Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19.Methods In this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19.Findings In BAL fluid from patients with severe COVID-19 (n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18.2 pM [1.2-1535.0], median [range], n = 9 vs 3.8 [0.0-22.0], n = 11; p = 0. 030), higher levels of the kinin peptide bradykinin-(1-5) (89.6 [0.0-2425.0], n = 21 vs 0.0 [0.0-374.0], n = 19, p = 0. 001), and higher levels of MPO-DNA complexes (699.0 ng/mL [66.0-142621.0], n = 21 vs 70.5 [9.9-960.0], n = 19, p < 0.001) compared to patients without COVID-19.Interpretation Our observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19.