Icatibant, a bradykinin 2 receptor antagonist, may improve oxygenation in patients with coronavirus disease 2019 (COVID-19), according to a study recently published in JAMA Network Open Infectious Diseases.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to pulmonary edema in severe COVID-19 cases based on how the virus enters the body. SARS-CoV-2 enters cells via angiotensin-converting enzyme 2 (ACE2), which is involved in degrading kinin des-Arg9-bradykinin. Kinin des-Arg9-bradykinin is a potent vasoactive peptide that can cause vascular leakage. The loss of ACE2 might lead to plasma leakage and further activation of the plasma kallikrein-kinin system, resulting in more bradykinin formation and more stimulation of bradykinin 2 receptors, which would ultimately contribute to pulmonary angioedema. This mechanistic pathway highlights potential for intervention in COVID-19 patients. Therefore, this case-control study investigated whether treatment with the bradykinin 2 receptor antagonist icatibant could be used as a treatment strategy in patients with COVID-19.
In total, 10 patients were included in this study and treated with 3 doses of 30 mg icatibant via subcutaneous injection at 6-hour intervals. The study included patients with polymerase chain reaction assay–confirmed SARS-CoV-2, an oxygen saturation <90% without supplemental oxygen, a computed tomography severity score ≥7, and a requirement of ≥3 L/min of supplemental oxygen. For 9 patients who received icatibant, 2 matched control patients admitted before approval of this treatment were selected; 1 patient who received icatibant was discharged on day 7, and no matched control was identified. Control patients with COVID-19 were matched for sex, age, body mass index, and day of illness. In total, 9 patients were matched with 18 controls. The primary outcome variable was a change in oxygen need and oxygenation expressed as absolute number of liters per hour. Secondary outcomes included changes in dimerized plasmin fragment D (D-dimer), fever, and safety.
Results showed that icatibant was well tolerated and improved oxygenation among COVID-19 patients. In all 9 patients who received icatibant, there was a marked decrease in oxygen supplementation. After 3 injections of icatibant, 4 (44%) patients were no longer dependent on oxygen supplementation within 10 to 35 hours. In 8 (89%) patients treated with icatibant, a reduction of ≥3 L/min in oxygen was observed after 24 hours. Of the 18 matched controls, 3 (17%) showed a spontaneous reduction of ≥3 L/min of oxygen after 24 hours. However, there was a resurgence in the need for oxygen in 3 patients treated with icatibant, which may be due to the 2-hour half-life of icatibant. Icatibant treatment was well tolerated in all 10 patients who received the drug, and no serious adverse events were reported. There was no clear association with D-dimer concentrations and fever.
An important limitation is that this study is exploratory and is not a randomized clinical trial.
Overall, the study authors conclude that, “This study found evidence of an association between receipt of icatibant and improved oxygenation, suggesting that targeting the kallikrein-kinin system in patients with COVID-19, especially in the early stages of disease when patients are hypoxic and are admitted to the hospital, might be beneficial.”
van de Veerdonk FL, Kouijzer IJE, de Nooijer AH, et al. Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19. JAMA Network Open. 2020;3(8):e2017708. doi: 10.1001/jamanetworkopen.2020.17708