Scientific Review of COVID-19 and MATH+
On August 18, 2020, a shortened version of this scientific review was published in “Expert Review of Anti-Infective Therapy” on Taylor & Francis online:
MATH+ protocol for the treatment of SARS-CoV-2 infection: The scientific rationale
Paul E. Marik, Pierre Kory, Joseph Varon, Jose Iglesias & G. Umberto Meduri
On December 14, 2020, the FLCCC Alliance peer-reviewed paper
Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19
was published in the Journal of Intensive Care Medicine (a shorter but more up-to-date version of this page). The MATH+ protocol potentially offers a life-saving approach to the management of hospitalized COVID-19 patients. The MATH+ protocol offers an inexpensive combination of medicines with well-known safety profiles based on strong physiologic rationale and an increasing clinical evidence base.
In December 2019, COVID-19, an illness characterized by pneumonia associated with the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. On March 13, 2020, the United States declared a national emergency in response to the pandemic. 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 advocated a primary focus on supportive care with avoidance of other therapies outside of randomized controlled trials, and with specific recommendations to avoid the use of corticosteroids.
However, several 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 that collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 and held 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” from these colleagues along with the insights derived from increasing publications and the panel members rapidly accumulating personal clinical experiences and investigations into the pathophysiology of COVID-19 patients, a treatment protocol named “MATH+” was created to guide the treatment of hospitalized patients. 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 involving patients with viral syndromes. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.
Paul E. Marik, MD; Pierre Kory, MD, MPA
The disease caused by the novel coronavirus SARS-CoV-2, called “COVID-19” progresses through a number of distinct phases, from the incubation stage, to the symptomatic stage to the pulmonary phases. The management of each phase is unique and specific. The pulmonary phase 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), a combination of anti-inflammatory agents to dampen the “cytokine storm” and to protect the vascular endothelium together with full anticoagulation to limit the microvascular and macrovascular clotting and supplemental oxygen to help overcome the hypoxia. The following is a review of the multitude of studies that have deepened our current understanding of the pathophysiology of COVID-19.
Overview of the Pathophysiology of COVID-19
One needs a good understanding of the pathophysiology of a disease to effectively treat the disease. In the middle of this pandemic, understanding the mechanisms of SARS-CoV-2 induced disease is critical in formulating a treatment strategy and ethically more sound than demanding and waiting for randomized placebo-controlled clinical trials to be completed. While many aspects of COVID-19 remain a mystery, we have witnessed an explosion of knowledge about this disease over the past 6 months. Fundamentally it is critical to appreciate that while COVID-19 is a remarkably heterogeneous disease, patients infected with SARS-CoV-2 progress though a number of phases (or stages) and that the treatment of COVID-19 is highly specific to each phase of the disease, as illustrated in Figure 1.
Human-to-human spread is thought to occur predominantly by large droplets although airborne transmission is clearly occurring with its contribution to disease spread currently underestimated by health authorities.3 Vector transmission by surface contact is thought to occur but only rarely.4 The receptor for cellular viral adhesion is the angiotensin-converting enzyme (ACE) 2 receptor located in the upper respiratory tract, endothelial cells and type two pneumocytes among others.5,6 SARS-CoV-2 undergoes active replication in the throat and nasopharynx reaching high concentrations just prior to and at the onset of symptoms. Active viral replication continues for at least 5 days after symptom onset.7,8 Patients who develop respiratory symptoms demonstrate a higher and later peak of viral loads. It appears that the overwhelming majority of infections are asymptomatic. Patients who enter the symptomatic phase complain of typical influenzae like symptoms, namely fever, cough and malaise. The course of the illness following onset of symptoms is generally quite predictable. Fever persists for a mean of 12 days while cough persists for about 19 days.9 Dyspnea usually begins on days 5 to 7 following symptom onset, with respiratory failure developing on about day 10 and the initiation of invasive mechanical ventilation on day 14.9 Approximately 20% of symptomatic patients require hospitalization predominately due to hypoxemic respiratory failure. Data from over 40,000 hospitalizations world-wide demonstrate that about 20% of hospitalized patients are admitted to the ICU, 17% will undergo mechanical ventilation and at least 24% of hospitalized patients will die.10–18 In one report on over 300 mechanically ventilated patients, 88% of them died.11
The pulmonary phase is characterized by the onset of dyspnea and hypoxemia. It is important to emphasize that patients may develop hypoxemia (including ambulatory desaturation) with minimal respiratory symptoms, a presentation most suggestive of a condition called organizing pneumonia. 19 Although organizing pneumonia is not considered a direct result of infection, it is associated with viral syndromes.19 Expert panel radiology reports of the imaging findings in patients with COVID-19 related lung disease describe a typical radiographic pattern of bilateral peripheral and peribronchial rounded ground-glass opacities most consistent with this organizing pneumonia pattern of lung injury.20 Further, autopsy examinations have repeatedly confirmed the presence of organizing pneumonia among multiple other patterns of lung injury. 21 Organizing pneumonia is a common histologic pattern of lung injury characterized by spindle-shaped fibroblasts and myofibroblasts often admixed with inflammatory cells (macrophages and T-lymphocytes) which lead to intraluminal plugs within alveoli and alveolar ducts that subsequently fill terminal bronchioles.22 When organizing pneumonia results from viral infections it is called secondary organizing pneumonia. viral-induced secondary organizing pneumonia from the H1N1, SARS, and MERS pandemics have been well-described.23 COVID19 induced secondary organizing pneumonia has a number of distinctive features, most notably a severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes.24,25 Histologic analysis of pulmonary vessels demonstrates widespread thrombosis with microangiopathy. The microvascular lesions contribute to the venation/perfusion mismatch and hypoxemia typical of the pulmonary phase of COVID-19. Furthermore, the infiltrating lymphocytes and macrophages are abnormally activated and responsible for the “cytokine storm”.26,27 While many “experts” have called the pulmonary phase of COVID-19 Acute Respiratory Distress Syndrome (ARDS),2 neither the radiographic appearance, physiologic characteristics nor histology are typical of ARDS.28,29 The well documented clinical and radiographic findings consistent with secondary organizing pneumonia in COVID-19 have important implications for an effective treatment strategy. Prompt treatment with corticosteroids leads to clinical, physiologic, and radiologic improvement in two-thirds of patients with secondary organizing pneumonia.30 Additionally, corticosteroids are essential for downregulating the cytokine storm, responsible for the severe hyper-inflammatory state which perpetuates the organizing pneumonia and associated microvascular injury. We suggest that the high reported mortality for patients with COVID-19 organizing pneumonia may be due to the fact that these patients were treated using mechanical ventilation with the ARDSnet treatment strategy (high PEEP), together with “supportive care” that failed to target the key pathophysiologic processes of COVID-19 organizing pneumonia.2,11
Clinically, the immune response induced by SARS-CoV-2 infection is two phased. During the incubation and early symptomatic stages, a specific adaptive immune response is generated which eliminates the virus and prevents disease progression to pulmonary stages. Analogous to infection with influenzae, the local replication of SARS-CoV-2 in the nasopharynx induces the local production of pro-inflammatory cytokines which are largely responsible for clinical symptoms of early COVID-19 infection.31,32 However, unlike influenzae, SARS-CoV-2 has a marked predilection to spread to the lower respiratory tract, in part related to the high expression of ACE-2 receptors on type II pneumocytes. The pulmonary phase is characterized by a fall in viral replication and viral load but with a marked increase in production of pro-inflammatory cytokines and progression of the ground-glass infiltrates. SARS-CoV ssRNA’s have powerful immunostimulatory activities which induce high levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-12 via toll like receptor-7 (TLR7) and TLR8 engagement.26,27,33 Furthermore, ssRNA activation of inflammasomes contributes to excess IL-1β and IL-17 production. Activation of Th1 and Th17 lymphocytes and high levels of cytotoxicity of CD8 T cells, further contribute to the severe immune injury in these patients.34 CD4+T lymphocytes are rapidly activated to become pathogenic Th1 helper cells and generate granulocyte-colony stimulating factor (G-CSF), interferon-γ, inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), etc.35 It should be noted that while increasing the expression of inflammatory cytokines and chemokines this highly pathogenic virus downregulates the expression of type-1 interferons, the host’s primary antiviral defense mechanism.26 Low innate antiviral defenses and high pro-inflammatory mediators contribute to ongoing and progressive lung injury. In a highly detailed analysis of tissues from 11 autopsies, one group found that the presence of SARS-CoV-2 RNA and protein had little correlation with the inflammation and organ dysfunction, supporting the observations that virus-independent immunopathology is the primary mechanism underlying fatal Covid-19.36 This supports the concept that it is the host’s response to the SARS-CoV-2 virus, rather the virus itself that is killing the host. The role of specific anti-viral therapies in the pulmonary phase of COVID-19 would therefore appear to be limited.
In addition to generating a profound hyper-inflammatory state, SARS-CoV-2 activates the coagulation system resulting in an intense pro-coagulant state. Activation of clotting is likely multifactorial, however, damage to the endothelium with clotting activation likely plays an important role. Furthermore, cleavage of the spike protein of the SARS coronavirus by protease factor Xa was associated with activation and release of factor Xa.37 Yuriditsky et al demonstrated that in excess of 70% of patients with COVID-19 disease have hypercoagulable thromboelastography (TEG) profiles.38
An understanding of the pulmonary stages of COVID-19 leads to the unambiguous and irrefutable conclusion that three related pathophysiologic processes are driving the disease process and that all three of these derangements must be treated in order to reduce the mortality and morbidity of this deadly disease. These include i) an organizing pneumonia (steroid responsive) with a dysregulated immune system with the overproduction of pro-inflammatory mediators and a severe microvascular injury (steroid, ascorbic acid and thiamine responsive), ii) a hypercoagulable state with systemic micro- and macro-vascular disease (heparin, steroid and ascorbic acid responsive) that potentiates the microvascular injury, iii) with both these processes leading to severe ventilation/perfusion mismatching leading to severe hypoxemia (Not ARDS). The core components of the MATH+ treatment protocol target all three major pathophysiologic processes with readily available, inexpensive and safe FDA approved interventions (see Figure 2 and Figure 3).
The medications that make up the core components of the MATH+ protocol are listed below, followed by a brief review of these medications as they apply specifically to COVID-19. The reader is referred to comprehensive reviews which discusses the pharmacology and mechanism of actions of these drugs.39–44 It should be noted that the MATH+ protocol was developed (and published online https://www.evms.edu/covid-19/medical_information_resources/) in early March 2020 as a modification of the Hydrocortisone, Ascorbic acid and Thiamine (HAT Rx) protocol for the treatment of severe bacterial sepsis.42,45 The MATH+ protocol was based on common sense and a comprehensive review of the basic science and clinical literature as it applied to COVID-19. With the passage of time almost all of the components of the MATH+ protocol have been validated by high level scientific studies.
- World Health Organization: Coronavirus Disease 2019 (COVID-19): Situation Report -54 (14th March 2020). https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200314-sitrep-54-covid-19.p… . 2020. acessed 7-9-2020.
- Alhazzani W, Moller MH, Arabi YM et al. Surviving Sepsis Campaign: Guideliens on the management of critically ill adults with coronavirus disease 2019 (COVID-19) (March 20, 2020 Version). Crit Care Med 2020.
- Morawska L, Cao J. Airborne transmission of SARS-CoV-2: THe world should face the reality. Environment International 2020; 139:105730.
- How Coronavirus spreads. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covid-spreads.html Coronavirus Disease 2019 (COVID-19)(Coronavirus Disease 2019 (COVID-19)). 2020. Centers for Disease Control and Prevension. Acessed 7/12/2020
- Wiersinga WJ, Rhodes A, Cheng AC et al. Pathophysiology, transmission, diagnosis, and treatment of Coronavirus Disease 2019 (COVID-19). A review. JAMA 2020.
- Bunyavanich S, Do A, Vincencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 2020.
- Wolfel R. Virological assessment of hospitalized cases of coronavirus disease 2019. medExiv 2020.
- Zou L. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020.
- Zhou F, Yu T, Du R et al. Clinical course and risk factor for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020.
- Docherty AB, Harrison EM, Green CA et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation protocl: prospective observational cohort study. BMJ 2020; 369:m1985.
- Richardson S, Hirsch JS, Narasimhan M et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA 2020.
- Effect of Dexamethasone in hospitalized patients with COVID-19-Preliminary report. medRxiv 2020.
- Rosenberg ES, Dufort EM, Udo T et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020; 323:2493-502.
- Cummings MJ, Baldwin MR, Abrams D et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York: a prospective cohort study. Lancet 2020; 395:1763-70.
- Arshad S, Kilgore P, Chaudry ZS et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect DIs 2020.
- Myers LC, Parodi SM, Escobar GJ et al. Characteristics of hospitalized adults with COVID-19 in an integrated health care system in California. JAMA 2020; 323:2195-97.
- Mikami T, Miyashita H, Yamada T et al. Risk factors for mortality in patients with COVID-19 in New York City. J Gen Intern Med 2020.
