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Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19

Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19 Research Letter | Infectious Diseases Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19 Frank L. van de Veerdonk, MD, PhD; Ilse J. E. Kouijzer, MD, PhD; Aline H. de Nooijer, MD; Hans G. van der Hoeven, MD, PhD; Coen Maas, PhD; Mihai G. Netea, MD, PhD; Roger J. M. Brüggemann, PharmD, PhD Introduction Pulmonary edema is a prominent feature in patients with severe coronavirus disease 2019 (COVID- Author affiliations and article information are listed at the end of this article. 19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cell via angiotensin- 1 9 converting enzyme 2 (ACE2). ACE2 is involved in degrading the kinin des-Arg -bradykinin, a potent vasoactive peptide that can cause vascular leakage. Loss of ACE2 might lead to plasma leakage and further activation of the plasma kallikrein-kinin system with more bradykinin formation that could contribute to pulmonary angioedema via stimulation of bradykinin 2 receptors. We investigated whether treatment with the bradykinin 2 receptor antagonist icatibant in patients with COVID-19 could be used as a treatment strategy. Methods This case-control study was approved by CMO region Arnhem-Nijmegen, the local ethical committee, which granted a waiver of consent because treatment concerned a licensed drug that would be given in an off-label setting. Informed consent was obtained in all patients. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Patients with COVID-19 were admitted from March to May 2020. We included 10 patients for treatment with 3 doses of 30 mg of icatibant (Firazyr; Shire Pharmaceuticals Ireland Limited) by subcutaneous injection at 6-hour intervals. Patients were eligible for icatibant treatment if they had confirmed SARS-CoV-2 by polymerase chain reaction assay, an oxygen saturation of less than 90% without supplemental oxygen, needed 3 L/min supplemental oxygen or more, and had a computed tomography severity score of 7 or greater. Patients with acute ischemic events at time of eligibility were excluded. For 9 patients who received icatibant on the ward, 2 matched control patients admitted prior to approval of this treatment were selected. Control patients with COVID-19 were matched on the factors sex, age, body mass index, and day of illness. One patient started receiving icatibant in the intensive care unit and was transferred to the ward with high-flow oxygen supplementation within 24 hours and discharged on day 7. We did not identify a matched control for this patient, so we were not able to evaluate the association of icatibant with outcomes for this individual. A change in oxygen need and oxygenation expressed as absolute number of liters per hour served as the primary outcome variable. Secondary outcomes included changes in D-dimer (dimerized plasmin fragment D), fever, and safety. Results Nine cases were matched to 18 controls. The mean (SD) age was 55 (12.8) years for cases and 58 (10.5) years for controls. Most cases (9 of 10 [90%]) and controls (16 of 18 [90%]) were men. Patient and matched control characteristics are shown in the Table. Nine patients were prescribed icatibant on the ward. In all 9 patients, there was a marked decrease in oxygen supplementation (Figure). After 3 injections of icatibant, 4 patients (44%) were no longer oxygen dependent within 10 to 35 hours. In 5 patients (56%), there was a substantial decrease of oxygen supplementation after treatment with icatibant (Figure). Overall, in 8 of 9 patients (89%) treated with icatibant, a reduction of 3 L/min in oxygen supplementation or greater after 24 hours was observed (Figure). Of 18 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 1/4 JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 Table. Characteristics of 10 COVID-19 Patients With Icatibant Treatment and Matched Controls D-dimer, ng/mL Days of Temperature at a b Participant No./sex/age (decade) BMI illness At admission 24 h admission, °C Cases 1/M/30s 23 12 3760 11 530 39.9 2/M/50s 30 15 650 <500 40.0 3/M/60s 29 10 NA 690 38.4 4/M/40s 27 12 