Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 – A proof-of-concept study
Abstract 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 accumulation of bradykinin. In this open-label, randomized clinical trial, 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. Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in significant changes in disease mortality and time to clinical improvement. However, both compounds promoted significant improvement of lung computed tomography scores and increased blood eosinophils, which has been reported as an indicator of disease recovery. In this small cohort, we found evidence for a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery..
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Preprint| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 28. Jan. Zur Gesamtaufnahme - year:2021 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mansour, Eli [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2020.08.11.20167353 |
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| funding: |
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| PPN (Katalog-ID): |
XBI018613136 |
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| 520 | |a Abstract 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 accumulation of bradykinin. In this open-label, randomized clinical trial, 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. Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in significant changes in disease mortality and time to clinical improvement. However, both compounds promoted significant improvement of lung computed tomography scores and increased blood eosinophils, which has been reported as an indicator of disease recovery. In this small cohort, we found evidence for a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery. | ||
| 700 | 1 | |a Palma, Andre C. |e verfasserin |4 aut | |
| 700 | 1 | |a Ulaf, Raisa G. |e verfasserin |4 aut | |
| 700 | 1 | |a Ribeiro, Luciana C. |e verfasserin |4 aut | |
| 700 | 1 | |a Bernardes, Ana Flavia |e verfasserin |4 aut | |
| 700 | 1 | |a Nunes, Thyago A. |e verfasserin |4 aut | |
| 700 | 1 | |a Agrela, Marcus V. |e verfasserin |4 aut | |
| 700 | 1 | |a Bombassaro, Bruna |e verfasserin |4 aut | |
| 700 | 1 | |a Monfort-Pires, Milena |e verfasserin |4 aut | |
| 700 | 1 | |a Camargo, Rafael L. |e verfasserin |4 aut | |
| 700 | 1 | |a Araujo, Eliana P. |e verfasserin |4 aut | |
| 700 | 1 | |a Brunetti, Natalia S. |e verfasserin |4 aut | |
| 700 | 1 | |a Farias, Alessandro S. |e verfasserin |4 aut | |
| 700 | 1 | |a Falcão, Antônio Luís E. |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Thiago Martins |e verfasserin |4 aut | |
| 700 | 1 | |a Trabasso, Plinio |e verfasserin |4 aut | |
| 700 | 1 | |a Dertkigil, Rachel P. |e verfasserin |4 aut | |
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