The polarization in US medicine has never been so front and center as it is with COVID-19. Natural agents are off the table. Despite early clarity that the state of the host matters big time in susceptibility to the virus, natural strategies focusing on host susceptibility are routinely denigrated and dismissed.  So it was remarkable that within the course of 24 hours in late April, two colleagues independently sent news of a formal medical center protocol associated with a medical school that includes multiple natural agents. These are inlaid with conventional measures into a series of stages that the institution’s medical staff is following. Who are these people and how did this come to be? I was able to reach the primary author of the institution’s Critical Care COVID-19 Protocol, a South Africa educated internist, Paul Marik, MD, FCCP, FCCM.  Marik is a professor of medicine and chief of pulmonary and critical care medicine at Eastern Virginia Medical School (EVMS) who has previously stirred controversy for unorthodox approaches. The non-conventional reasoning that drove the COVID-19 protocol Marik calls “uncommon common sense.”

I reached Marik via phone message and email. He called from his clinical care post during a short break in his duties. His team had 21 COVID-19 patients at the time on his floor. While Marik’s protocol may be the most integrative, functional or naturopathic in any medical institution in the US, I quickly discovered that this medical doctor has little direct connection with, alliance with, or knowledge of, these fields. He is, however, no stranger to controversy. Bumping up against orthodoxy seems to be in his blood, as going down a rabbit hole at his Wikipedia page on his sepsis protocol makes clear. His EVMS bio notes that he studied medicine at University of the Witwatersrand, Johannesburg, South Africa. He has diplomas in pharmacology, anesthesia and tropical medicine and is board certified in internal medicine, critical care medicine, neurocritical care and nutrition science.

Integrator: Let’s jump in. Your COVID-19 protocol is rare. I’ve seen nothing like it anywhere in US medicine in its valuing of vitamins and other natural agents as potentially helpful. How did you develop it?

Marik: It’s been an evolution like most things. I’m an internist and critical care specialist and I also have a background in nutrition. That influenced me.  Our basic premise is, it doesn’t matter what it is, if it has good scientific basis, use it. And if it is cheap and plentifully available, all the better. It’s common sense.

Integrator: Sounds like a classic integrative approach – and I would add the specific addition that the safety profile makes the agents selected low risk.

Marik:  It really grew out of work we have been doing since 2016 with Vitamin C and steroids for sepsis. That’s been a difficult battle. Most people don’t believe that Vitamin C can have that value.  COVID and sepsis have some external similarities. We started with our protocol for patients with septic shock then I thought – let’s make it an overall guideline. Honestly a part of it was intuitive. We brought in things that make sense – that we knew had low adverse effects – and now we increasingly have more evidence to prove the value of what we created.  The protocol is evolving, changing doses, as we learn more. Once you put it out there, then you draw a community. We are working with a network of doctors who are trying things.

The First Three Stages of the Eastern Virginia Medical School (EVMS) Guidance

Integrator: Take us through the protocol’s development.

Marik: We began by putting things together that make good sense. For instance, we included melatonin in the first version of our protocol in early March. At that time, it was based on what we knew about the molecule and the presumption that it may be beneficial. Subsequently, scientific publications have emerged, suggesting that it may have benefit in the treatment of COVID-19. Apart from being a very powerful antioxidant, it appears that this molecule has direct viricidal properties. Zinc also has viricidal properties. We added Vitamin D because its role in the prevention of influenza. We have just published a paper linking low Vitamin D levels to an increased mortality from COVID-19.  A number of scientific papers have recently been published validating this concept. [See papers below.]

