Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection

Finally some doctors putting together treatment prior to hospital. Although maybe HCQ is no longer considered, so ask your doctor.

Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection

• Peter A. McCullough, MD, MPH
• Ronan J. Kelly, MD
• Gaetano Ruocco, MD
• 
  
• William W. O'Neill, MD
• Marcus Zervos, MD
• Harvey A. Risch, MD, PhD
• Show all authors

Open AccessPublished:August 06, 2020DOI:https://doi.org/10.1016/j.amjmed.2020.07.003

Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.

Keywords

Ambulatory treatment

Anticoagulant

Anti-inflammatory

Antiviral

COVID-19

Critical care

Epidemiology

Hospitalization

Mortality

SARS-CoV-2

Clinical Significance

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  COVID-19 hospitalizations and death can be reduced with outpatient treatment.
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  Principles of COVID-19 outpatient care include: 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy 5) administration of oxygen, monitoring, and telemedicine.
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  Future randomized trials will undoubtedly refine and clarify ambulatory treatment, however we emphasize the immediate need for management guidance in the current crisis of widespread hospital resource consumption, morbidity, and mortality.

The pandemic of severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) is rapidly expanding across the world with each country and region developing distinct epidemiologic patterns in terms of frequency, hospitalization, and death. There has been considerable focus on 2 major areas of response to the pandemic: containment of the spread of infection and reducing inpatient mortality. These efforts, although well-justified, have not addressed the ambulatory patient with COVID-19 who is at risk for hospitalization and death. The current epidemiology of rising COVID-19 hospitalizations serves as a strong impetus for an attempt at treatment in the days or weeks before a hospitalization occurs.¹ Most patients who arrive to the hospital by emergency medical services with COVID-19 do not initially require forms of advanced medical care.² Once hospitalized, approximately 25% require mechanical ventilation, advanced circulatory support, or renal replacement therapy. Hence, it is conceivable that some, if not a majority, of hospitalizations could be avoided with a treat-at-home first approach with appropriate telemedicine monitoring and access to oxygen and therapeutics.³ As in all areas of medicine, the large randomized, placebo-controlled, parallel group clinical trial in appropriate patients at risk with meaningful outcomes is the theoretical gold standard for recommending therapy. These standards are not sufficiently rapid or responsive to the COVID-19 pandemic.⁴ One could argue the results of definitive trials were needed at the outset of the pandemic, and certainly are needed now with more than 1 million cases and 500,000 deaths worldwide.⁵ Because COVID-19 is highly communicable, many ambulatory clinics do not care for patients in face-to-face visits, and these patients are commonly declined by pharmacies, laboratories, and imaging centers. On May 14, 2020, after about 1 million cases and 90,000 deaths in the United States had already occurred, the National Institutes of Health (NIH) announced it was launching an outpatient trial of hydroxychloroquine (HCQ) and azithromycin in the treatment of COVID-19.⁶ A month later, the agency announced it was closing the trial because of the lack of enrollment with only 20 of 2000 patients recruited.7 No safety concerns were associated with the trial. This effort serves as the best current working example of the lack of feasibility of outpatient trials for COVID-19. It is also a strong signal that future ambulatory trial results are not imminent or likely to report soon enough to have a significant public health impact on clinical outcomes.⁸ If clinical trials are not feasible or will not deliver timely guidance to clinicians or patients, then other scientific information bearing on medication efficacy and safety needs to be examined. Cited in this article are more than a dozen studies of various designs that have examined a range of existing medications. Thus, 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. Because COVID-19 expresses a wide spectrum of illness progressing from asymptomatic to symptomatic infection to fulminant adult respiratory distress syndrome and multiorgan system failure, there is a need to individualize therapy according to what has been learned about the pathophysiology of human SARS-CoV-2 infection.⁹ It is beyond the scope of this article to review every preclinical and retrospective study of proposed COVID-19 therapy. Hence, the agents proposed are those that have appreciable clinical support and are feasible for administration in the ambulatory setting. SARS-CoV-2 as with many infections may be amenable to therapy early in its course but is probably not responsive to the same treatments very late in the hospitalized and terminal stages of illness.¹⁰For the ambulatory patient with recognized early signs and symptoms of COVID-19, often with nasal real-time reverse transcription or oral antigen testing pending, the following 4 principles could be deployed in a layered and escalating manner depending on clinical manifestations of COVID-19-like illness¹¹ and confirmed infection: 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, and 4) antiplatelet/antithrombotic therapy. Because the results of testing could take up to a week to return, treatment can be started before the results are known. For patients with cardinal features of the syndrome (ie, fever, body aches, nasal congestion, loss of taste and smell, etc.) and suspected false-negative testing, treatment can be the same as those with confirmed COVID-19.11 Future randomized trials are expected to confirm, reject, refine, and expand these principles. In this article, they are set forth in emergency response to the growing pandemic as shown in Figure 1.

Figure 1Treatment algorithm for COVID-19-like and confirmed COVID-19 illness in ambulatory patients at home in self-quarantine. BMI = body mass index; CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; Dz = disease; HCQ = hydroxychloroquine; Mgt = management; O₂ = oxygen; Ox = oximetry; Yr = year.

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