by Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF, FNLA, FCRSA1 2 3 4 5
1Baylor University Medical Center, 2Baylor Heart and Vascular Institute, 3Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; 4Baylor Scott & White Research Institute, Dallas, TX; 5Texas A&M College of Medicine Health Science Center, Dallas, TX
Conflicts of Interest: None.
We are nearly one year into the SARS-CoV-2 (COVID-19) worldwide pandemic. This global disaster has influenced the lives of nearly every person on earth and has scorched a path of illness, hospitalization, and death through every country on earth. Many have said that this is a once in a century event, and thus it follows that no single individual or group would have experience in how to best handle the COVID-19 crisis that continues to ravage the globe. Since SARS-Co-V2 is a highly contagious virus that has a broad spectrum of clinical manifestations that range from typically little or no symptoms in the young, to fatal multi-organ system failure in older adults with comorbidities, it follows that our pandemic response would need to address all four pillars or applicable principles: 1) contagion control, 2) aggressive treatment of the infection at its onset to reduce the intensity and duration of symptoms in order to avoid hospitalization, 3) hospitalization as a safety net to prevent death, and 4) vaccination to complement herd immunity and bring the crisis to closure.
Pillar #1: Contagion Control
Contagion control simply implies methods to slow or prevent the spread of the airborne and contact transmissible SARS-Co-V2 virus. The reader will recognize that the vast majority of public policy communications and actions by health authorities deal with contagion control in one form or another. Face coverings, masks, hand sanitizer, social distancing, lock-downs, quarantines, contact tracing, and many more activities can be considered in the realm of contagion control. However, in the current pandemic, despite all of these efforts the numbers of new cases continues relatively unabated. Hence, more attention is needed on the next pillar.
Pillar #2: Early Outpatient Treatment
Early outpatient treatment is the second pillar of any viral pandemic with community spread. Since COVID-19 starts out like the common cold and progresses over many days into a fulminant syndrome in older adults, there is a unique opportunity for treatment while in quarantine taking advantage of the time and opportunity during the phase of early exponential viral replication. Government health agencies, while well funded at the start of the pandemic, typically failed at executing clinical trials of oral therapies for COVID-19 at home. With no public health mention or awareness, the media and public developed a hyper focus on contagion control while drawing a mental blank on what could be done when the infection starts. To this day, there are no large conclusive randomized placebo-controlled trials of single or multiple agents in combination to combat COVID-19 in the first few days. But why is it so? First, it’s not advisable to start a large clinical trial before a clear therapeutic approach is identified, which was obviously not the case at the beginning of the pandemic in March / April. Second, conclusive clinical trials, in general, would need to be very large in size, with ~20,000 patients, and have a placebo event rate of hospitalization or death of 5%, to detect a relative risk reduction of about 20% with an active treatment. Third, there are considerable ethical issues with placebo-controlled trials, as giving a placebo to a patient means denying the patient with a potentially life-saving therapy. Medical doctors need also to respect their hippocratic oath and refuse to let their patients participate in clinical trials that are not in their best interest. Since 1964, there are comprehensive ethical principles embedded in the Helsinki Declaration, developed by the World Medical Association, regarding clinical trials, and these need to be thoroughly respected. None of the treatment trials that have taken place so far are close to such standard. When it comes to large cohorts of patients, only the vaccine trials may have a proper level of statistical robustness, yet they also pose serious concerns when it comes to giving placebos, as trial participants may believe they are protected by the vaccine and may not take the steps to seek early treatment in case they develop the disease. As a result of such considerations, there has been a considerable interest in using clinical judgement and the available scientific evidence to craft an early multi-drug sequenced approach in order to address the early stage of the disease with the goal of curbing the viral replication, shortening symptoms duration and reducing their severity, enabling a prompt recovery and avoiding hospitalization. Such an approach was initially published August 7, 2020 in the American Journal of Medicine by an American-Italian Collaboration.