In terms of the whole prophylactic cocktail, we do not have high level scientific data that it is effective. We have relied on studies that looked at the efficacy of the components for other viral illnesses. I recently received a call from a long-term care facility where 59 of 60 patients got COVID. They are using a similar prophylactic-therapeutic protocol and after 3 weeks only one person has died. We are also using methyl-prednisone for the pulmonary phase even though other guidelines cautioned against steroids. Now we have very good data showing it’s good. My colleagues in Houston and New Jersey are also using this protocol. We have the cumulative experience of greater than 120 critically ill ICU patients. To date we have had only 2 deaths, both in octogenarians with severe co-morbidity.  However, a number of issues are critical. COVID-19 is a profoundly serious disease. It is nothing like the flu. One has to understand the disease to treat it effectively. Patients infected with SARS-CoV-2 transition through various phases of the disease – an incubation phase, a mildly symptomatic phase with fever, malaise, myalgia and et cetera to the pulmonary phase.  The pulmonary phase is manifest clinically by shortness of breath and most importantly arterial desaturation. The pulmonary phase is caused by a hyper-inflammatory phase, the cytokine storm. Once the patients enter the pulmonary phase, they need to be treated aggressively with anti-inflammatory agents to prevent disease progression. Timing is critical. We know that once patients progress to the stage that they require mechanical ventilation the mortality rate is close to 90% – most patients die.

Some Papers Sent by Marik Backing the EVMS COVID-19 Protocol

• Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock A Retrospective Before-After Study (October 2017; Marik lead author, here)
• Hydrocortisone, Ascorbic Acid and Thiamine(HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid (November 2018; Marik sole author – here)
• Vitamin C: an essential “stress hormone” during sepsis (February 2020; Marik sole author – here)
• Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease (April 2020; here)
• Early Short Course Corticosteroids in Hospitalized Patients with COVID-19 (May 2020; here)
• The antiviral properties of vitamin C (December 2019; Marik a co-author – here)
• Does vitamin D status impact mortality from SARS-CoV-2 infection? (April 2020; Marik a co-author – here

Integrator: You have hydroxychloroquine on your protocol as optional in a couple of phases. It’s been controversial of course and has a pretty significant adverse effects profile. [The New England Journal of Medicine published a negative observational trial post interview with Marik.] It’s still in your protocol. What is your experience?

Marik: The studies that have reported on the use of hydroxychloroquine [HCQ] to date, have used this drug very late – typically 12-20 days after onset of symptoms. No surprise, these studies have shown no benefit. HCQ may have a role in preventing disease progression when given in the early symptomatic phase. However we just do not have good data on its potential role when used earlier.

Integrator: You’ve referred to colleagues. Who are they? Why don’t we know about them?

Marik: Using these methods is sort of like being in the closet. A lot of doctors out there are using some if not all of these agents but they are afraid to speak out. It’s like shame – hiding it, afraid to come out, because the control of orthodoxy is so strong. But they are out there. There is physician in Houston who owns a hospital who is doing these things. This is like what happened with the work behind our sepsis strategy. By the end, we had 50 or 60 across the country working with the protocol. We have a growing network sharing information on our COVID-19 experience, and emerging papers. We make adjustments.

Integrator: You are part of what you are calling the Frontline COVID-19 Critical Care Working Group (FLCCC) – one of eight doctors listed there. The focus with this group is the use of intravenous vitamin C and corticosteroids. The other agents in your EVMS protocol aren’t listed. The Frontline focus is on the corticosteroids:

It is our collective opinion that the historically high levels of morbidity and mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst intensivists to employ anti-inflammatory and anticoagulant treatments, including corticosteroid therapy early in the course of a patient’s hospitalization. It is essential to recognize that it is not the virus that is killing the patient, rather it is the patient’s overactive immune system. The flames of the “cytokine fire” are out of control and need to be extinguished. [A 14 minute video on the protocol from the group is here.]

Integrator: You have called your COVID-19 protocol “common sense.” If so, why is the approach not commonly applied?

Marik: Common sense is remarkably uncommon. Despite what we have put together [and reported], no one will believe us. On hates to go there, but I think big pharma has had a role to play in why this approach is not more prominent. I think big pharma has a lot of control with what is research in COVID strategies. We’ve tried the NIH and the CDC and they don’t have much interest.

