key: cord-342857-vj6sw2ne
authors: McCullough, Peter A.; Kelly, Ronan J.; Ruocco, Gaetano; Lerma, Edgar; Tumlin, James; Wheelan, Kevin; Katz, Nevin; Lepor, Norman E.; Vijay, Kris; Carter, Harvey; Singh, Bhupinder; McCullough, Sean P.; Bhambi, Brijesh K.; Palazzuoli, Alberto; De Ferrari, Gaetano M; Milligan, Gregory; Safder, Taimur; Tecson, Kristen M.; Wang, Dee Dee; McKinnon; O'Neill, William W.; Zervos, Marcus; Risch, Harvey A.
title: Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection
date: 2020-08-07
journal: Am J Med
DOI: 10.1016/j.amjmed.2020.07.003
sha: 
doc_id: 342857
cord_uid: vj6sw2ne

Approximately 9 months of the SARS-CoV-2 virus 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 paper 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 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed in this paper 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.

The pandemic of 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 two major areas of response to the pandemic: 1) containment of the spread of infection, 2) reducing inpatient mortality. These efforts while 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, ~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 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 over 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 US had already occurred, the National Institutes of Health announced it was launching an outpatient trial of hydroxychloroquine (HCQ) and azithromycin in COVID-19.(6) A month later the agency announced it was closing the trial due to 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 upon medication efficacy and safety needs to be examined. Cited in this paper, more than a dozen studies of various designs 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. Since COVID-19 expresses a wide spectrum of illness progressing from asymptomatic to symptomatic infection to fulminant adult respiratory distress syndrome and multi-organ 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 paper 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. (10) For 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 four principles could be deployed in a layered and escalating manner depending on clinical manifestations of COVID-19 like illness(11) and confirmed infection: 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 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 (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 paper, they are set forth in emergency response to the growing pandemic as shown in Figure 1 .

A major goal of self-quarantine is control of contagion. 

It is well recognized that COVID-19 exists outside the human body in a bioaerosol of airborne particles and droplets. Since exhaled air in an infected person is considered to be -loaded‖ with inoculum, each exhalation and inhalation is effectively reinoculation. (15) In hospitalized patients, negative pressure is applied to the room air largely to reduce spread outside of the room. We propose that fresh air could reduce reinoculation and potentially reduce the severity of illness and possibly reduce household spread during quarantine. This calls for open windows, fans for aeration, or spending long periods of time outdoors away from others with no face covering in order to disperse and not re-inhale the viral bioaerosol.

Rapid and amplified viral replication is the hallmark of most acute viral infections.

By reducing the rate, quantity, or duration of viral replication, the degree of direct viral injury to the respiratory epithelium, vasculature, and organs may be lessened. (16) Additionally, secondary processes that depend on viral stimulation including activation of inflammatory cells, cytokines, and coagulation could potentially be lessened if viral replication is attenuated. Because no form of readily available medication has been designed specifically to inhibit SARS-CoV-2 replication, two or more of the nonspecific agents listed below can be entertained. None of the approaches listed below have specific regulatory approved advertising labels for their manufacturers, thus all would be appropriately considered acceptable -off-label‖ use. (17) 

Doxycycline is another common antibiotic with multiple intracellular effects that may reduce viral replication, cellular damage, and expression of inflammatory factors. (33, 34) This drug has no effect on cardiac conduction and has the main caveat of gastrointestinal upset and esophagitis. As with azithromycin, doxycycline has the 

Because ambulatory centers and clinics have been reticent to have face-to-face visits for COVID-19 patients, telemedicine is a reasonable platform for monitoring.

Clinical impressions can be gained with audio and video interviews by the physician with the patient. Supplemental information including vital signs and symptoms will be important to guide the physician. A significant component of safe outpatient management is maintenance of arterial oxygen saturation on room air or prescribed home oxygen under direct supervision by daily telemedicine with escalation to hospitalization for assisted ventilation if needed. Self-proning could be entertained for confident patients with good at-home monitoring. (55) Many of the measures discussed in this paper could be extended to seniors in COVID-19 treatment units in nursing homes and other non-hospital settings. This would leave the purposes of hospitalization being administration of intravenous fluid and parenteral medication, assisted pressure or mechanical ventilation, and advanced mechanical circulatory support.

Acute COVID-19 has a great range of clinical severity from asymptomatic to fatal.

In the absence of clinical trials and guidelines, with hospitalizations and mortality mounting, it is prudent to deploy treatment for COVID-19 based upon pathophysiological principles. We have proposed an algorithm based on age and comorbidities that allows for a large proportion to be monitored and treated at home during self-isolation with the aim of reducing the risks of hospitalization and death. 

Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection

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an antiviral for COVID-19

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Figure 1 COVID-19 Outpatient Treatment Algorithm