Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) 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 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. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.

Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia.

BACKGROUND: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality. METHODS: We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels. RESULTS: Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24-0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12-0.73) and more days off invasive MV (24.0 ±â€…9.0 vs 17.5 ±â€…12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84). CONCLUSION: In patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.

MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale.

INTRODUCTION: COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatment strategy to manage the pulmonary phase includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol). The rationale for the MATH+ protocol is reviewed in this paper. AREAS COVERED: We provide an overview on the pathophysiological changes occurring in patients with COVID-19 respiratory failure and a treatment strategy to reverse these changes thereby preventing progressive lung injury and death. EXPERT OPINION: While there is no single 'Silver Bullet' to cure COVID-19, we believe that the severely disturbed pathological processes leading to respiratory failure in patients with COVID-19 organizing pneumonia will respond to the combination of Methylprednisone, Ascorbic acid, Thiamine, and full anticoagulation with Heparin (MATH+ protocol).We believe that it is no longer ethically acceptable to limit management to 'supportive care' alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.