Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19
Eli Mansour,
Andre C. Palma,
Raisa G. Ulaf,
Luciana C. Ribeiro,
Ana Flavia Bernardes,
Thyago A. Nunes,
Marcus V. Agrela,
Bruna Bombassaro,
Milena Monfort-Pires,
Rafael L. Camargo,
Eliana P. Araujo,
Natalia S. Brunetti,
Alessandro S. Farias,
Antônio Luís E. Falcão,
Thiago Martins Santos,
Plinio Trabasso,
Rachel P. Dertkigil,
Sergio S. Dertkigil,
Maria Luiza Moretti,
Licio A. Velloso
Affiliations
Eli Mansour
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Andre C. Palma
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Raisa G. Ulaf
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Luciana C. Ribeiro
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Ana Flavia Bernardes
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Thyago A. Nunes
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Marcus V. Agrela
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Bruna Bombassaro
Obesity and Comorbidities Research Center, University of Campinas, 13083-864 Campinas, São Paulo, Brazil
Milena Monfort-Pires
Obesity and Comorbidities Research Center, University of Campinas, 13083-864 Campinas, São Paulo, Brazil
Rafael L. Camargo
Obesity and Comorbidities Research Center, University of Campinas, 13083-864 Campinas, São Paulo, Brazil
Eliana P. Araujo
Obesity and Comorbidities Research Center, University of Campinas, 13083-864 Campinas, São Paulo, Brazil
Natalia S. Brunetti
Autoimmune Research Lab, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, 13083-862 Campinas, São Paulo, Brazil
Alessandro S. Farias
Autoimmune Research Lab, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, 13083-862 Campinas, São Paulo, Brazil
Antônio Luís E. Falcão
Department of Surgery, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Thiago Martins Santos
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Plinio Trabasso
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Rachel P. Dertkigil
Department of Radiology, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Sergio S. Dertkigil
Department of Radiology, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Maria Luiza Moretti
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Licio A. Velloso
Department of Internal Medicine, School of Medical Sciences, University of Campinas, 13083-887 Campinas, São Paulo, Brazil
Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin–kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin–kallikrein system in two markers that indicate improved disease recovery.