- Vizcaychipi MP, Shovlin CL, Hayes M et al. Early detection of severe COVID-19 disease patterns define near real-time personalized care, bioseverity in males, and decelerating mortality rates. medRxiv 2020.
- Torrealba JR, Fisher S, Kanne JP et al. Pathology-radiology correlation of common and uncommon computed tomographic patterns of organizing pneumonia. Human Pathology 2018; 71:30-40.
- Kanne JP, Little BP, Chung JH et al. Essentials for radiologists on COVID-19: an Update-Radiology Scientific Expert Panel. Radiology 2020.
- Copin MC, Parmentier E, Duburcq T et al. Time to consider histologic pattern of lung injury to treat critically ill patietns with COVID-19 infection [letter]. Intensive Care Med 2020.
- Kligerman S, Franks TJ, Galvin JR. Organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radiographics 2013; 33:1951-75.
- Hwang DM, Chamberlain DW, Poutanen SM et al. Pulmonary pathology of severe acute respiratory syndrome in Toronto. Modern Pathology 2005; 18:1-10.
- Ackermann M, Verleden SE, Kuehnel M et al. Pulmonary vascular endothelialitis, Thrombosis, and Angiogenesis in COVID-19. N Engl J Med 2020; 383:120-128.
- Guglielmetti G, Quaglia M, Sainaghi PP et al. “War to the knife” against thromboinflammation to protect endothelial function of COVID-19 patients. Crit Care 2020; 24:365.
- Blanco-Melo D, Nilsson-Payant BE, Liu WC et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020.
- Giamarellos-Bouboulis EJ, Netea MG, Rovina N et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host & Microbe 2020.
- Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care 2020; 24:154.
- Chiumello D, Cressoni M, Gattinoni L. Covid-19 does not lead to a “typical” Acute Respiratory Distress syndrome. Lancet 2020.
- Drakopanagiotakis F, Paschalaki K, Abu-Hijleh M et al. Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis. Chest 2011; 139:893-900.
- Hayden FG, Fritz RS, Lobo MC et al. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 1998; 101:643-49.
- Kaiser L, Fritz RS, Straus SE et al. Symptom pathogenesis during acute influenza: Interleukin-6 and other cytokine responses. J Med Virol 2001; 64:262-68.
- Li Y. Extraordinary GU-rich singlestrand RNA identified from SARS coronavirus contributes an excessive innate immune response. Microbes and infection 2013; 15:88-95.
- Xu Z, Shi L, Wang Y et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Resp Med 2020.
- Zhou Y. Aberrant pathogenic GM-CSF T cells and inflammatory CD14CD16 monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv 2020.
- Dorward DA, Russell CD, Um IH et al. Tisse-specific tolerance in fatal Covid-19. medRxiv 2020.
- Du L, Kao RY, Zhou Y et al. Cleavage of spike protein of SARS coronavirus by protease factor Xa is associated with viral infectivity. Biochemical & Biophysical Research Communications 2007; 359:174-79.
- Yuriditsky E, Horowitz JM, Merchan C et al. Thromboelastography profiles of critically ill patients with Coronavirus disease 2019. Crit Care Med 2020.
- Ramamoorthy S, Cidlowski JA. Corticosteroids: Mechanisms of Action in Health and Disease. Rheum Dis Clin North Am 2016; 42:15-31.
- Chan ED, Chan MM, Chan MM et al. Use of glucocorticoids in the acute and critical care setting: science and clinical evidence. Pharmacol Therapeut 2020; 206: 107428.
- Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Therapeut 2018; 189: 63–70.
- Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients 2018; 10: 1762.
- Crook MA. Thiamine deficiency: The importance of recognition and prompt management. Nutrition 2014; 30: 953–54.
- Marik PE. Thiamine: An essential component of the metabolic resuscitation protocol. Crit Care Med 2018; 46: 1869–70.
- Marik PE, Khangoora V, Rivera R et al. Hydrocortisone, Vitamin C and Thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017; 151: 1229–38.
Pierre Kory, MD, MPA; Joseph Varon, MD; G. Umberto Meduri, MD
The rapid spread of COVID-19 from the epidemic in Wuhan, China to a global pandemic mandated that health care systems and societies create and coordinate a response to mobilizing resources, enacting effective infection control policies, and providing guidance for the treatment of the disease called COVID-19. The initial treatment recommendations consisted of “supportive care only” strategies with widespread adoption of therapies with almost no clinical familiarity amongst the majority of physicians and a similarly lacking evidence base for effectiveness. The early reports of excessive mortality rates associated with such a strategy prompted the authors to investigate, create, and employ treatments with which they had extensive clinical experience and decades of published evidence to guide them in targeting the key pathophysiologic processes that were identified as causing the morbidity and mortality of COVID-19. The following reviews the series of events, decisions, and actions which led to the formation of the Front Line Critical Care Alliance and the creation of the MATH+ treatment protocol.
Rationale for the Creation of a COVID-19 Treatment Protocol
In December 2019, an illness characterized by pneumonia associated with the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. By March 11, 2020, the World Health Organization (WHO) had characterized the novel coronavirus outbreak as a pandemic, with confirmed cases in 213 countries. On March 13, 2020, the United States declared a national emergency in response to the pandemic. The greatest impact this malady had was on intensive care units (ICUs), given approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission.1,2
Since COVID-19 was initially defined as a primary viral syndrome and no validated anti-coronavirus therapy existed, nearly all national and international health care societies advocated a primary focus on supportive care with avoidance of other therapies outside of randomized controlled trials, and with specific recommendations to avoid the use of corticosteroids.3–5
However, several 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.6 These reports led many physicians, including the authors of this manuscript, to question the supportive care-only approach, and to review the evidence behind therapies that could counteract the increasingly well-described syndrome of severe hypoxemia, hyper-inflammation, and hypercoagulability, with the rationale that an effective intervention could decrease dependence on mechanical ventilators and mortality in COVID-19 patients, and thus, have an immediate significant global impact on this public health emergency.6,7
As a group of clinical researchers in critical care with over a 100-year collective front-line, bedside ICU experience in the treatment of severe infections and acute respiratory distress syndrome (ARDS), we collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 disease, and held multiple discussions with many front-line clinical acute care and ICU experts from the initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of “what was working and what wasn’t working” from these colleagues along with the increasing publications and our rapidly accumulating personal clinical experiences and investigations into the pathophysiology of COVID-19 patients, we formulated a treatment protocol in March 2020, adapted from a protocol initiated by one of the authors (P.E.M) at their home institution. The protocol aggressively targeted the hyperinflammation and hypercoagulation and consisted of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH). These core medicines were all highly familiar, low-cost, FDA-approved medications with known therapeutic mechanisms and well-established safety profiles. The protocol quickly evolved with the addition of “adjunctive” medicines supported by either promising early clinical data, strong scientific rationale, and/or a pre-existing clinical evidence base for the critical care conditions identified as part of COVID-19, with the protocol then relabeled as “MATH+”.
The efforts we made to develop an empiric treatment protocol was not unique in that many centers across the country and world developed “treatment guidelines”, and although they primarily emphasized supportive respiratory care techniques, many also included approaches either quickly retracted as obviously harmful, such as “early intubation” or therapeutic agents and interventions whose mechanisms of action held only theoretical anti-SARS-CoV-2 activity.8–12
To study the efficacy of the proposed MATH+ protocol against COVID-19, a collective decision was made to do so via the formation of a patient registry to measure and compare the outcomes of patients treated with MATH+, not only against the prevailing “supportive-care only” strategy, but also against other novel proposed treatment approaches employed throughout the country and world. 8–10
We were troubled by editorials in major peer-reviewed medical journals, arguing that such treatments were “experimental”, and thus use should be restricted to only within randomized controlled trials (RCT).14 “Experimental” therapies, best defined as those with either no clinical evidence to support or near nil clinical familiarity with use, were indeed adopted and widely used, particularly in the early weeks of the pandemic when drugs such as hydroxychloroquine, remdesivir, lopinavir/ritonavir and tocilizumab were employed. However, these agents stand in marked contrast to core MATH+ therapies which had extensive clinical experience achieving positive outcomes in treating patients with similar diseases and conditions. In some instances, several were already incorporated into standard ICU treatment protocols for conditions such as ARDS or sepsis in their institutions. Each element of MATH+ has been extensively studied in critical illness, almost all sufficiently so that meta-analyses have been published on their use and indications, thus none could be viewed as an “experimental therapy,” given they are considered more in-line with “standard” or “supportive care” for many critical illness states.
Although we too place immense value and importance in the need for RCT’s in such a novel disease syndrome, it must be recognized that not all institutions possess the necessary experience, resources, or infrastructure to design and conduct such trials, especially during a pandemic. Further, our group decided against a randomized, placebo-controlled trial design given that such trials require investigators to possess “clinical equipoise”, which is the belief by the investigator that neither intervention in the control or experimental group is “better”. With respect to each of the individual “core” therapies of MATH+, all authors felt the therapies superior to any placebo, based on not only the rapidly accumulated knowledge and insight into COVID-19 but also from our collective knowledge, research, and experience with each of the component medications in critical illness and other severe infections.
Conversely, we believe it is within the immense power and resources of such institutions to conduct such trials. A powerful example of such an accomplishment is the RECOVERY trial conducted by researchers at Oxford University, a trial which also serves as an example of the importance of clinical equipoise in the conduct of human subject research.17 Specifically, the design and execution of the RECOVERY trial depended on investigators with clinical equipoise around the use of corticosteroids in the treatment of a severe viral syndrome. The MATH+ authors did not possess such equipoise, as we held a collective belief as to the critical importance of corticosteroid therapy in COVID-19, best evidenced by one author’s (G.U.M.) publication of a paper early in the pandemic which contradicted the World Health Organization (WHO) recommendation against the use of corticosteroids, based on what was argued to be their inaccurate representation and interpretation of corticosteroid studies from the prior pandemics of SARS, MERS, and H1N1.18
Thus, it came as no surprise to the authors that the RECOVERY trial was stopped early due to excess deaths in a control group consisting of over 4000 patients given placebo. A conservative estimate of avoidable death in the placebo group if they had instead received corticosteroids is that 91 lives would have been saved in the group of patients requiring oxygen while another 80 lives would have been saved for those on mechanical ventilation.19
The scientific and clinical rationale which underpins the collective lack of clinical equipoise amongst the authors of MATH+ will be reviewed in the following sections through a review of the published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies involving the treatment of viral syndromes. The review will conclude with a report on the preliminary outcomes data from the two hospitals that adopted the MATH+ protocol in the treatment of COVID-19 patients.
- Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. Int J Infect Dis. 2020;0(0). https://doi.org/10.1016/j.ijid.2020.06.099
- Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: Prospective observational cohort study. BMJ. 2020; 369 (March): 1–12. https://doi.org/10.1136/bmj.m1985
- Wilson KC, Chotirmall SH, Bai C, Rello J. COVID-19: Interim Guidance on Management Pending Empirical Evidence. Am Thorac Soc Int Task Force. Published online 2020.
- CDC. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19. Public Heal Media Libr. Published online 2020.
- WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. interim guidance. WHO. Published online 2020.
- Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA – J Am Med Assoc. 2020; 323(20): 2052–2059. https://doi.org/10.1001/jama.2020.6775
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Published online 2020. https://doi.org/10.1016/S0140-6736(20)30566-3
- Emanuele Nicastri NP, Bartoli TA, Luciana Lepore AM, Fabrizio Palmieri GD, Luisa Marchioni SM, Giuseppe Ippolito AA. National Institute for the Infectious Diseases “L. Spallanzani”, IRCCS. Recommendations for COVID-19 clinical management. Infect Dis Rep. 2020;12:8543. https://doi.org/10.4081/idr.2020
- Ye Z, Rochwerg B, Wang Y, et al. Treatment of patients with nonsevere and severe coronavirus disease 2019: An evidencebased guideline. Cmaj. 2020;192(20):536-545. https://doi.org/10.1503/cmaj.200648
- Mu A. 済無No Title No Title. J Chem Inf Model. 2019;53(9):1689-1699. https://doi.org/10.1017/CBO9781107415324.004
- Treatment S, Treatment S. Patient with confirmed POSITIVE SARS-CoV-2 by PCR NO YNHHS Initial Treatment Algorithm for Hospitalized ADULTS with Severe COVID-19 Respiratory failure , including Mechanical ventilation and ECMO PLUS confirmed POSITIVE SARS-CoV-2 by PCR .
- Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). http://kjfy.meetingchina.org/msite/news/show/cn/3337.html
- Soares AT, Echenique LS, Pereira AJ, Freitas FGR, Gebara OCE. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. Published online 2020. https://doi.org/10.1056/NEJMoa2019014
- Waterer GW, Rello J, Wunderink RG. COVID-19: First Do No Harm. Am J Respir Crit Care Med. 2020; 201(11): 1324–1325. https://doi.org/10.1164/rccm.202004-1153ED
- Vincent JL. We should abandon randomized controlled trials in the intensive care unit. Crit Care Med. 2010;38(10 SUPPL.). https://doi.org/10.1097/CCM.0b013e3181f208ac
- Santacruz CA, Pereira AJ, Celis E, Vincent JL. Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review. Crit Care Med. 2019; 47(12): 1680–1691. https://doi.org/10.1097/CCM.0000000000004000
- Horby P, Lim WS, Emberson J, et al. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv. Published online 2020. https://doi.org/10.1101/2020.06.22.20137273
- Confalonieri M, Pastores SM, Meduri GU. Rationale for Prolonged Corticosteroid Treatment. Critical Care Explorations (Journal of the Society of Critical Care Medicine): 1–12. https://journals.lww.com/ccejournal/fulltext/2020/04000/rationale_for_prolonged_corticosteroid_treat…
- Horby P, Lim WS, Emberson J, Haynes R, and Landray MJ. 2020. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. The New England Journal of Medicine. Published online July 2020. https://doi.org/10.1056/NEJMoa2021436
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. Published online March 2020. https://doi.org/10.1016/S0140-6736(20)30628-0
Evidence based scientific reviews supporting MATH+ components:
G. Umberto Meduri
The early reports of COVId-19 causing predominantly hypoxemic respiratory failure with frequent progression to ARDS with an associated mortality rate far higher than in prior studies of ARDS led many to question whether there was a role for corticosteroid therapy. During the first 6 months of the pandemic, the near universal and unwavering recommendations from all international and national health care societies was to avoid corticosteroid therapy in COVID-19. This inaccurate interpretation of the published literature from the prior viral pandemics of SARS, MERS, and H1N1 will be reviewed below, along with a summary of the literature in support of corticosteroid therapy in non-viral ARDS. This section concludes with a summary of the increasing studies in COVID-19 showing dramatic mortality benefits associated with corticosteroid therapy from centers around the world.
Methylprednisolone and COVID-19
Methylprednisolone was chosen based on the following criteria: (i) evidence of corticosteroid responsive disease, (ii) results of relevant clinical studies involving more than 10,000 patients, with many studied during prior viral pandemics, and (iii) pharmacological characteristics.
The dysregulated inflammation and coagulation observed in COVID-19 (see Pathophysiology) is similar to that of multifactorial ARDS where ample evidence has demonstrated the ability of prolonged corticosteroid treatment (CST) to downregulate – systemic and pulmonary – inflammation-coagulation-fibroproliferation and accelerate disease resolution20,21 Additionally, the computed tomography findings of ground-glass opacities and the histological findings of organizing pneumonia, hyaline membranes, inflammatory exudates, and acute fibrinous and organizing pneumonia are all compatible with CST-responsive inflammatory lung disease.22,23
Relevant clinical studies include randomized controlled trials (RCTs) in adult patients with non-viral ARDS, large-scale observational studies in patients with SARS-CoV (n=7008), H1N1 (n=2141) influenza, and early results from multiple COVID-19 observational studies.24–30 In non-viral ARDS, aggregate data from ten RCTs (n=1093) showed that CST was associated with a sizable increase by day 28 in MV-free days (WMD 6.18 days, 95% CI 3.45 days to 8.90 days), ICU-free days (WMD 8.12 days, 95% CI 3.87 days to 12.37 days) and a reduction in hospital mortality (RR 0.67, CI 0.52-0.870) with the greatest impact observed with methylprednisolone treatment.27,31,32 Importantly, the survival benefit observed during hospitalization persisted after hospital discharge with follow-up observations extending up to one year.31 Except for transient hyperglycemia (mostly within the 36 hours following an initial bolus), CST was not associated with increased risk for neuromuscular weakness, gastrointestinal bleeding, or nosocomial infections (RR 0.83 (95% CI 0.67 to 1.02).
The evidence of benefit in viral pneumonia (SARS, H1N1) relies on large-scale studies (n=9149) which included adjustment for confounders and analysis of CST variables (type, timing, dose, and duration) on the outcome.26,27 These studies reported a significant reduction in mortality with dosage and duration of CST similar to the one recommended by the Corticosteroid Guideline Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) (Figure 1).31,33 In the largest SARS-CoV study, after adjustment for possible confounders, methylprednisolone 80mg/day was safe and decreased the risk for death by 63% (HR 0.37, 95% CI: 0.24–0.56).26 In the H1N1 study, subgroup analysis among patients with PaO2:FiO2 <300 mm Hg (535 vs. 462), low-to-moderate-dose CST (methylprednisolone 25–150 mg/day) significantly reduced both 30-day mortality (aHR 0.49 [95% CI 0.32–0.77]) and 60-day mortality (aHR 0.51 [95% CI 0.33-0.78]) despite having a higher rate of nosocomial infections.27
Methylprednisolone, for the greater penetration in lung tissue, longer residence time, and great inhibitory activity of transcription factor nuclear factor-kB (driver of lung inflammation) is the most frequently used intravenous corticosteroid for the treatment of severe acute inflammatory lung diseases.34–36 The initial daily dose of 1 mg/Kg of ideal body weight (approximately 80 mg) was the one shown to be associated with the highest mortality reduction in RCTs of non-viral ARDS and large observational studies in SARS-CoV and H1N1 pneumonia.26,27,31 A recent study that matched the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5,694 FDA-approved drugs, found methylprednisolone to be the drug with the greatest potential to revert the changes induced by COVID-19, while other closely related corticosteroids, such as dexamethasone or prednisone, were not.37
The risk for decreased viral clearance with CST is overstated and the most frequently quoted article by Arabi et al., in patients that received greater than seven days CST there was a trend toward lower 90-day mortality [aOR 0.51, 95% confidence interval (CI) 0.26-1.00; p=0.05] and no impact on viral clearance [aOR 0.94, 95% confidence interval (CI) 0.36–2.47; p=0.90].38 There is no evidence linking delayed viral clearance to worsened outcomes in critically ill COVID-19 patients, and it is unlikely that it would have a greater negative impact than the hosts own “cytokine storm”.20
Subsequent to the introduction of the MATH+ protocol, even more definitive support for CST was provided by a large randomized trial along with prospective observational studies. The RECOVERY trial investigated dexamethasone (6 mg once daily for up to ten days) in a randomized, controlled, open-label, adaptive, platform trial with a primary outcome of 28-day mortality.17 The RCT studied 2104 patients randomly allocated to receive dexamethasone compared to 4321 patients concurrently allocated to usual care. CST was associated with a significant reduction in mortality (21.6% vs. 24.6%) with an age adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). Dexamethasone reduced deaths by one-third in the subgroup of patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs.13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Dexamethasone is the corticosteroid associated with greater suppression of the adrenal gland. Notably, the RECOVERY RCT utilized a small dose of dexamethasone and did not incorporate tapering to prevent rebound inflammation.
An Italian multicenter, prospective observational study explored the association between exposure to prolonged CST (a pre-designed protocol: methylprednisolone 80 mg for 9 days followed by tapering based on improvement in predefined laboratory parameters) and the need for ICU referral, intubation or death within 28 days (composite primary endpoint) in patients (83 on CST vs. 90 matched control) with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units.39 The composite primary endpoint was met by 19 vs. 40 [adjusted hazard ratio (HR) 0.41; 95% confidence interval (CI): 0.24-0.72]. Transfer to ICU and need for invasive MV was necessary in 15 vs. 27 (p=0.07) and 14 vs. 26 (p=0.10), respectively. By day 28, the MP group had fewer deaths (6 vs. 21, adjusted HR=0.29; 95% CI: 0.12–0.73) and more days off invasive MV (24.0 ± 9.0 vs. 17.5 ± 12.8; p=0.001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels without affecting lymphocyte count. The complication rate was similar for the two groups (p=0.84). No difference was observed in viral shedding, determined as the number of days between hospital referral and the first negative nasopharyngeal swab.
A Spanish semi-randomized study investigated methylprednisolone (three days each, 80 mg and 40 mg, respectively) in 85 COVID-19 (56 CST, 29 control) hypoxemic patients; the primary composite outcome similar to the Italian study.40 CST was associated with reduced risk of the composite endpoint in the intention-to-treat, age-stratified analysis (combined risk ratio -RR- 0.55 [95% CI 0.33-0.91]; p=0.024).
The Henry Ford COVID-19 Management Task Force conducted a single pre-test, single post-test quasi-experiment in a multi-center health system in Michigan.29 They investigated 213 patients with confirmed moderate to severe COVID admitted over a two weeks period; the first week 81 patients received standard of care (SOC), the second week 132 patients also received SOC and early initiation of CST (methylprednisolone 0.5 to 1 mg/kg/day for 3 days, and longer duration if they required MV). In the first week, half of the patients in the SOC group received CST but with a later initiation. The primary composite outcome was similar to the Italian study, and was reached by fewer patients in the CST group (34.9% vs. 54.3%, p=0.005).39 This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (8 vs. 5 days, p < 0.001). Hospital length of stay was decreased by three days (p < 0.001).29
- Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest. Published online 2009. https://doi.org/10.1378/chest.08-2408
- Tang L, Zhang X, Wang Y, Zeng X. Severe COVID-19 Pneumonia: Assessing Inflammation Burden with Volume-rendered Chest CT. Radiol Cardiothorac Imaging. Published online 2020. https://doi.org/10.1148/ryct.2020200044
- Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. Published online 2020. https://doi.org/10.1016/S2213-2600(20)30076-X
- Chen RC, Tang XP, Tan SY, et al. Treatment of severe acute respiratory syndrome with glucosteroids: The Guangzhou experience. Chest. Published online 2006. https://doi.org/10.1378/chest.129.6.1441
- Yin-Chun Yam L, Chun-Wing Lau A, Yuk-Lin Lai F, Shung E, Chan J, Wong V. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. J Infect. Published online 2007. https://doi.org/10.1016/j.jinf.2006.01.005
- Long Y, Xu Y, Wang B, et al. Clinical recommendations from an observational study on MERS: Glucocorticoids was benefit in treating SARS patients. Int J Clin Exp Med. Published online 2016.
- Li H, Yang SG, Gu L, et al. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia. Influenza Other Respi Viruses. Published online 2017. https://doi.org/10.1111/irv.12456
- Wu C, Chen X, Cai Y, et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. Published online 2020. https://doi.org/10.1001/jamainternmed.2020.0994
- Fadel R, Morrison AR, Vahia A, et al. Early Short Course Corticosteroids in Hospitalized Patients with COVID-19. Clin Infect Dis. Published online 2020. https://doi.org/10.1093/cid/ciaa601
- Fernández Cruz A, Ruiz-Antorán B, Muñoz Gómez A, et al. Impact of Glucocorticoid Treatment in Sars-Cov-2 Infection Mortality: a Retrospective Controlled Cohort Study. Antimicrob Agents Chemother. 2020;(June). https://doi.org/10.1128/aac.01168-20
- Villar J, Confalonieri M, Pastores SM, Meduri GU. Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019. Crit Care Explor. Published online 2020. https://doi.org/10.1097/cce.0000000000000111
- Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RAC, Kocak M. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. Published online 2016. https://doi.org/10.1007/s00134-015-4095-4
- Pastores SM, Annane D, Rochwerg B. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. Published online 2018. https://doi.org/10.1007/s00134-017-4951-5
- Greos LS, Vichyanond P, Bloedow DC, et al. Methylprednisolone achieves greater concentrations in the lung than prednisolone: A pharmacokinetic analysis. Am Rev Respir Dis. Published online 1991. https://doi.org/10.1164/ajrccm/144.3_pt_1.586
- Li S MG, Miller DD YC. Evaluation of AP-1 and NF-kB inhibitory potency for oral glucocorticoids. In: The American Review of Respiratory Disease. ; 2003:5(S1):R6173.
- Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged Methylprednisolone Treatment Suppresses Systemic Inflammation in Patients with Unresolving Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. Published online 2002. https://doi.org/10.1164/ajrccm.165.7.2106014
- Draghici S, Nguyen T-M, Sonna LA, et al. COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases. medRxiv. Published online 2020. https://doi.org/10.1101/2020.05.06.20076687
- Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir Crit Care Med. Published online 2018. https://doi.org/10.1164/rccm.201706-1172OC
- Salton F, Confalonieri P, Santus P, et al. Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia. medRxiv. Published online 2020. https://doi.org/10.1101/2020.06.17.20134031
- Corral L, Bahamonde A, Revillas FA delas, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. Published online 2020. https://doi.org/10.1101/2020.06.17.20133579
Jose Iglesias, MD
The fact that humans suffered mutation during evolution which thereafter prevented their ability to generate ascorbic acid (Vitamin C) in response to illness is little known. This event rendered the substance a “vitamin” , in that, it became vital to obtain the substance from exogenous sources to ensure survival. This mutation makes humans unique among almost all mammals, who in contrast, will increase the production of ascorbic acid many fold in in states of injury or illness. The myriad actions of ascorbic acid in supporting both immune and endothelial functions during states of illness are reviewed here along with the clinical studies demonstrating large physiologic and mortality benefits of high-dose intravenous administration in conditions such as sepsis and ARDS.