Integrator: Interesting. I interviewed the director of the NIH National Center for Complementary and Integrative Health about what they were doing. Not sure if you know that the Center exists. It has a roughly $145-million budget. They are linked to the NIH Office of Dietary Supplements. The director did not indicate that anything was being explored in these areas. The Center has historically been challenged by the ambiguities of multi-modal, multi-agent practices such as this. It might be a direction to pursue for funding. Have you got any trials coming?

Marik: We had something of a breakthrough yesterday. One of the members of our Working Group [Pierre Kory, MD, MPA, Department of Pulmonary Medicine, University of Wisconsin] testified before the Senate yesterday [May 6]. His Senator [Ron Johnson (R-WI)] is the chair of the committee. I understand that the protocol reached the White House but it was pushed back by the CDC.

Integrator: When I first saw your protocol, I shared it with my spouse, who is an integrative physician and MPH. I told her my read was that what you have published there as a formal protocol is one-of-a-kind that is “out” – as you put it – in US medicine regarding dominant school medical delivery and COVID-19. She immediately Googled you up. The next thing I heard from the other room was: “He’s not trained here. He’s from South Africa. That explains it.” Perhaps a bit reductionist and yet an interesting observation.

Marik: I was trained in a really good medical school [University of the Witwatersrand, Johannesburg, South Africa]. The school taught me how to think. I see the students here, they are like automatons, out of a production line. Independent thinking is not their best trait.

Integrator: Your “HAT” sepsis strategy – hydrocortisone, ascorbic acid (vitamin C) and thiamine – first published in a small observational trial in 2017 in Chest was roundly rebuked earlier this year in JAMA, as you shared with me. The negative paper the VITAMINS study had 20 authors from a multi-centered trial. They concluded that “treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.” It ran with an accompanying JAMA editorial. You shared another paper that was also summarily dispensed with as negative in JAMA on Vitamin C for acute respiratory distress syndrome. These do raise question of why your COVID-19 protocol would be expected to fare better with closer scrutiny and a larger trial.

Marik: The VITAMINS study was designed to fail. The trial was poorly designed with enormous delays in the administration of the treatment protocol. This study in no shape or form replicates our treatment strategy. Unfortunately, there are a number of medical journals that are more than eager to publish negative trials on the use of ascorbic acid. [Marik’s more lengthy critique is here.]

Integrator: Well, any of us who are outside of the dominant school of medicine will know that prejudice can often play a role, and at the same time, we know that the science is sometimes is not there to back what integrative clinicians perceive is happening. Sometimes both are true. I personally was quite pleased to see that at last one institution – Eastern Virginia Medical School – is willing to try these practices that do indeed seem to have common sense, and little apparent downside. Closing thoughts?

Marik: They may try and mislead, deny, suppress, and reject the truth, but ultimately one cannot stop scientific progress and the truth will emerge.

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Comment: This article has been a journey. I started with the excitement of learning that at least one medical institution was using multiple natural agents integratively. How much cleaner if Marik’s HAT sepsis protocol from Chest in 2017 had been reported positively in JAMA last January!  Then his present COVID-19 protocol would be following on a prior scientific success – whatever the actual clinical merits for Marik’s renegade strategy. Does it help or harm that the protocol still includes hydroxycloroquine – which Wisconsin’s Senator Johnson is also promoting to the White House? Marik references the colleague who used the protocol in a residential rehabilitation facility were 59 of 60 patients got sick with the virus and only one had died three weeks later. Amidst the clinical frenzy to help patients with COVID-19, that experience needs to be retrospectively examined.

Meantime, we have Marik’s suggestive “common sense” evidence, positive perceptions of some front-line clinicians, a set of publications that are low on the classic evidence pyramid, mainly proposing the science behind the treatment strategy. This is coupled with – or better said, uncoupled from – a mainstream of COVID-19 practice that is yet to show significant interest in examining the science behind the global interest in integrative options. In usual times, the resistance until more research is completed is arguably appropriate. But in a time of such desperation and funded explorations of pharma agents with extensive known adverse effects, failure to invest in examination of such integrative methods with their high safety profiles reeks more of prejudice than of patient-centeredness. It is impossible, in this context, for truth to emerge, however it speaks.