Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome
- Radboud University Medical Center, Netherlands
- Radboud University Medical Centre, Netherlands
Abstract
COVID-19 patients can present with pulmonary edema early in disease. We propose that the this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Here we hypothesize that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19. We propose that blocking the B2 receptor and inhibiting kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents.
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Author details
Frank L van de Veerdonk
Funding
No external funding was received for this work.
Copyright
© 2020, van de Veerdonk et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome
eLife 9:e57555.
https://doi.org/10.7554/eLife.57555
Further reading
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- Medicine
- Microbiology and Infectious Disease
- Epidemiology and Global Health
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eLife has published articles on a wide range of infectious diseases, including COVID-19, influenza, tuberculosis, HIV/AIDS, malaria and typhoid fever.
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Background:
Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer.
Methods:
This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate.
Results:
Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%).
Conclusions:
Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit.
Funding:
No external funding was received for this work.
Clinical trial number:
ClinicalTrials.gov: NCT05880927
