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Neurology, Neurosurgery, & Ophthalmology, MS and Neuroimmunology Center, The Dell Medical School at The University of Texas at Austin, United States of America. Teresa.frohman@austin.utexas.edu, Elliot.fohman@austin.utexas.edu

Elliot Frohman: conception, critical revision of manuscript for intellectual content. Nicole Villemarette-Pittman: critical revision of the manuscript for intellectual content. Esther Melamed: critical revision of manuscript for intellectual content. Roberto Alejandro Cruz: critical revision of manuscript for intellectual content. Reid Longmuir: conception: critical revision of manuscript for intellectual content. Thomas Varkey: Critical revision of manuscript for intellectual content. Lawrence Steinman: critical revision for intellectual content and accurate immunologic foundations. Scott Zamvil: conception, critical revision of the manuscript for intellectual content. Teresa C Frohman: conception critical revision of manuscript for intellectual content.

The authors wish to express our gratitude to our medical illustrator, Mr. Jason Ooi, for his evidence-based and hypothetical renditions of the putative pathobiological underpinnings of the SARS-CoV-2 induced ‘Prolific Activation of a Network Immune-Mediated Inflammatory Crisis’ [PANIC] Attack as the basis for severe COVID-19. Furthermore, we express our gratitude for his exceptional illustrations underscoring the pleiotropic mechanisms of action afiliated with high dose methotrexate with leucovorin rescue; as a hypothetical intervention for the purposes of preventing or abolishing the SARS-CoV-2 mediated ‘Prolific Activation of a Network Immune-Mediated Inflammatory Crisis’ [PANIC] Attack.

We also express appreciation to Dr. Matthew S. Parsons (Department of Pathology and Laboratory Medicine, Emory University) for providing critical feedback on our hypotheses regarding SARS-CoV-2 mediated PANIC and the use of HDMTX-LR for therapeutic purposes.

Elliot Frohman: Has received speaker fees from Genzyme, Alexion, Novartis, and consulting fees from Biogen and Serono. Nicole Villemarette-Pittman: Serves as Managing Editor for the Journal of the Neurological Sciences. Esther Melamed: served as a consultant and received honoraria from EMD Serono and Genentech. Roberto Alejandro Cruz: Has received speaker fees from Alexion. Reid Longmuir: consultant for Horizon. Thomas C. Varkey: Nothing to disclose.

Lawrence Steinman: Dr. Steinman is on the Editorial Boards of The Proceedings of the National Academy of Sciences, and the Journal of Neuroimmunology. He has served on the Editorial Board of the The Journal of Immunology and International Immunology. He has served as a member of grant review committees for the National Institutes of Health (NIH) and the National MS Society.

He has served, or serves, as a consultant and received honoraria from Atara Biotherapeutics, Atreca, Biogen-Idec, Celgene, Centocor, Coherus, EMD-Serono, Genzyme, Johnson and Johnson, Novartis, Roche/Genentech, Teva Pharmaceuticals, Inc., and TG Therapeutics. He has served on the Data Safety Monitoring Board for TG Therapeutics. He serves on the Board of Directors of Tolerion and Chairs the Scientific Advisory Board for Atreca.

Currently, Dr. Steinman receives research grant support from the NIH and Atara Biotherapeutics.

Scott Zamvil: Dr. Zamvil is Deputy Editor of Neurology, Neuroimmunology and Neuroinflammation and is an Associate Editor for Frontiers in Immunology and Frontiers in Neurology. He serves on the Advisory Committee for the American Congress on Treatment and Research in Multiple Sclerosis (ACTRIMS) and is a standing member of the research grant review committee for the National Multiple Sclerosis Society (NMSS). He has served on the Editorial Board of the Journal of Clinical Investigation, The Journal of Immunology and The Journal of Neurological Sciences, and has been a charter member of the National Institutes of Health (NIH) Clinical Neuroimmunology and Brain Tumors (CNBT) grant review committee.

He has served, or serves, as a consultant and received honoraria from Alexion, Biogen-Idec, EMD-Serono, Genzyme, Novartis, Roche/Genentech, and Teva Pharmaceuticals, Inc., and has served on Data Safety Monitoring Boards for Lilly, BioMS, Teva and Opexa Therapeutics. Currently, Dr. Zamvil receives research grant support from the NIH, NMSS, Weill Institute, Race to Erase MS and the Maisin Foundation. Teresa Frohman: Has received consulting fees from Alexion.

Subjects:

Keywords:

  • Cytokine
  • Methotrexate
  • Complement
  • Innate immunity
  • Adaptive immunity
  • Alveoli
  • Gas exchange
  • SARS-CoV-2
  • COVID-19
  • Spike protein
  • ACE-2-r

Part I. SARS-CoV-2 triggered ‘PANIC’1 attack in severe COVID-19

Tools:

Journal Title:

JOURNAL OF THE NEUROLOGICAL SCIENCES

Volume:

Volume 415

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

The coronavirus disease 2019 (COVID-19) pandemic has produced a world-wide collapse of social and economic infrastructure, as well as constrained our freedom of movement. This respiratory tract infection is nefarious in how it targets the most distal and highly vulnerable aspect of the human bronchopulmonary tree, specifically, the delicate yet irreplaceable alveoli that are responsible for the loading of oxygen upon red cell hemoglobin for use by all of the body's tissues. In most symptomatic individuals, the disease is a mild immune-mediated syndrome, with limited damage to the lung tissues. About 20% of those affected experience a disease course characterized by a cataclysmic set of immune activation responses that can culminate in the diffuse and irreversible obliteration of the distal alveoli, leading to a virtual collapse of the gas-exchange apparatus. Here, in Part I of a duology on the characterization and potential treatment for COVID-19, we define severe COVID-19 as a consequence of the ability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to trigger what we now designate for the first time as a ‘Prolific Activation of a Network-Immune-Inflammatory Crisis’, or ‘PANIC’ Attack, in the alveolar tree. In Part II we describe an immunotherapeutic hypothesis worthy of the organization of a randomized clinical trial in order to ascertain whether a repurposed, generic, inexpensive, and widely available agent is capable of abolishing ‘PANIC’; thereby preventing or mitigating severe COVID-19, with monumental ramifications for world health, and the global pandemic that continues to threaten it.

Copyright information:

© 2020 The Author(s)

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