NA 920 40.0 5/M/60s 26 11 530 630 39.3 6/M/70s 24 7 NA <500 39.1 7/M/30s 25 8 1730 3560 38.3 8/M/60s 33 10 870 1240 37.1 9/F/50s 32 11 1590 1030 40.1 10/M/40s 28 15 1600 1000 37.1 Controls 1a/M/30s 23 2 1360 NA 38.1 1b/M/40s 27 13 1750 NA 37.8 2a/M/50s 26 15 1360 780 36.9 2b/M/50s 27 15 1500 NA 39.9 3a/M/60s 25 9 NA NA 37.1 3b/M/70s 25 9 3710 3710 39.2 4a/M/50s 28 10 760 700 39.4 4b/M/50s 27 8 620 500 39.6 5a/M/60s 22 11 1520 940 37.1 Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters 5b/M/60s 27 11 1550 1340 39.4 squared); COVID-19, coronavirus disease 2019; 6a/M/60s 25 6 700 840 38.2 D-dimer, dimerized plasmin fragment D; F, female; M, 6b/M/70s 29 8 3660 2080 37.7 male; NA, not applicable. 7a/M/40s 21 5 33 790 7060 36.9 SI conversion: To convert D-dimer to nmol/L, multiply 7b/M/40s 31 12 2210 1660 38.0 by 5.476. 8a/F/60s 36 4 1740 NA 38.7 Days of illness at start icatibant or 24 hours after 8b/F/60s 27 11 510 600 38.0 admission (controls). 9a/M/50s 22 10 <500 <500 39.5 D-dimer 24 hours after icatibant or 48 hours after 9b/M/50s 22 14 3300 2150 38.8 admission (controls). Figure. Changes in Oxygen Supplementation at Baseline and 24 Hours in Individual Patients and Controls T = 0 T = 24 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Patient Control Oxygen supplementation in individual patients (n = 9) and matched controls (n = 18). JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 2/4 O , L/min –3 L/min –1 L/min –5 L/min –4 L/min –3 L/min –3 L/min –4 L/min –5 L/min –4 L/min –3 L/min 3 L/min 0 L/min 0 L/min –2 L/min 0 L/min –2 L/min 0 L/min 0 L/min –1 L/min 2 L/min –1 L/min –3.5 L/min –2 L/min 1 L/min 1 L/min 0 L/min –4 L/min JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 matched controls, only 3 (17%) showed a spontaneous reduction in oxygen supplementation of 3 L/min or greater within 24 hours. We noted that in 3 patients treated with icatibant there was a resurgence in the need for oxygen supplementation. Icatibant treatment was well tolerated in all 10 patients who received the drug. There were no severe adverse events. There was no clear association with D-dimer concentrations and fever. Discussion 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. An important limitation of the current study is that it is exploratory and not a randomized clinical trial. The observed resurgence of oxygen need in some patients after icatibant may be due to icatibant’s short half life of about 2 hours. We propose that treatment strategies targeting the kallikrein-kinin system should be investigated in randomized trials for patients with COVID-19. ARTICLE INFORMATION Accepted for Publication: July 11, 2020. Published: August 13, 2020. doi:10.1001/jamanetworkopen.2020.17708 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020van de Veerdonk FL et al. JAMA Network Open. Corresponding Author: Frank L. van de Veerdonk, MD, PhD, Department of Internal Medicine, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands (frank.vandeveerdonk@radboudumc.nl). Author Affiliations: Radboudumc Institute for Molecular Life Sciences, Department of Internal Medicine, Radboudumc, Nijmegen, the Netherlands (van de Veerdonk, Kouijzer, de Nooijer, Netea); Radboudumc Center for Infectious Diseases, Nijmegen, the Netherlands (van de Veerdonk, Kouijzer, Netea, Brüggemann); Department of Intensive Care Medicine, Radboudumc, Nijmegen, the Netherlands (van der Hoeven); Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands (Maas); Life and Medical Sciences Institute, Department for Genomics & Immunoregulation, University of Bonn, Bonn, Germany (Netea); Radboud Institute for Health Sciences, Department of Pharmacy, Radboudumc, Nijmegen, the Netherlands (Brüggemann). Author Contributions: Drs van de Veerdonk and Kouijzer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs van de Veerdonk and Kouijzer share first authorship. Concept and design: van de Veerdonk, Kouijzer, Maas, Netea, Brüggemann. Acquisition, analysis, or interpretation of data: van de Veerdonk, Kouijzer, de Nooijer, van der Hoeven, Brüggemann. Drafting of the manuscript: van de Veerdonk, Kouijzer, de Nooijer, Brüggemann. Critical revision of the manuscript