The article contends that, in the context of present knowledge, given the severity of the outcomes and the relative availability, cost, and toxicity of the therapy, each physician and patient must make a choice: watchful waiting in self-quarantine or empiric treatment with the aim of reducing hospitalization and death. The empiric treatment algorithm recommended in the article relies on 4 principles to be deployed in a layered and escalating manner: 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, and 4) antiplatelet/antithrombotic therapy. Since the article was published, clinicians largely working in isolation without institution or government agency support have been further innovating and attempting to combat the infection with variations in the multi-drug sequenced approach which commonly include additional vitamins and supplements and inhaled medicinal agents. The principles however, have remained the same—that is early outpatient treatment, which can be made even more effective with the prior administration of a prophylactic regimen comprising supplements such as Vitamin D and Zinc. This constitutes the only method to reduce the severity and duration of symptoms and as a result to lower the risk of hospitalization and likely death. Such an early treatment approach has also been shown to work in aged care facilities by reducing mortality. In Western countries, the vast majority of deaths occurs in hospitals and in aged care facilities.
Pillar #3: Hospitalization
The third pillar of pandemic response is hospitalization. This realm of COVID-19 response is more tractable and observable with evolving standards including less early mechanical ventilation, the use of antiviral agents, corticosteroids, and anti-thrombotic agents. Because hospitalizations are invariably late-stage, often after two or more weeks after the first symptoms, the therapies applied have reduced impact and the hospitalizations tend to be very prolonged with the need for respiratory support. Unfortunately, hospitalization is not an adequate safety net to prevent death in COVID-19. Event with the best possible care, at the point a hospitalized patient requires supplemental oxygen, the mortality rate often exceeds 12% and if the intensive care unit is required, it can reach ~25% or more.
Pillar #4: Vaccination and Herd Immunity
The fourth and final pillar of pandemic response, when feasible is vaccination. For a pathogen that is amenable to vaccination, this approach if applied widely can generate herd immunity and a substantial reduction in the prevalence of the disease. SARS-CoV-2 does appear amenable to vaccination with the generation of neutralizing antibodies to the spike protein which the virus uses for entry into cells via the ACE2 receptor. There are also other vaccination mechanisms that are being developed. However, many challenges exist in vaccine development including viral mutation, the need for cellular and antibody based immune response, safety, efficacy. Finally, the durability of a vaccine is critical to understand as the one predictable consequence of vaccination will be less interest and effort in contagion control. A long term hazard of a vaccine with limited period of immunity, is recurrent waves of SARS-Co-V2 infection across the globe from unvaccinated to vaccinated but now not immune individuals and so on. At the same time, immunity may develop naturally in many people, from prior SARS-Co-V2 or other coronavirus infections, and there are indications that T Cell immunity may play an important role for the development of herd immunity. Despite its vast promotion with the population, there remains considerable uncertainty about the implementation timing and ultimate effectiveness of this fourth vaccination / herd immunity pillar.
In conclusion, early outpatient treatment is the pillar that has been widely overlooked and that urgently requires the world’s attention. Efforts at contagion control may curb the spread of the disease, but they are not suitable for long-term implementation. Promised COVID-19 vaccines are not ready, hospitals are increasingly full, and more and more people are contracting COVID-19 everyday. Understanding the four pillars of pandemic response should bring public health officials to immediately diversify their teams to include experts and medical resources for the early outpatient treatment of COVID-19. Such policy pivot towards outpatient early treatment, is fully feasible, as all the knowledge required for implementation already exists. Such pivot would demonstrate compassion and care for those of us most vulnerable as they fall ill with COVID-19, in an attempt to reduce the need for hospitalization and to reduce mortality. Outpatient early treatment makes of course considerable sense, not only from a medical but also from an economic perspective. Compared to hospitalization, and even vaccines, it is extremely cheap to implement, will generate huge savings for health care systems, and will help to safely reopening the economy. Conversely, a continued policy of no early outpatient treatment will not significantly reduce hospitalizations and deaths, will further stress our hospitals and health care systems, and will sadly demonstrate a lack of genuine interest in reducing the loss of life during this crisis, especially among the most vulnerable.
The author is grateful to Jean-Pierre Kiekens, a former lecturer at the University of Brussels and Editor of Covexit News & Policy Analysis, for comments on an earlier draft of this paper.
You may want to watch our Webinar with Dr McCullough at this LINK.
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