Paul E Marik1,4, Jose Iglesias2,4, Joseph Varon3,4 and Pierre Kory4
Abstract
International Journal of Immunopathology and Pharmacology Volume 35: 1–16
© The Author(s) 2021
Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/20587384211048026 journals.sagepub.com/home/iji
COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled in!ammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-in!ammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.
Peter A. McCullough, MD, MPH,a,b,c Ronan J. Kelly, MD,a Gaetano Ruocco, MD,d Edgar Lerma, MD,e James Tumlin, MD,f Kevin R. Wheelan, MD,a,b,c Nevin Katz, MD,g Norman E. Lepor, MD,h Kris Vijay, MD,i Harvey Carter, MD,j
Bhupinder Singh, MD,k Sean P. McCullough, BS,l Brijesh K. Bhambi, MD,m Alberto Palazzuoli, MD, PhD,n
Gaetano M. De Ferrari, MD, PhD,o Gregory P. Milligan, MD, MPH,a Taimur Safder, MD, MPH,a Kristen M. Tecson, PhD,b Dee Dee Wang, MD,p John E. McKinnon, MD,p William W. O’Neill, MD,p Marcus Zervos, MD,p Harvey A. Risch, MD, PhD
Abstract
American Journal of Medicine
Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID- 19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and exe- cution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS- CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospi- talization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic ther- apy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.
! 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) The American Journal of Medicine (2021) 134:16−22
Peter A. McCullough, MD, MPH,a,b,c Ronan J. Kelly, MD,a Gaetano Ruocco, MD,d Edgar Lerma, MD,e James Tumlin, MD,f Kevin R. Wheelan, MD,a,b,c Nevin Katz, MD,g Norman E. Lepor, MD,h Kris Vijay, MD,i Harvey Carter, MD,j
Bhupinder Singh, MD,k Sean P. McCullough, BS,l Brijesh K. Bhambi, MD,m Alberto Palazzuoli, MD, PhD,n
Gaetano M. De Ferrari, MD, PhD,o Gregory P. Milligan, MD, MPH,a Taimur Safder, MD, MPH,a Kristen M. Tecson, PhD,b Dee Dee Wang, MD,p John E. McKinnon, MD,p William W. O’Neill, MD,p Marcus Zervos, MD,p Harvey A. Risch, MD, PhD
Abstract
American Journal of Medicine
Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID- 19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and exe- cution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS- CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospi- talization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic ther- apy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.
! 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) The American Journal of Medicine (2021) 134:16−22