for important intellectual content: van de Veerdonk, van der Hoeven, Maas, Netea, Brüggemann. Statistical analysis: Kouijzer, Brüggemann. Administrative, technical, or material support: de Nooijer, Brüggemann. Supervision: van de Veerdonk, van der Hoeven, Netea, Brüggemann. Conflict of Interest Disclosures: Dr Netea reported serving as scientific founder for TTxD outside the submitted work. No other disclosures were reported. Additional Contributions: The authors would like to thank Nico A. F. Janssen, MD; Inge Grondman, MD; Jos W. M. van der Meer, MD, PhD; Marcel van Deuren, MD, PhD; Rosanne van Crevel, MSc; Leo A. B. Joosten, PhD; Matthias Prokop, MD, PhD; Heiman F. L. Wertheim, MD, PhD; Jeanette C. Rahamat-Langendoen, MD, PhD; David M. Burger, PharmDl, PhD; Monique H. E. Reijers, MD, PhD; Peter Pickkers, MD, PhD; Lennie P. G. Derde, MD, PhD; Steven de Maat, PhD; Quirjin de Mast, MD, PhD; Arjan van Laarhoven, MD, PhD; Anna Simon, MD, PhD; Jacobien J. Hoogerwerf, MD, PhD; Meta Michels, MD, PhD; Michelle Gompelman, MD, PhD; Olivier Richel, MD, PhD; Simone Smits, PhD; Wouter Hoefsloot, MD, PhD; Kit Roes, PhD; and C. M. Mulders-Manders for their contribution to this JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 3/4 JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 proof-of-concept study. We also thank the RCI COVID-19 research team. They were not compensated for their contributions. REFERENCES 1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052 2. van de Veerdonk FL, Netea MG, van Deuren M, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020;9:e57555. doi:10.7554/eLife.57555 3. EPAR Assessment Report 09-020-2018. Accessed April 2, 2020. https://www.ema.europa.eu/en/medicines/ human/EPAR/firazyr 4. Li K, Fang Y, Li W, et al. CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19). Eur Radiol. 2020;30(8):4407-4416. doi:10.1007/s00330-020-06817-6 JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 4/4 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19

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Abstract

Research Letter | Infectious Diseases Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19 Frank L. van de Veerdonk, MD, PhD; Ilse J. E. Kouijzer, MD, PhD; Aline H. de Nooijer, MD; Hans G. van der Hoeven, MD, PhD; Coen Maas, PhD; Mihai G. Netea, MD, PhD; Roger J. M. Brüggemann, PharmD, PhD Introduction Pulmonary edema is a prominent feature in patients with severe coronavirus disease 2019 (COVID- Author affiliations and article information are listed at the end of this article. 19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cell via angiotensin- 1 9 converting enzyme 2 (ACE2). ACE2 is involved in degrading the kinin des-Arg -bradykinin, a potent vasoactive peptide that can cause vascular leakage. Loss of ACE2 might lead to plasma leakage and further activation of the plasma kallikrein-kinin system with more bradykinin formation that could contribute to pulmonary angioedema via stimulation of bradykinin 2 receptors. We investigated whether treatment with the bradykinin 2 receptor antagonist icatibant in patients with COVID-19 could be used as a treatment strategy. Methods This case-control study was approved by CMO region Arnhem-Nijmegen, the local ethical committee, which granted a waiver of consent because treatment concerned a licensed drug that would be given in an off-label setting. Informed consent was obtained in all patients. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Patients with COVID-19 were admitted from March to May 2020. We included 10 patients for treatment with 3 doses of 30 mg of icatibant (Firazyr; Shire Pharmaceuticals Ireland Limited) by subcutaneous injection at 6-hour intervals. Patients were eligible for icatibant treatment if they had confirmed SARS-CoV-2 by polymerase chain reaction assay, an oxygen saturation of less than 90% without supplemental oxygen, needed 3 L/min supplemental oxygen or more, and had a computed tomography severity score of 7 or greater. Patients with acute ischemic events at time of eligibility were excluded. For 9 patients who received icatibant on the ward, 2 matched control patients admitted prior to approval of