Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced ‘PANIC’ 1 attack

Elliot M. Frohman, Nicole R. Villemarette-Pittman, Roberto Alejandro Cruz, Reid Longmuir, Vernon Rowe, Elizabeth S. Rowe, Thomas C. Varkey, Lawrence Steinman, Scott S. Zamvil, Teresa C. Frohman

Research output: Contribution to journalReview articlepeer-review

25 Scopus citations


Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish ‘PANIC’, thereby ‘left-shifting’ severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered ‘PANIC Attack’. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.

Original languageEnglish (US)
Article number116935
JournalJournal of the Neurological Sciences
StatePublished - Aug 15 2020
Externally publishedYes


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

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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