Ascorbic Acid (AA) and COVID-19
Approximately 15% of patients with Covid-19 infection progress to severe pneumonia and about 5–10% eventually develop ARDS and an accompanying cytokine storm characterized by vasoplegia, hypercoagulability and multiorgan failure.7,20,21 Ascorbic acid (AA) is the most potent and important antioxidant in mammals with pleiotropic modes of action targeting multiple molecules and biological pathways involved in inflammatory states such as sepsis, ARDS, trauma, and burns.41–43
A significant body of preclinical and clinical evidence in septic shock and other types of stress responses demonstrate that intravenous AA can attenuate many of the life threatening complications of a dysregulated immune system during Covid-19 infection.43
There are two distinct phases in the host response commandeered by the innate and adaptive immunity in illness, including Covid-19 which consists of an initial antiviral response followed by an inflammatory response.20,44 In contrast to influenza and other respiratory viruses, there is a blunted antiviral response with low interferon production and increase in pro-inflammatory cytokines. In a minority of patients, cytokine storm ensues with overwhelming production of pro-inflammatory cytokines and reactive oxygen species leading to progressive organ failure.20,21,45–47
The innate immune and adaptive response provides an essential role in the antiviral response and is mediated by the release of type I interferon α/β by macrophages, lymphocytes and infected immune cells.45,48 Several experiments employing H1N1 infected knockout mice unable to synthesize AA found that administration of AA increases interferon production, restores expression of genes necessary for production of interferons and decreases proinflammatory gene expression with a subsequent decrease in the release of proinflammatory cytokines.48,49 AA is thus an essential factor in the anti-viral immune response during the early phase of virus infection through the production of type I IFNs.48
Ascorbic acid is also a cofactor for the production of endogenous catecholamines and corticosteroid synthesis (please see references 25–38 in the Methylprednisolone section). Given that humans are unable to synthesize AA, in states of stress plasma AA levels are markedly decreased.43,57 AA reverses ROS induced oxidant stress impairment of glucocorticoid receptor function.58,59 Thus, AA is synergistic with endogenous and exogenous corticosteroids in reversal of shock.43,59 In clinical studies AA given with or without steroids results in decreases in vasopressor requirement and reversal of shock.43,56,57,59 AA antioxidative and ROS scavenging properties may counteract cytokine, chemokine and inflammatory cell mediated excessive production of reactive oxygen species which are known to cause decreased vascular tone and endothelial injury.57,59
In animal models, intravenous ascorbic acid was shown to improve arteriolar responsiveness to vasoconstrictors and decrease microvascular permeability.57,60 The hemodynamic effects of AA have been demonstrated in septic shock, trauma, and burns where administration of ascorbic acid reduced vasopressor and volume resuscitation requirement.41,43,61,62
Marik et al, in a propensity adjusted study of patients with sepsis, administered intravenous AA, hydrocortisone, and thiamine in patients with severe sepsis and found a significant survival benefit.41 CITRIS-ALI, the largest double blind placebo controlled trial of high dose AA in ARDS patients found that both mortality and decreased ICU length of stay were markedly reduced in the treatment arm.63 The reasons for the lack of immediate adoption of this therapy in ARDS can only be explained by the fact that the original primary outcome analysis failed to account for all the early excess deaths in the control group, where no severity of illness (SOFA) score was assigned to the patients who died. A subsequent letter to the editor demanded an analysis accounting for these early deaths.64 The study authors complied and reported the primary outcome of SOFA score to be statistically significantly decreased at 96 hours. Thus, CITRIS-ALI, although inexplicably portrayed as a negative trial, was instead, profoundly positive in terms of its primary outcome and important secondary outcomes.
Two large meta-analyses involving critically ill patients demonstrated intravenous vitamin C administration showed no adverse reactions, reduced the need for fluids and vasopressor support and reduced intubation time.44,65
In summary, due the pleiotropic effects of AA on important physiologic functions, its properties as powerful antioxidant/ROS scavenger, and previous successful clinical use as a pharmacologic agent in the treatment of ARDS and hyperinflammatory conditions, intravenous AA was included in the MATH+ treatment protocol to target the Covid-19 associated cytokine storm along with its impeccable safety profile and low cost in critical illness.
- Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. Published online 2020. https://doi.org/10.1016/S0140-6736(20)30566-3
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. Published online 2020. https://doi.org/10.1016/S0140-6736(20)30628-0
- Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest. Published online 2009. https://doi.org/10.1378/chest.08-2408
- Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before–After Study. Chest. Published online 2017. https://doi.org/10.1016/j.chest.2016.11.036
- Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: A randomized, prospective study. Arch Surg. Published online 2000. https://doi.org/10.1001/archsurg.135.3.326
- Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. Published online 2018. https://doi.org/10.1186/s13054-018-2217-4
- Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. Published online 2018. https://doi.org/10.1177/2050312118807615
- Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. Published online 2020. https://doi.org/10.1016/j.cell.2020.04.026
- Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. Published online 2020. https://doi.org/10.1093/cid/ciaa248
- Acharya D, Liu GQ, Gack MU. Dysregulation of type I interferon responses in COVID-19. Nat Rev Immunol. Published online 2020. https://doi.org/10.1038/s41577-020-0346-x
- Kim Y, Kim H, Bae S, et al. Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection. Immune Netw. Published online 2013. https://doi.org/10.4110/in.2013.13.2.70
- Cai Y, Li YF, Tang LP, et al. A new mechanism of vitamin C effects on A/FM/1/47(H1N1) virus-induced pneumonia in restraint-stressed mice. Biomed Res Int. Published online 2015. https://doi.org/10.1155/2015/675149
- Shah A. Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19. Front Immunol. Published online 2020. https://doi.org/10.3389/fimmu.2020.01021
- Sang X, Wang H, Chen Y, et al. Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS. Inflammasome. Published online 2016. https://doi.org/10.1515/infl-2016-0001
- Zuo Y, Yalavarthi S, Shi H, et al. Neutrophil extracellular traps in COVID-19. JCI insight. Published online 2020. https://doi.org/10.1172/jci.insight.138999
- D. L, Y. X, H. C, et al. A novel cell-based assay for dynamically detecting neutrophil extracellular traps-induced lung epithelial injuries. Exp Cell Res. Published online 2020. https://doi.org/10.1016/j.yexcr.2020.112101
- Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. Published online 2009. https://doi.org/10.1038/nm.2053
- Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C: A novel regulator of neutrophil extracellular trap formation. Nutrients. Published online 2013. https://doi.org/10.3390/nu5083131
- Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. Published online 2015. https://doi.org/10.1186/s13054-015-1131-2
- Wilson JX. Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endothelium. BioFactors. Published online 2009. https://doi.org/10.1002/biof.7
- Okamoto K, Tanaka H, Makino Y, Makino I. Restoration of the glucocorticoid receptor function by the phosphodiester compound of vitamins C and E, EPC-K1 L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6- yl hydrogen phosphate] potassium salt), via a. Biochem Pharmacol. Published online 1998. https://doi.org/10.1016/S0006-2952(98)00121-X
- Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. Published online 2018. https://doi.org/10.1016/j.pharmthera.2018.04.007
- Tyml K. Vitamin C and microvascular dysfunction in systemic inflammation. Antioxidants. Published online 2017. https://doi.org/10.3390/antiox6030049
- Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. Published online 2014. https://doi.org/10.1186/1479-5876-12-32
- Iglesias J, Vassallo A V., Patel V V., Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial. Chest. Published online 2020. https://doi.org/10.1016/j.chest.2020.02.049
- Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. In: JAMA – Journal of the American Medical Association. ; 2019. https://doi.org/10.1001/jama.2019.11825
- De Grooth HJ, Elbers PWG, Vincent JL. Vitamin C for Sepsis and Acute Respiratory Failure. JAMA –J Am Med Assoc. Published online 2020. https://doi.org/10.1001/jama.2019.21981
- Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: A meta-regression analysis. J Intensive Care. Published online 2020. https://doi.org/10.1186/s40560-020-0432-y
G. Umberto Meduri
The importance of thiamine, known as Vitamin B1, in multiple, critical biochemical processes to achieve homeostasis in both health and illness will be reviewed here along with the deleterious effects of the often-overlooked high incidence of thiamine deficiency in critical illness states. Studies demonstrating the impacts of thiamine supplementation on clinical outcomes relevant to COVID-19 are also detailed below.
Thiamine and COVID-19
Thiamine is a water-soluble vitamin passively absorbed in the small intestine. After ingestion, free thiamine is converted to the active form thiamine pyrophosphate (TPP), commonly known as vitamin B1, by thiamine pyrophosphokinase. The majority of TPP in the body is found in erythrocytes and accounts for approximately 80% of the body’s total storage.66 TPP is a key co-factor for pyruvate dehydrogenase, the gatekeeper for entry into the Krebs Cycle, without which pyruvate would be converted to lactate as opposed to acetyl-coenzyme A. 66
Multiple other non-cofactor roles of thiamine exist within the immune system, gene regulation, oxidative stress response, cholinergic activity, chloride channel function, and neurotransmission.66 In experimental rheumatoid arthritis, thiamine increased the ability of corticosteroids to suppress production of TNF-á and IL-6.67
The human adult can store around 30 mg of thiamine in muscle tissue, liver and kidneys, however, these stores can become depleted in as little as 18 days after the cessation of thiamine intake.66 A thiamine deficiency syndrome, beriberi, bears a number of similarities to sepsis, including peripheral vasodilation, cardiac dysfunction, and elevated lactate levels.43 In critical illness, the prevalence of thiamine deficiency is in 10–20% upon admission and can increase up to 71% during ICU stay, suggesting rapid depletion of this vitamin.68,69 Based on limited data, no association was detected between thiamine levels, markers of oxidative stress and mortality.69,70
In one study, a significant negative correlation was reported between thiamine and lactic acid levels in patients with sepsis without liver dysfunction.68 In a pilot randomized controlled trial (RCT) of patients with septic shock (n=88), the administration of thiamine (200 mg twice a day for 7 days) reduced lactate levels and improved mortality over time in a pre-defined subgroup of patients with thiamine deficiency (35% of cohort).71 In a retrospective, single-center, matched cohort study, administration of thiamine within 24 hours of septic shock (n=123) was associated with improved likelihood of lactate clearance and a reduction in 28-day mortality.72 In a randomized study of patient undergoing gastrointestinal surgery, thiamine administration (200 mg/daily for 3 days) was associated with significant reduction in post-operative delirium.73
Given these promising results and favorable safety profile, the MATH+ protocol included thiamine supplementation as part of the combination therapy in critically ill COVID-19 patients.
- Collie JTB, Greaves RF, Jones OAH, Lam Q, Eastwood GM, Bellomo R. Vitamin B1 in critically ill patients: Needs and challenges. Clin Chem Lab Med. Published online 2017. https://doi.org/10.1515/cclm-2017-0054
- Menezes RR, Godin AM, Rodrigues FF, et al. Thiamine and riboflavin inhibit production of cytokines and increase the anti-inflammatory activity of a corticosteroid in a chronic model of inflammation induced by complete Freund’s adjuvant. Pharmacol Reports. Published online 2017. https://doi.org/10.1016/j.pharep.2017.04.011
- Donnino MW, Carney E, Cocchi MN, et al. Thiamine deficiency in critically ill patients with sepsis. J Crit Care. Published online 2010. https://doi.org/10.1016/j.jcrc.2010.03.003
- Costa NA, Gut AL, de Souza Dorna M, et al. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. Published online 2014. https://doi.org/10.1016/j.jcrc.2013.12.004
- Corcoran TB, O’Neill MA, Webb SAR, Ho KM. Prevalence of vitamin deficiencies on admission: Relationship to hospital mortality in critically ill patients. Anaesth Intensive Care. Published online 2009. https://doi.org/10.1177/0310057×0903700215
- Donnino MW, Andersen LW, Chase M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. Published online 2016. https://doi.org/10.1097/CCM.0000000000001572
- Woolum JA, Abner EL, Kelly A, Bastin MLT, Morris PE, Flannery AH. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. Published online 2018. https://doi.org/10.1097/CCM.0000000000003311
- Moslemi R, Khalili H, Mohammadi M, Mehrabi Z, Mohebbi N. Thiamine for prevention of postoperative delirium in patients undergoing gastrointestinal surgery: A randomized clinical trial. J Res Pharm Pract. Published online 2020. https://doi.org/10.4103/jrpp.jrpp_19_124
Pierre Kory, MD
The early identification of a high incidence of venous and arterial thrombotic complications, often as the proximate cause of death in COVID-19 patients, have led to numerous and increasing investigations into the pathophysiologic causes of this hypercoagulability. These studies along with clinical reports on both the incidences in varying populations of COVID-19 patients and the associations of anti-coagulant therapy with survival are reviewed below.
Anticoagulation and COVID-19
From the earliest clinical experiences with COVID-19 patients, reports of both severe inflammation and excess clotting emerged from China and Italy.74,75,76 Infections are recognized activators of inflammatory and coagulation responses as part of the host defense, and in COVID-19, although patients present with prominent elevation of D-dimer and fibrin/fibrinogen degradation products as is typically seen in traditional disseminated intravascular coagulation DIC, either little or no abnormalities in prothrombin time (PT), partial thromboplastin time (PTT), and platelet counts are seen initially.74 The term COVID-19 Associated Coagulopathy (CAC) was created to describe these abnormalities in tests although typical impaired clotting that results in increased bleeding is not observed.74 Conversely, nearly all published clinical reports describe CAC as a “hypercoagulable” condition.