this treatment were selected. Control patients with COVID-19 were matched on the factors sex, age, body mass index, and day of illness. One patient started receiving icatibant in the intensive care unit and was transferred to the ward with high-flow oxygen supplementation within 24 hours and discharged on day 7. We did not identify a matched control for this patient, so we were not able to evaluate the association of icatibant with outcomes for this individual. A change in oxygen need and oxygenation expressed as absolute number of liters per hour served as the primary outcome variable. Secondary outcomes included changes in D-dimer (dimerized plasmin fragment D), fever, and safety. Results Nine cases were matched to 18 controls. The mean (SD) age was 55 (12.8) years for cases and 58 (10.5) years for controls. Most cases (9 of 10 [90%]) and controls (16 of 18 [90%]) were men. Patient and matched control characteristics are shown in the Table. Nine patients were prescribed icatibant on the ward. In all 9 patients, there was a marked decrease in oxygen supplementation (Figure). After 3 injections of icatibant, 4 patients (44%) were no longer oxygen dependent within 10 to 35 hours. In 5 patients (56%), there was a substantial decrease of oxygen supplementation after treatment with icatibant (Figure). Overall, in 8 of 9 patients (89%) treated with icatibant, a reduction of 3 L/min in oxygen supplementation or greater after 24 hours was observed (Figure). Of 18 Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 1/4 JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 Table. Characteristics of 10 COVID-19 Patients With Icatibant Treatment and Matched Controls D-dimer, ng/mL Days of Temperature at a b Participant No./sex/age (decade) BMI illness At admission 24 h admission, °C Cases 1/M/30s 23 12 3760 11 530 39.9 2/M/50s 30 15 650 <500 40.0 3/M/60s 29 10 NA 690 38.4 4/M/40s 27 12 NA 920 40.0 5/M/60s 26 11 530 630 39.3 6/M/70s 24 7 NA <500 39.1 7/M/30s 25 8 1730 3560 38.3 8/M/60s 33 10 870 1240 37.1 9/F/50s 32 11 1590 1030 40.1 10/M/40s 28 15 1600 1000 37.1 Controls 1a/M/30s 23 2 1360 NA 38.1 1b/M/40s 27 13 1750 NA 37.8 2a/M/50s 26 15 1360 780 36.9 2b/M/50s 27 15 1500 NA 39.9 3a/M/60s 25 9 NA NA 37.1 3b/M/70s 25 9 3710 3710 39.2 4a/M/50s 28 10 760 700 39.4 4b/M/50s 27 8 620 500 39.6 5a/M/60s 22 11 1520 940 37.1 Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters 5b/M/60s 27 11 1550 1340 39.4 squared); COVID-19, coronavirus disease 2019; 6a/M/60s 25 6 700 840 38.2 D-dimer, dimerized plasmin fragment D; F, female; M, 6b/M/70s 29 8 3660 2080 37.7 male; NA, not applicable. 7a/M/40s 21 5 33 790 7060 36.9 SI conversion: To convert D-dimer to nmol/L, multiply 7b/M/40s 31 12 2210 1660 38.0 by 5.476. 8a/F/60s 36 4 1740 NA 38.7 Days of illness at start icatibant or 24 hours after 8b/F/60s 27 11 510 600 38.0 admission (controls). 9a/M/50s 22 10 <500 <500 39.5 D-dimer 24 hours after icatibant or 48 hours after 9b/M/50s 22 14 3300 2150 38.8 admission (controls). Figure. Changes in Oxygen Supplementation at Baseline and 24 Hours in Individual Patients and Controls T = 0 T = 24 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Patient Control Oxygen supplementation in individual patients (n = 9) and matched controls (n = 18). JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 2/4 O , L/min –3 L/min –1 L/min –5 L/min –4 L/min –3 L/min –3 L/min –4 L/min –5 L/min –4 L/min –3 L/min 3 L/min 0 L/min 0 L/min –2 L/min 0 L/min –2 L/min 0 L/min 0 L/min –1 L/min 2 L/min –1 L/min –3.5 L/min –2 L/min 1 L/min 1 L/min 0 L/min –4 L/min JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 matched controls, only 3 (17%) showed a spontaneous reduction in oxygen supplementation of 3 L/min or greater within 24 hours. We noted that in 3 patients treated with icatibant there was a resurgence in the need for oxygen supplementation. Icatibant treatment was well tolerated in all 10 patients who received the drug. There were no severe adverse events. There was no clear association with D-dimer concentrations and fever. Discussion 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. An important limitation of the current study is that it is exploratory and not a randomized clinical trial. The observed resurgence of oxygen need in some patients after icatibant may be due to icatibant’s short half life of about 2 hours. We propose that treatment strategies targeting the kallikrein-kinin system should be investigated in randomized trials for patients with COVID-19. ARTICLE INFORMATION Accepted for Publication: July 11, 2020. Published: August 13, 2020. doi:10.1001/jamanetworkopen.2020.17708 Open Access: This is an open access article distributed under the terms of the CC-BY License.