight the fundamental and often neglected role of complement in the ICU, with a special focus on targeted complement inhibition. We will also consider complement substitution therapies to temporarily counteract a disease/treatment-related complement consumption.