Thromboelastography (TEG) has best elucidated the hypercoagulable nature of CAC given its ability to assess both the pro-thrombotic and coagulopathic dynamics of whole blood as it forms clot under conditions of low shear stress. TEG studies consistently reveal markers of hypercoagulability, notable for rapid and large amplitudes of clot formation with little to no fibrinolytic activity present.77,78
Incidence of thrombotic complications
Given that CAC is “hypercoagulable”, it is unsurprising that the majority of published data report a higher than previously reported frequency of clotting in critically ill COVID-19 patients despite receiving thromboprophylaxis. Helms et al. from France reported an incidence of 16.7% of VTE (mainly pulmonary embolism); an incidence six-fold higher than a matched population of non-COVID ARDS patients. Equally alarming, 96.6% of patients on continuous renal replacement therapy developed circuit clotting. In two studies from Holland the incidence of VTE in ICU patients was up to one third by day 7 and greater than 50% after day 14. 79,86
In a lower extremity ultrasound screening study of an ICU population with 2/3 on systemic anticoagulation and 1/3 on thromboprophylaxis, VTE was found in 69% of the patients, with a 100% incidence in those on prophylaxis and 56% in patients on anti-coagulation.79 The VTE rates reported in the above ICU populations of COVID-19 patients are magnitudes higher than the approximate 8% rate of VTE reported in previous studies of non-COVID-19 ICU patients receiving thromboprophylaxis.80
In contrast to COVID-19 ICU patients, the rates of VTE in COVID-19 hospitalized ward patients have been lower but still remain concerning. Middeldorp reported a cumulative 9.2% incidence of VTE, similar to pre-COVID-19 incidences in non-ICU patients, however another study found a cumulative incidence of 27% with 4% arterial thrombosis resulting in a composite incidence of 29%.81,82 However, not all studies of hospital ward patients found such high incidences, for instance Lodigiani et al reported a 6.6% incidence in this population while Cattaneo et al found that in a population of 388 COVID-19 patients, 64 of whom underwent screening leg ultrasound, no patient developed VTE.83 However, it should be noted that the patients in this study were only mildly ill as evidenced by a mean Pa02/FI02 ratio of 300, respiratory rate of 20/minute, and a D-dimer level of .46 ug/ml, with no patient requiring non-invasive or mechanical ventilation.
In addition to the consistently and markedly elevated incidence of “macrovascular” thrombosis reported among both hospital ward and ICU patients, autopsies have also revealed extensive microvascular thromboses, with one report finding severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes and widespread thrombosis with microangiopathy.84 In one report alveolar capillary microthrombi were nine times as prevalent in COVID-19 patients than patients with influenza (p<0.001).85 Thrombosis is also a prominent feature in multiple organs, in some cases despite full anticoagulation and regardless of timing of the disease course, suggesting that thrombosis plays a role very early in the disease process. 86
Outcomes associated with Anti-Coagulation in COVID-19
A major clinical question addressed by a multitude of hematologic societies is whether anti-coagulant therapy can improve the outcomes of COVID-19 patients. Tang first reported on 449 patients with “severe” COVID-19 and found that low-molecular weight heparin (LMWH), the majority of the time in prophylactic doses, was associated with a large mortality benefit in the sub-group of patients meeting sepsis-induced coagulopathy score ≥4 (40.0% vs 64.2%, P=0.029), or D-dimer > 6 fold of upper limit of normal (32.8% vs 52.4%, P=0.017).87 A large study on 2,777 patients from Mt. Sinai Hospital in New York City also reported a large mortality reduction in mechanically ventilated patients on systemic anti-coagulation where mortality was 29.1% in those treated with systemic anti-coagulation compared to 62.7% who did not receive treatment dose.88
Although the association of treatment dose anticoagulation with survival among ICU patients is encouraging, what is more worrisome are the multiple reports of “coagulation failure” in which severe thrombotic complications occurred in COVID-19 patients despite therapeutic anti-coagulation. 79,81,89 A possible explanation for this phenomena was provided by Maier et al, where they used capillary viscometry in 15 severely ill COVID-19 ICU patients, almost all in ARDS, and found that all patients had a blood viscosity exceeding 95% of normal, a condition they termed “COVID-19 associated hyperviscosity”.90 The 4 patients with the highest viscosity all suffered thrombotic complications despite the majority of patients having been on either systemic AC or intermediate dose prophylaxis. Given that hyperviscosity is thought due to increased plasma proteins such as fibrinogen or immunoglobulin which then damage endothelium, this suggests that therapeutic plasma exchange (TPE) may play a role. Early supportive evidence for this theory can be seen in the report by Khamis et al who published the results of 31 COVID-19 patients in moderate to severe ARDS where 11 of the more severely ill patients all received TPE with a slightly higher proportion of the TPE group also receiving tocilizumab than in the control group. They reported that compared to the ICU patients who did not receive TPE, both large improvements in extubation rates (73% vs. 20%, p=.018) and mortality (0% vs 35%, p=.03) were observed, strongly suggesting not only a possible critical role for TPE therapy in severe COVID-19 but also for the need for a prospective study. 91
Anti-Coagulation Treatment Recommendations
To the best of our knowledge, no major national or international medical society to date has recommended therapeutic anti-coagulation be administered as standard practice in any sub-group of COVID-19 patients. Many have recommended standard thromboprophylaxis for all hospitalized patients with COVID-19. This therapeutic conservatism is puzzling, given that, based on the best available evidence to date, the benefits of a more aggressive AC regimen appear to far outweigh the risks of a less aggressive anticoagulation regimen based on the large magnitude of survival associated with therapy and the paucity of reports of bleeding complications.87,88 Lacking strong data from a randomized controlled trial and based on the best available evidence to date, we believe that, in hospitalized patients, an aggressive thromboprophylaxis regimen is warranted while in critically ill patients therapeutic anti-coagulation be administered unless specifically contra-indicated.
The “intermediate” dose thromboprophylaxis we recommend in hospital ward patients is based on pharmacokinetic and anti-Xa level monitoring studies and suggest use of weight-based prophylaxis with 0.5 mg/kg twice daily of low-molecular weight heparin (LMWH) .92
In ICU patients, we recommend treatment dose anti-coagulation be provided using 1mg/kg LMWH twice daily. Further, we recommend monitoring of Anti-Xa levels aiming for an anti-Xa activity of 0.6-1.1 IU/ml due to reports that heparin resistance appears to be common in COVID-19.93 In addition, due to augmented renal clearance, COVID-19 patients may have reduced anti-Xa activity despite standard dosages of LMWH.94
- Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033–2040. https://doi.org/10.1182/blood.2020006000
- Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421–1424. https://doi.org/10.1111/jth.14830
- Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020;41(19):1858. https://doi.org/10.1093/eurheartj/ehaa254
- Panigada M, Bottino N, Tagliabue P, et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost. 2020;(April):1738–1742. https://doi.org/10.1111/jth.14850
- Mortus JR, Manek SE, Brubaker LS, et al. Thromboelastographic Results and Hypercoagulability Syndrome in Patients With Coronavirus Disease 2019 Who Are Critically Ill. JAMA Netw open. 2020;3(6):e2011192. https://doi.org/10.1001/jamanetworkopen.2020.11192
- Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020;(April):1–4. https://doi.org/10.1111/jth.14869
- Lim W, Meade M, Lauzier F, et al. Failure of anticoagulant thromboprophylaxis: Risk factors in medical-surgical critically Ill patients. Crit Care Med. Published online 2015. https://doi.org/10.1097/CCM.0000000000000713
- Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. Published online 2020:0–2. https://doi.org/10.1111/jth.14888
- Thomas W, Varley J, Johnston A, et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. Published online 2020. https://doi.org/10.1016/j.thromres.2020.04.028
- Cattaneo M, Bertinato EM, Birocchi S, et al. Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Thromb Haemost. Published online 2020. https://doi.org/10.1055/s-0040-1712097
- Wichmann D, Sperhake J-P, Lütgehetmann M, et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Ann Intern Med. 2020;25(4). https://doi.org/10.7326/m20-2003
- Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–128. https://doi.org/10.1056/NEJMoa2015432
- Rapkiewicz A V, Mai X, Carsons SE, et al. thrombosis at autopsy in COVID-19 : A case series. EClinicalMedicine. 2020;000:100434. https://doi.org/10.1016/j.eclinm.2020.100434
- Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. Published online 2020. https://doi.org/10.1111/jth.14817
- Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020;76(1):122–124. https://doi.org/10.1016/j.jacc.2020.05.001
- Klok FA, Kruip MJHA, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191(April):148–150. https://doi.org/10.1016/j.thromres.2020.04.041
- Maier CL, Truong AD, Auld SC, Polly DM, Tanksley CL, Duncan A. COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Lancet. 2020;395(10239):1758–1759. https://doi.org/10.1016/S0140-6736(20)31209-5
- Khamis F, Al-Zakwani I, Al Hashmi S, et al. Therapeutic Plasma Exchange in Adults with Severe COVID-19 Infection. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. Published online June 2020. https://doi.org/10.1016/j.ijid.2020.06.064
- Lim SY, Jeon K, Kim HJ, et al. Antifactor Xa levels in critically ill Korean patients receiving enoxaparin for thromboprophylaxis: A prospective observational study. J Korean Med Sci. 2013;28(3):466–471. https://doi.org/10.3346/jkms.2013.28.3.466
- White D, MacDonald S, Bull T, et al. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020;(0123456789). https://doi.org/10.1007/s11239-020-02145-0
- Tomasa-Irriguible TM, Martínez-Vega S, Mor-Marco E, Herraiz-Ruiz A, Raguer-Pardo L, Cubells-Larrosa C. Low molecular weight heparins in COVID-19 patients: Beware of augmented renal clearance! Crit Care. 2020;24(1):4–5. https://doi.org/10.1186/s13054-020-03058-3
Paul E. Marik, MD
Melatonin, a substance most often associated with use as a sleep induction aid, has multiple additional therapeutic properties based on myriad physiologic effects. Several of these have been shown to be of particular relevance in not only limiting the ability of SARS-CoV-2 to invade cells but also in counteracting several of the inflammatory processes it over-stimulates. These properties will be reviewed along with both a clinical and drug-repurposing analysis study that support the potential therapeutic value of melatonin in COVID-19.
Melatonin and COVID-19
Melatonin (N-acetyl-5-methoxytryptamine) is synthesized from tryptophan in the pineal gland and in the mitochondria of almost all cell in the body.96 Melatonin is released from the pineal gland into the systemic circulation achieving plasma concentration between 80 and 120 pg/mL at night and 10–20 pg/mL during the day. Melatonin binds to two receptor subtypes: MT1 and MT2.97 The melatonin receptors are G-protein coupled receptors (GPCRs) which both activate and inhibit a constellation of intracellular signaling pathways.
In addition to its role in regulating the circadian rhythm, melatonin is a potent antioxidant and immune regulator that controls both the innate and adaptive immune response96,98 The anti-oxidative effect of melatonin cooperates with its anti-inflammatory actions by up-regulating anti-oxidative enzymes (e.g. superoxide dismutase), down-regulating pro-oxidative enzymes (e.g. nitric oxide synthase), and by interacting directly with free radicals, functioning as free radical scavenger.96,99 Melatonin plays an important role in protecting the mitochondria from oxidative injury, thereby playing a critical role in maintaining energy production.96 Melatonin has significant anti-inflammatory, anti-apoptotic properties, anti NF-κB activation and has been demonstrated to reduce pro-inflammatory cytokines levels. 100–103
Melatonin levels falls off dramatically after age 40; these are also the patients at highest risk of developing COVID-19 and from dying from the disease.104,105
SARS-CoV-2 induced endothelial dysfunction is initiated by increases in the phosphorylation levels of JAK2 and STAT3, producing increased amounts of reactive oxygen species.109 These changes can be reversed by administration of melatonin by abating the production of superoxide anion, hydrogen peroxide and peroxynitrite by inhibiting the JAK2/STAT3 signaling pathway and by inhibiting endothelial apoptosis by preventing Bax activation.100 The clinical utility of melatonin in COVID-19 was first demonstrated in a large prospective registry created to identify risk factors for the development of a positive SARS-CoV-2 test.110 Researchers found that the most potentially impactful intervention to lower risk of testing positive were if patients were taking melatonin, paroxetine, or carvedilol, all medications that had been previously identified in drug-repurposing studies to have specific activity and potential benefit against SARS-CoV-2.103,110
Oral melatonin use by humans is exceedingly safe, with only minor side effects such as headache and drowsiness. The lethal dose 50 (LD 50) of melatonin is reported to be infinity; i.e., it is impossible to administer a large enough dose of melatonin to kill an animal. It should be noted that there is marked variability in first-pass hepatic metabolism, resulting in marked unpredictability in serum levels.109 Furthermore, the optimal dose of melatonin in “healthy individuals” and those with inflammatory disorders is unknown. For patients with COVID-19 we suggest a dose of between 6–12 mg, taken at night.100 However, a dose of up to 400 mg has been suggested.102
- Biancatelli RMLC, Berrill M, Mohammed YH, Marik PE. Melatonin for the treatment of sepsis: The scientific rationale. J Thorac Dis. Published online 2020. https://doi.org/10.21037/jtd.2019.12.85
- Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT 1 and MT 2 Melatonin Receptors: A Therapeutic Perspective . Annu Rev Pharmacol Toxicol. Published online 2016. https://doi.org/10.1146/annurev-pharmtox-010814-124742
- Carrillo-Vico A, Reiter RJ, Lardone PJ, et al. The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs. Published online 2006.
