Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
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.
Article activity feed
-
-
SciScore for 10.1101/2020.08.11.20167353: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Inclusion criteria were age at least 18 years at the time of signing the consent form, symptom duration of 12 days or less upon recruitment, SARS-CoV-2 diagnosis by RT-PCR method according to the Berlin-Charité protocol 56, diagnosis of COVID-19 typical pneumonia confirmed by CT of the chest and scored by two lung expert radiologists, SpO2 ≤ 94% in ambient air or Pa02/FiO2 ≤ 300 mmHg, willingness of study participants to accept randomization to any assigned treatment arm, patient or responsible family member signing the consent form, and agreement that patient should not enroll in any other experimental study prior to completion of the 28-day … SciScore for 10.1101/2020.08.11.20167353: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Consent: Inclusion criteria were age at least 18 years at the time of signing the consent form, symptom duration of 12 days or less upon recruitment, SARS-CoV-2 diagnosis by RT-PCR method according to the Berlin-Charité protocol 56, diagnosis of COVID-19 typical pneumonia confirmed by CT of the chest and scored by two lung expert radiologists, SpO2 ≤ 94% in ambient air or Pa02/FiO2 ≤ 300 mmHg, willingness of study participants to accept randomization to any assigned treatment arm, patient or responsible family member signing the consent form, and agreement that patient should not enroll in any other experimental study prior to completion of the 28-day follow-up.
IACUC: This trial has been registered at the Brazilian Clinical Trials Registry (http://www.ensaiosclinicos.gov.br/rg/?q=U1111-1250-1843); Universal Trial Number (UTN): U1111-1250-1843 and approved by the local Ethical Review Committee of the Clinics Hospital of the University of Campinas (protocol CAEE: 30227920.9.0000.5404).Randomization Study design and patients: This was a phase II, single center, three-arm parallel group, open-label randomized clinical trial (RCT) conducted at the Clinics Hospital, University of Campinas. Blinding Blinding: This was an open-label trial; thus, neither the trial participant nor the care providers were blinded. Power Analysis not detected. Sex as a biological variable Exclusion criteria were pregnant or breastfeeding women (a beta-HCG level was determined in all eligible women of childbearing age); severe renal impairment (estimated glomerular filtration rate ≤ 30 ml/min/1.73 m2), patients receiving continuous renal replacement therapy (hemodialysis or peritoneal dialysis), or previous renal transplant; severe liver disease (AST or ALT 5X above the reference value); HIV infection (HIV was tested for in all eligible patients); or patients with any other immunodeficiencies, previous diagnosis of cancer, previous diagnosis of hereditary angioedema, previous ischemic myocardial disease, previous thromboembolic disease, current use of immunosuppressive drug therapy, or use of any experimental treatment for SARS-CoV-2 infection within 30 days prior to screening. Table 2: Resources
Software and Algorithms Sentences Resources All data (outcomes, questionnaires, clinical data, CT, and laboratory measurements) were retrieved from the online official medical records of the hospital and were immediately uploaded into REDCap (https://redcap.vanderbilt.edu). REDCapsuggested: (REDCap, RRID:SCR_003445)Statistical analysis: All statistical analyses were performed using SPSS version 22.0 and GraphPad Prism 8.0. SPSSsuggested: (SPSS, RRID:SCR_002865)GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The main weaknesses of this study are the small number of patients, and the fact that pharmacological intervention was instituted approximately eight days after the beginning of symptoms. An important reason for restricting the cohort to 30 patients was that, during enrollment, it was demonstrated that dexamethasone could reduce mortality in patients with severe COVID-19 8. Thus, we consider that the continuity of ongoing protocols or beginning of new protocols should ethically include dexamethasone in all arms. Conversely, regarding the fact that the mean time for patient inclusion was eight days, which could be a late stage for interventions targeting bradykinin, there is little that could be done, because of the natural course of the disease, which prompts patients to seek medical attention at this stage. Even if patients were advised to seek medical attention at an earlier stage, most of them would not progress to severe COVID-19. Therefore, only the development of methods that predict severe progression of disease at an early stage could reduce time to inclusion. In conclusion, this is the first clinical trial reporting the impact of pharmacological inhibition of the kinin-kallikrein system in patients with severe COVID-19. The lack of findings regarding mortality and time to clinical improvement could be attributed to small sample size and beginning the intervention at a late stage. Nevertheless, improvement in CT lung scores and increased blood eosinophils suggest that...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
