Abstract: Review J Clin Med Res. 2022;14(2):53-79 “MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale Pierre Korya, f, Ginfranco Umberto Medurib, Jose Iglesiasc, Joseph Varond, Flavio Adsuara Cadegianie, Paul E. Marika Abstract Keywords: MATH plus; Methylprednisolone; Ascorbic acid; Thiamine; Heparin In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended “supportive care only” avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of “what was working and what wasn’t working”, the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. Manuscript submitted January 5, 2022, accepted February 8, 2022 Published online February 24, 2022 aFront Line Critical Care Consortium (FLCCC.org), Washington DC, USA bDepartment of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA cJersey Shore University Medical Center, Hackensack School of Medicine at Seton Hall, NJ, USA dUniversity of Texas Health Science Center, Houston, TX, USA eCorpometria Institute, Brasilia, Brazil fCorresponding Author: Pierre Kory, Front Line Critical Care Consortium (FLCCC.org), Washington DC, USA. Email: pierrekory@icloud.com doi: https://doi.org/10.14740/jocmr4658