- Espino J, Pariente JA, Rodríguez AB. Oxidative stress and immunosenescence: Therapeutic effects of melatonin. Oxid Med Cell Longev. Published online 2012. https://doi.org/10.1155/2012/670294
- Dominguez-Rodriguez A, Abreu-Gonzalez P MP et al. Melatonin, cardiovascular disease and COVID-19: A potential therapeutic strategy? Melatonin Res. 2020;3:318-321.
- Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A, Marik PE, Abreu-Gonzalez P. Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis. Med Drug Discov. Published online 2020. https://doi.org/10.1016/j.medidd.2020.100044
- Reiter RJ, Abreu-Gonzalez P, Marik PE, Dominguez-Rodriguez A. Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19. Front Med. Published online 2020. https://doi.org/10.3389/fmed.2020.00226
- Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. Published online 2020. https://doi.org/10.1038/s41421-020-0153-3
- Wurtman RJ. Age-Related Decreases in Melatonin Secretion—Clinical Consequences. J Clin Endocrinol Metab. Published online 2000. https://doi.org/10.1210/jcem.85.6.6660
- Zhang R, Wang X, Ni L, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. Published online 2020. https://doi.org/10.1016/j.lfs.2020.117583
- Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. Published online 2020. https://doi.org/10.1056/nejmoa2015432
- Teuwen LA, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol. Published online 2020. https://doi.org/10.1038/s41577-020-0343-0
- Favero G, Franceschetti L, Buffoli B, et al. Melatonin: Protection against age-related cardiac pathology. Ageing Res Rev. Published online 2017. https://doi.org/10.1016/j.arr.2016.11.007
- Aldhous M, Franey C, Wright J, Arendt J. Plasma concentrations of melatonin in man following oral absorption of different preparations. Br J Clin Pharmacol. Published online 1985. https://doi.org/10.1111/j.1365-2125.1985.tb02679.x
- Linko R, Karlsson S, Pettilã. V, et al. Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand. Published online 2011. https://doi.org/10.1111/j.1399-6576.2011.02425.x
Paul E. Marik, MD
Zinc is an essential trace element for both pathogens and hosts. Zinc deficiency is common in sepsis patients and represents the innate immune systems attempt to deprive pathogens of zinc. The inability to store zinc in the body likely renders humans particularly susceptible to zinc deficiency. The importance of zinc in multiple physiologic processes will be reviewed along with both the consequences of zinc deficiency and the benefits of zinc supplementation in viral illnesses.
Zinc and COVID-19
Zinc likely has an important role in the prophylaxis of COVID-19, in the treatment of the early symptomatic phase, and in limiting the immune dysregulation and associated cytokine storm in the pulmonary phase.111 Zinc is a nutritionally fundamental trace element and is the second most abundant trace metal in the human body after iron. Since zinc does not have a major storage depot in the body, zinc deficiency is easily and rapidly produced. It should be recognized that the same dietary factors leading to deficiency of zinc frequently result in the deficiency of other micronutrients. Zinc plays an important role in the host’s anti-viral (and antibacterial) immune response. In addition, zinc is directly viricidal. Zinc is a component of over 1000 transcription factors, including DNA binding proteins and is required in over 300 metalloenzymes. Zinc plays a central role in cellular differentiation and proliferation, and its deficiency causes impaired immune response, increased susceptibility to infections and impaired wound healing.112,113 Zinc is necessary for optimal functioning of both innate and adaptive immunity. Zinc status strongly affects T- and B-lymphocyte function and antibody formation. Additionally, Zinc deficiency increases the production of proinflammatory cytokines, including interleukins IL-1, IL-6, and tumor necrosis factor (TNF)-α. Zinc has several antioxidant properties; it is a cofactor of the Cu/Zn-SOD enzyme and it inhibits NADPH oxidases.112 Impaired immune function due to inadequate zinc status may be the most common cause of secondary immunodeficiency in humans. Zinc deficiency is an important public health problem affecting 2 billion people worldwide, including a considerable proportion of the Western population.112,114–116 Zinc levels are reported to be very low in critically ill patients, particularly those with sepsis and acute respiratory failure.113,117,118 Low zinc levels have been reported to be associated with recurrent infections and increased hospital mortality.119 In addition, zinc deficiency has been demonstrated to potentiate ventilator induced lung injury.120
Previous studies have demonstrated the benefit of zinc supplementation in viral infections, most notably upper respiratory tract infections. Meta-analyses of RCTS have demonstrated that Zinc lozenges at a dose of ≥ 75mg/day (elemental zinc) administered within 24 hours of onset of symptoms and taken for at least 5 days significantly reduced the duration of common cold symptoms, school absence and the use of antibiotic.121,122 Trials of low dose zinc lozenges (< 75 mg/day zinc) found no effect on the duration of colds. However, when combined with vitamin C, low dose zinc was reported to reduce the duration of symptoms of the common cold.116 When used prophylactically for at least 5 months zinc lozenges at a dose ≥ 75mg/day reduced the risk of developing a common cold. Zinc supplementation of nursing home elderly patients was reported to reduce the incidence of pneumonia.123 Adverse events of Zinc lozenges include a bad taste and increased incidence of nausea.
The therapeutic benefit of zinc in hospitalized patients with COVID-19 was demonstrated in a retrospective observational study reported by Carlucci and colleagues.129 The authors demonstrated that Zinc when combined with hydroxychloroquine and azithromycin was associated with a significantly lower hospital mortality as compared to hydroxychloroquine and azithromycin.
- Skalny A V., Rink L, Ajsuvakova OP, et al. Zinc and respiratory tract infections: Perspectives for CoviD’19 (Review). Int J Mol Med. Published online 2020. https://doi.org/10.3892/ijmm.2020.4575
- Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. Published online 2017. https://doi.org/10.3390/nu9060624
- Heyland DK, Jones N, Cvijanovich NZ, Wong H. Review: Zinc supplementation in critically ill patients: A key pharmaconutrient? J Parenter Enter Nutr. Published online 2008. https://doi.org/10.1177/0148607108322402
- Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. Published online 2012. https://doi.org/10.1016/S0140-6736(12)61766-8
- Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet. Published online 2008. https://doi.org/10.1016/S0140-6736(07)61693-6
- Maggini S, Wenzlaff S, Hornig D. Essential role of vitamin c and zinc in child immunity and health. J Int Med Res. Published online 2010. https://doi.org/10.1177/147323001003800203
- Linko R, Karlsson S, Pettilã. V, et al. Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand. Published online 2011. https://doi.org/10.1111/j.1399-6576.2011.02425.x
- Mertens K, Lowes DA, Webster NR, et al. Low zinc and selenium concentrations in sepsis are associated with oxidative damage and inflammation. Br J Anaesth. Published online 2015. https://doi.org/10.1093/bja/aev073
- Hoeger J, Simon TP, Beeker T, Marx G, Haase H, Schuerholz T. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients – A pilot study. PLoS One. Published online 2017. https://doi.org/10.1371/journal.pone.0176069
- Boudreault F, Pinilla-Vera M, Englert JA, et al. Zinc deficiency primes the lung for ventilator-induced injury. JCI insight. Published online 2017. https://doi.org/10.1172/jci.insight.86507
- Singh M, Das RR. Zinc for the common cold. Evidence-Based Child Heal. Published online 2012. https://doi.org/10.1002/ebch.1859
- Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. Published online 2017. https://doi.org/10.1177/2054270417694291
- Meydani SN, Barnett JB, Dallal GE, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. Published online 2007. https://doi.org/10.1093/ajcn/86.4.1167
- te Velthuis AJW, van den Worml SHE, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. Published online 2010. https://doi.org/10.1371/journal.ppat.1001176
- Maret W. Zinc in cellular regulation: The nature and significance of “zinc signals.” Int J Mol Sci. Published online 2017. https://doi.org/10.3390/ijms18112285
- Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One. Published online 2014. https://doi.org/10.1371/journal.pone.0109180
- Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O’Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: From hepa 1–6 cells to a liposome model. J Agric Food Chem. Published online 2014. https://doi.org/10.1021/jf5014633
- Shittu MO, Afolami OI. Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives – A better synergy for future COVID-19 clinical trials. Le Infez Med. Published online 2020.
- Carlucci P, Ahuja T, Petrilli CM, Rajagopalan H, Jones S, Rahimian J. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv. Published online 2020. https://doi.org/10.1101/2020.05.02.20080036
Pierre Kory, MD; Paul E. Marik, MD
Vitamin D deficiency is a major global public health problem in all age groups and it has been estimated that in excess of one billion people world- wide have vitamin D deficiency. Although it has been quickly recognized that number of factors, including age, co-morbidities, race, access to healthcare and genetic factors (and the complex interactions between these factors), determine the clinical course after exposure to SARS-CoV-2, in the below section, the physiologic importance of vitamin D, the implications of Vitamin D deficiency, and the impacts of Vitamin D supplementation in influencing the risk of dying from SARS-CoV-2 will be reviewed.
Vitamin D and COVID-19
Vitamin D is obtained via the diet or produced in the skin by UVB light. Aside from its known role in calcium metabolism and bone health it also has important roles in the immune system including support of endothelial barriers, and innate and adaptive immunity.133 The innate immune system in COVID-19 produces both pro-inflammatory and anti-inflammatory cytokines while vitamin D reduces the production of pro-inflammatory Th1 cytokines such as tumor necrosis factor α and interferon γ and increase the expression of anti-inflammatory cytokines by macrophages.134–136
Given it’s important roles in immune function, many have hypothesized that vitamin D deficiency increases susceptibility to infections and that supplementation may improve outcomes, particularly in COVID-19.137,138 Data supportive of the theory that deficiency leads to infections largely rest on the fact that seasonal influenza infections generally peak in conjunction with times of the year when 25(OH)D concentrations are lowest.139 Further, the onset of the epidemic and higher case load in countries during the winter season also raises the possible association with low vitamin D status.140 Rhodes et al first identified this link by comparing the mortality of COVID-19 in relation to country latitude and found that, even after adjusting for age, there was a 4.4% increase in mortality for each degree latitude north of 28 degrees. Further, ethnic minorities in both the United States and the United Kingdom have high rates of Vitamin D deficiency, potentially explaining why the mortality rates in these populations are much higher.141
Given the strong associations of Vitamin D deficiency with higher rates of viral infections, multiple studies have tested whether vitamin D supplementation can reduce this risk. Although studies have conflicted in their findings, a recent meta-analysis from 2018 found that regular supplementation with vitamin D decreased the risk of acute respiratory tract infections, with the most profound effects in patients with severe vitamin D deficiency.142
In the critically ill, the benefits of supplementation are even more profound. First, vitamin D deficiency in the ICU is common and levels decrease rapidly after admission.143,144 Deficiency has strong negative correlations with poor outcomes, namely higher mortality.145,146 Overall, less than 800 patients have been included in RCTs worldwide, but a meta-analysis of these studies found that supplementation in the ICU, largely using high doses, improved survival.147,148 Currently there are two large RCT’s together enrolling over 5000 patients which will provide more definitive evidence to guide therapy.