©2020van de Veerdonk FL et al. JAMA Network Open. Corresponding Author: Frank L. van de Veerdonk, MD, PhD, Department of Internal Medicine, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands (frank.vandeveerdonk@radboudumc.nl). Author Affiliations: Radboudumc Institute for Molecular Life Sciences, Department of Internal Medicine, Radboudumc, Nijmegen, the Netherlands (van de Veerdonk, Kouijzer, de Nooijer, Netea); Radboudumc Center for Infectious Diseases, Nijmegen, the Netherlands (van de Veerdonk, Kouijzer, Netea, Brüggemann); Department of Intensive Care Medicine, Radboudumc, Nijmegen, the Netherlands (van der Hoeven); Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands (Maas); Life and Medical Sciences Institute, Department for Genomics & Immunoregulation, University of Bonn, Bonn, Germany (Netea); Radboud Institute for Health Sciences, Department of Pharmacy, Radboudumc, Nijmegen, the Netherlands (Brüggemann). Author Contributions: Drs van de Veerdonk and Kouijzer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs van de Veerdonk and Kouijzer share first authorship. Concept and design: van de Veerdonk, Kouijzer, Maas, Netea, Brüggemann. Acquisition, analysis, or interpretation of data: van de Veerdonk, Kouijzer, de Nooijer, van der Hoeven, Brüggemann. Drafting of the manuscript: van de Veerdonk, Kouijzer, de Nooijer, Brüggemann. Critical revision of the manuscript for important intellectual content: van de Veerdonk, van der Hoeven, Maas, Netea, Brüggemann. Statistical analysis: Kouijzer, Brüggemann. Administrative, technical, or material support: de Nooijer, Brüggemann. Supervision: van de Veerdonk, van der Hoeven, Netea, Brüggemann. Conflict of Interest Disclosures: Dr Netea reported serving as scientific founder for TTxD outside the submitted work. No other disclosures were reported. Additional Contributions: The authors would like to thank Nico A. F. Janssen, MD; Inge Grondman, MD; Jos W. M. van der Meer, MD, PhD; Marcel van Deuren, MD, PhD; Rosanne van Crevel, MSc; Leo A. B. Joosten, PhD; Matthias Prokop, MD, PhD; Heiman F. L. Wertheim, MD, PhD; Jeanette C. Rahamat-Langendoen, MD, PhD; David M. Burger, PharmDl, PhD; Monique H. E. Reijers, MD, PhD; Peter Pickkers, MD, PhD; Lennie P. G. Derde, MD, PhD; Steven de Maat, PhD; Quirjin de Mast, MD, PhD; Arjan van Laarhoven, MD, PhD; Anna Simon, MD, PhD; Jacobien J. Hoogerwerf, MD, PhD; Meta Michels, MD, PhD; Michelle Gompelman, MD, PhD; Olivier Richel, MD, PhD; Simone Smits, PhD; Wouter Hoefsloot, MD, PhD; Kit Roes, PhD; and C. M. Mulders-Manders for their contribution to this JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 3/4 JAMA Network Open | Infectious Diseases Outcomes Associated With Kinin B2 Receptor Antagonist for Treatment of COVID-19 proof-of-concept study. We also thank the RCI COVID-19 research team. They were not compensated for their contributions. REFERENCES 1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-280.e8. doi:10.1016/j.cell.2020.02.052 2. van de Veerdonk FL, Netea MG, van Deuren M, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020;9:e57555. doi:10.7554/eLife.57555 3. EPAR Assessment Report 09-020-2018. Accessed April 2, 2020. https://www.ema.europa.eu/en/medicines/ human/EPAR/firazyr 4. Li K, Fang Y, Li W, et al. CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19). Eur Radiol. 2020;30(8):4407-4416. doi:10.1007/s00330-020-06817-6 JAMA Network Open. 2020;3(8):e2017708. doi:10.1001/jamanetworkopen.2020.17708 (Reprinted) August 13, 2020 4/4

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Published: Aug 13, 2020

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