Ivermectin for COVID-19 Treatment: Clinical Response at Quasi-Threshold Doses Via Hypothesized Alleviation of CD147-Mediated Vascular Occlusion
22 Pages Posted: 1 Jul 2020 Last revised: 17 Mar 2021
Date Written: June 26, 2020
The worldwide spread of the COVID-19 pandemic has prompted clinical testing of existing drugs with indicated activity against the SARS-CoV-2 virus. Among antimalarial drugs of such potential is ivermectin (IVM), a macrocyclic lactone of Nobel Prize-winning distinction. A retrospective study of 173 COVID-19 patients treated with IVM in four Florida hospitals at a dose of 200 µg/kg yielded a 40% reduction in mortality compared with 107 controls (15.0% vs. 25.2%, p=0.03). Mortality was cut by 52% with IVM for patients having severe pulmonary disease (38.8% vs. 80.7%, p=0.001). Stabilization and then improvement over 1-2 days frequently occurred for patients who had rapidly deteriorating oxygen status.
It is proposed that higher doses of IVM could yield sharply greater clinical benefits. In several clinical studies, IVM at doses of up to 2,000 µg/kg, ten times that used in the Florida study, were well tolerated. The potential for major dose-response gains is evaluated based upon studies indicating that IVM shields SARS-CoV-2 spike protein and that this spike protein binds to the CD147 transmembrane receptor as well as to ACE2. The abundant distribution of CD147 on red blood cells (RBCs) suggests a hypothesized “catch” and “clump” framework whereby virally-mediated bindings of RBCs to other RBCs, platelets, white blood cells and capillary walls impede blood flow, which in turn may underlie key morbidities of COVID-19.
The proposed catch and clump scenario for COVID-19 has a parallel in malaria, for which CD147 is central to the infectious process. The core morbidity of severe malaria is caused by similar clumps and adhesions to endothelium centering around infected RBCs. These underlie the much greater incidence of severe malaria for blood groups A or B vs. O, caused by adhesive RBC membrane trisaccharides associated with blood groups A and B. COVID-19 is likewise much more prevalent for blood groups A or B vs. O. More generally, hemagglutination, the formation of such RBC-pathogen clusters, is common for enveloped viruses. Under this hypothesized framework, a significantly higher rate of capillary flow in younger people could explain a corresponding decreased severity of COIVD-19. This proposed hypothesis and the associated potential for major IVM dose-response gains could be tested, for example, by monitoring blood flow in COVID-19 patients before and after IVM intake using nailfold capillaroscopy.
Note: Funding: This research received no external funding.
Conflict of Interest: The author declares no conflict of interest.
Keywords: SARS-CoV-2, COVID-19, ivermectin, CD147, basigin, BSG, EMMPRIN, red blood cell, RBC, erythrocyte, hemagglutination, spike glycoprotein, ACE2, hydroxychloroquine, chloroquine, azithromycin, doxycycline
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