LAUSR

COVID‐19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement over‐activation, has a pivotal role in severe COVID‐19 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet–neutrophil activation, and hypercoagulability. SARS‐CoV‐2 can directly activate the complement system by the classic, alternative, and lectin pathways, and infected cells can produce intracellular complement (the complesome). COVID‐19 severity appears to be associated with the degree of complement activation, and it has been hypothesized that patients with COVID‐19 may benefit from therapeutic complement inhibition. Different complement cascade molecules may be targeted with potential advantages and disadvantages. Which target(s) is the most effective and when is the best timing for intervention remain open questions. Early phase I and phase II clinical trials have shown promising but conflicting results, warranting phase III controlled randomized trials. Upstream complement inhibition appears to better and more effectively block hyperinflammation with potential clinical significance. Understanding how SARS‐CoV‐2 exploits the complement system can add precious information about the pathogenesis of other infections, inflammatory, and autoimmune diseases beyond COVID‐19.