The available data suggest that high-dose vitamin D supplementation is beneficial not only in the prevention of viral infections but also in improving outcomes of the critically ill. Although the impact of supplementation varies by deficiency status as well as severity of illness, vitamin D supplementation is safe; one meta-analysis of healthy patients found no adverse events, while in the critically ill, mild hypercalcemia was the most common adverse effect.142,149
Levels greater than 50nmol/L (20ng/mL) are thought sufficient for protection against acute respiratory tract infections.142 One report mentioned that “doses up to 10,000 IU/day is safe, although well above what is needed” and that “only 1,000–2,000 IU may be needed to obtain optimal effects on bone and immunity”.150 Thus to reduce the risk of infection, one expert recommended that people at risk of COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L).150
In the critically ill, the doses used from published RCT’s ranged from 200,000–600,000 IU.147 Han et al gave either 50,000 or 1000,000 IU for 5 days straight while in the largest trial, Amrein et al gave a single enteral dose of 540,000 IU then monthly doses of 90,000 IU for 5 months.151,152
- Rondanelli M, Miccono A, Lamburghini S, et al. Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds – Practical Advice on Dosages . Evidence-based Complement Altern Med. Published online 2018. https://doi.org/10.1155/2018/5813095
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. Published online 2020. https://doi.org/10.1016/S0140-6736(20)30183-5
- Sharifi A, Vahedi H, Nedjat S, Rafiei H, Hosseinzadeh-Attar MJ. Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial. APMIS. Published online 2019. https://doi.org/10.1111/apm.12982
- Rossi GA, Fanous H, Colin AA. Viral strategies predisposing to respiratory bacterial superinfections. Pediatr Pulmonol. Published online 2020. https://doi.org/10.1002/ppul.24699
- Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin d supplementation could reduce risk of influenza and Covid-19 infections and deaths. Nutrients. 2020;12(4):1–19. https://doi.org/10.3390/nu12040988
- Quraishi SA, Bittner EA, Blum L, Hutter MM, Camargo CA. Association between preoperative 25-hydroxyvitamin D level and hospital-acquired infections following roux-en-Y gastric bypass surgery. JAMA Surg. Published online 2014. https://doi.org/10.1001/jamasurg.2013.3176
- Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. Published online 2006. https://doi.org/10.1017/S0950268806007175
- Youssef DA, Ranasinghe T, Grant WB, Peiris AN. Vitamin D’s potential to reduce the risk of hospital-acquired infections. Dermatoendocrinol. Published online 2012. https://doi.org/10.4161/derm.20789
- ONS. Coronavirus (COVID-19) related deaths by ethnic group, England and Wales – Office for National Statistics. 2020;(April):1–10. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/coronav…
- Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017;356. https://doi.org/10.1136/bmj.i6583
- Venkatesh B, Nair P. Hypovitaminosis D and morbidity in critical illness: Is there proof beyond reasonable doubt? Crit Care. 2014;18(3):7–9. https://doi.org/10.1186/cc13863
- Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med. Published online 2009. https://doi.org/10.1056/NEJMc0809996
- Zhang YP, Wan YD, Sun TW, Kan QC, Wang LX. Association between vitamin D deficiency and mortality in critically ill adult patients: A meta-analysis of cohort studies. Crit Care. 2014;18(6):1–8. https://doi.org/10.1186/s13054-014-0684-9
- Amrein K, Zajic P, Schnedl C, et al. Vitamin D status and its association with season, hospital and sepsis mortality in critical illness. Crit Care. 2014;18(2). https://doi.org/10.1186/cc13790
- Putzu A, Belletti A, Cassina T, et al. Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials. J Crit Care. 2017;38:109–114. https://doi.org/10.1016/j.jcrc.2016.10.029
- Amrein K, Martucci G, McNally JD. When not to use meta-analysis: Analysing the meta-analyses on vitamin D in critical care. Clin Nutr. 2017;36(6):1729–1730. https://doi.org/10.1016/j.clnu.2017.08.009
- Christopher KB. Vitamin D supplementation in the ICU patient. Curr Opin Clin Nutr Metab Care. Published online 2015. https://doi.org/10.1097/MCO.0000000000000147
- Bergman P. The link between Vitamin D and Covid-19: distinguishing facts from fiction. J Intern Med. Published online 2020:0–3. https://doi.org/10.1111/joim.13158
- Han JE, Jones JL, Tangpricha V, et al. High dose Vitamin D administration in ventilated intensive care unit patients: A pilot double blind randomized controlled trial. J Clin Transl Endocrinol. 2016;4:59–65. https://doi.org/10.1016/j.jcte.2016.04.004
- Amrein K, Schnedel C, Holl A, et al. Correction of vitamin D deficiency in critically ill patients: A randomized placebo-controlled trial. Clin Nutr. Published online 2014. https://doi.org/10.1016/S0261-5614(14)50030-1
Pierre Kory, MD
Statins are first-line lipid-lowering therapies with well-tolerated side effects, are low in cost, and are broadly available worldwide, including in developing countries. The potent anti-inflammatory and immunomodulatory effects of statins suggest they could be beneficial to counter coronoviral infections, including for SARS-CoV-2.
Although retrospective cohort studies reported a reduced risk of influenza death among statin users, there is theoretical risk that statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. In the section below, we review the relevance of the pathophysiologic actions of statins and the emerging clinical evidence base associating statin use with improved survival in COVID-19.
Statin Therapy and Covid-19
Statins are medicines that lower lipid levels but also have multiple anti-inflammatory actions. Over a decade of observational studies, both matched and non-matched showed largely consistent benefits in patients with sepsis and/or ARDS.153 Multiple randomized controlled trials were then conducted using various statins and doses, however, in a well-conducted meta-analysis of RCT’s in sepsis involving 2628 patients, no difference in mortality between groups was found.154 Similarly, in ARDS trials, a meta-analysis from 2016 found no difference in important outcomes.155 However, in an editorial that reviewed the outcomes from the STATInS and HARP-2 trials, they found that an alteration of just three events would have yielded statistically significant results in favor of statin use based on mortality outcomes.156–158 This low “fragility index” suggests that benefits in subgroups exist but are then “lost” in the heterogenous populations that are often included in RCT’s of critical illness syndromes such as ARDS and sepsis. This hypothesis was seemingly validated by a secondary analysis of the HARP-2 trial in which the authors split patients into two phenotypes of ARDS, a “hyperinflammatory” and “hypoinflammatory” type.159 The hyperinflammatory group had higher values of sTNFr-1 and IL-6, lower platelet counts, more vasopressor use, fewer ventilator free days and much higher 28-day mortality. When the hyperinflammatory phenotype received simvastatin 80 mg, a large and statistically significant reduction in mortality was found. Further, in COVID-19, two retrospective studies have demonstrated a strong association of statin use with survival. In a large study of 13,981 patients in China, among which 1,219 received statins, the all-cause mortality was almost halved in the statin treated patients (HR=.58, (95% CI, 0.43–0.80, p=.001).160 In a smaller study in the US, one group found that among a group of 88 patients, 55% of whom died, atorvastatin use was associated with a 73% lower risk of progression to death (aHR 0.38 (95% CI 0.18–0.77, p=.008).161 Thus, given the frequent hyperinflammation and elevated levels of IL-6 in COVID-19 associated ARDS, it appears reasonable to employ statin therapy for COVID-19 ARDS. Atorvastatin is favored due to its more favorable drug-interaction profile and a higher dose of 80mg should be used, similar to the HARP-2 trial.
- Wan YD, Sun TW, Kan QC, Guan FX, Zhang SG. Effect of statin therapy on mortality from infection and sepsis: A meta-analysis of randomized and observational studies. Crit Care. 2014;18(2):1–13. https://doi.org/10.1186/cc13828
- Pertzov B, Eliakim-Raz N, Atamna H, Trestioreanu AZ, Yahav D, Leibovici L. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults – A systematic review and meta-analysis. Clin Microbiol Infect. 2019;25(3):280–289. https://doi.org/10.1016/j.cmi.2018.11.003
- Gao X qing, Li Y fang, Jiang Z li. Impact of statins on ALI/ARDS: A meta-analysis. Pulm Pharmacol Ther. 2016;39:85–91. https://doi.org/10.1016/j.pupt.2016.06.010
- Kruger P, Bailey M, Bellomo R, et al. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013;187(7):743–750. https://doi.org/10.1164/rccm.201209-1718OC
- Kruger PS, Terblanche M. Statins in patients with sepsis and ARDS: is it over? No. Intensive Care Med. 2017;43(5):675–676. https://doi.org/10.1007/s00134-016-4564-4
- McAuley DF, Laffey JG, O’Kane CM, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371(18):1695–1703. https://doi.org/10.1056/NEJMoa1403285
- Calfee CS, Delucchi KL, Sinha P, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. Published online 2018. https://doi.org/10.1016/S2213-2600(18)30177-2
- Report T. Clinical and Translational Report In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Published online 2020:1–12. https://doi.org/10.1016/j.cmet.2020.06.015
- Rodriguez-Nava G, Trelles-Garcia DP, Yanez-Bello MA, Chung CW, Trelles-Garcia VP, Friedman HJ. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study. Crit Care. 2020;24(1):429. https://doi.org/10.1186/s13054-020-03154-4
Pierre Kory, MD
Famotidine and COVID-19
Famotidine, a histamine-2 receptor antagonist (H2RA), although commonly used to suppress acid production in the stomach, is also known to have in-vitro properties which not only inhibit viral replication such as in HIV but also exert stimulatory effects on almost all immune cells of the innate and adaptive immune system.162 It can also prevent H2R cytokine inhibition and prevent inhibition by histamine on Th-1 cytokine release.163,164
H2RA’s have proven effective in the past against other viruses. Cimetidine, and less so famotidine exhibited reduced viral infection with HIV in vitro, increased the clearance of warts caused by human papilloma virus, and appeared effective in improving the symptoms associated with chronic Epstein-Barr virus infection.165–167 In fact, ranitidine bismuth citrate effectively inhibited the nucleoside triphosphate hydrolase and DNA unwinding activities of the SARS coronavirus helicase and dramatically reduced its replication levels in infected cells.168
Given prior evidence of anti-viral, and in particular anti-SARS-CoV and immune system effects, Freedberg et al performed a retrospective cohort study using propensity score matching in COVID-19 patients at a single medical center. The treatment group all received famotidine within 24 hours of admission. 1620 patients were included with 81 having received famotidine. They found that the use of famotidine was associated with a large reduced risk for death or intubation (adjusted hazard ratio (aHR) 0.42, 95% CI 0.21–0.85) and also with reduced risk for death alone (aHR 0.30, 95% CI 0.11–0.80).169 An interesting associated finding was that in patients on proton pump inhibitors, no reduced risk for any patient outcomes was observed. Although an observational study, propensity score matching was performed between groups, and a large difference in intubation and death was observed, Although such a study should be strictly be considered as hypothesis generating only with the need for an RCT to optimally validate, in the interim, given the biologic plausibility, prior efficacy against other viruses along with a well-known safety profile, low cost, high availability and potentially large associated reduction in mortality, use of famotidine in the treatment of COVID-19 appears reasonable. Doses used in the Freedberg study were 10mg in 17%, 20mg in 47%, and 40mg in 35% with a median of 5.8 days of use.169
- Jafarzadeh A, Nemati M, Khorramdelazad H, Hassan ZM. Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases. Int Immunopharmacol. Published online 2019. https://doi.org/10.1016/j.intimp.2019.02.026
- Smolinska S, Groeger D, Perez NR, et al. Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. Published online 2016. https://doi.org/10.1097/MIB.0000000000000825
- Morichika T, Takahashi HK, Iwagaki H, et al. Histamine inhibits lipopolysaccharide-induced tumor necrosis factor-α production in an intercellular adhesion molecule-1- and B7.1-dependent manner. J Pharmacol Exp Ther. Published online 2003. https://doi.org/10.1124/jpet.102.042515
- Bourinbaiar AS, Fruhstorfer EC. The effect of histamine type 2 receptor antagonists on human immunodeficiency virus (HIV) replication: Identification of a new class of antiviral agents. Life Sci. Published online 1996. https://doi.org/10.1016/s0024-3205(96)00553-x
- Goldstein JA. Cimetidine, ranitidine, and Epstein-Barr virus infection. Ann Intern Med. Published online 1986. https://doi.org/10.7326/0003-4819-105-1-139_2
- Gooptu C, Higgins CR, James MP. Treatment of viral warts with cimetidine: An open-label study. Clin Exp Dermatol. Published online 2000. https://doi.org/10.1046/j.1365-2230.2000.00608.x
- Yang N, Tanner JA, Zheng BJ, et al. Bismuth complexes inhibit the SARS coronavirus. Angew Chemie – Int Ed. Published online 2007. https://doi.org/10.1002/anie.200701021
- Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Gastroenterology. Published online 2020. https://doi.org/10.1053/j.gastro.2020.05.053
Pierre Kory, MD; Joseph Varon, MD; Paul Marik, MD
Management of Respiratory Failure
Although a comprehensive review of the optimal support of oxygenation and ventilation in COVID-19 respiratory failure is beyond the scope of this manuscript, several key physiologic insights should be recognized.
Early publications quickly highlighted the puzzling discordance between the degree of hypoxemia and modest work of breathing observed in COVID-19 patients, describing it as “silent hypoxemia” and such patients as “happy hypoxemics”.183,184 Similarly, soon after mechanical ventilation was instituted, unexpectedly high degrees of lung compliance in conjunction with severe hypoxemia was deemed a new ‘L’ phenotype. Although reasons for lack of dyspnea are multiple, the largest contributors are; 1) early COVID-19 is an “organizing pneumonia” representing a cellular infiltration into the alveoli and ducts rather than alveolar fluid accumulation/edema as in classic ARDS making the lung “dry and light” versus “heavy and fluid-filled”and thus leads to less energy work to inflate and counter-act de-recruitment, 2) the as yet un-explained, paradoxical hyperperfusion of the foci of organizing pneumonia suggesting a failure of typical hypoxic pulmonary vasoconstriction and causing disproportionate hypoxemia (Figure 2), and 3) the likely early and extensive micro and/or macrovascular clotting not detected on routine imaging studies.8,185,186
These differences from “traditional ARDS” were unfortunately both widely minimized and overlooked as evidenced by frequent recommendations for “early intubation” in what was an unfounded fear of the mechanically well-tolerated hypoxemia. Such approaches likely contributed to not only the unacceptably high mortality first reported but also the widespread shortages of ventilators, ICU beds, ventilators, nurses and medications in some of the earliest hard-hit areas. Such approaches curiously departed from the long held therapeutic principle of instituting mechanical ventilation, “neither too early, nor too late”, with decisions to intubate resting upon an assessment of the patients work of breathing WOB) and their ability to sustain that work rather than solely on a presumed necessary level of oxygen saturation. When WOB is felt excessive or unsustainable despite non-invasive modes, then and only then should initiation of invasive mechanical support be pursued. Our recommended strategy for COVID-19 respiratory failure is illustrated in Figure 3. With similar approaches, many centers quickly learned that adopting a such a primary focus on the support of oxygenation using non-invasive means and methods (self-proning) led to less need for ventilators and ICU beds with improved outcomes.
- Kory P, Kanne JP. CoV-2 organising pneumonia : “Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?” BMJ Open Resp Res. Published online 2020:1-4. https://doi.org/10.1136/bmjresp-2020-000724
- Tobin MJ, Laghi F, Jubran A. Why COVID-19 Silent Hypoxemia is Baffling to Physicians. Am J Respir Crit Care Med. 2020;0:1-20. https://doi.org/10.1164/rccm.202006-2157cp
- Couzin-Frankel J. The Mystery of the Pandemic’s ‘Happy Hypoxia.’ Science. 2020 May1;368(6490) https://doi.org/10.1126/science.368.6490.455
- Cobes N, Guernou M, Lussato D, Queneau M, Songy B, Bonardel G, Grellier JF. Ventilation /perfusion SPECT / CT findings in different lung lesions associated with COVID-19 : a case series. European Journal of Nuclear Medicine and Molecular Imaging (2020) 47:2453–2460 https://doi.org/10.1007/s00259-020-04920-w
- Patel B V, Arachchillage DJ, Ridge CA, Bianchi P, Doyle JF, Garfield B, Ledot S, Morgan C, Passariello M, Price S, Singh S, Thakuria L, Trenfield S, Trimlett R, Weaver C, Wort JS, Xu T, Padley SPG, Devaraj A, Desai SR. Pulmonary Angiopathy in Severe COVID-19 : Physiologic , Imaging, and Hematologic Observations. 2020;202(5):690-699.
Pierre Kory, MD
Salvage Therapy and COVID-19
It has become increasingly recognized that the pathophysiologic mechanisms leading to hospitalization in COVID-19 occur in phases (Figure 4) are largely driven by the systemic host response phase rather than the cytopathic viral replicative phase.187 Since the host response is now understood as a complex interaction of inflammation, endotheliopathy, cytokine storm, and hypercoagulability, some have argued that therapeutic plasma exchange could offer unique benefits by removing cytokines, stabilizing endothelial membranes, and reversing the hypercoagulable state.188
In several of the authors clinical experiences, they have encountered a subset of patients who have failed to respond physiologically to the combined therapies that make up the MATH+ protocol, largely thought secondary to advanced disease at the time of presentation or extensive co-morbidity. In the first such cases, therapeutic plasma exchange (TPE) was trialed with temporally associated physiologic improvements observed which then led to both extubation and discharge. In two of the authors experiences (PEM, PK), at the time of this writing, they encountered a total of 16 patients that demonstrated little physiologic improvement despite being treated with high-dose MATH+ protocol who were then empirically treated with TPE. 13 of the 16 were extubated and discharged while 3 failed to respond and later died. Increasing publications of case series and case reports from centers across the world have now described the efficacy of TPE in over 60 COVID-19 patients that did not respond to initial therapies, with the majority having been treated with corticosteroids. 189–200 Nearly all describe similar positive physiologic and clinical responses temporally associated with initiation or completion of TPE. Further, three retrospective, observational cohort studies including a total of 74 patients treated with plasmapheresis have reported dramatic differences in both extubation and survival.109, 201, 202 The largest, a study from Pakistan of 45 COVID-19 patients treated with plasmapheresis compared to 45 propensity matched controls, reported that the mortality in the plasmapheresis treated group was 8.9% vs 38.5% in controls, HR 0.21, 95% CI 0.09-0.53, log rank .002.202 Khamis et al in Oman published on 31 COVID-19 patients in moderate to severe respiratory failure where 11 of the more severely ill patients received TPE with a slightly higher proportion of the TPE group also receiving tocilizumab compared to controls.109 They reported both large improvements in extubation rates (73% vs. 20%, p=.018) and mortality (0% vs 35%, p=.03).
Although these studies are strongly suggestive of a role for TPE in the management of COVID-19 patients unresponsive to now standard therapies such as corticosteroids, both prospective and/or randomized studies should be done to better establish the indications, duration, and efficacy of TPE.
- Khamis F, Al-Zakwani I, Al Hashmi S, Al Dowaiki S, Al Bahrani M, Pandak N, Al Khalili H, Memish Z. Therapeutic Plasma Exchange in Adults with Severe COVID-19 Infection. Published online June 23 2020. Int J Infect Dis. https://doi.org/10.1016/j.ijid.2020.06.064
- Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel treatment approach to the novel coronavirus: An argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care. 2020;24(1):1-3. https://doi.org/10.1186/s13054-020-2836-4
- Fernandez J, Gratacos-Ginès J, Olivas P, Costa M, Nieto S, Mateo D, Sanchez MB, Aguilar F, Bassegoda O, Ruiz P, Caballol B, Pocurull A, Llach J, Mustieles MJ, Cid J, Reverter E, Toapanta ND, Hernandez-Tejero M, Martinez JA, Claria J, Fernandez C, Mensa J, Arroyo V, Castro P, Lozana M. Plasma Exchange: An Effective Rescue Therapy in Critically Ill Patients With Coronavirus Disease 2019 Infection. Crit Care Med. 2020;(9):1-6. https://doi.org/10.1097/CCM.0000000000004613
- Adeli SH, Asghari A, Tabarraii R, Shajari R, Afshari S, Kalhor N, Vafaeimanesh J. Therapeutic plasma exchange as a rescue therapy in patients with coronavirus disease 2019: A case series. Polish Arch Intern Med. 2020;130(5):455-458. https://doi.org/10.20452/pamw.15340
- Vardanjani E, Ronco C, Rafiei H, Golitaleb M, Pishvaei MH, Mohammadi M, Early Hemoperfusion for Cytokine Removal May Contribute to Prevention of Intubation in Patients Infected with COVID-19. Published online June 26, 2020. Blood Purif. https://DOI.ORG/ 10.1159/000509107
- Altmayer V, Saheb S, Rohaut B, Marois C, Cao A, Gallo A, Le Guennec L, Weiss N, Demeret S. Therapeutic plasma exchange in a critically ill Covid-19 patient. J Clin Apher. 2020;(June):4-7. https://doi.org/10.1002/jca.21830
- Akkoyunlu Y, Cetin G, Bolukcu S, Durdu B, Okyaltirik F, Karaaslan K. The successful management of an elderly Covid-19 infected patient by plasmapheresis. Transfus Apher Sci. 2020;(xxxx):102924. https://doi.org/10.1016/j.transci.2020.102924
- Faqihi F, Alharthy A, Alodat M, Kutsogiannis DJ, Brindley PG, Karakitsos D. Therapeutic plasma exchange in adult critically ill patients with life-threatening SARS-CoV-2 disease: A pilot study. J Crit Care. Published online 2020:1-6. https://doi.org/10.1016/j.jcrc.2020.07.001
- Tian H, Sui Y, Tian S, Zou X, Xu Z, He H, Wu T. Case Report: Clinical Treatment of the First Critical Patient With Coronavirus Disease (COVID-19) in Liaocheng, Shandong Province. Front Med. 2020;7(May):1-7. https://doi.org/10.3389/fmed.2020.00249
- Morath C, Weigand MA, Zeier M, Speer C, Tiwari-Heckler S, Merle U. Plasma exchange in critically ill COVID-19 patients. Crit Care. 2020;24(1):1-4. https://doi.org/10.1186/s13054-020-03171-3
- Zhang L, Zhai H, Ma S, Chen J, Gao Y. Efficacy of therapeutic plasma exchange in severe COVID-19 patients. Br J Haematol. 2020;190(4):e181-e183. https://doi.org/10.1111/bjh.16890
- Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, Lin K, Zhou C, Zhang X, Zha Y. Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19. Int J Antimicrob Agents. 2020;56(2):105974. https://doi.org/10.1016/j.ijantimicag.2020.105974
- DePace NL, Soloway S, Roshal D, Soloway AM, Colombo J. Unexpected SARS-CoV-2 cardiorespiratory arrest in a myopathy patient undergoing immunosuppressive treatment: A case report. Medicine (Baltimore). 2020;99(30):e21377. https://doi.org/10.1097/MD.0000000000021377
- Gucyetmez B, Atalan HK, Sertdemir I, Sertdemir I, Cakir U, Telci L. Therapeutic plasma exchange in patients with COVID-19 pneumonia in intensive care unit: A retrospective study. Crit Care. 2020;24(1):4-7. https://doi.org/10.1186/s13054-020-03215-8
- Kamran SM, Mirza ZH, Naseem A, Liaqat J, Fazal I, Alamgir W, Saeed F, Azam R, Hussain M, Yousaf MA, Ashraf N, Nisar S, Zafar Ali M, Saleem S, Sajjad K, Zaman A, Adeeem Azam M, Hussain M, Iftikhar R. PLEXIT – Therapeutic plasma exchange ( TPE ) for Covid-19 cytokine release storm ( CRS ), a retrospective propensity matched control study. Published online 2020. medRxiv. https://doi.org/10.1101/2020.07.23.20160796
Pierre Kory, MD; Joseph Varon, MD; Paul Marik, MD
The MATH+ treatment protocol for COVID-19 has not been subjected to randomized controlled trial study design due to the multiple reasons stated in the above “Rationale” section. However, a cohort comparison is planned, however, to date, such a comparison has not been completed given the need for large amounts of the accumulating registry data required to do so along with the need for a detailed analysis and reporting of demographic and clinical factors. Further, to our knowledge, only two centers have systematically employed MATH+ in the treatment of COVID-19 patients. Below, the institutionally reported hospital mortality outcomes of admitted patients in the MATH+ hospitals are favorably compared with the reported outcome data obtained from numerous publications from centers across the world.
Mortality outcomes in COVID-19 among MATH+ hospitals
The MATH+ protocol reviewed above has been implemented in the treatment of COVID-19 patients at two hospitals in the United States; United Memorial Hospital in Houston, Texas (J.V) and Norfolk General Hospital in Norfolk, Virginia (P.E.M). MATH+ was systematically provided upon admission to the hospital at United Memorial while at Norfolk General, the protocol was administered upon admission to the ICU. Available hospital outcome data for COVID-19 patients treated at these two hospitals as of July 20, 2020, are provided in Table 1, including comparison to the published hospital mortality rates from multiple COVID-19 publications across the United States and world. The average hospital mortality at these two centers as of July 15, 2020, in over 300 patients treated was 5.1 %, which represents more than a 75 % absolute risk reduction in mortality compared to the average published hospital mortality of 22.9 % among COVID-19 patients in multiple countries across the world. Although this is a limited comparison due to a lack of data regarding severity of illness and treatments provided, the low reported mortality at the two centers within a considerable sample size of patients provide supportive clinical evidence for the physiologic rationale and efficacy of the MATH+ treatment protocol. One limitation with this comparison is that the comparative studies were all published before the RECOVERY trial identified the mortality improvements with corticosteroid use, and thus, with more widespread use of steroids the reported mortality from other centers may decrease over time. However, it should be noted that in the RECOVERY trial, even in the patients who benefited from corticosteroids such as those on oxygen or who required mechanical ventilation, the 28-day mortality rates were still between 20–30 % respectively, while the patients who were not on oxygen had mortality rates between 10–20 % depending on whether corticosteroids were used, all higher than the centers using MATH+.
- Docherty, A.B., Harrison, E.M., Green, C.A., et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: Prospective observational cohort study. BMJ. 2020;369(March):1-12. https://doi.org/10.1136/bmj.m1985
- Richardson, S., Hirsch, J.S., Narasimhan, M., et al. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-2059. https://doi.org/10.1001/jama.2020.6775
- Horby, P., Lim, W.S., Emberson, J., et al. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM. Published online ahead of print, July 17, 2020. https://doi.org/10.1056/NEJMoa2021436
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- Arshad, S., Kilgore, P., Chaudhry, Z.S., et al. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19. Int J Infect Dis. 2020;0(0). https://doi.org/10.1016/j.ijid.2020.06.099
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In conclusion, the varied pathophysiologic mechanisms identified in COVID-19 requires multiple therapeutic agents working in concert to counteract the diverse, deleterious consequences of this abberrant immune response. It is exceedingly unlikely that a “magic bullet” will be found, or even a medicine which would be effective at multiple stages of the disease. The Math+ treatment protocol instead offers an inexpensive combination of medicines with a well-known safety profile based on strong physiologic rationale and an increasing clinical evidence base which potentially offers a life-saving approach to the management of COVID-19 patients. Data collection is ongoing and outcomes data will be reported and compared with other published treatment approaches. A search for other promising or emerging therapies is ongoing and the MATH+ protocol will evolve (or devolve) as scientifically indicated.